Caregiver self-care may be impacted by the household environment. We evaluated the impact of support quality  and total household occupancy on a validated measure of self-care neglect in caregivers of patients with heart failure. Multivariate regression modeling was used to examine predictors of self-care neglect and we introduced an interaction term between support quality and household occupancy. The main effects model included terms for years of caregiving experience, hours caregiving daily, support quality, and total household occupancy . The interaction term between support quality and household occupancy contributed significantly (p < .05) to the respecified model . We suggest that the potential benefit of total household occupancy on caregiver self-care depends on perceived support quality. Clinicians should assess quality of household resources with caregivers during interactions.


We report on launching a dental initiative that addresses healthy aging and oral health, focusing on prevention and changing the false belief that aging inevitably involves deterioration in oral health. Our project integrates the age-friendly health system's principles into specialty dental care at Eastman Institute for Oral Health, URMC. We established an oral health-centered framework with project elements of the 4Ms - what matters, medication, mentation, and mobility. We developed pilot 4Ms templates integrated into dental charts to implement healthy-aging key oral health processes, including oral health assessment, treatment planning, and oral hygiene support. We engaged all members of the dental team through educational sessions for providing care for patients affected by Alzheimer’s disease and related dementias. We leveraged on locally available interdisciplinary resources and the collaboration reflecting undergoing efforts at the University of Rochester Division of Geriatrics and the Finger Lakes Geriatric Education Center, a Geriatric Workforce Enhancement.


TM. The library simulates even complex bio-models and supports deterministic Ordinary Differential Equations; Stochastic Differential Equations; constraint-based analyses; recent SBML and SED-ML versions; exchange of results, and visualization of in silico experiments; open modeling exchange formats (COMBINE archives); hierarchically structured models; and compatibility with standard testing systems, including the Systems Biology Test Suite and published models from the BioModels and BiGG databases.Studying biological systems generally relies on computational modeling and simulation, e.g., model-driven discovery and hypothesis testing. Progress in standardization efforts led to the development of interrelated file formats to exchange and reuse models in systems biology, such as SBML, the Simulation Experiment Description Markup Language (SED-ML) or the Open Modeling EXchange format. Conducting simulation experiments based on these formats requires efficient and reusable implementations to make them accessible to the broader scientific community and to ensure the reproducibility of the results. The Systems Biology Simulation Core Library (SBSCL) provides interpreters and solvers for these standards as a versatile open-source API in Javahttps://draeger-lab.github.io/SBSCL/ and via Maven Central.SBSCL is freely available at Bioinformatics online. TM programming library that numerically solves systems biology models in multiple mathematical frameworks. A popular file format for representing computational models in a standard way and facilitating the exchange of models between different tools is the Systems Biology Markup Language  is an open-source, cross-platform pure JavaDifferential equation solver: The most fundamental feature of SBSCL is simulating ODEs. Version 2.1 adds interpreters and solvers for SDEs to support the latest SBML standards. SBSCL efficiently implements three deterministic numerical solvers (Constrained optimization solver: SBML Level 3 (http://www.scpsolver.org), a linear programming API with support for various solver backends. This lightweight abstraction allows users to define model constraints and an objective function and solve the corresponding optimization problem.Result tables and plots: Since viewing is an essential aspect of understanding the results of a simulation experiment, SBSCL provides experiment output in graphical and tabular form, which it can export in conventional formats such as Comma-Separated Values (CSV).Archival format support: Working toward exchangeability and reproducibility, SBSCL v2.1 supports the Open Modeling EXchange format (OMEX) format as input. These archive files contain the information on running simulation experiments based on SBML and SED-ML (Hierarchical model simulations: The SBML extension package comp enables encoding complex and coupled biological systems that can be distributed or hierarchically structured. SBSCL v2.1 efficiently supports the simulation of this addition, including the automatic assembly of models from multiple and possibly remote input files.Tests against benchmark suites: A crucial part of implementing new features is providing robust testing of the added functionality and use-cases. SBSCL tests all newly added features against the SBML Test Suite in a continuous integration approach. SBSCL provides full testing support against the genome-scale models from the BiGG Models database and kinetic models from the BioModels database.in silico experiment definition SED-ML file or wrapped within OMEX archives. Benchmarks of SBSCL using the SBML Test Suite and a broad range of published models from relevant databases ensure its correctness and reliability (see The open-source library SBSCL simulates complex biological models in various frameworks specified in SBML format, optionally together with their lity see . With thbtab669_Supplementary_DataClick here for additional data file.


Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors. Throughout the 20th century, chemotherapy rapidly evolved from using single agents as a monotherapy to highly integrated multicombination therapy, utilizing multiple chemotherapeutic agents combined with surgery, radiation, molecularly targeted therapies and immuno-oncology agents . Each agTo date, the most mature immuno-oncology agents are immune checkpoint blockade (ICB) antibodies, which enable an already present immune infiltrate to promote tumor killing. While seven ICB agents have been FDA approved in multiple cancer indications as monotherapy , they doengage the immune system through the induction of tumor-antigen specific immunity, expand the specific tumor immune response, enable the immune response to ensure prolonged and persistent antitumor activity, and ensure an evolving immune response, preventing tumor escape . Th. ThQuick


This positioning paper aims to discuss current challenges and opportunities for artificial intelligence (AI) in fungal lung disease, with a focus on chronic pulmonary aspergillosis and some supporting proof-of-concept results using lung imaging. Given the high uncertainty in fungal infection diagnosis and analyzing treatment response, AI could potentially have an impactful role; however, developing imaging-based machine learning raises several specific challenges. We discuss recommendations to engage the medical community in essential first steps towards fungal infection AI with gathering dedicated imaging registries, linking with non-imaging data and harmonizing image-finding annotations. Aspergillus species are ubiquitous, saprophytic fungi with airborne conidia that grow on organic matter. Aspergillus fumigatus is the principal causative agent of human aspergillosis, which can range from allergy to invasive aspergillosis (IA), a life-threatening infection in immunocompromised hosts, with a further cohort of susceptible individuals developing chronic pulmonary aspergillosis [Relatively few fungal species can infect humans; however, certain fungi can cause life-threatening systemic infections in susceptible patient populations. gillosis  (CPA). Cgillosis . The agegillosis , 4. CPA gillosis .Individuals with both invasive and chronic pulmonary aspergillosis unfortunately have significant morbidity and high mortality. In part, this relates to challenges in diagnosis, difficulty in distinguishing fungal infection from other infections/illnesses and detecting breakthrough infection or treatment failure . DiagnosWithin clinical medicine, over the last decade there has been significant increased interest in the application of machine learning and artificial intelligence (AI) for complex decision making including diagnosis  and guiding therapeutic decision making .Regarding in vivo medical imaging, AI is transforming radiological diagnosis with mature developments related to oncology in breast  and chesComputed tomography (CT) represents the imaging modality of choice for lung infection diagnosis. AI for lung CT imaging bears some specific risks and challenges due to the lack of image standardization and multiple sources of variability . However, radiological societies are working toward reporting standards for AI tools –17 that detection with predictive value for inference of CPA severity or mortality within a time frame rather than mimicking expert precise contouring.CT enables localization of CPA-related pathological signs  such as We have shown , 23 Fig that a wAlthough quantitative scoring algorithms have been developed, further work is needed in defining a standard protocol for reporting radiological findings on CPA lung lesions. This is important to refine future annotation task and to benchmark new imaging AI tool against human radiological scoring . Given tTo progress the field, there is a need to develop a dedicated imaging cohort with a critical size, large diversity , and linked with diagnostic data , and treatment information as possible in international registry datasets  . For iniFor an imaging cohort to be used in AI, it requires some annotation, and here, a concerted community effort will be required from a number of specialists  to agree on the ground-truth expert source  and the granularity of the image annotation . Building large imaging cohorts remains tedious but can have very clear impact for fungal lung disease which currently suffers from two challenges: (1) current diagnostic uncertainty and need for subjective amalgamation of multiple observations with high levels of uncertainty; (2) difficulty in determining treatment response because of challenges in monitoring effects using quantitative radiological markers.Further integration with other omics  and electronic health record data –29 is alIn summary, the application of machine learning and AI presents a unique opportunity within fungal lung infection with the potential to improve diagnosis through early detection, standardization of imaging markers and their quantitative longitudinal monitoring , to impr


This study describes the development of a prototype bi-spectral microbolometer sensor system designed explicitly for radiometric measurement and characterization of wildfire mid- and long-wave infrared radiances. The system is tested experimentally over moderate-scale experimental burns coincident with FLIR reference imagery. Statistical comparison of the fire radiative power  retrievals suggest that this novel system is highly reliable for use in collecting radiometric measurements of biomass burning. As such, this study provides clear experimental evidence that mid-wave infrared microbolometers are capable of collecting FRP measurements. Furthermore, given the low resource nature of this detector type, it presents a suitable option for monitoring wildfire behaviour from low resource platforms such as unmanned aerial vehicles (UAVs) or nanosats. This could include combining MWIR and LWIR bands in a single camera—for example, by using butcher block filters near the focal plane array, or with a filter wheel. Moreover, the development of a less resource-intensive thermal offset compensation method would likely be required. This could potentially be achieved by using a lightweight mechanical shutter, or by using temperature measurements at strategic points in the camera and correcting the images accordingly.


Candida, Cryptococcal, Aspergillus and Trichophyton species is described herein, highlighting the need for defined species-specific antifungal breakpoints, and for Malassezia and Wickerhamomyces anomalus species which also have zoonotic potential. Novel compound phendione showed promising antimicrobial activity, with MICs determined for both fungal and bacterial species. The biocidal options investigated also showed potential to act as intermediate-level disinfectants, where peracetic acid proved most effective against fungal spore formers. Fungal skin infections and iatrogenic disease of companion animals continue to be an ongoing issue for veterinarians, where misdiagnosis or inapt medical treatment result in secondary conditions within animals. The widespread use of antifungals in both modern medicine and agriculture has resulted in concomitant resistance in species, where zoonotic transfer poses a risk to public health. Studies described herein assess the resistance of pathogenic species isolated from companion animals to a battery of conventional antimicrobial agents. Levels of resistance were detected using recognised in vitro methods, where additional novel therapeutic and biocide options were also extensively investigated. Results show high levels of resistance to the three main families of antifungal agents, namely caspofungin, Amp B and fluconazole. Resistance in  Microsporum, Trichophyton, and Epidermophyton species. Superficial zoophilic skin infections (dermatomycosis) are also caused by non-dermatophyte fungal species such as Malassezia, Aspergillus and Candida . Dermal tissue may become infected following colonisation of the cutaneous tissue and dermal follicles with opportunistic and pathogenic fungi. Animal mycoses is a common reoccurring issue globally, with zoonosis a risk in companion animals, where humans are continually exposed to infectious propagules . Dermal Invasive and systemic fungal disease can result from movement of the fungal species transdermally via open wounds . SystemiWickerhamomyces anomalus  is a zoonotic and nosocomial yeast, associated with the production of lethal mycotoxins having a mortality rate of 38% in adults and 42% in paediatric patients globally . Student’s T tests were conducted to determine significance levels (p < 0.05) of bacterial susceptibility to treatment using Minitab 16 . All the experiments were performed three times with three plate replicates for each experimental data point, providing a mean result for each test species and antifungal susceptibility (±standard deviation). The logC. albican to non-albican species, as well as rarer  non-Candida species. This study presents eight examples of specific clinical cases that required greater application of existing fungal diagnostics and improved overall fungal diagnostic capability, where CBPs were lacking for many fungal pathogens. The presence of resistant species in companion animals such as those described herein, represents an often-unrecognised route of disease transmission, where zoonosis poses a significant risk. The development of new treatment options is, therefore, essential for both animal and human medicine, where test agent phendione showed promising potential as both an antifungal and antibacterial agent. Additionally, test biocidal options triameen and peracetic acid both showed high levels of antifungal activity. In particular, the peracetic acid-based disinfectant shows promise for controlling the spread of microbial species in veterinary settings, also being active against spore formers. The phenomenon of immunosuppression  has been recognised as a major contributor of increasing fungal disease, where more and more patients with chronic immunosuppressing conditions require antifungal treatment as part of their treatment plan. This rising rate of infection has been accompanied by increasing levels of antifungal resistance, where fungal pathogens are following the same pattern of exposure-resistance as seen with bacteria in the imminent antibiotic crisis. In order to defeat AMR, accurate and timely diagnosis is of utmost importance, where selection of fungal therapy must now also consider the shift in predominance from


Widowhood is associated with decreased emotional well-being, particularly increased depression. Religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine this relationship using different dimensions of religiosity. This study analyzed data from the 2006-2016 waves of the nationally representative Health and Retirement Study (HRS). Trajectories of depression among older adults >50 years  were examined to explore patterns of depression among those entering widowhood and the potential impact of religiosity on depressive symptoms during widowhood. Ordinary least squares (OLS) regression analysis was used to examine the association between widowhood and depression as well as the role of religiosity as a moderator of this association. Older adults experienced an increase in depressive symptomology after the onset of widowhood, and although the levels of depressive symptomology decrease post-widowhood, they do not return to their pre-widowhood levels. Additionally, high religious service attendance and higher intrinsic religiosity were both associated with lower depressive symptomology. High religious service attendance moderated the relationship between widowhood and depression. The relationship between high religious service attendance and depression was stronger among widowed older adults living alone. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. The findings also suggest that higher religious service attendance can lessen the effects of widowhood on depressive symptoms, especially for those living alone. These findings may inform intervention development around increased screening and treatment for depression.


Testosterone treatment increases muscle mass, strength, and leg power in menopausal women, hypogonadal men, older men with mobility limitation, COPD and ESRD. Testosterone's effects on muscle mass and strength are augmented by exercise training and growth hormone. Testosterone treatment improves some measures of physical performance, such as stair climbing power and aerobic capacity; the improvements in gait speed have been modest. Testosterone increases muscle mass by inducing the hypertrophy of type 1 and 2 muscle fibers, and by increasing satellite cell number. Testosterone promotes the differentiation of mesenchymal progenitor cells into myogenic lineage and inhibits their differentiation into adipogenic lineage by activating Wnt-target genes, including follistatin that plays an important role in mediating testosterone's effects on the muscle. Testosterone also increases polyamine synthesis in the muscle. Combined administration of testosterone plus multi-component exercise intervention that includes functional training may be needed to improve function and mobility in older adults.


Crocidura sp.) and a single rodent (Lophuromys sikapusi). Although these cases were only once-off detections, it provided evidence of the first known lyssavirus species has an association with non-volant small mammals. To investigate further, retrospective surveillance was conducted in 575 small mammals collected from South Africa. Nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay of 329 brain samples did not detect any lyssavirus ribonucleic acid (RNA). Serological surveillance using a micro-neutralisation test of 246 serum samples identified 36 serum samples that were positive for the presence of MOKV neutralising antibodies (VNAs). These serum samples were all collected from Gerbilliscus leucogaster (Bushveld gerbils) rodents from Meletse in Limpopo province (South Africa). Mokola virus infections in Limpopo province have never been reported before, and the high MOKV seropositivity of 87.80% in these gerbils may indicate a potential rodent reservoir.The reservoir host of Mokola virus (MOKV), a rabies-related lyssavirus species endemic to Africa, remains unknown. Only sporadic cases of MOKV have been reported since its first discovery in the late 1960s, which subsequently gave rise to various reservoir host hypotheses. One particular hypothesis focusing on non-volant small mammals  is buttressed by previous MOKV isolations from shrews ( Lyssavirus genus, all capable of causing a fatal encephalitic disease  and dogs (Canis familiaris), most commonly reported to be infected with MOKV. This has led to the hypothesis that the reservoir of MOKV might be a prey species that interacts with domesticated animals via a prey-to-predator pathway , four in Nigeria and one in Cameroon  in the Central African Republic , a rabies-related lyssavirus, represents one of 17 recognised species within the Non-volant small mammals were captured and sampled in accordance with the field procedure guidelines of Sikes and Gannon  during tn = 329)  using TRIzol™ reagent , followed by nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay as previously described   were subjected to serological surveillance using a micro-neutralisation test as previously described   were extracted from brain samples (Gerbilliscus leucogaster) tested from Meletse at the cut-off 1:25 serum dilution  between the individual gerbils is expected since previous molecular characterisation assays performed on the Gerbilliscus genus have recorded intra-species genetic variation that range from 1% to 20% (Aghová et al. Of the 36 gerbils showing MOKV seropositivity, only 28 were genetically identified with the CytB barcoding PCR assay . The samGerbilliscus genus are nocturnal and terrestrial, exhibit no sexual dimorphism (Skinner & Chimimba Gerbilliscus leucogaster, however, is less arid adapted and can be found along rivers and drainage lines in open grasslands and wooded savannas (Dempster G. leucogaster rodents are not well-understood, however, studies have reported a communal nature (De Graaff Steatomys and Rhabdomys genera occurring at Meletse.Members of the Dempster . The breMore nucleic acid and serological surveillance studies in non-volant small mammal populations are required to obtain a better understanding of MOKV distribution, prevalence and its potential reservoir species. Brain and serum samples in this study were collected from seemingly healthy small mammals in areas that do not coincide with areas where previous MOKV cases have been reported in South Africa. Surveillance should be expanded to areas where MOKV spillover infections in cats and dogs have previously been reported. Furthermore, because lyssavirus distribution and dynamics might be influenced by seasonality, surveillance efforts should also include samples that were collected in different seasons and over multiple years. This expansion, together with representative sample sizes of certain non-volant small mammal species, will collectively increase the possibility of identifying more of these animals that are infected or that have previously been exposed to MOKV.


Mountain regions are important places for biodiversity, where organisms could persist throughout prolonged periods and accumulate genetic divergence as well as promote speciation. Roles of mountains for biodiversity have been exclusively discussed in regions that have specifically diverse species or covered with ice-sheets during the Pleistocene glacial periods, whereas the importance of mountainous regions in East Asia has been less disputed. High mountains in the Japanese Archipelago, located at the eastern edge of the Eurasia continent, have one of southernmost populations of alpine and arctic-alpine plants that are also distributed in the northern Pacific and/or the circumarctic regions. Phylogeographic studies on the Japanese alpine plants have excluded their possible ephemeral occurrence during the current warm period, and rather, suggest persistence of alpine plants throughout several cycles of climate changes in the Pleistocene on high mountains in central Honshu, the main island of the Japanese Archipelago. In this review, I look through decade long phylogeographic studies and show complicated patterns of range dynamics of Japanese alpine plants. In addition, I note recent findings of genetic relationships of Japanese populations of alpine and/or arctic-alpine plants with those in northern regions and their possible ecological divergence in the Japanese Archipelago. Taken together, I provide several issues for understanding historical processes that established distribution of alpine plants following climate changes as well as their diversification and propose importance of Japanese populations of alpine plants on biodiversity in alpine communities across broader range, especially in the northern Pacific region. Mountain regions harbour a high terrestrial biodiversity  Gift et Kron et P. F. Stevens ex Galasso, Banfi et F. Conti mostly dominate in the plant communities on the high mountain ridges, whereas snow-bed species occurring in the northern Pacific region including Phyllodoce aleutica (Spreng.) A. Heller, Primula cuneifolia Ledeb., and Sieversia pentapetala (L.) Greene form large communities at moist part of mountains covered with snow until late summer. Accordingly, alpine plants in the Japanese Archipelago have long been recognized to have originated by cold-adapted species in northern regions that spread southward during the Pleistocene cold periods and have survived climatic warming on high mountains , which has small seeds with moderate dispersal ability in capsule, using three inter genetic spacers of plastid DNA   D.Don  A.Heller  strongly supported the scenario of colonization history occurring at least twice during different glacial periods. Such scenario was likely shared among 11 species including five preliminary investigated species   Fig. , whereasC. nipponica and K. procumbens  and only a few alpine plants are distributed  compared to central Honshu (ca. 3000 m), species exclusively occurring in higher part of mountains such as ens Fig. b have li500 m comComparing geographic patterns of genetic variation enables us to infer a shared history of prolonged refugial isolation and/or postglacial range expansion. In particular, comparative phylogeography would be an efficient approach to identify locations of refugia during the last glacial period and infer postglacial dispersal processes in various temperate and alpine species in Europe and North America  Makino provides the first sufficient evidence for the lack of genetic structure in pDNA haplotypes , which encodes one of red and far-red light receptors, evolved with divergent selection, where amino acid replacements exclusively occurred on a domain for light perception (the PHY domain). In addition, a similar study on A. nana found that natural selection on amino acid changes resulted in clinal patterns of allele frequencies on PHYE between its northern and southern populations (Ikeda and Setoguchi PHYE (Ikeda and Setoguchi C. nipponica) and higher latitude (Cardamine bellidifolia) (Ikeda et al. A. thaliana, this finding implies that light and temperature sensitivity of phytochromes may be involved in ecological divergence between these sister species. In A. thaliana, phyE is involved in regulation of ecologically important traits such as flowering or seed germination at lower temperature (Halliday and Whitelam PHYE truly reflected divergence in ecologically important traits are required to address this issue. Since genome-wide investigations could examine natural selection through genomic scan (Luikart et al. Furthermore, genetic footprints of divergent selection between the northern and southern populations suggest ecological roles for maintaining genetic structure. Ikeda et al.  investigDecades long phylogeographic studies confirmed the importance of high mountains in central Honshu for alpine plants to persist throughout the climate changes in the late Pleistocene. On the contrary, these studies show that genetic uniqueness exclusively in central Honshu is not the single common pattern of genetic structure across Japanese alpine plants. Instead, there are four major patterns of genetic structure including the lack of genetic structure. Owing to the less glaciated history and subsequent possible prolonged persistence of alpine plants in the Japanese Archipelago, genetic structures of Japanese alpine plants were likely shaped by multiple historical events including migrations and/or range separation occurring during different periods. In addition, Japanese alpine plants contain species with various ecological characters as well as habitat preference, which may have influenced genetic structures as well. Thus, assessing demographic history as well as ecological characters is crucial to fully understand historical processes how alpine plants shaped the current distribution patterns in Japan.Notably, the recent phylogeographic studies demonstrated that some alpine plants in Japan could have migrated northward, especially into the northern Pacific region, providing novel insight that alpine plants in Japan are not necessarily relict of cold adapted species distributed around Bering Straits. Further comparative studies could open new avenue for understanding the Pleistocene dynamics of alpine communities across broader ranges encompassing the northern Pacific region. Given potential ecological divergence of alpine plants within Japan, high mountains in Japan may have definitely played important roles for diversification of alpine plants not only in the archipelago but in northern East Asia as well as the northern Pacific region.


Recent efforts to identify novel bacterial structured noncoding RNA (ncRNA) motifs through searching long, GC-rich intergenic regions (IGRs) have revealed several new classes, including the recently validated HMP-PP riboswitch. The DIMPL (Discovery of Intergenic Motifs PipeLine) discovery pipeline described herein enables rapid extraction and selection of bacterial IGRs that are enriched for structured ncRNAs. Moreover, DIMPL automates the subsequent computational steps necessary for their functional identification.https://github.com/breakerlab/dimpl.The DIMPL pipeline is freely available as a Docker image with an accompanying set of Jupyter notebooks. Full instructions for download and use are available at Bioinformatics online. Discovery and validation of the over 45 known classes of metabolite- or elemental ion-binding riboswitches , 2017. HIn this article, we introduce DIMPL (Discovery of Intergenic Motifs PipeLine), a bioinformatics pipeline which automates the process of total genome analysis by extracting IGRs, filtering them by length and nucleic acid composition, and collecting the data necessary to identify candidate motifs and assign their possible functions. DIMPL also provides reproducible techniques for identifying genomic regions enriched for ncRNA through support vector machine (SVM) classifiers. Although our primary objective in creating DIMPL was to accelerate the discovery of novel riboswitch classes, it can also be used to identify a wide-range of other intergenic nucleic acid and protein motifs such as upstream open reading frames, short open reading frames, ribosomal protein leader sequences, selfish genetic elements and other structured RNA motifs of unknown function.The DIMPL computational pipeline consists of two primary stages: (1) genome analysis and (2) draft motif analysis. For the genome analysis stage of DIMPL, the user begins by entering the Uniprot ID for a microbial genome for which there are Rfam annotations. DIMPL proceeds to automatically request the latest genomic sequence and protein annotations  accessibIn the next step, the tool uses a SVM classifier  to identThe draft motif analysis portion of DIMPL is performed in parallel on all IGRs that have met the selection criteria. The process begins by using Infernal 1.1.3  to searcde novo for each genome analyzed using the IGR %GC content and nucleotide length as the features, the presence/absence of a structured RNA as the class labels and a set of hyperparameters that have been weighted to select a contiguous region of a genome’s %GC versus length plot. The primary purpose of the SVM classifier is to perform an enrichment of IGRs that reduces the number subjected to the more computationally intensive steps in the pipeline. Applying the SVM-RBF algorithm allows DIMPL to accomplish this goal in a systematic and reproducible manner.The SVM enrichment of IGRs in DIMPL uses a radial basis-function (RBF) kernel and is implemented with scikit-learn (www.github.com/breakerlab/dimpl. The DIMPL pipeline is built primarily in Python and is distributed as a Docker image  with allDIMPL provides an integrated collection of tools to streamline the process of identifying novel structured ncRNA motifs, including new riboswitch candidates, on a genome-wide scale. It relies on established methods of enriching bacterial IGRs for ncRNA motif discovery (btab624_Supplementary_DataClick here for additional data file.


Bone fracture healing and osteoblast differentiation are impaired with advanced age. Using a combination of parabiosis and proteomic models, we identified apolipoprotein E (ApoE) to be an aging factor in bone regeneration. Circulating levels of ApoE increased with age in patients and in mice. ApoE impaired bone fracture healing by decreasing bone deposition in the fracture callus which subsequently decreased the mechanical strength of healed tissue. Osteoblasts serve as the sole bone forming cells within the body. In tissue culture models, ApoE treatment decreased osteoblast differentiation and activity which led to decreased matrix formation and mineralization. This inhibition of osteoblast differentiation relied on down-regulation of the Wnt/β-catenin pathway. In mouse models, aged bone repair was rejuvenated when we lowered circulating ApoE levels using a hepatotropic AAV-siRNA model – serving as a proof of concept that ApoE can be targeted to improve bone repair in an older population. While promising, knockdown of circulating ApoE in such a fashion is likely not translatable to patient care. Thus, current work in our laboratory is focused on developing treatment strategies that temporally decrease circulating ApoE levels and consequently improve bone healing after acute injury and/or surgical orthopedic procedure in the geriatric population.


N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SNARE proteins embedded in opposing membranes spontaneously assemble to drive membrane fusion and cargo exchange in vitro. Evolution has generated a diverse complement of SNARE regulatory proteins (SRPs) that ensure membrane fusion occurs at the right time and place in vivo. While a core set of SNAREs and SRPs are common to all eukaryotic cells, a specialized set of SRPs within neurons confer additional regulation to synaptic vesicle (SV) fusion. Neuronal communication is characterized by precise spatial and temporal control of SNARE dynamics within presynaptic subdomains specialized for neurotransmitter release. Action potential-elicited Ca2+ influx at these release sites triggers zippering of SNAREs embedded in the SV and plasma membrane to drive bilayer fusion and release of neurotransmitters that activate downstream targets. Here we discuss current models for how SRPs regulate SNARE dynamics and presynaptic output, emphasizing invertebrate genetic findings that advanced our understanding of SRP regulation of SV cycling.Membrane fusion is a universal feature of eukaryotic protein trafficking and is mediated by the soluble  Regulated secretion is mediated by a large cohort of SNARE regulatory proteins (SRPs) that control the timing and localization of SNARE assembly , the soluble NSF attachment proteins (SNAPs) and Unc18 function in both constitutive and regulated secretion, others like Unc13, Complexin (Cpx), Synaptotagmin 1 (Syt1), Rab3-interacting molecule (RIM), and Tomosyn (Tom) provide unique temporal and spatial control of regulated secretion.Eukaryotes rely on membrane-bound organelles to organize and transport material between cellular compartments . Transpoassembly . AlthougSaccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster   for SV fusion can be approximated by measuring AZ Pr, which varies across neuronal subclasses and within the AZ population of a single neuron  . Followi+ influx . Releasee neuron . Most SV sorting . Reforme release .2+-dependent fusion. After fusion, NSF and SNAPs disassemble the SNARE complex to recharge individual SNARE proteins for further cycles of release. Intrinsic SNARE properties protect SNAREs from spontaneous reassembly post-fusion with help from the SRPs Unc18 and Tomosyn. Finally, RIM and Rab3 cooperate with Unc13 to re-position endocytosed SVs for subsequent docking and priming. Each of these steps provide avenues for modulation of SV release that can impact synaptic strength and plasticity.In this review we examine current models for how SRPs guide SNAREs through their assembly/disassembly cycle, focusing on insights from invertebrate genetic studies of SV fusion. We also highlight biochemical approaches that guided reverse genetic experiments and provided context for interpreting genetic studies. The biochemistry and genetics of mammalian SV fusion have been described in prior reviews . Key invLipids form stable bilayer membranes that innately repel each other through electrostatic forces and hydration repulsion . Bindingtrans-SNARE complex, with transmembrane segments residing on separate compartments and full SNARE assembly being temporarily arrested  are immobile and lack detectable SV release  are embryonic lethal, but retain uncoordinated movements that indicate a low level of residual SV release  in the second SNARE motif of the protein  displays a similar phenotype, indicating multiple t-SNARE mutations can alter SNARE dynamics in a manner that enhances fusion at lower temperatures and blocks release at elevated temperature  have not been characterized electrophysiologically though they display locomotor defects that suggest RIC-4 is essential for normal synaptic function  and enhance SV fusion in C. elegans  is essential for SV fusion, yet strongly inhibits both evoked and spontaneous release when overexpressed  is highly stable and resistant to SDS denaturation, indicating a large input of cellular energy is required to break the complex apart  mediates neuronal SNARE complex disassembly (comatose)  . Many coex apart . Althougaralysis . Accumularalysis  and a praralysis  mirror taralysis , 2001. Tcomatose mutations cause adult paralysis and synaptic transmission defects, the role of NSF at larval NMJs has been difficult to ascertain. NSF1 null mutants are lethal, but die over a developmental window that spans from late embryogenesis to the pharate adult stage  mutants, suggesting SNAPs are not fully redundant  cargo release and for some SVs at a few central mammalian synapses  on the plasma membrane, impaired neurotransmitter release and enlarged SVs  have normal AZ dense body projections and Ca2+ channel clustering, but fail to accumulate SVs that normally surround the AZ due to defective Cpx binding  show a dramatic increase in evoked neurotransmitter release  prevents its ability to inhibit SV availability, thereby enhancing SV release to facilitate plasticity and memory formation . Additioclusters . In Drosclusters . Short iisoforms , suggestBoth authors wrote and edited the manuscript, contributed to the article, and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Dementia is an increasingly important public health problem with known vascular contributors. Respiratory function, measured by peak expiratory flow (PEF), may be a novel modifiable risk factor in reducing the risk of dementia along the vascular pathway. We investigated the association between PEF and incident dementia in older adults from the National Health and Aging Trends Study (NHATS). Using NHATS criteria, participants were categorized as having or not having probable incident dementia during NHATS Rounds 2-4, spanning three years. Of 3,622 participants with available PEF and covariate data, 543 (15.0%) had incident cases of dementia. Quartile of baseline PEF was analyzed as a predictor of incident dementia using logistic regression models, while controlling for several health and sociodemographic covariates. The fourth quartile of PEF had statistically significantly decreased odds of incident dementia when compared to the first PEF quartile . Significantly reduced odds of incident dementia were found when comparing the third and second PEF quartiles to the first PEF quartile, as well . These relationships were dose-dependent so that increasing PEF quartile levels were more protective against incident dementia. PEF may be considered as an easily administered, low-cost measure of respiratory function and a possible screening tool for dementia risk. Improving PEF may reduce dementia risk through vascular mechanisms . Future research should explore these potential causal pathways between PEF and dementia.


The COVID-19 pandemic has led to social distancing protocols, subsequently increasing social isolation for older adults. The purpose of this study was to explore the relationship between social connectedness and mental health outcomes. Leveraging NHATS, a nationally representative study , we examined the association between the method of social connectedness and mental health outcomes. Descriptive analyses revealed older adults are using various methods  to remain connected with their social networks during COVID-19. Findings from all of the linear regression analyses indicated phone or video calls are associated with negative affect, whereas in-person visits are associated with lower levels of negative affect. These findings suggest substituting in-person visits with video calls or phones may not be sufficient to relieve their loneliness and negative affect. Future studies should investigate this effect on physical or emotional health outcomes.


We developed comprehensive multi-domain profiles of psychosocial stress in urban-dwelling, racially and ethnically diverse adults  and evaluated associations with cognitive function. Participants completed psychosocial stress measures tapping into ten domains and tasks of processing speed, working memory, and episodic memory. Latent profile analyses controlling for age yielded four-profiles: high neighborhood stress, moderate versus high work stress and daily discrimination, and high health and relationship stress. Profiles significantly differed in income, age, and employment status. The profile with moderate work stress and daily discrimination and the profile with high neighborhood stress each had significantly lower working memory than the other profiles. The finding of lower working memory among individuals in the moderate work stress and daily discrimination profile was not due to sociodemographic variables. Results highlight the potentially cumulative influence of different contextual stressors on cognition.


ABSTRACT IMPACT: As newborn screening is now available for X-linked adrenoleukodystrophy, there is a need to establish meaningful disease markers to detect the onset of the severe demyelinating cerebral form of this disease at the earliest possible stage, and to quantify early disease progression to evaluate the relative efficacy of therapies. OBJECTIVES/GOALS: Longitudinal testing of neurocognitive and motor function using smartphone and tablet-based applications holds promise for early detection and quantification of brain white matter changes in patients with adrenoleukodystrophy (ALD) and other rare demyelinating diseases, but this methodology requires validation in pediatric populations. METHODS/STUDY POPULATION: We developed an iPad application with a game-like interface to assess interhemispheric transfer across the corpus callosum, the brain structure where cerebral demyelinating disease typically begins in patients with ALD. Feasibility data from remote test administrations with healthy children were collected to analyze and speed and timing of finger tapping movements requiring bimanual coordination on a touchscreen. RESULTS/ANTICIPATED RESULTS: Among our pilot sample of healthy school-aged children, age-related improvements in finger tapping speed were observed in both single-hand and alternating-hand conditions. Results indicate that remote testing using iPad applications is a viable way to collect psychometric testing data rapidly in pediatric populations and is feasible during a pandemic. Next steps in this research project will be: (1) evaluating the stability of repeated test administrations (test-retest reliability), (2) assessing agreement between performance on our iPad application and validated measures of interhemispheric transfer and fine motor function, and (3) comparing performance of children with known corpus callosum white matter abnormality to performance of healthy children. DISCUSSION/SIGNIFICANCE OF FINDINGS: Brief neurocognitive tests that can be frequently administered may have the ability to capture subtle brain changes in developing children. Approaches enabling remote  testing will facilitate research during the covid-19 pandemic and are especially well-suited for data collection in rare disease populations.


Older adults with dementia rely on others to recognize and treat their pain and will ultimately become dependent. Family caregivers (FCGs) play a crucial role in pain management, yet limited data is available regarding the factors that impact their abilities. This qualitative descriptive study sought a deep understanding of FCGs perception of their abilities to manage pain for a loved-one with dementia. A sample of 25 adult family caregivers of community-based older adults with dementia was recruited in central Virginia. Participants were 29 to 95 years old, predominantly white, married, female, and high school graduates. We conducted semi-structured interviews that were audio recorded and analyzed using constant comparative analysis. Participants’ who perceived greater competence with pain management reported less pain for their loved-one, and their level of confidence was influenced by 3 factors: progress and stage of dementia: this increases the complexity of care, affecting FCGs ability to manage pain and engendering a self-perception of incompetence; developing adaptive mechanisms: built self-efficacy and improved FCGs perceived competence;, and support from professionals: a greater degree of support alleviated FCGs concerns and instill new skills, Effective pain management depended on family caregivers’ belief in their own abilities, and perceived competence could be improved by learning new skills or making adaptations. Professional care givers need to routinely assess FCGs abilities and provide adequate interventions.


We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015–2016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens. Zika virus (ZIKV) infection during pregnancy can cause severe brain and eye malformations and is associated with neurodevelopmental abnormalities in affected infants   within 12 hours of collection, and stored according to Food and Drug Administration and CDC guidelines (https://www.hologic.com) at Vitalant Research Institute   performed quality-control testing by singleplex NAAT   years; specimen collection was evenly distributed by trimester of pregnancy . Of the specimen . A totalAmong 28 women who tested positive by NAAT, 8 were by whole blood, 10 by urine, and 20 by serum . Among tThis study provides information about laboratory testing to maximize detection of ZIKV infection among asymptomatic pregnant women. In this small sample of ZIKV NAAT–positive asymptomatic pregnant women, no additional ZIKV-positive cases were identified by whole-blood NAAT beyond those identified through tests of other samples. This finding contrasts with other studies that note prolonged detection, higher viral load, and greater sensitivity of whole-blood NAAT versus NAAT on other specimens (All asymptomatic ZIKV-positive women had detectable ZIKV in NAAT of urine or serum samples in our study. Although previous studies detected ZIKV RNA in urine more frequently than in serum (This large study comparing NAAT for ZIKV on serum, urine, and whole-blood specimens is unique in that the study population is among asymptomatic pregnant women. Although studies have mentioned lack of overlap between different specimens tested by NAAT (Our detection of acute ZIKV infections by NAAT is likely low because the study occurred 2–3 months after the peak of the Puerto Rico outbreak (These findings support CDC guidance to perform NAAT on asymptomatic pregnant women during outbreaks when ZIKV is widely circulating (


Pediatric fecal matter transplant (FMT) clinical trials relying on “healthy” donor stool use screened adult donor stool, likely assuming safety and efficacy. However, we consider how adult donor stool could instead be posing risks of atypical development or transmission of early disease, which could be prevented with age-matching donors and recipients for FMT.The gut microbiome has been identified as a potential therapeutic target to combat pediatric intestinal and extraintestinal diseases through FMT. FMT involves the transfer of “nondiseased” stool into the gastrointestinal (GI) tract of an individual with the disease in attempts to replenish the gut microbiota and ameliorate adverse GI symptoms. Currently, no standard methodology exists for clinical trials investigating FMT efficacy. Key elements such as donor selection processes are often based on drastically different criteria but usually involve adult stool donors even in pediatric FMT clinical trials. We consider how the usage of adult donors may be of concern when considering the long-term implications of FMT on pediatric health. The pediatric microbiome plays an important role in immune, GI, and neurological development and to introduce adult donor stool to an already dysbiotic microbiome could lead to atypical maturation. Furthermore, selection of nondiseased stool is based on current screening protocols. Screened and deemed “nondiseased” adult donor microbiota could be showing early disease markers for diseases that are not yet visible with current donor screening protocols, putting pediatric recipients at risk for disease development. Current pediatric guidelines have yet to consider these specific pediatric risks, which could be jeopardizing the long-term health and development of pediatric patients and influencing the future of pediatric therapeutics.The microbiota is largely shaped in early childhood. Antibiotic usage in early childhood has shown to increase the risk of acquiring conditions such as inflammatory bowel disease (IBD), asthma, allergy, and eczema , 2. ThisThroughout childhood, adolescence, and adulthood, age is associated with drastic differences in composition and functional gene potential of the microbiome . Age greIn a pediatric FMT clinical trial, considerations for donor stool should include both microbial factors, such as similarity of microbial species between donor and recipient, as well as factors for host intestinal tolerance toward the donor microbes. Because the gut microbiota of young children, adolescents, and adults are all distinct, the necessary microbiota across development is crucial for typical neurological, immunological, and GI development –4, 6. IfClostridioides difficile infection (rCDI) (NCT02134392). In these pediatric trials, the age of the stool donor is listed as either an adult or is not mentioned in study record details.In the pediatric population, active FMT clinical trials include treatment of intestinal colonization of extended-spectrum resistant Enterobacteriaceae (NCT02543866), IBD (NCT03399188), autism spectrum disorder (NCT03426826), ulcerative colitis (NCT03582969), Crohn's disease (NCT03378167), and refractory Methodology within FMT clinical trials vary with donor selection procedures being a particular area of heterogeneity . Fecal dScreening efforts are established to not only ensure stool viability but robustly reduce the chance of transmitting infection or active medical comorbidities from donor to recipient . ScreeniDonor selection methodology is a particularly large area of ambiguity. For example, a systematic review of FMT clinical trials reported before 2017 determined that out of 85 FMT clinical trials, almost 50% of published studies did not report donor selection eligibility criteria in their publications . This reTrial method heterogeneity and uncertainty surrounding true efficacy further exacerbates the concerns for safety in FMT clinical trials. Safe stool is as safe as how it has been screened, and screening can only include testable pathogens already established to directly cause disease. However, the definition of what can cause disease is constantly evolving. For example, FMT has revealed the possibility of transmission of diseases previously assumed as nontransmissible. A patient developed issues with significant weight gain following an FMT from a healthy, but overweight, donor leading to FMT guidelines to suggest screening for donor body mass index . This poCurrent pediatric guidelines suggest donor selection should involve adults aged 18 and older based on medicolegal considerations . While aEarly life disruptions to the microbiota can already increase an individual's susceptibility to a variety of immune, metabolic, neurological, and psychiatric diseases . This phEarly disease markers for a variety of gut microbiome associated diseases have not yet been identified. These early disease markers could be characteristic changes occurring in the gut of an adult donor, years before diagnosis of disease, and invisible with current stool-screening guidelines. It is established that bidirectional communication between the brain and GI tract has been implicated in a variety of neurological diseases. Transmission of early disease markers from a variety of diseases could occur; here, we will illustrate the issue using Parkinson's disease (PD) as an example. PD has characteristic changes in the GI tract including constipation and gut dysbiosis with increased inflammation and reduced short-chain fatty acid production. Adults with REM-sleep behavior disorder, a prodromal stage of PD, already have the same pattern of dysbiosis . ConstipTo contextualize early disease marker transmission using specific evidence from pediatric FMT, a study of the gut microbiome of pediatric recipients following FMT with “healthy” adult donor stool showed the potential for acquisition and persistence of antimicrobial genes from the donor . AlthougWe are concerned that adult donors beginning to generate characteristic microbiome profiles of adult-onset disease could be acting as FMT donors for pediatric FMT trials, potentially generating long-term implications for the recipient child with their GI tract being introduced to characteristic pathogenic changes in childhood. Matching pediatric FMT recipients with pediatric donors could largely reduce the possibility of adult-onset neurodegenerative disease marker transmission and allow for less interruption of age-specific maturation of the gut microbiota.With past efforts focused on the promotion of immediate safety for pediatric FMT recipients, the field is ready for conversations surrounding long-term safety and healthy development in pediatric FMT recipients. Optimal donor selection should be a focus of these conversations, with considerations of matching donors and recipients by age being prioritized. Age-matching could reduce the exacerbation of the child's atypical immune, GI, metabolic, and neurological development to allow for parallel interplay of microbiota development with typical physiological development.The idea of age-matching is not without an introduction of its own novel risks, such as possible transmission of childhood-onset diseases including asthma or allergy to pediatric recipients. However, we argue this phenomenon could still occur with the introduction of adult donor microbiota because it could be affecting typical immunological development. Furthermore, screening for risk factors for allergy and asthma, such as antibiotic usage, mode of delivery, and formula feeding in pediatric donors, could aid to protect against this occurrence.A joint-position paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition similarly argues that further research into age-matching is warranted due to concerns of long-term efficacy and safety with adult donors . Age-matCurrently pediatric FMTs are changing children's lives, treating persistent, and sometimes otherwise incurable, diseases, demonstrating the power of the approach. FMT trials explore increasingly diverse applications for pediatric intestinal and extraintestinal diseases and long-term clinical considerations for health and development will be increasingly important. Given the increasingly recognized role of the gut microbiome in adult diseases including neurodegenerative disorders, we believe choosing age-matched donors for pediatric FMTs will likely be the best safe-guard to reduce potential future complications.At time of submission all clinical trials statuses mentioned in the manuscript are listed as: NCT02543866 (recruiting), NCT03399188 (recruiting), NCT03426826 (recruiting), NCT03582969 (recruiting), NCT03378167 (recruiting), and NCT02134392 (recruiting).https://clinicaltrials.gov/.Current trial statuses can be accessed at AM conceived the opinion and drafted manuscript. BF and SA-C contributed expertise to review and critique final manuscript. All authors contributed to the article and approved the submitted version.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.


Transposable element sequences are usually vertically inherited but have also spread across taxa via horizontal transfer. Previous investigations of ancient horizontal transfer of transposons have compared consensus sequences, but this method resists detection of recent single or low copy number transfer events. The relationship between humans and domesticated animals represents an opportunity for potential horizontal transfer due to the consistent shared proximity and exposure to parasitic insects, which have been identified as plausible transfer vectors. The relatively short period of extended human–animal contact (tens of thousands of years or less) makes horizontal transfer of transposons between them unlikely. However, the availability of high-quality reference genomes allows individual element comparisons to detect low copy number events. Using pairwise all-versus-all megablast searches of the complete suite of retrotransposons of thirteen domestic animals against human, we searched a total of 27,949,823 individual TEs. Based on manual comparisons of stringently filtered BLAST search results for evidence of vertical inheritance, no plausible instances of HTT were identified. These results indicate that significant recent HTT between humans and domesticated animals has not occurred despite the close proximity, either due to the short timescale, inhospitable recipient genomes, a failure of vector activity, or other factors. Drosophila was the first case of inferred HTT [Transposable elements (TEs) are DNA sequences that can move or copy themselves to new locations in genomes . This prrred HTT , with thrred HTT . While Hrred HTT , evidencrred HTT ,18. Probrred HTT ,19.Despite an increasing number of ancient HTT events being detected, studies evaluating evidence for more recent HTT are lacking. The use of consensus TE sequences when inferring HTT, while necessary for evaluating large-scale transfers across millions of years between many genomes, also prevents the detection of transfers currently in single or low copy numbers in the recipient genome. Human domestication of animals is a ready example of species sharing an environment conducive to HTT on a shorter timescale, on the order of tens of thousands of years or less . FeatureThe existence of high-quality reference genomes for humans and most domesticated animals finally makes the detection of low- and single-copy HTT events possible. Despite the close physical contact and other factors that make HTT more likely to be present, we expected the rarity of successful TE invasion and a lack of adequate time for any transferred TEs to become ubiquitous in the population to result in no detectable HTT events, even when searching millions of individual elements between human and domestic animal genomes. Here, we provide a comprehensive search for individual HTT events between humans and domestic animal species.https://genome.ucsc.edu/ accessed on 30 May 2021). Only intervals longer than 100 bp were included. The search was also limited to retrotransposons based on a lack of evidence for significant DNA TE activity in mammals outside of the Vespertilionidae family of bats for a time period far exceeding the history of animal domestication by humans [https://www.R-project.org/ accessed on 30 May 2021), and reference genomes downloaded from UCSC. TE intervals from non-chromosomal scaffolds were removed for species with chromosomal assemblies, while TE intervals were used in full for genomes without chromosome-level assemblies. A 400 bp decoy sequence (hg38 chr1:1000000–1000400) containing no TEs was appended to each retrotransposon multifasta; this sequence served as a positive control to verify that megablast was functional in the event of zero high-identity hits for a given pairwise comparison. Pairwise comparisons of reference mRNA sequences downloaded from UCSC were also performed as a positive control for vertical inheritance in a subset of domestic animal species.Reference genomes and retrotransposon genomic intervals  for human (GRCh38/hg38) and thirteen domestic animal species  were downloaded from UCSC Table Browser using the RepeatMasker (rmsk) track  were performed in the command line using BLAST+ version 2.8.1 . The humper year . Using tper year . Verticaper year .Pairwise megablast queries of 27,949,823 retrotransposons from the reference genomes of humans and thirteen domestic animal species revealed zero insertion events consistent with HTT . InitialThirty-seven human TEs also yielded high-identity hits in two or more domestic animal species ; high idHelicoverpa armigera [For the eight SINE hits initially detected as unique to human and one other species, manual inspection with the 100 Species MultiZ alignment track in UCSC Genome Browser revealed strong conservation across multiple vertebrate genera and orders , providiarmigera . Indicatarmigera ,54. WhilThe lack of HTT between humans and domestic animal species was consistent with the study expectations. We chose domestic species due to humanity’s history of unnaturally close proximity, shared parasitization by plausible HTT vectors (which have served as HTT vectors in other clades), and rapid expansion of human and domestic animal population sizes. An illustrative case is the BovB element, which has proliferated rapidly in species as divergent as bovines and squamates and ultimately makes up 12% of the cattle genome . HoweverOur search demonstrates a lack of evidence for recent HTT between humans and domestic species. Prior identification of HTT events used consensus sequences of transposons derived from multiple paralogs within a species, compared to consensus or individual insertions in an unrelated species. The advantage of our study is in the ability to detect HTT resulting in few or even single insertion events. Still, the use of reference genomes allows for the possibility of HTT detection failure due to population heterogeneity, somatic HT, inadequate genome coverage or errors (particularly over repetitive regions) or other factors. However, the lack of plausible horizontally transferred elements within human and animal reference genomes provides adequate evidence to assume that the phenomenon is not common or widespread.


This case study explores an employer-initiated biweekly group support call for home care aides implemented by a large New York City-based home care agency during the COVID-19 pandemic. Specifically, we investigate how agency staff used information gathered through these calls to intervene into existing agency communication and support systems for aides. Our single-site case study analyzes detailed notes from almost 100 support calls that took place between April 2020 and March 2021, as well as interviews with agency staff from communications, human resources, nursing, and other departments that support aides. We compare and contrast new communication and support mechanisms advanced in conjunction with these calls with agency systems pre-pandemic. Our findings suggest that while calls were initially targeted toward providing emotional and operational support, staff also advocated for more systemic supports. We discuss the sustainability of these new efforts, as well as ongoing barriers and gaps.


ABSTRACT IMPACT: Up to 33% of patients of patients who undergo reconstruction have hostile defects with coexisting soft tissue and osseous defects due to prior radiation, prior failed cranioplasty or concurrent infections we seek to identify optimal strategies for these patients based on the experience of a southeastern tertiary referral center. OBJECTIVES/GOALS: Scalp and calvarial defects in patients may result from a number of etiologies including trauma, burns, tumor resections, infections, osteoradionecrosis, or congenital lesions. Our objective was to retrospectively evaluate the use of alloplastic reconstruction alongside autologous reconstruction for high risk cranial defects. METHODS/STUDY POPULATION: An IRB approved retrospective review of patients who underwent cranioplasty of a hostile site at a Southeastern tertiary referal center between January 2008 and December 2018 was performed. The patients were stratified into three groups based on the type of implant used: autogenous (bone), alloplastic , or mixed (combination of both types of graft). The primary outcome metric was a complication in the year following cranioplasty, identified by flap or bone graft failure, necrosis, or infection. Statistical analysis included t-tests and chi-square tests where appropriate using SPSS. RESULTS/ANTICIPATED RESULTS: There were 43 total cases in this time period; 15 autogenous, 23 alloplastic, and 5 mixed. The purely autogenous group had the highest complication rate (85%) and the alloplastic group had the lowest complication rate (38%). When stratified by specific material used for reconstruction , overall complication rate was statistically significant  with PEEK implants having the lowest complication rate (21%). The analysis documented an overall complication rate that was statistically different between the three groups (p=0.012). DISCUSSION/SIGNIFICANCE OF FINDINGS: This analysis interestingly found that in the setting of hostile cranial defects, cranioplasties would benefit from the use of prosthetic implants instead of autologous bone grafts, not only for avoidance of donor site morbidity but also for decrease in overall complications.


ABSTRACT IMPACT: This study will be used to culturally tailor interventions to reduce maternal and infant health disparities in a Marshallese community. OBJECTIVES/GOALS: Inadequate prenatal care is associated with adverse birth outcomes including preterm births, low birth weight infants, and neonatal mortality. Marshallese Pacific Islanders are less likely to receive early and consistent prenatal care compared to other racial/ethnic groups and are thus at a higher risk for maternal and infant health disparities. METHODS/STUDY POPULATION: This article used a qualitative comparative analysis method to compare and contrast the perceived barriers to prenatal care for the prospective of Marshallese mothers and Maternal Health Care Providers (MHCPs). RESULTS/ANTICIPATED RESULTS: Marshallese mothers and MHCPs identified the same structural barriers to prenatal care: health insurance, transportation, and language. The socio-cultural barriers to prenatal care were depicted quite differently by Marshallese mothers verses MHCPs. DISCUSSION/SIGNIFICANCE OF FINDINGS: While the description of structural barriers were consistent among Marshallese mothers and MHCPs, the socio-cultural barriers and the value assigned to those barriers was quite different. Understanding the perspectives from both lenses is an important step towards addressing the barriers to prenatal care among Marshallese.


Vulnerable older adults, such as physically impaired or care-dependent individuals, are vastly underrepresented in psychotherapy research. Improving their inclusion in randomized controlled trials is necessary to determine the effectiveness of psychotherapy in this population. This study is the first to systematically evaluate strategies to recruit home-living vulnerable older adults with clinically significant depression into a large randomized controlled psychotherapy trial. Potential participants were approached directly  or via cooperation with gatekeepers .The initiator of the first contact with the study team and successful recruitment strategies were recorded. Referral strategies were compared with respect to number of inquiries and inclusion rates; study personnel’s time investment; and participant characteristics .Most of the N=197 participants were included via gatekeeper-referral  and referral by medical practitioners led to highest inclusion rates =8.964, p<.05). Most participants were referred from a hospital setting (50.3%), whereas referral numbers by medical practices were low (15.9%). Participants who initiated the first contact themselves had higher inclusion rates and were less functionally and cognitively impaired.Including home-living vulnerable older adults into psychotherapy trials requires simultaneous implementation of diverse recruitment strategies. Medical practitioners and psychologists, especially in hospitals, are the most effective recruitment strategy, but self-referral via media is most cost-efficient in terms of time investment.


Lasionycteris noctivagans (silver-haired bat), Tadarida brasiliensis (Mexican free-tailed bat), and Eptesicus fuscus (big brown bat)  after bat exposures that occurred during August 2021. This increase in bat-associated human rabies deaths in the United States followed only three deaths during the previous 48 months. The cases during fall 2021 occurred in two adults and one child, all male, from Idaho, Illinois, and Texas. Initial symptoms included pain and paresthesia near the site of exposure progressing to dysphagia, altered mental status, paralysis, seizure-like activity, and autonomic instability. All three patients had recognized direct contact  with a bat approximately 3–7 weeks before symptom onset and died approximately 2–3 weeks after symptom onset. The deaths were associated with three bat species: own bat) . All thrRabies is a zoonotic disease transmitted primarily through virus-laden saliva from the bite of an infected mammal. The typical incubation period from exposure to symptom onset is 3–12 weeks. Rabies is nearly always fatal once symptoms develop but nearly always preventable when PEP is administered in accordance with the recommendations of the Advisory Committee on Immunization Practices.Preventing transmission of rabies from bats to humans can be accomplished by 1) avoiding contact with bats, 2) safely capturing and testing bats implicated in human exposures, and 3) seeking rapid evaluation for PEP when direct bat contact occurs and rabies cannot be ruled out. Two of the bat-associated cases in fall 2021 were considered avoidable exposures: one was attributed to a bat roost in the patient's home, the other to the patient picking up the bat with his bare hands. Safely excluding bats from homes and instructing persons not to touch bats can prevent rabies exposures.Bats are ecologically critical species with seasonal activity patterns. Although bat activity is reduced in winter months, increased human-bat contacts often occur again in late spring to early fall (


Older adults with mild behavioral impairment (MBI), or the presence of late-life neuropsychiatric symptoms, have a unique cognitive phenotype. However, the neural correlates associated with MBI-related cognitive changes is not well understood. The goal of this study is to examine if specific regions of the brain moderate the relationship between the presence of MBI and performance on tasks of cognition. Data from the National Alzheimer’s Coordinating Center was utilized for this study. Participants  were included in our analyses if they were cognitively healthy or had mild cognitive impairment (MCI). Multiple domains of cognitive performance were evaluated. The neuroanatomical regions included hippocampus, caudal anterior cingulate (ACC), rostral ACC, entorhinal, and parahippocampal gray matter volume; and caudal ACC, rostral ACC, entorhinal, and parahippocampal mean cortical thickness. Hippocampal, entorhinal, and parahippocampal cortical gray matter volume moderated the relationship between MBI and performance on tasks of episodic memory. Left rostral ACC cortical gray matter volume and entorhinal and parahippocampal mean cortical thickness moderated the relationship between MBI and performance on language tasks. Hippocampi cortical gray matter volume also moderated the relationship between MBI and performance on processing speed tasks. Persons with smaller brain sizes in these areas were more negatively affected in these cognitive domains if they had MBI. These results suggest that the association between smaller brain volumes and cognition was stronger among persons with MBI. These findings suggest that older adults with MBI may perform worse on these tasks due to neurodegeneration that is present.


Institutions of higher education need to become more age friendly. Creating an on-campus lifelong learning program can offer older adults opportunities to audit classes and engage in multigenerational classrooms, but can also promote intergenerational learning when instructors consciously use pedagogy that fosters engagement between learners from various generations. Promoting intergenerational learning to facilitate reciprocal sharing of expertise between generations is also the fourth principle of the Age Friendly University framework. This qualitative interview study examines the perspectives of 27 faculty members who have opened their face to face classrooms to older adult auditors to 1) Explore perceived benefits and challenges associated with having older adults in the college classroom and to 2) Determine what levels of intergenerational learning may be taking place. Compared to lecture-based courses, faculty whose pedagogy promotes discussion, sharing, and small group work reported detailed examples of older adult learners and traditionally-aged college students engaging in course-related discussion. The unique, historical and diverse perspectives of older adults improved the quality of education for students, and fostered in-depth learning. Challenges related to older adult auditors included poor/limited attendance, sharing of strong opinions/dominating class discussion, sensory/mobility and technology accessibility. Recommendations include training to promote intergenerational engagement in college classrooms.


Bradyrhizobium diazoefficiens . Using gene-level network and duplication functional traits to predict accessory gene distributions across environments, genes predicted to be superfluous are more likely lost in high stress, while genes with multi-functional roles are more likely retained. Genes with higher probabilities of being lost with stress contain significantly higher proportions of codons under strong purifying and positive selection. Gene loss is widespread across the entire genome, with high gene-retention hotspots in close spatial proximity to core genes, suggesting Bradyrhizobium has evolved to cluster essential-function genes  in discrete genomic regions, which may stabilise viability during genomic decay. In conclusion, pangenome evolution through genome streamlining are important evolutionary responses to environmental change. This raises questions about impacts of genome streamlining on the adaptive capacity of bacterial populations facing rapid environmental change.Bacteria have highly flexible pangenomes, which are thought to facilitate evolutionary responses to environmental change, but the impacts of environmental stress on pangenome evolution remain unclear. Using a landscape pangenomics approach, I demonstrate that environmental stress leads to consistent, continuous reduction in genome content along four environmental stress gradients  in naturally occurring populations of  A pervasive challenge in microbial ecology is detecting how natural microbe populations respond to environmental change. Prokaryotes have highly variable intraspecific genome content, described as a pangenome , 2. WithOne approach in detecting changes in evolutionary pressures on genome evolution, such as ecological adaptation, is to determine how natural environmental variation, putative agents of natural selection, predict the distribution of genomic variation. Landscape genomics has been a powerful approach in uncovering the genetic basis of adaptation, traditionally detecting putative adaptive loci or SNPs on a single reference genome, and effectively concentrating adaptive discovery to the core genome of a species. However, little attention so far has been given to uncovering patterns of accessory genome variation across the environment . Here, IGenome reduction represents a major change in the accessory genome. Prokaryotic genomes are thought to be under constant decay due to a mutational bias towards deletion , 13. OneBradyrhizobium diazoefficiens, which was previously sampled across a contiguous and environmentally complex heterogeneous landscape  or low stress [large negative z-score]) appear to be under strong selection  are under stronger selective pressure, having significantly higher proportion of codons under purifying or positive selection compared to accessory genes randomly distributed with respect to environmental stress. Because accessory genes that only occur in extreme ends of the stress gradient  and increase in population differentiation (Fst) with high stress in core genes, when compared to aridity and acidity. The observed decrease in the efficiency of selection provides strong evidence of either weaker selection and/or smaller effective population size in the core genome at high heat and salinity stress. Consistent with this study’s finding, theoretical models predict that increased population differentiation (Fst) can be a result of decreased effective population size through increased population sub-division . The conThe pervasive genome decay along soil and climate-related stress gradients also has implications regarding evolvability in bacterial populations. The observed loss of genetic diversity (at the gene level) with increasing stress prompts future questions and experiments on the upper bounds of genome decay that microbial populations can tolerate with increasing environmental stress. The loss of genetic diversity also raises questions about how genome streamlining impacts the ability for bacterial populations to evolutionarily respond to environmental change when already faced with stressful conditions.Supplemental InformationSupplementary interactive 3D version of Figure 6


Nature Photonics (2022)10.1038/s41566-021-00921-9Thermal radiation is commonplace in our everyday life, exemplified by natural sunlight and infrared thermometers. When an object emits thermal radiation, a radiative cooling process carrying away energy from the object occurs spontaneously. Hence, the control of thermal radiation or radiative cooling is beneficial not only to the development of practical cooling techniques, but also to the exploitation of renewable energy resources. An emerging field of thermal photonics provides exciting opportunities for manipulating the radiative process artificially. In this review article, Shanhui Fan from Stanford University and Wei Li from Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences have discussed fundamental concepts involved in radiative cooling and summarized principles for tailoring thermal radiation with photonic structures. The story starts with the demand of daytime radiative cooling and introduces photonic concepts and recent advances in this area. Inspired by the daytime radiative cooling, more scenarios such as solar cell cooling, thermal management of outdoor colored objects and cooling textiles have been proposed. Thermodynamics in radiative cooling is finally discussed for harvesting outgoing thermal radiation. We anticipate these fruitful discussions can help readers walk into thermal photonics and motivate researchers to find novel applications of radiative cooling.


ABSTRACT IMPACT: This study aims to provide insight into naturally acquired immunity against severe malaria, thereby laying the foundation for the design of novel vaccine candidates to prevent severe disease as well as monoclonal antibody therapies to treat severe malaria. OBJECTIVES/GOALS: Severe malaria is caused by parasite surface antigens that contain high sequence diversity. Nevertheless, P. falciparum-exposed individuals develop antibody responses against these antigens. Our goal is to isolate antibodies with broad reactivity to understand how disease protection is acquired. METHODS/STUDY POPULATION: Our study cohort consists of Ugandan adults living in a malaria-endemic region with high transmission intensity, who are protected against severe malaria. Using fluorescently labeled probes of parasite surface antigens, we have isolated antigen-specific B cells from these donors. We then expressed the corresponding monoclonal antibodies in vitro. These antibodies were screened against a library of variant surface antigens to determine antibody breadth and potential to inhibit interaction of the parasite surface antigen with host receptors, a critical step in pathogenesis. Additionally, using a panel of variant surface antigen mutants, we have predicted the epitopes targeted by the broadest monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: We have identified three monoclonal antibodies with exceptionally broad reactivity and inhibitory activity against our panel of severe disease-inducing variant surface antigens. We have identified two major sites targeted by these broadly reactive antibodies. The first site was associated with the largest breadth, but limited inhibitory potential, while the second site showed high-affinity antibody binding and inhibition of receptor binding. Interestingly, two of these three antibodies were very similar in structure, even though they were isolated from different donors. Isolation of antigen-specific B cells from additional donors will enable us to identify how common such broadly reactive antibodies are and allow the identification of additional epitopes DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is the first to isolate broadly reactive antibodies that are likely to protect against severe malaria in naturally immune individuals. Further characterization of antibody-antigen interactions will inform the development of this surface antigen as a vaccine candidate for malaria.


Exercise training decreases abdominal fat in an intensity-dependent manner. The fat loss effect of exercise has been intuitively thought to result from increased fat burning during and after exercise, defined by conversion of fatty acid into carbon dioxide in consumption of oxygen. Nevertheless, increasing exercise intensity decreases oxidation of fatty acids derived from adipose tissue despite elevated lipolysis. The unchanged 24-h fatty acid oxidation during and after exercise does not provide support to the causality between fat burning and fat loss. In this review, alternative perspectives to explain the fat loss outcome are discussed. In brief, carbon and nitrogen redistribution to challenged tissues (muscle and lungs) for fuel replenishment and cell regeneration against abdominal adipose tissue seems to be the fundamental mechanism underlying the intensity-dependent fat loss effect of exercise. The magnitude of lipolysis (fatty acid release from adipocytes) and the amount of post-meal carbon and nitrogen returning to abdominal adipose tissue determines the final fat tissue mass. Therefore, meal arrangement at the time when muscle has the greatest reconstruction demand for carbon and nitrogen could decrease abdominal fat accumulation while increasing muscle mass and tissue repair. Exercise decreases abdominal fat mass, especially at high intensity. This outcome is not causally associated with fat burning, but better explained by carbon and nitrogen redistribution. Since abdominal fat tissue constantly releases fatty acids into circulation under post-absorptive condition with natural cell deaths, exercise diverts more post-meal carbon and nitrogen to muscle for energy repletion and cell regeneration after phagocytosis and stem cell homing. This in turn leads to concurrent fat mass loss and muscle mass gain. Respiratory ventilation during high-intensity aerobic exercise amplifies the competition for post-meal carbon and nitrogen against adipose tissues. TherefoLipolysis appears to be more relevant with fat loss than fatty acid oxidation. Exercise increases plasma epinephrine levels at high intensities . EpinephThe physiological significance of the enhanced release of fatty acids from lipolysis without the corresponding increase in fatty acid oxidation during and after exercise remains unclear. However, a proposed role of adipocyte-derived fatty acids in tissue repair has been recently described elsewhere . Fatty aThe first basic assumption of fat burning theory is that fat cell death has no role in fat loss. However, this assumption is unlikely valid since fat cells are continuously dying and regenerating throughout our life. Approximately 8.4% of subcutaneous abdominal adipocytes are renewed annually with an average half-life of 8.3 years in human adults . AbdominThe second basic assumption of the fat burning theory is that muscle and fat cells are not interconvertible in a human body. However, we could not preclude the possibility that the fat mass loss concurrent with muscle mass gain after exercise training is associated with conversion between muscle and fat progenitor cells, derived from circulating bone marrow stem cells. Conversion from muscle satellite cells to an adipogenic lineage contributes the development of obesity and muscle mass loss in animals . GlucoseFurther evidence of this mechanism comes from the wide array of exosomes (containing nucleic acids or peptide) released from exercising skeletal muscle implicating the crosstalk between muscle and fat tissues. Adipose tissues are a major source of circulating exosomes containing a variety of mediators, which may influence muscle development . Some nuThe third assumption of the fat burning theory is that the increased carbon and nitrogen demands for airway epithelial cells regeneration in lungs does not contribute to fat loss during and after exercise. However, the possibility that the fat loss effect of high-intensity aerobic training due to competition for carbon and nitrogen between lungs and adipose tissues cannot be excluded . The lunDuring unfed conditions, visceral adipose tissues continuously releases fatty acids into circulation , togetheStudies employing dual energy X-ray absorptiometry have also provided solid support for the carbon and nitrogen redistribution effect of exercise training by the evidence of concurrent increases in lean body mass and decreases in fat mass . This nuLipoprotein lipase (LPL) attached on the surface of endothelial cells in capillary lumen determines relative partition of circulating triglycerides to muscle and adipose tissues after meals. The molecular size of triglyceride carried by chylomicron and VLDL is too large to transport across cell membrane of adipocytes from blood unless it is locally hydrolyzed by LPL in the adipose and muscle tissues. Relative LPL expression in adipose tissue and muscle tissues thus determines the daily distribution of circulating triglycerides (chylomicron and VLDL) partitioning into adipose tissues and skeletal muscle after meals. This ratio is substantially influenced by exercise training, in which trained women have relatively higher (∼8 times) muscle-to-adipose tissue LPL ratio compared to their untrained state . This suFatty acids (from lipolysis) are continuously released from abdominal adipose tissue into the circulation and fat cells are continuously dying in normal human adults. The size of adipose tissue is determined by the magnitude of nutrient competition from muscle and lungs for cell regeneration and energy replenishment after exercise. This is varied by types of exercise (aerobic or resistance exercise). Despite the fact that lower exercise intensity relies more on fatty acid oxidation, high-intensity exercise training (anaerobic in nature) provides a superior abdominal fat loss effect than low- and moderate-intensity exercise training. Given the fact that exercise does not increase 24-h fatty acid oxidation during and after exercise training, the carbon and nitrogen redistribution theory is more suitable to explain the abdominal fat loss outcome of exercise training than fat burning theory. This reasonably explains why low- and moderate-intensity exercise often fail as strategies for fat loss despite the greater percentage of fatty acid oxidation compared with high intensity exercise. Studies on inter-tissue communication during exercise (such as muscle-derived extracellular vesicles) for post-meal carbon and nitrogen redistribution are promising and may provide useful application to normalize body composition and prevent obesity. Furthermore, the role of fatty acids on repairing post-exercise damage deserves further investigation. More data are needed to support the carbon and nitrogen redistribution theory on fat loss effect of exercise.Both authors contributed significantly to this work.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.


Objective: This study aims to identify multiple dimensions of religiosity among young adults at the beginning and end of the transition to adulthood, and describe how transition patterns of religiosity in early adulthood are associated with filial elder-care norms in midlife. Background: There is a broad consensus that religiosity is multidimensional in nature, but less is known regarding transitions in multiple dimensions of religiosity from early to middle adulthood and predicted filial eldercare norms as a function of those religiosity transitions. Methods: The sample consisted of 368 young adults participating in the Longitudinal Study of Generations in 2000 (mean age = 23 years) and 2016 waves. We conducted a latent class and latent transition analyses to address our aims. Results: We identified three religious latent classes among young adults in both 2000 and 2016 waves: strongly religious, weakly religious, and doctrinally religious. Staying strongly religious young adults between 2000 to 2016 waves reported higher filial elder-care norms in the 2016 Wave than those who were in staying weakly religious, staying doctrinally religious, and decreasing religiosity transition patterns between 2000 to 2016 waves. Conclusion: Our findings suggest that religiosity is still an important value for young adults shaping their intergenerational relationships with their aging parents. Keywords: religiosity, filial eldercare norms, young adults, transition to adulthood


A major component of The Middle Tennessee GWEP involves delivery of an annual regional geriatrics update conference. Formerly in-person, the planning committee transformed the 34th Annual Update Conference to a virtual platform within a six-month period. The University partner provided a Zoom platform with licensing and training of program staff. National marketing was achieved through professional societies and purchased e-mailings. Participants numbered 79, including 8 disciplines. Presenters were instructed on platform techniques including screen sharing, polling function, and breakout rooms to enhance audience participation. REDCap registration captured demographic information and facilitated evaluations and post-attendance intention-to-change surveys. Lessons learned were shared with community partners and advisory board members who demonstrated changes in service delivery models and training of new staff to support care to greater numbers of clients and participants. Virtual platforms can extend outreach for valuable learning and service outcomes and maintain high levels of satisfaction among target audiences.