Exploring the natural occurring genetic variation of the wild barley genepool has become a major target of barley crop breeding programmes aiming to increase crop productivity and sustainability in global climate change scenarios. However this diversity remains unexploited and effective approaches are required to investigate the benefits that unadapted genomes could bring to crop improved resilience. In the present study, a set of Recombinant Chromosome Substitution Lines (RCSLs) derived from an elite barley cultivar ‘Harrington’ as the recurrent parent, and a wild barley accession from the Fertile Crescent ‘Caesarea 26–24’, as the donor parent  have been utilised in field and controlled conditions to examine the contribution of wild barley genome as a source of novel allelic variation for the cultivated barley genepool.Twenty-eight RCSLs which were selected to represent the entire genome of the wild barley accession, were genotyped using the 9 K iSelect SNP markers  and phenotyped for a range of morphological, developmental and agronomic traits in 2 years using a rain-out shelter with four replicates and three water treatments. Data were analysed for marker traits associations using a mixed model approach.We identified lines that differ significantly from the elite parent for both qualitative and quantitative traits across growing seasons and water regimes. The detailed genotypic characterisation of the lines for over 1800 polymorphic SNP markers and the design of a mixed model analysis identified chromosomal regions associated with yield related traits where the wild barley allele had a positive response increasing grain weight and size. In addition, variation for qualitative characters, such as the presence of cuticle waxes on the developing spikes, was associated with the wild barley introgressions. Despite the coarse location of the QTLs, interesting candidate genes for the major marker-trait associations were identified using the recently released barley genome assembly.This study has highlighted the role of exotic germplasm to contribute novel allelic variation by using an optimised experimental approach focused on an exotic genetic library. The results obtained constitute a step forward to the development of more tolerant and resilient varieties.The online version of this article (10.1186/s12870-018-1527-7) contains supplementary material, which is available to authorized users. Breeding programmes have successfully increased yield and quality traits of major cereals including barley , 2. HoweHordeum are preserved in gene banks worldwide, second only to rice  and wheat  (FAO 2010) and provide an enormous potential resource for allele mining. There have been many descriptive and comparative studies examining diversity in wild and landrace barleys, but few examples utilising the allelic diversity have been reported ) and the recurrent parent ([Hv]) alleles obtained for the significant peak region were used to calculate the relative contribution (RP) of the exotic parent alleles on the trait performance as follows:The Best Linear Unbiased Estimates (BLUEs) for each trait for the donor ([2) were used to identify possible putative candidate genes underlying the predicted phenotypic variation. In this case the number of genes in the targeted regions was first estimated by looking at the physical position of the iSelect SNP markers in the newly released barley genome assembly [The position of major determinant genes related to plant phenology and morphology was estimated from previous studies and public gene databases to support the results obtained from this analysis. Additionally, some genomic regions accounting for a significantly large proportion of a trait’s variance  of the k-th principal component axis, γik and δjk are the genotype and the environment scores (eigenvectors) for the k-th principal component axis, ρij is the interaction residual and εijk is the random error.Values for yield (DY) and grain weight (TGW) for each of the RCSLs were used to investigate the effect of the exotic genome in the performance and stability of the crop across the environmental conditions imposed in the field. Genotype by environment (GE) interaction was studied by means of an additive main effects and multiplicative interaction model (AMMI) for which six environments were defined as the combination of growing season and water treatment. Using this method, the overall variation observed for yield traits such as dry yield and thousand grain weight was partitioned into genotype main effects, environment main effects and GE interaction . The modAs a result, the interaction principal components generated (IPCA1 and IPCA2) are used to graphically summarise (biplots) the GE variation observed. The AMMI2 biplot uses the genotypes and environments scores for the first two IPCA components (IPCA1 on the X-axes and IPCA2 on the Y-axes) giving information about the GE patterns observed. Genotypes with IPCA scores close to zero are more stable or widely adapted to the tested environments whereas specific adaptation of the genotypes is determined by the length of the orthogonal projection of the genotype points onto the environmental vectors. In addition, the AMMI1 biplot tests the genotypes yield potential and stability simultaneously by plotting in the same diagram the average yields (X-axes) and the first dimension measure of GE interaction (IPCA1) for both genotypes and environments (Y-axes). AMMI model was computed using Genstat 17 .Additional file 1:Table S1. RCSLs genotypes determined for 1848 SNP markers from the 9 K SNP chip for barley [r barley .  2013 and (B) 2014. Accumulated rainfall (mm) values per week (x axes), air maximum and minimum average temperature values per week (± SE). Data obtained from James Hutton Institute weather station . Field trials were established in the week 16 both years. (DOCX 28 kb)Additional file 3:Figure S2. Volumetric water content (ml cm− 3) in the soil profile at (A) 100 mm, (B) 200 mm, (C) 300 mm and (D) 400 mm depth in the full irrigated (blue), partial irrigated (green), and drought (red) water treatment in 2013 (left) and 2014 (right) field trials. Vertical dashed lines indicate beginning and end of heading time referred to days after sowing (DAS) for year. Error bars indicate standard error of the mean. (DOCX 258 kb)Additional file 4:Table S2. Climate data before sowing, during seedling establishment, before heading and during heading in the 2013 and 2014 growing seasons. Air and soil mean temperature values (± SE) and accumulated rainfall (mm) values obtained from the James Hutton Institute weather station . (DOCX 15 kb)Additional file 5:Table S3. Genotypic mean values (± SE) for the morphological, developmental and agronomic traits registered in 2013 and 2014 field trials. Genotypes are arranged in ascending order from top to bottom of the table for collar height (COL), peduncle length (PdL), ear length (EAR), seed area (SdA), seed length (SdL), seed width (SdW), heading date (HEA), number of tillers (TILL), dry yield (DY), thousand grain weight (TGW), biomass yield (BY) and harvest index (HI). Best linear unbiased estimators (BLUEs) for genotypes labelled with different letters differ significantly . Harrington mean values highlighted in bold. (XLSX 20 kb)Additional file 6:Table S4. Significant quantitative trait locus (QTLs) detected on the RCSLs exotic genetic library associated with thirteen morphological, developmental and agronomic traits. One trait per tab. (XLSX 167 kb)


Scientific Reports 10.1038/s41598-019-48007-5, published online 16 August 2019Correction to: The Acknowledgements section in this Article is incomplete.“The authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.”should read:“This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) under an Industrial Case Studentship (BB/J012483/1). The authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.”In addition, this Article contains ambiguous wording in the Results section, under subheading ‘Duration of carriage and hazard of clearance’. To clarify the findings, the following text should be disregarded:“these trends were non-linear with categories 2 and 4 associated with a longer duration (lower hazard) compared to category 3, and category 4 (highest density) associated with the longest subsequent carriage duration (Table 3).”


Korean grandparents raising their grandchildren play significant roles as social and family resources in Korea. They experience caregiving stress that negatively influences their mental health while struggling with limited social support from peers, and minimal respite care and community resources. Despite a need for resources and information concerning this growing population, there is limited knowledge on Korean custodial grandparents, especially the distinctive cultural factors influencing their multigenerational caregiving experiences. This qualitative study explored Korean custodial grandparents’ experiences of raising grandchildren and cultural meanings of multigenerational caregiving. Using a phenomenological approach, semi-structured interviews with 23 custodial grandparents were conducted from December 2018- January 2019 in two urban and three rural places in Korea. Among the grandparents, five were grandfathers. The mean age of the grandparents was 72 years old (range: 61-82), and the mean age of their grandchildren was 13 years old (range: 1-21). On average, the grandparents had raised 1.5 grandchildren (range: 1-3) for 11 years (range: 1.5-20). Four key themes emerged from the general structure of the lived experiences of Korean grandparents: a) intensive child care support from the grandchildren’s uncle and aunt; (b) stigma of a child’s divorce and custodial grandparenting; (c) different social expectations toward maternal grandparents; and (d) increased needs on financial educational support for grandchildren. The finding reinforces the significant function of collectivistic and family-based Asian culture in understanding experiences of Korean custodial grandparents. It also highlights society’s view of only men carrying forward family lineage and its implications on grandparents’ perceptions about multigenerational caregiving.


Hypertrophic cardiomyopathy (HCM) is a common genetic diseases with prevalence of 1 in 200-500 in general population, and it can result in sudden cardiac death (SCD) . FurtherIn our recent study, we sought to address this knowledge gap by evaluating cardiac Magnetic resonance (CMR) in 1423 HCM patients with preserved EF for presence and extent of scar in the LV by late gadolinium enhancement (LGE) . Our stuIn the current AHA/ACC guidelines, CMR carries a weak recommendation (class IIB) (Level of evidence C) for use to assess presence of LGE in case of patients with inconclusive SCD risk stratification by conventional factors . Several


Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10 Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas  of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014–2016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity. Rubivirus genus, which has been recently moved from the Togaviridae to a new family, Matonaviridae  [76 [7674] . Brieflyrrection .An 904-nt fragment of the E1 gene (nt 8672–9577 in the RV genome) was amplified from RNA isolated from a clinical sample or viral stock using the RV genotyping primers  and PlatComplete sequences of iVDRV genomes have been deposited in the NCBI database under accession numbers MK787188—MK787191 and MK780807- MK780812.http://accelrys.com/products/collaborative-science/biovia-discovery-studio/visualization.html; Accelrys Inc., CA).The structures of the rubella E1 protein  were used as templates for computer modeling. The mutations were modeled as described earlier using the software package ECMMS  for molecular mechanics modeling , 84. TheECau, Enrichment  for uCa mutation signature is:We first created the list of 993 (out of 1074) mutations, in which ambiguous nucleotides were excluded from the analysis . These mMutCau−counts of mutations in cytosines falling into uCa motif of the positive strand in a virus isolateConCau−counts of uCa trinucleotide motifs in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine basesMutC−counts of mutations in cytosines of the positive strand in a virus isolateConC−counts of C nucleotides in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine bases.http://hci-bio-app.hci.utah.edu:8081/Bass/InosinePredict) and [Unlike the exquisitely specific to single stranded RNA and DNA APOBEC cytidine deaminases, ADARs act on adenines imbedded into double stranded RNA folds, so prediction of ADAR deamination sites should account for combination of knowledge about experimentally defined short nucleotide motifs and a potential to form double stranded structure. The prediction scores for ADAR activity on adenines were generated using the web-based tool InosinePredict (ict) and . A one-sS1 FigDouble immunofluorescent staining of granulomas with M2 macrophage-specific antibodies, CD206 (green), and either RV capsid antibody (Abcam) (red) or measles (MeV) nucleoprotein antibody 83KKII (Millipore)  was performed as described in Methods. Nuclei were counterstained with DAPI. Note strong staining for RV antigen and the lack of staining for measles antigen.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 DataSequences are shown in DNA format (T instead of U) to maintain compatibility with other outputs of mutation signature R-script.(XLSX)Click here for additional data file.S2 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S3 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S4 DataGenetic distances was computed using the Maximum Composite Likelihood method with Mega7.(XLSX)Click here for additional data file.S5 DataData for each gene are located in a separate sheet.(XLSX)Click here for additional data file.S6 Data(XLSX)Click here for additional data file.


During the workshop, results from a systematic evidence review prepared by an Agency for Healthcare Research and Quality Evidence-based Practice Center to inform the workshop were presented, focusing on long term osteoporosis drug treatment. This talk will describe the goals of the systematic review, which addressed four questions: (1) What are the effects of long-term (>3 years) osteoporosis drug treatment versus control on risks of incident fractures and harms; (2) Do effects of long-term osteoporosis drug treatment vary as a function of patient, bone, or osteoporosis drug characteristics; (3) Among individuals receiving osteoporosis drug treatment to prevent fracture, what are the benefits and harms of continuing versus discontinuing treatment ; and (4) Do outcomes of drug discontinuation or drug holidays vary as a function of patient, bone, or osteoporosis drug characteristics?


Women continue to have higher prevalence rates of functional impairment and depressive symptoms than men. In addition, women from certain ethnic groups experience disproportionately higher rates of ADL limitation, and are less likely to be screened for depression. The current study examines the association between race/ethnicity and depressive symptoms on functional limitations in Black, White and Hispanic women. We examined prevalence and adjusted odds of ADL limitations by race in n=9,846 women aged 50+ with low (CESD <4) and high (CESD =>4) depressive symptoms from the 2014 wave of the Health and Retirement Study. Overall, Black and Hispanic women had significantly higher rates of depression (p <.001) and ADL limitations (p<.001) than White women. Among those with high depressive symptoms, Black OR 1.98  and Hispanic OR 2.82  women have significantly higher rates of ADL limitations as compared to White women.


The application of image processing techniques for the analysis of CT scan images corresponding to lung cancer cells is gaining momentumin recent years. Therefore, it is of interest to discuss the use of a Computer-Aided Diagnosis (CAD) system using Computed Tomography(CT) images to help in the early diagnosis of lung cancer . We discuss and explorethe design and significance of a CAD-CT image processed model in cancer diagnosis. Small cell lung cancer and non-small cell lung cancer are commontypes of lung cancer . The genThe performance of Multilayer and Neural Network classifiertrained by 11 training algorithms with Independent ComponentAnalysis feature extraction is known . It is sA set of real patient CT scan images are obtained from the LungImage Database Consortium (LIDC) archive is used in this analysis.LIDC database contains lung cancer screening CT images fordevelopment, training, and evaluation of computer-assisteddiagnostic methods for lung cancer detection and diagnosis. TheNational Cancer Institute initiated it. It consists of 1018 cases ofdataset contributed by seven academic centers and eight medicalimaging companies  has deveThe CAD System has the following features: (1) It improves thediagnosis accuracy; (2) Assist in cancer detection at its earlier stageand (3) Reduces the time of the radiologist in evaluation.It is of interest to develop a CT scan image processed model for theearly detection of lung cancer where (1) preprocessing usingintensity measure helps to locate small particles in an image such asnode, speculation and angular margin; (2) high detection andclassification accuracy is established; and (3) removes noises thatcreate false detection.The first step is pre-processing of the image to locate particles usingintensity measure. The processed image is segmented using astandard segmentation technique. Thus, cancer nodules are markedin the image. In addition to features like area, perimeter andeccentricity, other features like centroid, diameter and pixel meanintensity have been extracted during feature extraction. Theclassification module follows this where distinction between benignand malignant tumors based on CT scan images is established.Extracted features are used as training features and thecorresponding trained model is generated for the classificationfollowed by model evaluation for detection and classification withimproved accuracy, specificity and sensitivity.The salient features of the method includes (1) image preprocessingby using filtering techniques and it smoothes the image andremoves speckle noise; (2) It segments the cancer nodule from theCT scan image. The segmentation method separates and identifiesthe touching objects in the image. This feature helps in propersegmentation of cancer nodules when it is touching to other falsenodules. (3) Features extraction where features like area, perimeter,centroid, diameter, eccentricity and mean intensity are extractedfrom the image. These features are used as training features todevelop the classifier; and (4) The classification module classifiesthe detected nodule as malignant or benign by using the trainedclassification method.Strengths of the method includes: (1) The improved accuracy ofcancer nodule detection; (2) classifies the detected lung cancer asmalignant or benign; and (3) Removes the noises that create falsedetection of cancer.We describe and discuss the application of a Computer-AidedDiagnosis (CAD) system using Computed-Tomography (CT)images to help in the early diagnosis of lung cancer . We report a framework forthe development of a model for early cancer detection using CADCTimage analysis.


As we observe the 100th anniversary of the 1918 influenza pandemic, we are reminded ofthe importance of preparedness for and adequate response to influenza, and the criticalrole of influenza surveillance through laboratory detection. Influenza virus detectionhas helped drive the development of diagnostic and virology laboratories in the WorldHealth Organization (WHO) Western Pacific Region over the last 10–15 years, atthe same time strengthening their capacity to detect and respond to infectious threatsbeyond influenza. Such cross-cutting approaches are advocated under the Asia PacificStrategy for Emerging Diseases and Public Health Emergencies (APSED III),  laboratory network. . GISRS monitoring of circulatinginfluenza viruses in humans enables timely detection and reporting of significantchanges in seasonal influenza viruses such as the emergence of the influenza A(H1N1)pandemic virus in 2009 and the rapid global spread of oseltamivir-resistant seasonalH1N1 viruses in 2007–2008.  techniques developed in the past 25 years enabled therapid and specific detection of viral nucleic acid sequences, becoming the gold standardfor diagnosis and surveillance. Since 2004, PCR has been instrumental in the earlydetection of various zoonotic influenza viruses in humans, including A(H5N1), A(H5N6),A(H7N9), A(H9N2) and others in the Western Pacific Region. (NICs are mandated to maintain high technical capacity for influenza testing (As the majority of NICs in the Region actually test a broad range of infectious diseasesor are housed in institutions that do, the benefits of technical and human resourcestrengthening through GISRS have been crosscutting. Annual NIC meetings bring togetherexperts to discuss progress, obstacles and best practices, helping to strengthencountries’ laboratory technical capacity through better coordination, a keystrategic action in APSED III. Molecular testing available in the GISRS laboratorynetwork has also formed the basis of regional preparedness for detection of emergingpathogens, including Middle East respiratory syndrome coronavirus (Since the 1918 pandemic and the later introduction of GISRS, regional NICs have beenmaintaining traditional methods, incorporating new technologies and building humanresource capacity to help strengthen preparedness and response to influenza. Thecross-cutting advantages generated and the benefits of sharing and collaboration throughGISRS contribute to better preparedness for future outbreaks of influenza and otherinfectious diseases.


Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies.Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here,  The mu opioid (mu) receptor is a G protein-coupled receptor (GPCR) that neuromodulates several physiological functions, in particular nociception , and/or disruption of physical contact by an interfering peptide. The use of interfering peptide and/or mice deficient for one receptor also significantly contributed to demonstrate the specificity of the functional changes associated with heteromer formation and to establish a causal link with behavioral outputs. In native tissue, the mu receptor heteromerizes with the delta opioid (delta) or kappa opioid (kappa) receptors or with the non-opioid receptors ORL1, cannabinoid CB1, galanin Gal1, adrenergic α2a, somatostatin sst2, dopamine D1, chemokine CCR5, and vasopressin V1b. Association between the mu receptor splice variant MOR1D and the gastrin-releasing peptide receptor (GRPR) has also been reported as well as mu physical proximity with the ion channel NMDA  is dynamically regulated and increased in hypertensive rats  binding and ERK1/2 signaling in SK-N-SH neuroblastoma cells  allosterically decreased dihydromorphine binding at the mu receptor in rat striatal membranes -C neuroblastoma cells co-expressing mu and ORL1 receptors, pretreatment with nociceptin decreased DAMGO potency and efficacy to inhibit adenylate cyclase  system of the leucine rich motif responsible for the receptor V1B-β-arrestin interaction increased morphine-induced analgesia and reduced adenylate cyclase supersensitization and morphine-induced tolerance and physical dependence  p38 activation in the mouse DRGs  pathway and contributes to morphine tolerance  hydrolysis inhibitor JZL184 increased the concentration of the endogenous ligand and enhanced social play behavior in adolescent rodents (Manduca et al., 1 receptors. Indeed, opiate hyperlocomotion and locomotor sensitization were abolished in dopamine D1 receptor in knock-out mice or following local injection of the D1 antagonist SCH23390 in the Nacc (Tao et al., Mu receptors are also involved in other aspects of opiate addiction such as locomotor sensitization and could achieve their modulatory control through heteromerization with dopamine DPharmacological and knock-out based studies linked an anxiogenic and depressant phenotype to mu receptor activation and, on the opposite, associated an anxiolytic and antidepressant phenotype with delta receptor activation (Lutz et al., Systemic administration or local micro-infusion in the Nacc of the delta agonist UFP512 promoted anxiolytic- and anti-depressant-like activity (Vergura et al., 2a heteromers in the NTS were correlated with increased blood pressure in hypertensive rats (Sun et al., 2a heteromerization induced by the mu agonist DAMGO was paralleled by increased blood pressure. Treatment with the mu antagonist CTAP antagonized DAMGO changes in normotensive rats and reduced mu-α2a heteromerization and blood pressure in hypertensive rats (Sun et al., 2a adrenergic receptors thereby potentiating hypertension.Mu receptors are known to control autonomous functions. Higher levels of mu-αInteractions between mu and somatostatin receptors have been postulated to influence tumor cell growth (Hatzoglou et al., The bivalent ligand MDAN-21 composed of the mu agonist oxymorphone and the delta antagonist naltrindole tethered by a 21 amino acid long linker was developed to selectively target mu-delta heteromers (Daniels et al., More recently, the bivalent ligand MCC22 linking the mu agonist oxymorphone to the CCR5 antagonist TAK220 has been proposed to inhibit inflammatory and neuropathic pain by targeting mu-CCR5 heteromers (Akgün et al., A major limitation to the therapeutic use of bivalent ligands is their poor capacity to cross the blood brain barrier (Le Naour et al., in vivo and their functional interactions addressed in a handful of tissue or brain areas. Moreover, heteromer expression is dynamically regulated depending on physiopathological conditions. No doubt that both novel functions and receptor pairs will be uncovered in the future, which further emphasizes their potential as innovative therapeutic targets.Our current appreciation of the role of mu heteromer is still in its infancy and their contribution to mu receptor-dependent behavior likely underestimated. So far, physical proximity has only been validated for a limited number of receptor pairs All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Augmented reality (AR), superimposing digital assets onto the real-world —offers a paradigm shift in delivering immersive interventions for aging adults. Reminiscence and life review are robust intervention techniques that have decades of empirical support to boost mood and meaning in older adults. In this presentation, we demonstrate the applied research and technology development process to create an AR reminiscence and life review engine for aging adults and their caretakers. We conducted 25 needs assessment interviews with community-dwelling older adults, and assisted living facility directors, nurses, and residents. Initial analyses revealed the need for: (1) finding scalable and cost-effective solutions to alleviate time burden for caregivers; (2) increasing variety of activities that do not need much instruction; (3) producing activities that grab and maintain attention; and, (4) generating more personalized activities that do not divert too much time from caretakers. We integrated the findings to develop a working prototype AR engine called “Project Phonado.” From preliminary user testing, Project Phonado aids in boosting mental health and meaning in aging adults—at least temporarily (immediate and one day follow-up). We will show clips of some pilot user testing of the engine and discuss the next evaluation and development steps.


Sphenocentrum jollyanum (SJ) seed has many health benefits due to its very potent anti-inflammatory and antioxidant properties. Despite its widespread use, it has not been validated for use in the treatment of benign prostatic hyperplasia (BPH). This study was conducted to examine histomorphological effects of SJ seed on BPH that usually causes bladder outlet obstruction.There were a total of six groups of animals each comprising 5 adult male rats. Apart from group 1 , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction; groups 3 and 4 received the extract at 300 and 600 mg/kg respectively by gavages for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) simultaneously with the steroid administration for thirty days. The animals’ were weighed before the experiment and subsequently every three days until the end of the study.The extract caused marked decrease in prostate weight of rats with BPH with histo-morphology of the tissue showing degenerated stromal and epithelial cells with few epithelial involutions of glandular tissue. Prostate specific antigen (PSA) level as well as testosterone level significantly (p<0.05) decreased in the treated groups compared to negative control. BPH animals treated with extract/finasteride exhibited remarkable increases in anti-oxidant enzymes level with concurrent decreases in peroxidative activity.SJ effectively ameliorated prostatic hyperplasia in BPH animals causing marked degenerative changes in prostate stromal and epithelial cells and also exhibited marked anti-oxidant effect. Benign prostatic hyperplasia (BPH) is a noncancerous cell growth in the prostate gland. This clinical condition elicited by uncontrolled growth of glandular epithelial and stromal cells, induces lower urinary tract symptoms (LUTS) which include weak urinary stream, incomplete bladder emptying, nocturia, dysuria and bladder outlet obstruction , an active metabolite formed by enzymatic conversion of testosterone by steroid 5α-reductase enzyme  Pierre (Menispermaceae) is a perennial plant that grows naturally along the West Coast sub-region of Africa that includes Nigeria. It is deep rooted with few branches bearing fruits that contain a single large oval shaped seed , Ibadan where a voucher specimen was deposited (FHI/108203).Preparation of the petroleum ether extract of Sphenocentrum jollyanum seedoC) in three cycles using a Soxhlet extractor. The crude oil extract of SJ seed was concentrated in vacuo at 30 oC to obtain 146 g residue which was an equivalent of 9.3 % w/w. The residue was stored in an air-tight bottle kept in a refrigerator at 4 oC till used.A smooth powder was made of the dried seeds using an electric grinder. The seed powder, (1.57 kg) was extracted by petroleum ether  guidelines on the use and care of animals, in experimental studies  obtained from the Animal House of the University of Ibadan, Oyo State, Nigeria, were kept under standard environmental conditions of 12 hr /12 hr light/dark cycles. They were housed in polypropylene cages , and maintained on mouse chow (Livestock Feeds Nigeria Ltd) and provided with water TestosteroneThis is a steroid hormone from the androgen group and is found in mammals, reptiles and other vertebrates  for three weeks , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction while groups 3 and 4 received the extract at 300 and 600 mg/kg body weight (bwt) doses, respectively by gavage for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) with simultaneous steroids injection (BPH induction) for thirty days. The animals were weighed prior to the commencement of the experiment and subsequently every three days till the end of the experiment. Assay for testosterone and prostate specific antigen (PSA) Enzyme immunoassay technique was used for the quantitative determination of testosterone concentration and PSA evaluation  was assayed utilizing the technique of Kakkar  activity was assayed colorimetrically at 620 nm and expressed as μmoles of HEstimation of glutathioneThe glutathione (GSH) level was determined by the method of Ellman  and hydroperoxides (HP) were measured by the method of Niehaus and Samuelsson . The tissue was thereafter treated with acetone and then cleared in xylene for 30 min to enhance the tissue transparency followed by impregnation and embedding in paraffin wax. The embedded tissue was sectioned at 5 μm, mounted on a slide and stained with hematoxylin and eosin (H&E) stains  has been reported to block testosterone/prazosin- induced increase in rat prostate weight  testosterone in the blood stream is noted for its key role in BPH progression. Studies showed that high levels of free testosterone promote the stimulation of 5α-reductase found mainly within the stromal cells which converts testosterone to a potent androgen, DHT that is responsible for the pathogenesis of prostate gland (Wong et al., 2000Several studies have shown that BPH is associated with increased oxidative stress which increases with increasing age (Aydin et al., 2006SJ seed extract which is recognized for its potent anti-inflammatory and antioxidant properties, effectively ameliorated prostatic hyperplasia by causing marked degenerative changes in prostatic tissue stromal and epithelial cells of the extract-treated animals. The extract also exhibited significant anti-oxidant effect with considerable prophylactic activity. However, further investigation is needed for its validation.


OBJECTIVES/SPECIFIC AIMS: To establish a conceptual framework todevelop a CTS-IDP with data analytics, and an e-Learning Faculty DevelopmentGuide on best practices and use of the IDP over the CTS academic life-course.METHODS/STUDY POPULATION: To accomplish our goal, we propose thefollowing methods: (1) an online survey, using a convenience sample of the 24KL2 CTSA IDP Collaborative members (conducted in 2017), to assess perceivedneeds for a universal CTS-IDP, current IDP practices, barriers to IDP use, andto discern and align each CTSA Hub’s interests, expertise andcommitment to specific areas of the study; (2) A scoping narrative literaturereview, utilizing the Arksey and O’Malley framework covering the timeperiod corresponding to the initiation of funding (1999) of the original K30Clinical Research Curriculum Awards through to the present CTSA funding period,incorporating Medical Subject Heading (MeSH) keywords , initially delineated by USC referencelibrarian and to be expanded by reference librarian services from the IcahnSchool of Medicine at Mount Sinai and University of Rochester, and performed onNIH searchable databases including NCBI PubMed, Central and Medline &Worldwide Science; Web of Science, ProQuest, ProQuest Abi/Inform,Google Scholar, Cochrane, Ovid MEDLINE databases, as well as Google forpublished papers in English and Spanish. For this portion of the work, we willdescribe and characterize (1) research career development or progressionconstructs, domains, and milestones; (2) establish the presence or absence ofdefined and/or pre-specified timed milestone objectives and inclusionof SWOT analytics and/or Gantt chart approaches; (3) delineate IDPs structure, toolkitsand their key features ; (4) and identify specific gaps to best address the need forpersonalized career development education. Based on this review, we willsynthesize CTS milestones, develop a time frame for meeting RCD expectations,and establish RCD benchmarks for achieving these milestones, all in consensuswith the IDP Collaborative Workgroup. RESULTS/ANTICIPATED RESULTS:Seventy-seven percent of the IDP CTSA’s responded to the onlinesurvey, led by University of Rochester, and the results can be summarized asfollows: (1) 100% agreed that the IDP process is important and shouldbe considerably improved to optimize effectiveness; (2) a range of diverse IDPformats are utilized, making comparisons across programs difficult; (3)50% of CTSA hubs report only fair to good compliance with the IDPprocess; (4) a major barrier to the IDP process is lack of instruction regardinghow best to utilize; (5) poor alignment of currently available IDPs designed forbasic science PhDs with CTS investigators; (6) an absence of a CTS specific IDPto best foster RCD for this specific career trajectory. When asked: What are thebarriers to writing a detailed and thoughtful IDP, responses in order ofagreement from greatest to least were: No verification of acquired competencies,beyond self-report (56%), Static platform (38%), Notconstructed for clinical and translational researcher (31%), Noanalytical or documentation on use (31%), No instruction given toscholars on how to use it effectively and efficiently (31%), The IDPwe are using is more constructed for PhD students and postdoctoral fellows(25%), No instruction given to the scholars on why it is important asadult learners (19%), and Not constructed for early careerphysicians/scientist (13%). Additional progress has beenmade on our Scoping review: An initial ABI/Inform and PubMed USCresearch librarian conducted search using Author names yielded 72 articles, ofwhich only 2 were relevant to the topic at hand. A ProQuest™ searchyielded 19 potentially relevant articles, 11 of which were of relevance to thetopic of IDPs; and a Google Scholar search yielded 18 and 25 on careerdevelopment and self-management, respectively. This has enabled us to put forthan initial model of factors that impact the purpose and design of IDPs thatincludes? DISCUSSION/SIGNIFICANCE OF IMPACT: Discussion: Our initialdata suggests that many CTSA institutions see the need to further enhance thementoring process with a more informed and personalized IDP template andprocess. Furthermore, our initial scoping review suggests a framework upon whichto build specific components of a more ideal and useful IDP to best guidementored research career development of CTS trainees. Significance: Developingand evaluating collaborative evidence-based CTS IDP and corresponding e-LearningGuide could potentially prevent or reduce important delays in RCD, a commonroadblock for the translation of clinical interventions. Ultimately, the CTS-IDPserves not only to support and frame a scholar’s RCD“habits of mind” during training and early careerdevelopment but to also to achieve a sustainable long-term career at a CTSresearcher equipped to meet the ever challenging and dynamic researchlandscape.


Dear Editor,Enterobacterales, and it matched cases who had extended-spectrum cephalosporin (EC)–resistant enteric uropathogens (EUs) 1:1 with controls with EC-susceptible EUs to predict a scoring system tool for EC resistance [We read with great pleasure the recently published study by Weinstein et al. . This caEnterobacterales [Escherichia coli isolates and 81.3% (608 of 748) of EC-resistant Klebsiella pneumoniae [E. coli after treatment with oral nitrofurantoin was 3.2% (1/31) at 4 weeks after finishing therapy [This clinical scoring system is highly useful for empiric antibiotic treatment for urinary tract infections (UTIs), especially the complicated ones, which often require treatment based on in vitro antibiotic susceptibility testing. The Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases (ESCMID) guidelines for UTI emphasize the importance of empiric treatment of uncomplicated UTI without a urine culture and susceptibility testing. Those guidelines recommend either a single dose of oral fosfomycin, 5 days of oral nitrofurantoin, 3–7 days of pivmecillinam (which is only available in Europe and is not licensed for use in North America), 3–7 days of oral β-lactam , or 3 days of oral trimethoprim-sulfamethoxazole  [ 608 of 78 of EC-r Additionally, urine cultures are regularly ordered in healthy outpatient women with urinary symptoms even though they are often of limited value given the delay in obtaining results, the cost and inconvenience to the patient, and the high predictive value of symptoms alone in diagnosing acute cystitis . In someThe clinical tool developed by Weinstein et al. to predict EC resistance included recent trimethoprim-sulfamethoxazole exposure as unexpectedly the only antibiotic found to be significantly associated with EC resistance after multivariate analysis . Althoug In conclusion, the clinical prediction tool for EC resistance developed by Weinstein et al. could be most useful in the setting of empiric treatment choice for complicated UTI, but may be used less often in the case of uncomplicated UTI, where adherence to the IDSA and ESCMID UTI treatment guidelines would be the gold standard for empiric antimicrobial treatment . One cou


OBJECTIVES/SPECIFIC AIMS: The aims of this project are to: (1) examine placebo effects on subjective and objective outcome measures, (2) determine if an increase in the placebo is associated with changes in benefit, (3) evaluate if the trauma related insomnia placebo group in our study has different side effect reports compared with insomnia placebo participants in previous suvorexant trials, and (4) (Exploratory) examine associations between the placebo group’s characteristics  and placebo effects. METHODS/STUDY POPULATION: The parent study is a randomized double-blind placebo-controlled clinical trial  of suvorexant for treatment of adults (age 18–55) with insomnia that started or worsened after trauma exposure. Suvorexant is a first in class orexin antagonist and is approved by the FDA for the indication of insomnia. In this 6-week trial, all participants initially take 10 mg of suvorexant/placebo, and the dose will be increased to 20 mg if participants continue to experience clinically significant insomnia symptoms 1 week after starting the medication. Sleep outcomes will be measured by polysomnography, daily sleep diary, and the Insomnia Severity Index. RESULTS/ANTICIPATED RESULTS: We hypothesize that (1) within the placebo group data both subjectively and objectively measured outcomes will similarly show improvement in insomnia symptoms, (2) the increase of the placebo medication dose will result in an increased benefit, (3) the trauma-related insomnia placebo group will have the same type and similar rate of side effects reported in previous suvorexant trials. DISCUSSION/SIGNIFICANCE OF IMPACT: Most previous studies examining placebo effects focused on pain and depression. Information obtained from this project will complement our current understanding of placebo effects by characterizing placebo effects on trauma-related insomnia. This study will inform the development of novel strategies to maximize utility of placebos in future clinical trials.


Context: Tuberculosis (TB) has remained a devastating global public health problem. In the continuing search for effective treatment, polyherbal remedies used as alternative medicines in the Eastern Cape Province of South Africa were surveyed.Objective: The survey collected information and documents the list of ingredients such as the name of the plants used including the non-herbal inclusions, type and dosage of polyherbal formulations used for the treatment of TB.Materials and methods: The survey was conducted over a period of 6 months using semi-structured questionnaires amidst informal conversations with the traditional healers in five communities in the study area. The chosen study area is the third infected Province with TB in South Africa.Results: A total of nine polyherbal preparations were collected. Information on the parts of the plant used, mode of preparation and the dosage used were documented. In total, the herbs belong to 20 families of which Apiaceae, Liliaceae, Strychnaceae, Rutaceae and Hypoxidaceae are the most prominent. However, members of Apiaceae were commonly mentioned for the preparation of the remedies. The two most frequently used plants were Allium sativum L. (Liliaceae) and Strychnos decussata (Pappe) Gilg. (Strychnaceae). Rhizome was the commonest parts used, followed by the roots and barks.Conclusions: This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in the study area. The therapeutic claims made on medicinal plants used for the preparations are well supported by the literature, with many of the species having antimicrobial properties. Mycobacterium tuberculosis has remained one of the most prevalent causes of mortality in developing nations, especially in the Asian and African continents. The disease remains a big problem in these countries probably due to inadequate means for the management and treatment of the disease. According to World Health Organization (2002), about 95% of the approximately eight million cases of TB occur each year in Africa having the highest incidence. However, South Africa is the third highest incidence country after India and China with about 80% of the population infected with the disease. This rate has increased by 400% over the past 15 years most especially among the people living with human immuno-deficiency virus (HIV)  caused by M. tuberculosis to commonly prescribed antimicrobials has made people fall back on herbal medicines for various therapeutic purposes . Ethnobotanical surveys have extensively studied South African populations of adults and children with several illnesses Bodkin .A total of nine polyherbal medicines used for the treatment of TB were recorded and collected from the study area ; these aThe polyherbal remedies in the study area were prepared from 24 plants. The six most commonly mentioned plant families used in the preparation of the polyherbal formulations in terms of number and percentage are Apiaceae [5(25%)], followed by Liliaceae [4(20%)], Strychnaceae [4(20%)], Rutaceae [4(20%)], Solanaceae [2(10%)] and Primulaceae [2(10%)] . MembersAllium sativum L. (Liliaceae) [4(17%)], Strychnos decussata (Pappe) Gilg. (Strychnaceae) [4(17%)], Daucus carota L. (Apiaceae) [3(13%)] and Hypoxis argentea (Fiscand) (Hypoxidaceae) [3(13%)]. Other plants such as Agathosma betulina (Berg) (Rutaceae) [2(8%)], Capsicum annuum L. (Solanaceae) [2(8%)] and Rapanea melanophloeos L. (Primulaceae) [2(8%)] are used for a few polyherbal preparations in the Province as represented in The most frequently used plant parts in this study was rhizomes [10(27%)], followed by bark [8(22%)], and roots [8(22%)]. Others are leaves [6(16%)], corms (3(8%)] and vegetable [2(5%)] as shown in S. decussate, which should be chewed immediately after KWTb remedy has been administered ] and decoction [2(22%)] with the exception of nistered . This isnistered . The intMycobacterium tuberculosis. Probably, these therapies have gained popularity in both developed and developing countries because of their natural origin and fewer side effects for the treatment of various chronic and acute ailments (Ahmad et al. The diverse uses of each plant can be explicated by the fact that, a single plant can serve many medicinal purposes or perform different functions (Lawal et al. This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in Amathole District Municipality of Eastern Cape Province. Africa is endowed with a biodiversity of medicinal plants, many of which are currently used in the traditional management of TB. The study shows that people in the study area still depend on polyherbal medicines for the treatment and management of TB. The documented remedies reflect rich ethno-medicinal knowledge in the province. However, further test are required to validate the ethno-medicinal usage of these polyherbal remedies as anti-TB agents.


Data for this study originated the Oklahoma 100 Year Life Project. A total N = 7 volunteer actors  were recruited to participant as actors to play the role of centenarians in a living history play based on oral historical narratives. Actors participated in preliminary (prior to play performance) and post (after play performance) focus group sessions. Focus group questions addressed four key ideas: (1) Perceptions of aging and human longevity; (2) Loss and decline in aging; (3) Narrative storytelling and; (4) Personal life goal(s). Qualitative content analysis was performed to assess general thematic evidence stemming from actor perspectives. Four predominant themes emerged suggestive of adaptation in actor perceptions about human aging and longevity. These themes included: (1.) Purpose seeking (e.g. "It was interesting to see how much you can get out of life."); (2.) Age-embodiment ; (3.) Creative curiosity ; and (4.) Self-actualization . Results have implications relative to how oral historical narratives can be used to enhance the personification of aging on stage, as well as demystify personal myths about longevity. Applications for use within educational and community settings for theatrical performances will be shared.


OBJECTIVES/SPECIFIC AIMS: The overall goal of this project is to enhance the use of GCRA in Latina breast cancer survivors at high risk of hereditary breast and ovarian cancer to reduce disparities in GCRA uptake. The aims of the study are to (1) develop a cultural adaptation of an evidence-based TGC intervention that consists of phone genetic counseling and a booklet, (2) evaluate the impact of TGC Versus Usual Care, and (3) explore the communication patterns in TGC and genetic counseling sessions with an interpreter. METHODS/STUDY POPULATION: We are conducting a 2-phase, mixed methods study. In Phase I we will develop a cultural adaption of an evidence-based intervention (TGC) for high-risk Latina breast cancer survivors using the Learner Verification and Revision Framework (n=15). In Phase II we will use a cluster randomized design with four community sites randomized to Spanish TGC (n=2 sites) or usual care (n=2 sites) . The primary outcome is genetic counseling uptake. Among women who receive genetic counseling either through TGC (n~30) or with an interpreter (n~15), we will assess counseling quality by reviewing 20 randomly selected audiotaped sessions . We will evaluate women’s HBOC knowledge and satisfaction with counseling. Communication processes and outcomes will be assessed using gold standard RIAS quantitative coding system and qualitative discourse analysis. RESULTS/ANTICIPATED RESULTS: We elicited input from transdisciplinary team members to develop an initial adaptation of a TGC print booklet and intervention protocol for use with high-risk Latina breast cancer survivors with limited English proficiency. The booklet contains low-literacy information about HBOC, risk factors, pros and cons of testing, and management strategies. Based on these materials and prior work, we anticipate TGC will consist of one 1 hour or less TGC session by phone. Participants interested in pursuing testing will receive a saliva kit and will participate in a second TGC session (30 min) to discuss test results and management options. DISCUSSION/SIGNIFICANCE OF IMPACT: Given access barriers and the shortage of Spanish-speaking genetic counselors, adapting and translating TGC intervention is a promising strategy that could reduce disparities by broadening the reach and accessibility to genetic counseling while enhancing the quality of the service for Latinas with limited English proficiency.


Background: Death certificate inaccuracy increases at older ages. The Long Life Family Study (LLFS) utilizes a physician adjudication committee to review the death certificate, medical records and a family narrative about cause of death. We report here the adjudication process and the prevalent underlying causes of death for a subsample of those who have died so far. Methods: We first describe the adjudication process. There were ~1,250 deaths in LLFS. We report underlying causes of death for a subset of proband generation subjects enrolled and evaluated by two LLFS study centers. Results: As of May 2019, we have adjudicated 190 deaths  . Mean age 95 years (range 81-105 years). Top 5 causes of death for men: cancer (13%), coronary heart disease , dementia (13%), "other" (11%) and "unknown" (9%) and for women: dementia (21%), valvular heart disease (14%), coronary heart disease (12%), unknown (12%) and other (9%). Rate of death due to dementia was greater in women compared to men . Conclusions: In this pilot study, a significantly greater proportion of women died due to dementia compared to men. At least some portion of this difference may be due to the observation that women are known to survive chronic aging-related diseases more than men and thus have a greater opportunity to die from dementia at advanced ages. An additional cause to consider includes clinicians’ gender bias in ascribing diagnoses in the medical records that were relied upon as part of the adjudication process.


The House Calls and Behavioral Health Integration project was an inter-agency collaboration to address depression in the older adult population by increasing knowledge and awareness of the condition and providing better access to care. Rowan Medicine, New Jersey Institute for Successful Aging (NJISA) and Jewish Family and Children Services (JFCS) partnered to deliver a comprehensive education, screening and referral program for residents of 3 senior housing facilities serving an estimated 300 elderly and disadvantaged residents. The goal of this year long project was to provide depression education for both housing residents and staff; offer on-going access to free depression screens (using PHQ-9) for residents; and refer residents to an appropriate resource  depending on depression screen outcome. Depression education was provided to 15 housing staff and 78 older adult residents. A total of 34 depression screens were completed ; further evaluation of symptoms was indicated for 59% (n=20) of those screened. Seventeen of the 20 residents accepted a recommendation for a referral to supportive counseling; 3 declined. The average PHQ-9 score was 8.45 . Referrals to case management and house calls (n=4) were also made. Feedback from both housing residents and staff was positive and the project team learned valuable lessons about serving older adults in congregate living settings which has informed other programming. The project was successful in providing education, screening and referrals to residents who might not otherwise have access to specialized geriatric behavioral health interventions.


We examine trait and state subjective aging as antecedents of control beliefs in older adults with a daily diary design. Adults (n=116) ranging in age from 60 to 90 (M=64.71) completed a nine-day daily diary study online. Participants reported trait aging attitudes  on Day 1 and daily Awareness of Age-Related Change (AARC) of loss and gain experiences and control beliefs (Locus of Control and Perceived Competence) on Days 2-9. Controlling for demographics and known antecedents of control beliefs , daily increases in AARC gain were associated with increases in both Locus of Control and Perceived Competence, and a cross-level interaction revealed that Locus of Control decreased for those with more positive ATOA on days when they reported more AARC losses. Discussion will focus on interpreting the interaction between trait and state subjective aging.


The relationships between physical frailty and perceived neighborhood social cohesion (PNSC) and functional disability among community-dwelling older adults are poorly understood. This study aims to (1) examine the associations of frailty and PNSC with disability; and (2) evaluate low PNSC as a risk factor in the association between frailty and disability. A sample of 1645 older adults using multi-stage sampling method in Shanghai were randomly selected in this cross-sectional study. Frailty operationalized as Cardiovascular Health Study criteria  and PNSC measured as Neighborhood Cohesion Scale  were independently associated with basic and instrumental activities of daily living disability. A significant interaction of frailty and PNSC on disability =4.31, P=.014) was found, using a two-way analysis of covariance (ANCOVA). Compared to robust individuals with high PNSC, pre-frailty with high PNSC was not significantly associated with disability while pre-frailty with low PNSC was associated with approximate 4-fold increased prevalence of disability . Frailty with high PNSC was associated with higher likelihood of disability  and frail individuals with low PNSC stood out with 10-fold increased prevalence of disability . All analyses were controlled for demographical and clinical covariates. Our results suggest high level of social cohesion serves as a buffer against the impact of physical frailty on functional disability. These findings notably imply to the development of interventions for older frail adults from the neighborhood perspective.


Plants grow continuously, forming new meristem-derived organs and tissues throughout their post-embryonic life. As sessile organisms, plants need to constantly integrate and reflect environmental fluctuations in their growth and development, which can translate into high level of developmental plasticity in response to environmental changes  evidences of molecular mechanisms that mediate the crosstalk between phytohormone signaling, chromatin structure and gene expression (2) how this crosstalk may link to plant developmental plasticity and robustness and finally (3) why meristems may represent central places for this crosstalk allowing plasticity and environmental memory.Phytohormone and epigenetic regulation can interact on multiple levels : (1) phyFLOWERING LOCUS C (FLC), preventing precocious floral transition  1 and 2 with histone-methyltransferase activity playing a major role in transcriptional regulation during development  genes is positively regulated by BRM establishing local auxin maxima and stimulating the expression of the RAM-specifying PLETHORA genes PLT1 and PLT2  is associated with changes in jasmonic (JA), salicylic acid (SA) and ethylene responses  control of cell identity genes in meristems, (2) chromatin-mediated stabilization of gene expression beyond the hormonal initial signal, (3) chromatin-governed integration of separate hormone signaling pathways.WUSCHEL (WUS) is regulated by cytokinin signaling, DNA methylation, H3K27me, or chromatin remodeling  their central role in postembryonic morphogenesis, plasticity and memory, (2) their particularities for phytohomone signaling and chromatin remodeling, (3) first evidences reported for this crosstalk in SAM.The meristems represent major sites of stem cell niches in plants Scheres, . Apical Phytohormone and epigenetic pathways play overlapping/complementary roles in meristem functions and developmental plasticity or robustness, laying the basis for a biologically significant crosstalk. Importantly, meristems have been shown to be the place of epigenetic control for stem cell pluripotency, differentiation, and reprogramming  in the SAM of Arabidopsis clv3 mutants (Lafos et al., Major evidence for phytohormone-chromatin crosstalk was obtained using Arabidopsis mutants, or applying phytohormones or chemical inhibitors of chromatin modifiers in various developmental processes (Yamamuro et al., In conclusion, phytohormone action and chromatin modifiers seem to be tightly interacting but the extent to which they act jointly or independently remains unclear (Ojolo et al., Current knowledge leads to the opinion that this crosstalk in meristems can integrate environmental cues for developmental outcome. Erasure of this signaling may allow continuous adjustment to new environmental conditions. Its maintenance through persistent chromatin states can however stimulate mitotic memory that could prime later organ formation. How the balance between erasure and memory is achieved remains enigmatic .While the mechanistic events could be more easily deciphered in well-established model annuals such as Arabidopsis, it is important to establish perennial models where the impact of mitotic epigenetic memory is of importance in the context of climate change. In addition to SAM and RAM, cambium, whose activity is crucial for environmentally controlled wood formation, may be an appropriate and highly relevant model (Wang et al., SM suggested and designed the opinion article. MDS and SM designed the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The scarce knowledge of multimorbidity development hampers the effectiveness of clinical interventions. We aimed to identify multimorbidity clusters, trace their evolution in a cohort of older adults, and detect the clinical trajectories of single individuals as they move among clusters over 12 years. Population-based study including 2931 persons 60+ with ≥2 diseases participating in the SNAC-K study. A fuzzy c-means cluster algorithm was used to group participants by disease patterns at baseline and follow-ups. Migration from one cluster to another was tracked over time, and the association between the clusters and mortality was tested. At baseline 52% of participants were classified into five clinically meaningful disease clusters: psychiatric and respiratory (5%), heart (9%), respiratory and musculoskeletal (16%), cognitive and sensory impairment (10%), and eye diseases and cancer (11%). The remaining 48% of participants (unspecified group) were grouped in any cluster at baseline but greatly contributed to the other clusters at follow-ups. Multimorbidity clusters that included cardiovascular and neuropsychiatric diseases presented a significantly higher mortality risk (odds ratios ranging 1.58–6.00) than the group not part of any clusters. Clusters characterized by cardiovascular and neuropsychiatric diseases included 25% of the study population at baseline and 28% of participants at six years, and they accounted for 51% of deaths at six years and 57% of deaths at twelve years. Multimorbidity clusters and clinical trajectories of older adults with multimorbidity show great dynamism over time. The multimorbidity clusters and trajectories identified in this study may help identifying groups with similar needs and prognosis.


To address their needs for proactive self-care and end of life planning, we implemented a community based educational program that promotes future care planning (FCP) for community residing older adults. Extension specialists from Iowa State University implemented two brief FCP program sessions with older adults. Topics included both short-term and long-term future care planning activities and strategies. Baseline and post program surveys were completed by 216 community dwelling older adults (M=78.21). The program was successful in getting older Iowans in the rural area start end of life care preparation as well as helping them to make changes in their health care decisions. The majority of participants (89.6 %) reported high satisfaction with the programs. We also found a high rate of change (62%) in opinion regarding future care. The implication of future care planning for is discussed with recommendations for future research.


The quality check and determination of permitted and non-permitted additive colors in food products is very important for customer׳s right protection and health. This survey was undertaken to demonstrate the frequently use of additive colors and products targeted to color adulteration in Iranian foods and beverages. From the 1120 of the samples, 18.86% contained artificial colors, 11.89% contained natural colors and 69.25% of samples had no additive colors. Tartrazine (E102) was the only non-permitted artificial dye used in samples. Among products with additive colors, only 4.38% of samples failed to meet with national Iranian standard and 61.23% of non-compliance samples were from non-industrial sectors and mostly were saffron and food containing saffron such as saffron rock candy and saffron chicken. These places and products quality are main the concern to solve the color adulteration in Iranian food market. Specifications TableValue of the data•The dataset shows the amount of additive colors in local food and beverage products.•The dataset signifies the amount of permitted and non-permitted colors under Iranian laws.•The dataset of this article identifies products with non-authorized colors, which can be useful for other investigators working in area of quality assurance of foods.1The dataset provided here , Table 32The Iranian national standard organization only permits seven artificial dyes of Quinoline Yellow (E104), Sunset Yellow FCF (E110), Azorubine (E122), as well as Ponceau 4R (E124), Allura Red AC (E129), Indigotine (E132) and Brilliant Blue FCF (E133) in different type of products. The prevalence use of permitted and non-permitted artificial dyes has been reported from different states of Iran, previously. The required data were collected from the results documented in Kimia Test FAM Laboratory during the five years of 2011–2015. The additive color of 1120 samples, which represent 30% of samples analyzed in Tehran city for additive colors, was determined using thin layer chromatography methods (TLC) according to 2634 Iranian national standard and were compared to 740 Iranian national standard for permitted food additive colors. The data were entered into an Excel spreadsheet and were analyzed by descriptive statistics


The HER4 receptor tyrosine kinase is known to have promiscuous activity in malignant cells, last but not least in breast cancer. Evidently, the prognostic and predictive impact of HER4 expression depends on the expression of different receptor isotypes, the way of receptor activation (ligand dependent vs. independent), and on the complex interaction of the HER4 intracellular domain (4ICD) with intracellular regulative molecules which results in either oncogenic or rather tumor suppressive HER4 activity. Recent data suggest that HER4 unfavorably affects the endocrine treatment of postmenopausal breast cancer patients with tamoxifen and therefore might represent an additional therapeutic target in luminal breast cancer. The Human Epidermal Growth Factor Related (HER) receptor family comprises at least four cognate receptor tyrosine kinases  which - as a functional unit - drive breast cancer disease and have prognostic and predictive impact . Remarkably, HER4 plays an extraordinary role in the context of HER receptor coexpression and interaction . Upon itIn contrast to its differentiation enhancing activity Her4 has also been shown to promote the proliferation of breast cancer cells , 16. It Notably, HER4 does not only affect tumor cell growth and survival but also appears to significantly impact antigen specific tumor treatments by definite intracellular molecule interaction . In thisThe finding that HER4 impairs the tamoxifen treatment efficiency has clinical implications and facilitates extended treatment strategies that involve multiple tumor cell targeting. This can in case of ER/HER4 double positive BC potentially be accomplished by a dual targeting of both receptor types using for instance tamoxifen and an HER4 specific antibody with anti-tumorigenic activity , 32. Alt


Ventenata dubia, an invading non-native annual grass, in geographic and ordination  space over time.The data and analyses presented here were collected at the Zumwalt Prairie Preserve (ZPP), northeastern Oregon. Vegetation composition was measured within 124 (1-ha) plots using the line point intercept method . These data include vascular plant species abundance matrices at two different time periods, seven years apart (2008/2009 & 2015/2016); boxplots of species abundance (cover and frequency) change over time; Non-parametric Multiplicative Regression (NPMR) estimated abundance of  The preon space , Fig. 5.2The ZPP was categorized into prairie and canyon lands and the canyon lands were excluded from this data . The remVentenata dubia foliar cover and frequency within quadrats in both NMS ordination and geographic space (R2 (χR2) values were used to evaluate model fits and differ from the conventional R2 because it is based on the exclusion of each data point from the estimate of the response at that point Ventenata


The evaluation framework is developed for CO2 capture, geological utilization and storage (CCUS) project developments, including CO2 emission inventory, site suitability evaluation, and source–sink matching with techno-economic models. The data shows the matched source (CO2 source)-sink (onshore aquifer site) pairs with sites distribution and levelized cost under various scenarios. Data also shows the geographic distribution of source-sink pairs, cost curve, annual cumulative CO2 storage capacity and enhanced water production under various scenarios. Potential large-scale deployments of CO2-EWR projects with low cost in the modern coal chemical industry in China are shown and identified in the dataset. This data article is related to the research article “Cost curve of large-scale deployment of CO2-enhanced water recovery technology in modern coal chemical industries in China” .This data article presents the first systematic assessment on the potential of onshore CO The data show the details of matched source-sink pairs with potential costs. The data compiled in excel spreadsheets provides the inventory of several coal chemical processes, CO2 emission from industrial and dilute processes of each CO2 source, geographic distribution of potential integrated CCUS projects (source-sink pairs) with levelized costs and CO2 storage capacity, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites in China under various scenarios of actual operating capacity in 2015, designed full capacity in 2015, and total capacity in 2016. The data can be used to identify various potential low-cost large-scale deployment of CO2-EWR projects using pure CO2 from the coal chemical industry in China. Data sheet and figures are compiled using Excel software  with levelized costs, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites.The systematical evaluation framework is based on the


Inhibition of TORC1 has extended lifespan in multiple preclinical species. Thus drugs inhibiting TORC1 may have therapeutic benefit for aging-related conditions in humans. An aging-related condition that improves with TORC1 inhibition in old mice is immunosenescence (the aging-related decline in immune function). Immunosenescence leads to increased rates of infections including respiratory tract infections (RTIs) in the elderly. In two Phase 2 clinical trials in over 900 elderly subjects, the TORC1 inhibitor RTB101 was observed to improve immune function and decrease the incidence of RTIs. Decreasing the incidence of RTIs is important because RTIs are the fourth leading cause of hospitalization in people age 65 and above. Based on these findings, two Phase 3 studies are underway to determine whether RTB101 given for 16 weeks during winter cold and flu season decreases relative to placebo the percentage of elderly subjects with illnesses associated with RTIs.


Objectives: Occupational mobility at various stages in the life course may have a cumulative influence on health outcomes in later life. This study aims to (1) systematically review the association between occupational mobility and chronic illness in late life; and (2) identify potential mechanisms underlying this relationship. Methods: A systematic review of literature was carried out by searching two databases (PubMed and SocIndex) and reference lists. Eligible studies examined associations between occupational mobility and at least one measure of chronic illness among adults aged 50 years or above. Occupational disruptions  were reviewed as special cases of occupational mobility. Results: Downward occupational mobility and mid-life occupational disruptions have been consistently shown to predict higher risk of chronic illness in older adults. Several potential mechanisms were identified from the literature: (1) health behaviors, including dietary practices and alcohol consumption; (2) psychosocial factors, including stress, stigma, job control, job demands, and job satisfaction; (3) economic factors, including financial incentives or constraints; and (4) other individual characteristics, including personality traits and coping skills. There is also evidence that the timing of job mobility and the duration of (each) occupation modify the association between occupational mobility and health in late life. Discussion: These findings suggest that experiencing involuntary occupational mobility at various stages in the life course can increase the risk of chronic illness in late life. Health professionals and policymakers should target more resources to disadvantaged older adults who experience involuntary occupational transition.


Corneal blindness is one of the major causes of blindness worldwide, for which corneal transplantation has long been the only treatment method. In addition to penetrating keratoplasty, development of partial thickness corneal transplantation techniques including deep anterior lamellar keratoplasty (DALK), Descemet's stripping endothelial keratoplasty (DSEK), and Descemet's membrane endothelial keratoplasty (DMEK) allowed improved visual anatomical outcome. Keratoprosthesis including Boston keratoprosthesis (KPro) and osteo-odonto keratoprosthesis (OOKP) also enabled visual recovery in patients with serious ocular surface destruction. However, the demands for corneal transplant can never be met because of global shortage of donor corneal tissue.We have introduced in the call for papers for this special issue that various methods of corneal tissue engineering such as cultivation and expansion of corneal tissues using novel drugs and biomaterials have been studied. These novel methods are expected to allow the production of large amount of synthetic corneal tissues for transplantation without the risk of disease transmission. Further researches on corneal tissue engineering, i.e., cell therapy for corneal tissues including the epithelium, stroma, and endothelium; development of biomaterials, drugs, and imaging techniques that can be applied to corneal tissue engineering; application of artificial corneal tissue; and anterior segment reconstruction would provide even more improved visual and anatomical results.In this special issue, the authors contributed 4 original articles and 2 review papers regarding researches of corneal tissue engineering and its clinical application.The authors reported the results of their original researches on various topics in corneal tissue engineering: (1) outcomes of Descemet membrane endothelial keratoplasty for vitrectomized eyes with sutured posterior chamber intraocular lens; (2) generation of femtosecond laser-cut decellularized corneal lenticule using hypotonic trypsin-EDTA solution for corneal tissue engineering; (3) modern corneal eye-banking using a software-based IT management solution; and (4) preliminary investigation of the mechanical anisotropy of the normal human corneal stroma.This special issue also includes review articles on the following topics: (1) application of novel drugs for corneal cell regeneration and (2) from DMEK to corneal endothelial cell therapy: technical and biological aspects.We believe these articles will provide readers with valuable information on corneal tissue engineering and novel ideas for researches on related topics.


Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. We present the genomes of four serotypes of the dengue prototype strain that were continuously maintained in the laboratory. These genomes contain bases different from those of the original prototype strains in GenBank. Flaviviridae and the genus Flavivirus. Four serotypes of dengue virus are a cause of dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). The prototype strains of four dengue serotypes frequently used in the laboratory are DENV1 strain Hawaii, DENV2 strain 16681 and strain New Guinea C (NGC), DENV3 strain H87, and DENV4 strain H241. The prototype strains have been cultured and used for dengue study in laboratories since 1980 (Dengue virus (DENV) is the most prevalent arbovirus and is found mainly in tropical and subtropical regions. The virus belongs to the family Aedes albopictus cells by the cell culture laboratory of the Division of Dengue Hemorrhagic Fever Research . Five prototype strains were maintained in the laboratory for more than 10 years. The prototype strains were prepared for sequencing by using the 454 pyrosequencing GS FLX platform (Roche Applied Science) in the same run as that reported in our previous study  using BLASTn version 2.7.1+  database under the accession number


Infectious Diseases of Poverty claimed that undue influence on African programs by concepts developed by the Onchocerciasis Elimination Program of the Americas (OEPA) is detrimental to stopping mass drug administration (MDA) in Africa. This claim is made despite a record year for MDA stoppage in four African countries of > 3.5 million treatments in 2018, far exceeding any past OEPA or African Program for Onchocerciasis Control (APOC) stop MDA success.A recent article “Is onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes” in The online version of this article (10.1186/s40249-019-0558-0) contains supplementary material, which is available to authorized users. Please see Additional file Infectious Diseases of Poverty including the claims: (1) that the influence of the ongoing Onchocerciasis Elimination Program of the Americas (OEPA) is, “impeding progress towards decisions to stop intervention in many (African) areas that have reached the elimination point” and (2) that the introduction of testing for antibody to the Onchocerca volvulus 16 kDa antigen (OV16) in children  to assess for evidence of recent transmission “has delayed progress with stopping treatment which according to APOC evaluations should already be feasible for millions of people.” [Professor Dadzie with other distinguished directors of the former World Health Organization (WHO) African Regional Programs against River Blindness (the Onchocerciasis Control Programme in West Africa [OCP] and the African Programme for Onchocerciasis Control [APOC]) recently published an article in  claims:  that thetransmission suppression, at which point the adult Onchocerca volvulus worm population is in demise; (ii) transmission interruption determined by epidemiological and entomological studies of the Simulium vector black flies, at which time MDA may be halted; and lastly (iii) Post Treatment Surveillance (PTS) for 3–5 years, after which evaluations must successfully demonstrate lack of recrudescence, at which time transmission elimination may be declared. (3) Decisions to stop MDA and PTS based on these WHO Guidelines require transmission monitoring in children. On this point, it should be recognized that it was the WHO Geneva 2001 guidelines (not OEPA) that stipulated what we agree is a quite challenging 0.1% threshold to measure [O. volvulus 150 bp tandem repeat (O150) in pools of black fly heads (the threshold being < 1/2000 infective flies) rather than dissection. Because a laboratory was required for the PCR, in the mid-2000s OEPA successfully operationalized the use of OV16 antibody monitoring by Enzyme Linked Immunosorbant Assay (ELISA) testing of dried blood spots since it could be performed in the same facility. This test is currently known as the ‘OEPA’ OV16 ELISA [The OEPA programmatic model consists of five basic principles , 3: (1)  measure , 6, 7. T measure –10. Both16 ELISA . Under tThis five-step OEPA model had a positive influence in Africa due to two annual meetings that provided a forum for onchocerciasis warriors from six African countries  and six American ones  to exchange information. One of these meetings was the annual InterAmerican Conferences for Onchocerciasis , and the other was the annual Carter Center Program Review (held since 1996). On several occasions African country delegations attended IACO and at least one IACO an APOC Director (Dr. A. Seketeli) gave the keynote address. The Director of OEPA (Dr. M. Sauerbrey) attended at least one meeting of the APOC Technical Consultative Committee (TCC).The fruit of this African-American exchange first became apparent in 2006 when Sudan declared elimination of transmission of onchocerciasis as its goal. In doing so, Sudan embraced the 2001 WHO Geneva Elimination Guidelines and many OEPA principles to reorient its program. The national program independently took the decision to upgrade to OEPA’s twice-per-year treatment strategy and successfully adapted it to the APOC Community Directed Treatment with Ivermectin (CDTI) framework. It expanded MDA to low prevalence (hypoendemic) communities included under OEPA but excluded under the APOC paradigm. A national lab was established at the Ministry of Health, and OEPA OV16 ELISA and O150 PCR were successfully deployed to allow a stop MDA decision in Abu Hamad in 2012 and completion of 3-year PTS . The AbuSimulium neavei foci. The UOEEAC defined guidelines for elimination in S. neavei areas that were ultimately incorporated into the 2016 WHO guidelines. Representatives from onchocerciasis programs in the Democratic Republic of Congo and the Republic of South Sudan regularly attend UOEEAC meetings to discuss establishing SIZs in shared (cross-border) transmission zones with Uganda. Since the Ugandan program launched its elimination policy, approximately 1.9 million ivermectin treatments have been halted in the country. Active transmission now only occurs in two of the original foci. The S. neavei vector has been eliminated from many foci. Six foci have been determined to have met the WHO criteria for elimination by successfully completing the 3-year PTS period; an estimated 1.15 million persons living in these districts are no longer at risk of acquiring onchocerciasis [In 2007, Uganda declared a goal of onchocerciasis transmission elimination from all its 16 active transmission zones (foci) just months after a high-level delegation went to Guatemala for the 2006 IACO. The 2018 publication describing the history of the Uganda program includes in its introduction a section entitled ‘Inspiration from the Americas’ . The UgaEthiopia is now in its sixth year of executing a national twice-per-year treatment policy to accelerate onchocerciasis transmission elimination. In 2017, at its third meeting, the Ethiopian Onchocerciasis Elimination Expert Advisory Committee (EOEEAC) met with representatives from the Sudan program to review binational PCR and OV16 data –18. OverAt its fifth meeting, the Nigeria Onchocerciasis Elimination Committee (NOEC) reviewed results of 2017 OV16/PCR assessments in Plateau and Nasarawa States and determined that the WHO Geneva guidelines for stopping ivermectin MDA had been met . It recoWe conclude by noting that 2018 was the most successful year ever for stopping MDA for onchocerciasis in Africa, and that the OEPA elimination model was important in helping that success. Last year 3.8 million ivermectin treatments for onchocerciasis were halted in Africa, 64% of the cumulative 5.9 million treatments that have been stopped since Sudan’s initial Abu Hamad success in 2012. This is compared with under 1 million treatments stopped by OEPA in the Americas . These eAdditional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 321 kb)


Mitogen-Activated Protein Kinase (MAPK) cascades are conserved signaling modules that integrate multiple signaling pathways. One level of control on the activity of MAPKs is through their negative regulators, MAPK phosphatases (MKPs). Therefore, MKPs also play an integrative role for plants responding to diverse environmental stimulus; but the mechanism(s) by which these phosphatases contribute to specific signals remains largely unknown. In this review, we summarize recent advances in characterizing the biological functions of a sub-class of MKPs, dual-specificity phosphatases (DSPs), ranging from controlling plant growth and development to modulating stress adaptation. We also discuss putative regulatory mechanisms of DSP-type MKPs, which plants may use to control the correct level of responses at the right place and time. We highlight insights into potential regulation of cross-talk between different signaling pathways, facilitating the development of strategies for targeting such cross-talk and to help improve plant resistance against adverse environmental conditions without affecting the growth and development. To rapidly adapt to various environmental challenges, plants need to balance diverse signal inputs which involves crosstalk between different signaling pathways. A common strategy for integrating these signals is through use of shared components, including mitogen-activated protein kinase (MAPK) cascades that play essential roles in signal transduction and amplification for many distinct cellular responses. MAPK cascade modules are conserved in all eukaryotes and consist of three kinase components: MAPK kinase kinases (MAPKKKs) phosphorylate dual-specificity MAPK kinases (MAPKKs), which then phosphorylate and activate the terminal MAPKs in a Thr-X-Tyr activation loop  and metal-dependent protein phosphatases (PPMs), which are serine/threonine phosphatases, and tyrosine phosphatases (PTPs) Shi, . RepresePTPs are biochemically distinct protein phosphatases and include tyrosine specific phosphatases and dual-specificity (Ser/Thr and Tyr) phosphatases (DSPs)  phosphatases (DSPs) belong to a subfamily of the tyrosine phosphatases (PTPs) that can dephosphorylate both phosphoserine/phosphothreonine and phosphotyrosine within the activation loop of MAPKs , synthetic auxins and auxin transport inhibitors  and PDR9 genes were characterized, and these two genes encode ABC transporters implicated in the efflux of synthetic auxins  mutants, which display a defect in a microtubule-associated protein  in the putative kinase interaction motif (KIM) of MAPKs such that the mutation might interfere with interactions with the target MAPK(s). Therefore, it has been proposed that PHS1 may regulate multiple MAPKs; and a subset of its target kinases may be involved in the organization of cortical microtubules. To further investigate the mechanism underlying microtubule regulation, a screen for PHS1-interacting MAPKs was performed; and MPK12 and MPK18 were identified by yeast two-hybrid assays  was expressed in the background of phs1-5 to examine if the phosphatase-dead form of PHS1 functions as a dominant-negative microtubule destabilizer  which acts in the apical meristem to induce floral identity genes  treatment, including activation of MPK6 and MPK3, production of reactive oxygen species (ROS), accumulation of a subset of PAMP-regulated transcripts, and inhibition of seedling growth  DC3000 (hereafter referred to as DC3000)  dephosphorylates phospho-MPK3 and phospho-MPK6 ibr5-7 suppresses the chilling-induced defense responses of chs3-1  to stabilize CHS3 protein, thus increasing the accumulation of CHS3 . IBR5 interacts with and promotes the accumulation of SNC1  and DC3000 (avrRps4)  proteins. IBR5 plays a positive role in regulating R protein CHS3, as evidenced by that mutation of mkp1 mutant results in hypersensitivity to various genotoxic stresses , suggesting that MKP1 plays essential roles in genotoxic stress relief -induced nitric oxide (NO) production in guard cells , superoxide anion O2− and hydrogen peroxide levels in the TMKP1 transgenic seedlings  and downregulation of two ABA-repressed genes  , including hydrogen peroxide (H2O2), hydroxyl radical (HO.), singlet oxygen (1O2) and superoxide anion (mkp2 mutants was more severely inhibited by the oxidative agent methyl-viologen (MV) compared to wild type plants , mkp1 mutants produced more ROS than in wild type plants  are generated from partial reduction of oxygen  treatments , contributing to differences in amplitude and duration of signaling. Many examples have shown that the phosphatase activity of MKPs can be regulated by post-translational modification. Mammalian MKP1s (not an orthologue of plant MKP1s) and yeast Msg5 are phosphorylated by their own substrates MAPKs, and phosphorylation regulates not only the activities but also the abundance of the phosphatases, establishing an efficient negative feedback loop ; and phosphorylation of TMKP1 is required for the interaction , which was mainly localized in cytoplasm, the localization of both MAPKs also changed to the cytoplasm   substrates but decreases phosphatase activity on the phosphotyrosine of myelin basic protein (MBP), suggesting that calmodulin differentially regulates substrate specificity  but not CaMBDII mutant (W678R) can be activated by CaM, which indicates that CaMBDII plays a more important role than CaMBDI for the regulation of MKP1  binding proteins, where CaM is a CaThis review summarizes current knowledge of the roles of MKPs in multiple signaling pathways. MKPs are involved in many aspects of a plant's life cycle, including growth and development as well as the adaption to various biotic and abiotic stresses. As different signaling pathways integrate through MKPs, it is critical for MKPs to undergo precise regulation to generate correct biological outcomes. These investigations of regulatory mechanisms have provided insights into putative mechanisms that might explain how the phosphatases assist in producing specific signals. The potential combinatorial complexity of different transcriptional/post-transcriptional regulations, differential localization affecting subcellular pools of MAPKs, and the possibility to integrate information from other pathways may have profound effects on organizing the amplitude and duration of targeted kinases.As important as the MKPs appear to be, most of our knowledge regarding their functions is limited to their roles in negatively regulating MAPK signaling, and few other potential upstream and/or downstream targets have yet to be characterized. Genome-wide analyses will certainly facilitate a better understanding of MKPs-mediated signaling pathways by identification of both molecular players in the pathways as well as additional putative MKP targets. A better understanding of how plants coordinate and balance different signaling pathways in response to diverse environmental stimuli could lead to more rationally designed strategies for improving crop yield under changing environmental conditions. Promising results such as the deletion of MKP1 resulting in enhanced resistance to various biotic and abiotic stresses without compromising plant growth (Ulm et al., LJ and SP conceived the main subject of this review and wrote the manuscript. YC and LL provided the suggestions and revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sleep is important for memory consolidation, hence the disruption of normal sleep patterns as a result of age-related changes in the circadian system could be one of the contributors to memory impairment among older adults. It is now well-established that light is the main environmental element that synchronizes circadian rhythms. An appropriate lighting condition can be considered as a non-pharmacological solution to improve the sleep quality of individuals and consequently their overall health and well-being. The present study investigates the effectiveness of two proposed whole-day lighting interventions (L1 and L2) applied by Tunable White Lighting Technology (TWLT) on sleep quality and cognitive performance in older adults. Both lighting interventions provide a high illuminance level (500 lux) in the morning and then the illumination is dimmed gradually throughout the day and reached 100 lux in the evening. However, while L1 offers a constant Correlated Color Temperature (CCT) of 2700K, during the L2 intervention, the CCT is changing in the range of 6500K – 2700K from morning towards evening. Fifteen healthy older adults  participated in a 41-day counterbalanced crossover study. Participants were exposed to each lighting condition for 9 days. Actigraphy, standard questionnaires (PROMIS and PSQI), and tests (Trail Making Test (TMT) A & B and Digit Symbol Substitution Test (DSST)) were employed to measure sleep quality and cognitive performance before, during, and after lighting interventions. Significant improvements in sleep quality and cognitive performance were found for both lighting interventions with better outcomes for L2.