Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease with variable clinical intensity. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib). We searched the most recent English literature (1997-2017) regarding any article with the key word of “glycogen storage disease type I” in PubMed, Science Direct, Scopus, EMBASE, and Google Scholar. We will present all of the published articles about the molecular genetic characteristics and old-to-new diagnostic methods used to identify GSD I in regard of methodology, advantages and disadvantages. Diagnosis of GSD type I and its variants is challenging because it is a genetically heterogeneous disorder. Many molecular methods have been used to diagnose GSD I most of which have been based on mutation detection. Therefore, we discuss complete aspects of all of the molecular diagnostic tests, which have been used in GSD type I so far. With the advent of high throughput advanced molecular tests, molecular diagnosis is going to be an important platform for the diagnosis of storage and metabolic diseases such as GSD type I. Next-generation sequencing, in combination with the biochemical tests and clinical signs and symptoms create an accurate, reliable and feasible method. It can overcome the difficulties by the diagnosis of diseases with broad clinical and genetic heterogeneity. Glycogen storage diseases (GSDs) are a group of metabolic disorders determined by the accumulation of glycogen in different tissues. GSDs are caused by the enzyme deficiencies effect on glycogen synthesis, glycogen breakdown or glycolysis (glucose breakdown), typically within muscles and/or liver cells. The disorders were numbered as they were discovered which classified chronologically by GSD type I (von Gierke disease) to GSD type XI . MajoriGSD (Glycogen storage disease) type I or von Gierke disease is the second most common type of GSDs. GSD type I typically presents in early childhood. Von Gierke disease is an autosomal recessive disorder. There is no report regarding ethnic difference in the incidence of GSD type I, however there are different types of mutations in Caucasian, Hispanic, Asian and Jewish populations . The ovHistorically, in 1929, Edgar von Gierke was the first to describe a glycogen storage disease (GSD), which initially was named in his honor  regarding any article with the key word of “glycogen storage disease type I” in PubMed, Science Direct, Scopus, EMBASE, and Google Scholar.GSD I is characterized by accumulation of glycogen and fat in the liver and kidneys, leading to hepatomegaly and renomegaly. The clinical manifestations of von Gierke disease include growth retardation, hepatomegaly, hypoglycemia, lactic acidemia, hyperuricemia, osteoporosis and hyperlipidemia . The paThe clinical presentations of GSD Ib is quite similar to that of GSD Ia, however the symptoms of the patients with GSD Ia, such as hepatomegaly, a characteristic ''doll-like'' face, short stature, and chronic fatigue are more severe. Unlike patients with GSD-Ia, most patients with GSD-Ib also suffer from neutrophil dysfunction and neutropenia, lead to frequent bacterial infections. Clinical differential diagnosis of GSD-Ia from Ib is difficult because neutropenia is sometimes periodic or never develops in GSD-Ib  was codified the enzyme translocase and mutations within this gene in GSD Ib patients were described  to translocate glucose-6-phosphate (G6P) from the cytosol to the lumen of the endoplasmic reticulum (ER) and two other transport systems to transport the reaction products phosphate (Pi) and glucose (G6PT2 and G6PT3 respectively) to the cytosol , which al., 1997). G6PT1 al., 2002). It hasal., 2002). G6PC and most patients with GSD Ic and Id have mutations in the G6PT1 gene SLC37A4, therefore GSD I is now divided into two general subtypes GSD Ia and GSD I non-a, respectively  and GSD-Ib, a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) . But wial., 1995; Veiga-Dal., 1995). Howeveal., 1995; Kishnanal., 1995; Janeckeal., 1995). Among al., 2001).The final and conclusive diagnosis of GSD needed pathologic diagnosis in combination with biochemical and clinical findings; however, liver biopsy is an invasive procedure . PractiPrompt and accurate diagnosis is the most important point for the proper treatment of metabolic diseases. Diagnosis of GSD I is sometimes complicated because there are common features between GSD I and III, including hepatomegaly, hypoglycemia, and hyperlipidemia. Validated and clinically useful tools with a positive predictive value > 90 % are necessary for the diagnosis of GSD I. The diagnosis of GSD I currently relies on clinical features, pathologic diagnosis of liver biopsy, biochemical, and molecular genetic tests  and pathologic findings of the liver biopsy in favor of GSD .G6PC or G6PT1 gene unique to Caucasian, Hispanic, Chinese/Japanese/ Korean, and Jewish GSD I patients have been described, suggesting separate ethnic founder effects for some mutations . Transfal. (1999) has conal. (1999) analyzeal. (1999) showed al., 2000; Nakamural., 2000).Eventually, even a single base alteration can be detected by the altered mobility of the single-stranded DNA molecule in SSCP. In 2004, in one study the frequency of two prevalent mutations of GSD Ia patient in Caucasian (the Q347X and R83C mutation) was reported to screen the Ashkenazi Jewish population by SSCP method as an accurate and easy technique which leads to a predicted prevalence  five times higher than in the general Caucasian population .According to the above literature, disadvantages of SSCP method include the requirement of highly standardized electrophoretic conditions in order to get constant results. Furthermore, some mutations may remain undetected, and accordingly definite absence of mutation cannot be proven. In HD method single-base substitutions are less stable and excessively sensitive to environmental changes. This fact reduces the sensitivity of this method for this type of mutations, which is frequently found in GSD I , two deletions (540del5 and 158delC) and one nonsense mutation (Q347X). Three of them have not been described previously and the R83C was the most common mutation among the Czech and Slovak patients  has been applied for screening of unknown point mutations. Identification of mutations in the al., 2000). This tal., 2000).G6PC (GSD Ia) and SLC37A4 (GSD Ib) full genes can be used for confirming the diagnosis of these diseases precisely  have launched that are referred to as massively parallel or next-generation sequencing (NGS). Direct sequencing has proven extremely successful because of its accuracy and affordability, but it is inappropriate for large-scale screening projects because it has been developed to sequence only one amplified DNA molecule at one time  in a given sample on both strands . Moreoval., 2014; Janeckeal., 2014). Directal., 2014; Gerin eal., 2014). Directal., 2017). Since al., 2017; Lam et al., 2017; Ihara eal., 2017; Triocheal., 2017; Chiang al., 2017; Kozák eal., 2017; Reis etal., 2017; Yuen etal., 2017; Qiu et al., 2017; Ki et aal., 2017; Miltenbal., 2017; Qiu et al., 2017; Tamhankal., 2017; Liang eal., 2017; Gu et aal., 2017; Lu et aal., 2017; Mahmoudal., 2017, Choi etal., 2017), Koreanal., 2017), Brazilal., 2017), Chinesal., 2017; Chiang al., 2017; Qiu et al., 2017; Gu et aal., 2017; Lu et aal., 2017), Indianal., 2017; Karthi al., 2017), Japaneal., 2017), Czech al., 2017), Hungaral., 2017) and Freal., 2017) patiental., 2017), Chinesal., 2017; Qiu et al., 2017; Liang eal., 2017) Japanesal., 2017) populatiga, 2018). Converiga, 2018; Wang etiga, 2018). Briefliga, 2018). SuccesWang et al. (2013) have deSeveral approaches have been used for detection of known mutations. These methods usually started with the polymerase chain reaction (PCR) and additional assay steps are performed based on the type of mutation such as RFLP-PCR . Ihara non-A patients which is advantageous for a primary molecular genetic diagnostic approach. They concluded that the principal advantages of DHPLC are its semi-automated nature, with rapid results (a few minutes per sample), and the feasibility to collect eluted DNA for next analyses, but DHPLC alone cannot provide the details about the nature of mutations. Also, the sensitivity of the method is dependent on the temperature of analysis, the selection of which is dependent on operator experience  technique after PCR . Thoughal., 2000). Lam etal., 2000) have real., 2000).G6PC gene because it is a major cause of GSD-Ia among Japanese patients. The high reproducibility and sensitivity of this technique indicates that the method may be safely applied to clinical diagnosis. Afterward, Kojima et al.  combined with a TaqMan fluorogenic probe (TaqMan-ASA)  used a al. (2004) performal. .Lately, high resolution melting analysis (HRMA), a simple real-time PCR-based method for detecting sequence variations for GSD Ia was developed. The basis of this method is that changes in amplicons of HRM are dependent on their DNA melting curves in the presence of saturating DNA binding dyes . TherefIn the last decade, the use of DNA microarray technique for diagnosis of genetic diseases has been reported , the cost, speed and accuracy of detection increase. The authors declare that they have no conflicts of interest.


The prevalence and social cost of clinical depression are rapidly increasing, and the field continues to attract considerable research interest  and a major downstream target of the ERK signaling pathway, is upregulated both in depressive suicides and in animal models of depression induced by unpredictable chronic mild stress (UCMS) and social defeat  is associated with the diverse signs and symptoms of depression (see for example, Dwivedi et al., However, the authors did not mention other ways of regulating ELK-1 activity, which have been demonstrated in previous studies. For example, ELK-1 can be degraded by FBXO25, a ubiquitin ligase (Teixeira et al., There are also other issues to be resolved around ELK-1 regulation. SIRT6, a histone deacetylase, interacts with ELK-1 to suppress ELK-1-dependent transcription (Cea et al., Furthermore, ELK-1 has isoforms and splice variants (Rao and Reddy, Besides the issues raised above, the work presented by Apazoglou et al. provides clear evidence that ELK-1 is a promising drug target for clinical depression. Interestingly, ELK-1 has been implicated in diseases comorbid with depression (Mayeux et al., Although the signaling pathways and molecules involved in depression have been studied extensively over the decades (Duman and Voleti, The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HS and handling editor declared their shared affiliation at time of review.


The spatiotemporal control of DSB formation occurs within a specialized chromosomal structure characterized by sister chromatids organized into linear arrays of chromatin loops that are anchored to a proteinaceous axis. Although SPO11 and its partner proteins required for DSB formation are bound to the axis, DSBs occur preferentially within the chromatin loops, which supports the “tethered-loop/axis model” for meiotic recombination. In this mini review, we discuss insights gained from recent efforts to define and profile DSB hotspots at high resolution in eukaryotic genomes. These advances are deepening our understanding of how meiotic recombination shapes genetic diversity and genome evolution in diverse species.Homologous chromosomes must pair and recombine to ensure faithful chromosome segregation during meiosis, a specialized type of cell division that occurs in sexually reproducing eukaryotes. Meiotic recombination initiates by programmed induction of DNA double-strand breaks (DSBs) by the conserved type II topoisomerase-like enzyme SPO11. A subset of meiotic DSBs are resolved as crossovers, whereby reciprocal exchange of DNA occurs between homologous chromosomes. Importantly, DSBs are non-randomly distributed along eukaryotic chromosomes, forming preferentially in permissive regions known as hotspots. In many species, including plants, DSB hotspots are located within nucleosome-depleted regions. DSB localization is governed by interconnected factors, including  Meiosis is a specialized cell division program that is essential for sexual reproduction in eukaryotes. During this program, replication of chromosomal DNA to form sister chromatids is followed by two rounds of cell division. Maternal and paternal chromosomes (homologs) segregate at the first division and sister chromatids segregate at the second division. Chromosome number is thereby halved and, in diploid organisms, meiosis culminates in the production of haploid progeny cells (gametes). Chromosome segregation during meiosis is imperative for the continuation of the species, as it enables the formation of a zygote that inherits the full chromosome complement in the next generation by fusion of a male and a female gamete  and mouse, DSB hotspots have been defined as loci meeting or exceeding given thresholds for Spo11-oligo density and physical size  -based peak-calling approach  in gene promoters   than in wild-type budding yeast cells, indicative of a negative feedback loop in which homolog engagement following DSB formation suppresses Spo11 activity and prevents further breaks  group participate in the assembly of the synaptonemal complex and promote crossing over    targeted to meiotic hotspots suppresses crossover recombination , Copia LTR and LINE-1 classes less than expected (Choi et al., Arabidopsis and mouse, however, fewer-than-expected maize DSB hotspots occur in Copia LTR and LINE retrotransposons (He et al., Despite SPO11-1-oligo depletion in Arabidopsis, significant overlap occurs between comparable classes of DNA elements and DSB hotspots, many of which are located within functionally conserved sequences (Choi et al., Arabidopsis hotspots may be more evolutionarily stable. Nonetheless, comparisons between eukaryotes indicate that repeated sequences may influence meiotic recombination initiation landscapes in related ways.Citing the hotspot paradox hypothesis, Yamada et al.  speculatATM in budding yeast, suppresses the formation of clustered DSBs in cis over distances of ~70–100 kb (Garcia et al., ATM activity allows DSBs to form independently of one another over ±20–100-kb distances, giving rise to DSB formation in neighboring regions at frequencies comparable to those expected by chance. Over distances of ± ~7.5 kb, by contrast, Tel1ATM inactivation permits the formation of adjacent DSBs significantly more frequently than expected, generating localized regions of “negative DSB interference” (Garcia et al., cis-interference suggests that hotspots within the same loop domain are “primed” for cleavage. Cooper et al. (ATM-dependent cis-interference, which restricts DSB formation to only one of the primed intra-loop hotspots. Spatial regulation of meiotic DSB formation also occurs in trans via a mechanism involving Tel1ATM and Mec1ATR, another DDR signal transduction kinase (Zhang et al., trans-interference inhibits DSB formation at the corresponding locus on its sister, its homolog or frequently both. This mechanism is thought to ensure that an intact template is available for DSB repair, and to prevent DSB formation at allelic loci on both homologs (Zhang et al., Meiotic DSB hotspots are identified by mapping the DSB landscape in a population of cells. This landscape reveals a continuum of variation within which loci with high probabilities of DSB formation may be detected (Pan et al., r et al.  speculatGenome-wide DSB mapping in different eukaryotes has revealed diversity with regard to the hierarchical combinations of factors that shape meiotic recombination landscapes and hotspots. These distinctions highlight the importance of studying DSB landscapes in diverse eukaryotes and beyond model organisms. Efforts to elucidate the mechanisms that determine DSB hotspot designation may inform genetic or epigenetic manipulations intended to reshape naturally constrained meiotic recombination landscapes. For example, the presence of hotspots in conserved genomic elements, such as nucleosome-depleted promoters, has relevance for targeting crossover recombination to specific loci in plants (Sarno et al., AT and IH wrote and edited the manuscript. AT created Table 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.


DNA methylation is an epigenetic marker that has been shown to vary significantly across different tissues. Taking advantage of the methylation differences between placenta-derived cell-free DNA and maternal blood, several groups employed different approaches for the discovery of fetal-specific biomarkers. The aim of this study was to analyse whole-genome fetal and maternal methylomes in order to identify and confirm the presence of differentially methylated regions (DMRs). We have initially utilized methylated DNA immunoprecipitation (MeDIP) and next-generation sequencing (NGS) to identify genome-wide DMRs between chorionic villus sampling (CVS) and female non-pregnant plasma (PL) and peripheral blood (WBF) samples. Next, using specific criteria, 331 fetal-specific DMRs were selected and confirmed in eight CVS, eight WBF and eight PL samples by combining MeDIP and in-solution targeted enrichment followed by NGS. Results showed higher enrichment in CVS samples as compared to both WBF and PL samples, confirming the distinct methylation levels between fetal and maternal DNA for the selected DMRs. We have successfully implemented a novel approach for the discovery and confirmation of a significant number of fetal-specific DMRs by combining for the first time MeDIP and in-solution targeted enrichment followed by NGS. The implementation of this double-enrichment approach is highly efficient and enables the detailed analysis of multiple DMRs by targeted NGS. Also, this is, to our knowledge, the first reported application of MeDIP on plasma samples, which leverages the implementation of our enrichment methodology in the detection of fetal abnormalities in maternal plasma. Using a novel doubleenrichment approach (MeDIP in combination with insolution hybridization enrichment followed by NGS), we have confirmed the presence of a set of 331 DMRs in multiple CVS, WBF and PL samples. The results of this study demonstrate that there is a clear distinction between the methylation levels of fetal and maternal DNA for the selected DMRs. The utilization of a novel doubleenrichment approach in this study provides a significant expansion in the number of fetalspecific biomarkers. This increase in fetal biomarkers sets the foreground for the implementation of our approach in the detection of the most common fetal aneuploidies.2.2.1.In total, 11 WBF, 10 PL and 11 firsttrimester CVS (11–14 weeks of gestation) were used in this study . The stuet al., Peripheral blood was collected from women donors into two 8-mL EDTAcontaining tubes. An average of 8 mL of plasma was isolated using a doublecentrifugation protocol as previously described  and the QIAamp DNA Mini kit (Qiagen), respectively, according to the manufacturer's instructions. DNA from PL samples was extracted using the QIAsymphony DSP Virus/Pathogen Mini Kit (Qiagen).2.2.DMR identification was initially performed on three WBF, three CVS and two PL samples using wholegenome MeDIPNGS. Based on specific criteria (see Section 3.2) we selected 331 DMRs that were found to be hypermethylated in the fetal tissues and hypomethylated in maternal whole blood and plasma. Confirmation of the methylation status of the 331 DMRs was performed on eight CVS, eight WBF and eight PL samples using MeDIP followed by targeted insolution enrichment and NGS.2.3.βglobin loci, as described previously , according to the manufacturer's protocol. The remaining MeDIP experiments  were performed using mouse anti5′methylcytosine monoclonal antibody , as described previously using 18–30 ng of genomic DNA  were used in order to confirm primer specificity. PCR reactions were performed using MyTaq HS DNA Polymerase , as described elsewhere , 10× blocking agent (Agilent), blocking oligonucleotides  the regions selected exhibited consistent DNA hypermethylation profiles in all CVS and hypomethylation in all the female nonpregnant tissues; (b) selected regions had preferentially more than two CpG dinucleotides in the DNA sequence; (c) potential DMRs that were in copy number variable regions or in repetitive element regions were excluded; (d) selected DMRs should be located 200 bp away from repetitive elements; and (e) the adjusted (Bonferroni correction) et al., P value <0·1 were considered for subsequent analysis. These bins were merged into consecutive regions (DMRs) after specific criteria selection and filtering.Pairwise genomewide methylation comparisons between CVS, WBF and PL were performed using the MEDIPS package . The response variable in this model is the read depth, which in our experiments acts as a proxy for the methylation level of each region, while the categorical variable is the sample type and consists of three levels . The additional random effect allows for different methylation variability between the different DMRs. Subsequent od Holm, .3.3.1.Three WBF, three CVS and two PL samples were subjected to wholegenome MeDIPNGS analysis to enable genomewide identification of fetalspecific DMRs. The resulting alignment files were used as input for the R package MEDIPS, where the differential coverage between two groups of samples (i.e. CVS vs. WBF and CVS vs. PL) was calculated. Using MEDIPS criteria (see Section 2.7.1), 3574 DMRs were identified in the CVS vs. WBF comparisons, of which 1888 regions showed hypermethylation in CVS and hypomethylation in WBF samples, while 1686 regions showed hypomethylation in CVS and hypermethylation in WBF samples . Similar3.1.1.P < 2 × 10−16 for all three pairwise posthoc tests (The overlap of the DMRs obtained from the two comparisons (WBF vs. CVS and PL vs. CVS) provided 1453 common fetalspecific DMRs that showed hypermethylation in CVS and hypomethylation in maternal samples. Those ranged from 100 to 2300 bp in length. Comparison of the overall methylation status of the aforementioned DMRs showed a clear distinction of the methylation status between CVS and maternal tissues (WBF and PL), with adjusted oc tests a). Overa3.2.To further ascertain and characterize the identified biomarkers, a subset of 331 potential fetalspecific DMRs  was selected based on specific criteria (see Section 2.7.1). In addition, selection was focused on autosomal chromosomes and on regions located in significant regulatory regions such as potential promoters, CpG islands (CGIs) and exonic (coding) regions. Specifically, 294, 64 and 73 DMRs were located within coding regions (67·7% in gene bodies and 32·3% in exons), potential promoters and CGIs, respectively . Resulet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The methylation status of the selected DMRs was also compared with previous studies that utilized methylation differences between fetal and maternal tissue for the identification of fetalspecific biomarkers. Common DMRs were found between our approach and DMRs identified using bisulphite conversion, methylationsensitive restriction digestion and microarrays (Old 4.In this study, we undertook the genomewide biomarker discovery of DMRs between fetal and maternal DNA and confirmed the presence of a subset of these DMRs by combining for the first time MeDIP with insolution targeted enrichment and NGS.et al., Also, this is, to our knowledge, the first reported application of MeDIP in plasma samples. Previous studies have employed MeDIP in order to characterize the methylation status of different tissues using large amounts of input DNA. We were able to overcome this limitation and successfully enrich and characterize the methylome of multiple plasma samples using modifications of an existing MeDIP protocol (Borgel et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Previous studies have employed different methods for the discovery of fetalspecific biomarkers using methylation differences between fetal and maternal DNA, including sodium bisulphite conversion, methylationsensitive restriction digestion or affinitybased techniques (Gitan et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Comparison of the selected DMRs with previous reports showed that the methylation patterns of several DMRs that were confirmed in our study are consistent with other methylationbased approaches (Old Based on the characteristics of the validated DMRs and due to the great potential of this approach to be utilized in the clinical setting for the detection of the most common aneuploidies, future work will focus on the identification and characterization of additional DMRs on chromosomes 13, 18 and 21. In addition, the discovery of DMRs across all autosomes using our approach opens the way for identifying and validating markers associated with subchromosomal copy number changes, such us clinically relevant microdeletions and microduplications.


Sci., 2018, 9, 4071–4082.Correction for ‘Thermoreversible crystallization-driven aggregation of diblock copolymer nanoparticles in mineral oil’ by Matthew J. Derry  The authors regret that in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


The FruM proteins have a 101 amino acids (a.a.)-long extension at the N-terminus which is absent from FruCOM. We suggest that this N-terminal extension might confer male-specific roles on FruM interaction partner proteins such as Lola, which otherwise operates as a transcription factor common to both sexes. FruM-expressing neurons are known to connect with other neurons to form a sexually dimorphic circuit for male mating behavior. We propose that FruM proteins expressed in two synaptic partners specify, at the transcriptional level, signaling pathways through which select pre- and post-synaptic partners communicate, and thereby pleiotropic ligand-receptor pairs for cell-cell interactions acquire the high specificity for mutual connections between two FruM-positive cells. We further discuss the possibility that synaptic connections made by FruM-positive neurons are regulated by neural activities, which in turn upregulate Fru expression in active cells, resulting in feedforward enhancement of courtship activities of the male fly.The  The genfru gene spans over 150 kb of the genome, and harbors at least four promoters, P1–P4  in females  of the number of X-chromosomes over the number of autosome pairs  is 1.0  or larger, the cell adopts the female fate, whereas, when the X/A value is 0.5  or smaller, the cell adopts the male fate. Counting of the relative numbers of X-chromosomes is performed by a transcriptional two-directional switch at the Sex-lethal (Sxl) gene, which is transcribed only when X/A exceeds 1.0. Thus the Sxl gene typically produces the Sxl protein only in XX individuals. The female-specific Sxl protein functions as a splicing regulator that induces female-specific splicing of its target, the transformer (tra) gene primary transcript. Only a transcript spliced in the female pattern can encode a functional Tra protein, which in turn induces female-specific splicing distinct from a default splicing that occurs in males in its targets, e.g., the primary transcript from the P1 promoter of the fru gene (fru-P1). Upon binding to the Tra target motif in the fru-P1 primary transcript  in neurons and neuron-restricted FruM (P1 products) expression do not necessarily mean that FruCOM is “non-neural.” Lee et al. (P1-dependent fru-positive neurons (hereinafter fru[+]-neurons) that are sexually dimorphic derive from multiple neuroblasts rather than a few dedicated neuroblasts: in fact, all type II neuroblast lineages bring about sexually dimorphic fru[+]-neurons  leads to an increase in the proportion of female-typical neurons at the expense of the male-type neurons in the mAL cluster  acts on Or47b olfactory neurons in mature adult males to boost their ligand sensitivity, making these elder males more successful in copulation than younger males (Lin et al., fru[+] neurons called P1 neurons (Chen et al., IR52a-expressing fru[+]-chemosensory neurons on the wing margin mediate input to stimulate male-male courtship (He et al., fru expression in the IR52a-sensory neurons as positive regulators for male-male courtship is also modulated by neural activities during the adult stage.The nervous system of holometabolous insects such as  Jallon, . Notably Jallon, . These uon Hall, . Recent fru gene produces two major protein groups: FruM and FruCOM. The FruM proteins have an N-terminal extension that FruCOM proteins lack, but we do not know how important this structural difference is in terms of the protein functions. The expressions of the FruM and FruCOM proteins are mutually exclusive both spatially and temporally (e.g., neuroblasts vs. neurons in the postembryonic nervous system; Sato et al., The robo1 gene, a direct target of FruM (Ito et al., robo1 in males, whereas truncated Lola inhibits full-length Lola’s action to repress robo1, with the result that the ipsilateral neurite forms in males but not females (Sato et al., fru mutations that lost FruCOM while retaining FruM proteins (Song et al., fru mutants (Song et al., Molecular studies on the actions of FruBM protein have revealed that this protein forms a transcriptional complex with an isoform of Lola, a pleiotropic transcription factor, to transcriptionally repress the robo1 gene is the sole established target of FruM (more specifically, FruBM; Ito et al., The The loss of FruM expression by the olfactory receptor mutations observed in adult pheromone neurons (Hueston et al., fru gene became potentiated to achieve a specialist role—i.e., a neural masculinizer role—by creating structurally distinct FruM proteins in addition to FruCOM proteins. We assume that FruM proteins specify coherent signaling pathways in the pre- and postsynaptic neuron pair to form a Fru-labeled neural circuit. This circuit is probably consolidated by the fly’s experience via use-dependent synaptic enhancement. However, this model describing how the actions of fru could induce adaptive changes in the nervous system of a fly during its individual lifetime remains to be tested in future experiments.These considerations prompt us to speculate that the DY: conceptualization, review and editing. KS and DY: funding acquisition and writing the original draft. JG: experimental work. KS: result analysis and visualization.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The electrophysiology of the paralimbic network (“default mode”) for self-awareness has drawn much attention in the past couple of decades. In contrast, knowledge of the molecular organization of conscious experience has only lately come into focus. We here review newer data on dopaminergic control of awareness in humans, particularly in self-awareness. These results implicate mainly dopaminergic neurotransmission and the control of GABAergic function directly in the paralimbic network. The findings are important for understanding addiction, developmental disorders, and dysfunctional consciousness. Self-awareness is a conscious experience with the self as an object. It is an essential part of conscious experience of the world, and is a tool for conscious self-monitoring and for controlling behavior. Its default may have grave consequences. The “neural correlates” of self-awareness have been studied by several investigators, including Devue and Brédart  and D’Aractive during self-awareness , we have realized that a paralimbic network is indeed instrumental in self-awareness: the network is not only 1 and D2 receptor agonist pergolide is effective in increasing confidence in seeing words and in improving performance in a forced-choice word recognition task. This demonstrates neurotransmitter regulation of subjective conscious experience of perception and provides the first direct evidence that dopamine is instrumental in conscious experience (Lou et al., Functional brain imaging has indicated that abnormal conscious experiences in schizophrenia, like hallucinations and delusions, are associated with abnormal dopaminergic neurotransmission (Changeux and Lou, The site of dopamine-GABA interaction for self-awareness in the human brain was unknown until recently. To clarify this issue, we have used a PET ligand for GABA receptor binding. With this ligand, we were able to detect changes in dopamine-induced GABA binding under different physiological conditions at well-defined brain sites (Lou et al., The GABA receptors are constructed as ligand ion channels. According to Stephens et al. , they arIn premature infants, functional MR imaging together with diffusion tensor imaging-based tractography has been used to study the relationship between performance on the Bayley Scales of Infant Development and early myelination (Cui et al., Newborn infants already show a form of “basic consciousness” by establishing rudimentary eye contact with their mother (Lagercrantz and Changeux, A recent review showed that the default mode network follows an inverse U-shape, where it is weaker in children and elderly and stronger in adults. Cognitive function is positively correlated with default mode network functional connectivity (Mak et al., In later childhood and adulthood, disturbance of the paralimbic network is linked to severe pathology. Thus, deficient GABA neurotransmission is prominent in disorders with poor self-awareness and self-monitoring such as addiction (Lingford-Hughes et al., To determine if deficient GABA neurotransmission in pathology could be a primary event or secondary to toxic or pathological effects in more complex disorders, we examined if deficient dopamine-GABA neurotransmission was present in a relatively mono-symptomatic disorder such as gambling disorder (Møller et al., dopamine. It is also a prominent site of cholinergic activity. Interaction between the cholinergic and dopaminergic system via GABA receptors has been well described (Changeux and Lou, The basal forebrain part of the system is not only regulated by The widespread dysfunction of self-awareness in disease is likely to be a consequence of the exceedingly high oxygen demand of the paralimbic network. The high oxygen requirement is considered to be the result of dense concentrations of parvalbumin GABAergic interneurons in the richly connected hubs of the paralimbic network. In particular, the fast gamma oscillations are susceptible to metabolic disruptions because of their high energy-demand (Kann et al., via GABA receptors in the paralimbic network. This finding has already resulted in a large and promising study of disabled persons with faltering self-awareness and consciousness (Sanz et al., Until recently, conscious experience and self-awareness were considered off-limits for the natural sciences. Neurobiological research shunned the “hard question” of how conscious experience and self-awareness arise from a physical basis. Hence, it has been fashionable to limit neuroscience to try to identify neural “correlates” of conscious experience and self-awareness. The risk is evident for arriving at two parallel worlds: a mental and a physical, without understanding how they interact. This limitation has impeded our understanding of the biological function of self-awareness, and how it may account for disease. We have here reported data showing that self-awareness and conscious experience can be disturbed by electrophysiological manipulation of the paralimbic network (Lou et al., HL conceptualized the review and wrote the initial draft. KR and J-PC participated in writing the manuscript.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.


We assessed whether the risk of various psychotic disorders and non-psychotic bipolar disorder (including mania) varied by migrant status, a region of origin, or age-at-migration, hypothesizing that risk would only be elevated for psychotic disorders.We established a prospective cohort of 1 796 257 Swedish residents born between 1982 and 1996, followed from their 15th birthday, or immigration to Sweden after age 15, until diagnosis, emigration, death, or end of 2011. Cox proportional hazards models were used to model hazard ratios by migration-related factors, adjusted for covariates.migrants: 2.20, 95% CI 1.96–2.47; aHRchildren : 2.00, 95% CI 1.79–2.25), affective psychotic disorders , and other non-affective psychotic disorders . For all psychotic disorders, risks were generally highest in migrants from Africa  and elevated at most ages-of-migration. By contrast, risk of non-psychotic bipolar disorders was lower for migrants  overall, and across all ages-of-migration except infancy , while risk for their children was similar to the Swedish-born population .All psychotic disorders were elevated among migrants and their children compared with Swedish-born individuals, including schizophrenia and schizoaffective disorder (adjusted hazard ratio [aHR]Increased risk of psychiatric disorders associated with migration and minority status may be specific to psychotic disorders, with exact risk dependent on the region of origin. The Cause of Death register was used to obtain the date of death and the Migration Register was used to record date of migration. Individuals who died emigrated for the final time, or who were diagnosed with a psychiatric outcome before age 15 were excluded.et al., We linked participants to the National Patient Register to determine a psychiatric diagnosis in either inpatient or outpatient settings according to the International Classification of Diseases, 10th revision [ICD-10]. We studied four psychiatric outcomes: schizophrenia or schizoaffective disorder ; affective psychotic disorders , other non-affective psychotic disorders  and; bipolar disorder or manic symptoms without confirmed psychotic symptoms . For individuals who received diagnoses on multiple visits to in- or outpatient services, we adopted a hierarchal classification system, informed by clinical expertise  and consistent with earlier research  children of migrants if they were born in Sweden with one or both parents born outside of Sweden, and; (iii) Swedish-born if they were born in Sweden to two Swedish-born parents. The region of origin was defined by Statistics Sweden as Sweden, Finland, other Nordic countries, other European countries, Asia and Oceania, the Middle East, Africa, North America, South America, and unknown, based on country of birth. For migrants, we categorized age-at-first-migration into five groups: infancy (0–2 years), early childhood (3–6 years), middle childhood (7–12 years), adolescence (13–18 years) and early adulthood (19–29 years). We considered sex, current age, and follow-up period (see below) as a priori confounders. We also controlled for income in supplemental analyses, obtained from the Longitudinal Integration Database for Health Insurance and Labour Market Studies [LISA]. Since 1990, LISA has estimated total disposable family income from all sources each year , weighted for family size. As age 16 is the earliest an individual is included in the LISA, for most participants, we utilized information on their family income at age 15 via linkage to their parents, including adoptive parents where relevant. For migrants arriving in Sweden after age 15, we included their family income as first recorded in the LISA database. Where no income could be estimated, participants were excluded from these analyses (see below). We calculated income quintiles in each year for the entire population and assigned this value to participants in the year of their cohort entry. This method implicitly takes income inflation into account.We defined migrant status according to information in the Total Population and Multi-Generational registers. Participants were classified as (i) et al., et al., We first generated descriptive characteristics of the sample. Next, for each outcome, we investigated whether incidence varied by migrant status, region of origin, and age-at-migration using Cox proportional hazard regression. We estimated unadjusted and adjusted hazard ratios [aHR] and 95% confidence intervals [95% CI] for each exposure. To account for possible period effects , we split the data into 5-year bands of calendar time , modelled as a time-varying covariate. We also modelled age as a time-varying covariate , given risk of psychiatric disorders varies substantially by age , being highest amongst the Swedish-born population (59.2%) and lowest amongst migrants (45.0%). As expected, migrants with psychiatric diagnoses were more likely to be in the lowest income quintile (30.2%) compared to 5.3% of Swedish-born, and 8.6% of children of migrants . Additional cohort characteristics are presented in We identified 1 796 257 individuals who contributed over 12.79 million person-years of follow-up . Of thesRisk of all psychotic disorders was elevated among migrants and their children compared with Swedish-born individuals, after adjustment for confounding. For example, risk of schizophrenia and schizoaffective disorder was approximately doubled in migrants  and their children , with similar results obtained for other non-affective psychotic disorders . Risk ofThe excess risk of psychotic disorders in migrants persisted for participants from all regions of origin . Thus, fadolescence: 2.38, 95% CI 1.79–3.16; aHRearly adulthood: 2.77, 95% CI 1.64–4.69). For other non-affective psychotic disorders risk was elevated at all ages-of-migration, except early adulthood . Risk of affective psychosis was elevated among those who migrated in infancy , adolescence  and early adulthood , but not childhood. In contrast, bipolar disorder without psychosis was associated with lower risks at all ages-of-migration, except during infancy .Risks of all psychotic disorders were elevated across most ages-of-migration compared with the Swedish-born population . For schThese associations were partially attenuated following adjustment for income, but this did not substantially alter our findings (online Supplementary Tables S1–S3). A sensitivity analysis excluding possible prevalent cases in migrants  did not change the pattern of our results (online Supplementary Tables S4–S6). Schoenfeld tests and examination of log-log residual plots revealed no evidence of departure from proportionality across our main exposures for schizophrenia or affective psychosis (online Supplementary Table S7). These tests did suggest a departure from proportionality for our other two outcomes, but log-log residual plots revealed these effects were small and the departure from a zero-slope was negligible .This is the first longitudinal study to investigate how migrant status, region of origin, and age-at-migration affect the risk of schizophrenia, schizoaffective disorder, affective psychotic disorders, other non-affective psychotic disorders, and non-psychotic bipolar disorder. We discovered distinct signatures of risk, which varied according to the presence or absence of psychosis. Thus, migration-related exposures substantially increased the risk of psychotic disorders, albeit with more attenuated effect sizes for affective psychoses. In contrast, non-psychotic bipolar disorder showed a markedly different pattern, with generally lower risks across our three migration-related exposures compared with the Swedish-born population. Our results were impervious to adjustment for income and were unlikely to be explained by prevalent cases amongst migrants, or by age, sex, or period effects.et al., et al., We used to register data from a nationwide cohort of nearly 1.8 million people, with nearly complete coverage, and virtually no loss-to-follow-up. Clinical recording of schizophrenia spectrum disorders is known to be highly complete in the registers with good validity , which may have introduced bias vis-à-vis residual confounding; from the available data, however, any confounding effect appeared modest, and income may lie on the causal pathway between migration and mental health, making adjustment inappropriate.et al., et al., et al., et al., et al., Further sensitivity analyses suggested our results were unlikely to be attributable to prevalent cases amongst migrants, arguing against selective migration, consistent with previous observations (Selten et al., et al., et al., et al., et al., et al., et al., et al., Our results are consistent with previous research demonstrating an increased risk of schizophrenia-spectrum disorders among migrants and their children (Lloyd et al., et al., et al., Comparisons with previous findings with respect to age-at-migration and psychotic disorders require careful attention. In one study (Veling et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The different signatures of risk we observed between psychotic and non-psychotic disorders with respect to migration suggest that exposure to adversities related to migration and minority status could act specifically on psychotic rather than affective pathways. Emerging research supports the hypothesis that psychotic and non-psychotic bipolar disorder may have distinct neurodevelopmental origins (Murray et al., et al., et al., Repeated exposure to factors associated with migration – including social disadvantage, trauma or discrimination experienced prior to, during, or following migration – may also prime individuals to expect a greater level of threat from the environment (Reininghaus et al., et al., et al., et al., et al., We should also give credence to another possible explanation of our results: misdiagnosis. It has been suggested that higher rates of psychotic disorders in some ethnic minority groups are due to diagnostic bias, with people from the majority group less likely to receive a stigmatizing diagnosis such as schizophrenia compared with bipolar disorder (Schwartz and Blankenship, The shared patterns of risk across three categories of psychotic disorders with respect to various migration-related exposures suggest that migration may act specifically on psychotic rather than affective pathways to disorder. This provides potentially important clues to the aetiology of serious mental illnesses and should galvanise efforts to identify the exact social, environmental, and biological determinants of this preventable, gross inequality experienced by migrant and minority populations (Kirkbride,


Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer’s disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential. Tau is a microtubule-associated protein  assembled head-to-tail, which form a pseudo helical lattice , 269–284 (in R2), and 300–313 (in R3) is proposed, based on the attenuation of Tau NMR signal upon addition of paclitaxel-stabilized MTs  was used to compare Tau binding mode to Taxol-stabilized MTs and to tubulin when Tau is used as the sole inducer of the polymerization  of RB3 . Change in the isoform ratio has an indirect impact on MT assembly and the dynamics of the MT networks because the 3R Tau is known to have a lower capacity of MT stabilization and tubulin polymerization than the 4R Tau (Scott et al., in vitro assays. Surprisingly, R406W Tau is reported to be the most affected, despite the fact that the mutation is not near the MTBR (Hong et al., in vitro assays. However, there is no agreement on the extent of the specific effect of each of these mutations (Barghorn et al., Tau protein is encoded by the in vivo using Paclitaxel treatment in AD mouse models (Cash et al., One of the proposed strategies in seeking AD treatment consists of compensating the loss of the MT-stabilizing Tau function (Cash et al., Drosophila model of tauopathy (Quraishe et al., MT stabilizing peptides are another option chosen to restore MT stability (Quraishe et al., Drosophila, HDAC6 null mutation rescues MT defects through increased tubulin acetylation (Xiong et al., Finally, MTs could be stabilized not by mimicking MAP function, but by modulating MT PTMs, which have a crucial role in MT dynamics. Levels of total α-tubulin are reduced by approximately 65% in AD-patient brains compared to age-matched control brains but the relative ratio of acetylated tubulin is increased by approximately 31% compared to the controls (Zhang F. et al., Overall, Tau implication in neurodegenerative diseases, and other diseases where MTs play an important role, clearly shows the interest of the Tau/MTs interaction as a potential target for intervention (Pachima et al., The content of the manuscript was drafted and edited by all authors.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.


N- and O-sulfation and N-acetylation patterns. Its low concentration in crude extracts, containing other heterogeneous GAGs, leads to a purification process that is very complex, and which is well-guarded by manufacturing companies. Van der Meer et al. [The seven reviews and the eleven articles in this special issue provide an updated survey of recent research and developments in the ever-growing field of heparin, along with low molecular weight heparins (LMWHs) and glycosaminoglycans (GAGs). The complex biosynthetic process, and the variability of tissues and animal species, has led to heparin chains heterogeneous in size and both r et al. , throughAs a consequence of the “heparin crisis” in late 2007, an updating of heparin pharmacopeia monographies in the USA and the EU with new NMR and HPLC tests increased the quality control capabilities for crude and API porcine heparins, with some limitations in detecting the addition of non-porcine crude heparins or other GAG-like contaminants. An improvement to this process  [Lima M. et al.  reviewedTwo Italian teams   review tThe interactions and binding sites of heparin/HS with BMPs and cytokines of the TGF-β superfamily are reviewed by Rider C. and Mulloy B. . The actIn a collaborative study of 6 laboratories in the USA, Europe and India  [An article   reports 2 cells.Three Italian groups   exploredA collaborative study by an Israeli and Italian team   led to tThe review by authors from the Departments of Neurosurgery at two US Universities   suggestsA Belgian team (Minet V.)  reviewedCompositional analysis of both LMWH Dalteparin   and Danacis-Pt, have been studied “in vitro” and in xenograft models  [cis-Pt resistance in a cancer-resistant cell line. In vitro preliminary studies show that Tinzaparin has no effect on cis-Pt accumulation in cis-Pt-resistant xenografts but strongly increases the Pt content in non-cis-Pt-resistant ones.The interactions of Tinzaparin, a LMWH used as antithrombotic prophylaxis in clinical oncology with  et al.) . In vitrComponent fractionation of Semuloparin, an ultra LMWH obtained by a depolymerization process preserving the AT binding region, has allowed a team at Sanofi   to isola®, have also been defined on the basis of a determination of single-crystal X-ray conformation. Quantitative NMR were also used, confirming that this method shows intrinsic robustness for content determination  [An extended physico-chemical characterization of Fondaparinux, the synthetic α-methyl glycoside of the AT binding pentasaccharide, and the active ingredient of the anticoagulant drug Arixtra et al.) .A team from Heidelberg University   has syntAuthors from the Trondheim University (Norway) (Arlov Ø. and Skjåk-Bræk G.)  review t


Plants are the primary source of human food and animal feed and also form the basis of numerous industrial and pharmaceutical products. This special issue reflects the diversity of modern research in the field of plant molecular genetics. It covers a wide range of modern technologies and scientific approaches that aim to achieve a better understanding of the various aspects of molecular mechanisms underpinning the key traits in major crops and other commercially important plant species. Phytophthora capsici in Chili Pepper” reported on 11 novel molecular markers targeting resistance to the soil-borne pathogen Phytophthora capsici in chili pepper. The markers developed through high-resolution melting analysis, represent an excellent tool for marker-assisted selection. Another type of molecular markers, SSR, was used for the study of genetic diversity in cultivated and wild melon . The authors found enormous genetic variability within the collection, and deployment of the well-known SSR markers enabled the generation of a phylogenetic tree showing the relationships between melon accessions. An investigation presented by R. Ben Ayed and A. Rebai  revealed a significant link between the five SNP markers analysed and the biochemical composition and quality of olive fruits.Three papers in this issue deal with the development, study, and application of molecular markers in plant breeding. N. Kim et al. in “Development of Clustered Resistance Gene Analogs-Based Markers of Resistance toLinum usitatissimum L.)” presented by G. S. Krasnov et al. reported valuable results from RNAseq analysis and candidate gene identification for flax genotypes tolerant or sensitive to a high concentration of Al. The authors' conclusions on glutathione metabolism, oxidoreductase, and transmembrane transporters can be further applied both in academic study and in practical breeding. Very few investigations have been conducted on plant growth in the absence of gravity during space-shuttle orbit around our planet. The paper presented by O. Yu. Yurkevich et al. (“Molecular Cytogenetics of Pisum sativum L. Grown under Spaceflight-Related Stress”) describes a chromosome analysis of pea progenies derived from plants grown in space using a novel FISH approach. Minor chromosome rearrangements were observed in response to “spaceflight-related stress,” which could lead to better guidelines for biological experiments with plants during future space-shuttle missions.Several of the presented reports are related to the genetic control of plant response to abiotic stresses. Drought is one of the major challenges being faced in agriculture. The paper presented by N. M. Kamal et al. (“Stay-Green QTLs Response in Adaptation to Post-Flowering Drought Depends on the Drought Severity”) provides important findings on QTLs identified in sorghum grown in Sudan (Africa) under drought conditions. The presented data, generated in cooperation with the International Atomic Energy Agency (IAEA), Austria, can be used for the improvement of grain yield in drought-prone environments using a “stay-green” approach through the application of QTL analysis. Tolerance to aluminum toxicity represents an entirely different type of abiotic stress, but this too is an important agricultural problem, especially in acidic soils. The paper “Aluminum Responsive Genes in Flax .” This is an extremely intricate cytogenetic study of the centromeric nucleosomes in dividing cells. The authors presented some critical results from CENH3 gene analysis, a central player in this very complex cytological trait, offering promising potential outcomes.IAEA also supported a study on the generation of mutant bread wheat with improved micronutrient content in the grain. S. Kenzhebayeva et al. presented their paper “Mutant Lines of Spring Wheat with Increased Iron, Zinc, and Micronutrients in Grains and Enhanced Bioavailability for Human Health,” where stable breeding lines of wheat were produced from the M Phaseolus beans using diverse characteristics derived from the seed morphology of these species. L. Sinkovič et al. presented their paper “Morphological Seed Characterization of Common (Phaseolus vulgaris L.) and Runner (Phaseolus coccineus L.) Bean Germplasm: A Slovenian Gene Bank Example,” which contained an interesting comparison of seeds, accompanied by color images. The presented findings are essential for a better understanding of the wide diversity of bean species, which can be directly used for genetics and breeding of these nutritionally important crop varieties. In contrast, another paper “In Silico Genome-Wide Analysis of the ATP-Binding Cassette Transporter Gene Family in Soybean (Glycine max L.) and Their Expression Profiling,” presented by A. K. Mishra et al., reported on computer analyses of available databases concerning the important gene family of the ATP-binding cassette transporter, in soybean. The authors provided a very accurate and detailed analysis of all identified genes and protein isoforms, arranging these new findings within the context of other pertinent information and comparisons.A remarkable level of genetic polymorphism was found in a germplasm collection ofP. Soundararajan et al. presented a detailed review entitled “Insight on Rosaceae Family with Genome Sequencing and Functional Genomics Perspective.” The Rosaceae family is one of the most significant plant families, and the fruits, berries, flowers, and many other important parts of these plants are familiar to each of us from early childhood. The authors have provided a comprehensive overview on the modern level of genetic knowledge and technology employed in comparative genomics and functional genome analysis for many Rosaceae species. Whole genome sequences in this plant family are so important for genetics, breeding, and agriculture that the presented review will surely be of broad general interest to future investigations in this area.In conclusion, the review presented by N. Borisjuk et al., entitled “Genetic Modification for Wheat Improvement: From Transgenesis to Genome Editing,” summarizes the attempts and results of wheat improvement using various genetic engineering approaches. The authors reflect the progress achieved since the dawn of genetic transformation up until the recent emergence of precise modern genome editing using CRISPR/Cas9 and related systems in wheat. This comprehensive review can provide a strong stimulus for both current and future researchers to pursue work on wheat improvement, and deploy all available modern technologies to secure a sustainable supply of quality agricultural produce for our growing global population.Yuri ShavrukovNikolai BorisjukNarendra K. Gupta


Several physiological processes such as fertilization, apoptosis, muscle contraction, neuronal activity, and sensory perception are based on the spatial and temporal variation in intracellular Ca2+ and rely on a class of proteins that specifically respond to these highly dynamic stimuli. Neuronal calcium sensor (NCS) proteins are exclusively expressed or enriched in neurons, and their structural and biochemical diversity reflects the multiplicity of their biological roles, which include control of gene transcription, neuronal growth and survival, channel and receptor regulation, neurotransmitter release, synaptic plasticity, and regulation of enzymatic activity. Neurological disorders and neurodegenerative diseases are increasingly associated with altered functions of specific NCS proteins. This Research Topic includes original articles and reviews that provide an interdisciplinary collection of up-to-date biochemical and biophysical research on NCS proteins and their established and novel biological roles in normal and altered  conditions.The precise detection and regulation of free intracellular CaRatai et al. show that NCS-1 plays an important role in adipocyte function and its deficiency gives rise to obesity and diabetes type 2 in adult mice, thus suggesting a potential genetic link between psychiatric disorders and the risk of being obese. The progressive degeneration of dopaminergic neurons within the Substantia nigra is the hallmark of Parkinson's disease and causes its motor symptoms. The link between dopamine release and NCS-1 and its possible implications in Parkinson's disease has been reviewed by Catoni et al., who summarize the role of the interplay between Ca2+ and dopamine signaling in neuronal activity and cell death. Simons et al. provide novel data at the transcript level that link NCS-1 deficiency to impaired ATP-production and elevated metabolic stress in Substantia nigra dopaminergic neurons in mice. An overview of other novel roles of NCS-1 is provided by the review of Nakamura et al., which focuses on both the neuronal system and the heart, presenting NCS-1 as a regulator of voltage-gated Ca2+ channels, ionotropic dopamine receptors, and inositol 1,4,5-trisphosphate receptors. A complex interplay between Mg2+, Ca2+ and Zn2+ binding to NCS-1 leads to the appearance of multiple protein conformations and modulate its functional status as suggested by Tsvetkov et al., who demonstrate that NCS-1 binds Zn2+ with differential affinities favoring either the interaction with targets or protein aggregation. Choudhary et al., who focus on optical tweezers investigations to reveal a complex folding mechanism underlaid by a rugged and multidimensional energy landscape, provide insight into the structural and mechanistic details of the folding and misfolding processes of NCS-1 at the single molecule level.Neuronal calcium sensor-1 (NCS-1) is highly conserved from yeast to human, and it has been implicated in a number of psychiatric conditions including autism, bipolar disorder, schizophrenia, and X-linked mental retardation. At odds with other members of the NCS family, NCS-1 interacts with several cellular targets, which is reflected by a variety of roles. 2+-binding motifs and amino acids involved in target recognition has been investigated by Marino and Dell'Orco, who suggest for NCS-1, recoverin and GCAP1 an evolution-driven correlation between the amino acids mediating many persistent interactions and their conservation. An inter-domain interaction triggered by Mg2+-binding is essential for the ubiquitous Ca2+ sensor CIB2 to reach a fully functional conformation, as shown by Vallone et al., who found that the apparently conservative E64D mutation associated with Usher Syndrome 1J and non-syndromic hearing loss prevents this long-range allosteric mechanism. Mutations in calmodulin, another ubiquitous Ca2+ sensor, were long thought to be incompatible with life due to the completely conserved amino acid sequence across all vertebrates. The review by Jensen et al. provides an overview of the human missense mutations found in patients with severe cardiac arrhythmias.The importance of allosteric interactions between Ca2+ dependent. The review by Ames summarizes the results of recent studies on GCAPs, VILIP1 and recoverin dimerization. A paradigmatic example of the myristoyl-switch protein, recoverin is involved in the regulation of the phototransduction cascade in rods and cones as reviewed by Zang and Neuhauss. Four different recoverin isoforms exist in zebrafish photoreceptors. Their specific Ca2+-sensing properties and conformational changes have been investigated by Elbers et al., who found that binding of Ca2+ leads to less pronounced structural rearrangements compared to the bovine ortholog indicating either a modified Ca2+-myristoyl switch or no switch at all. Novel roles for recoverin in health and disease-associated conditions have been found by Zernii et al. who provide in vitro and in vivo evidence that illumination of the mammalian retina leads to the accumulation of disulfide dimers of recoverin, which are thought to favor light-induced oxidative stress and photoreceptor apoptosis.Many NCS proteins form dimers, a process that is often Ca2+. Rehkamp et al. present a chemical cross-link/mass spectrometry investigation on the interaction between GCAP2 and GC-E, while Wimberg et al. investigate five recently identified GC-E mutants associated with Leber Congenital Amaurosis, a cone-rod dystrophy, finding severe alteration of the cGMP synthesis. Another prototypical guanylate cyclase, the atrial natriuretic factor receptor guanylate cyclase is found to be regulated by the Ca2+ sensor neurocalcin δ and hormone ANF via two distinct and non-overlapping transduction modes, as elucidated by Duda et al.The complex between GCAPs and the retinal guanlylate cyclases is a crucial component of the vertebrate phototranduction machinery as it regulates the interplay between the second messengers cGMP and Ca2+-binding proteins have been found to be involved in the complex etiology of psychiatric disorders. By combining a stereology-based approach and molecular analyses Lauber et al. investigated the involvement of parvalbumin in autism spectrum disorder, finding a dysregulation of its expression in Cntnap2 knockout mouse. The review by Mundhenk et al. presents a detailed structural and biophysical characterization of the Ca2+-sensor proteins caldendrin and calneuron-1 and−2, focusing also on their cellular function and their role in neuropsychiatric disorders.Ca2-domain protein otoferlin in modulating the Ca2+-triggered exocytosis at the ribbon synapse in mouse inner hair cells is proposed by Takago et al. by a combination of electrophysiology and biochemical analyses. The importance of Ca2+-binding proteins in regulating the fundamental process of exocytosis and synaptic coupling is emphasized in the review by Maj et al., focusing on secretagogin and its novel roles in developing and adult neuronal cells and Bornschein and Schmidt, focused on synaptotagmin 1 and 2 and their role in presynaptic voltage-gated Ca2+ channel regulation.A role for the multi CPeraza et al. identifies by biochemical and biophysical investigations a novel ligand of DREAM that modulates Kv4 potassium channels currents, with consequences that are relevant for physiology and disease. The role of DREAM/KChIP3 in pain transmission and its possible involvement in emotional processing was studied by Guo et al., who assess the pain sensitivity and negative emotional behaviors of Kcnip3−/− rats and find a possible role for the protein in central nociceptive processing. Novel tools to regulate the role of DREAM in the endoproteolysis of endogenous presenilin-2 in mouse brain are presented by Naranjo et al., who suggest that the interaction between the two proteins may have a therapeutic potential in Alzheimer's disease. Finally, the review by Néant et al. summarizes the current knowledge regarding Ca2+ signaling in quiescent glioblastoma stem-like cells and discussed how Ca2+ via KCNIP proteins may affect gene expression in glioblastoma.Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3 exerts multiple functions, including the regulation of A-type outward potassium currents. The contribution by Taken together, this Research Topic delivers new visions to our knowledge on NCS proteins and will stimulate future research. We wish to thank all the authors for having submitted papers of high quality and all the reviewers that contributed with constructive and fruitful suggestions.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mops condylurus) trapped in the city of N’Zerekore and in a nearby village.In 2018, a previously unknown Ebola virus, Bombali virus, was discovered in Sierra Leone. We describe detection of Bombali virus in Guinea. We found viral RNA in internal organs of 3 Angolan free-tailed bats ( Ebolavirus (family Filoviridae), Bombali virus (BOMV), was discovered in Sierra Leone (Chaerephon pumilus (little free-tailed bat) and Mops condylurus (Angolan free-tailed bat). Both bat species are widespread in Africa, and their ranges include countries where human Ebola virus disease (EVD) outbreaks have occurred. Forbes et al.  and in a pool of liver and spleen tissues (Ct 28.2) of an M. condylurus bat from a school in the city of N’Zerekore in March 2019  in China, and another study showed that 3 distinct groups of unclassified filoviruses are circulating in Eonycteris spelaea and Rousettus spp. fruit bats in China (Marí Saéz et al. (EBOV IgG was detected in the human population of Sierra Leone in 2006, 8 years before the EVD outbreak began in that country (M. condylurus bats provides additional confirmation that BOMV could amplify in these bats and that this species is a reservoir host of this virus.Although BOMV had been detected in the northern part of Sierra Leone (Mops condylurus bats, Guinea.Additional information on Bombali virus in


Dear Editor,in vitro techniques of liver . In recal., 2013; Grinberal., 2013; Leist eal., 2013; Ghallabal., 2013), kidneyal., 2013; Jiang eal., 2013; Su et aal., 2013; Valenteal., 2013; Lee et al., 2013), neuronal., 2013; Yang etal., 2013; Colaianal., 2013; Sisnaisal., 2013) and deval., 2013, 2016[22al., 2013; Waldmanal., 2013). Stem cIndices have been developed to identify a possible hazard of developmental toxicity based on genome-wide expression data. A precondition is the definition of so-called developmental genes of a test system. Developmental genes are up- or down-regulated during the differentiation process in the absence of test compounds. Developmental potency describes the fraction of all developmental genes, whose expression is altered by test compounds (Shinde et al., 2017; WaldmanMuch progress has been achieved in analyzing disturbed developmental processes. However, it still remains challenging to differentiate stem cells to adult cell types that closely resemble the corresponding mature cell type in vivo (Godoy et al., 2015; Cameronin vitro, but there is still a long way to go until the techniques are ready for routine use and to replace animal studies in pharmacology and toxicology. Stem cell-based alternative test methods offer powerful tools to analyze developmental toxicity The author declares no conflict of interest.


Candida albicans and Staphylococcus aureus interactions, one from the Candida perspective  [Staphylococcus perspective (Todd and Peters) [Aspergillus fumigatus and Pseudomonas aeruginosa  [Candida albicans and Pseudomonas aeruginosa (Fourie and Pohl) [Cryptococcus neoformans (Mayer and Kronstad) [Candida albicans and the oral bacterial microbiome that contribute to the pathogenesis of oral candidiasis (Bertolini and Dongari-Bagtzoglou) [We would like to thank all the contributors to the Special Issue on Fungal–Bacterial Interactions—Current Knowledge and Future Perspectives. In total, seven 7) reviews/perspective papers were published in the issue. A wide range of various fungal–bacterial interactions were covered. Two papers covered  et al.) , and the Peters) . Another et al.) . Other snd Pohl) , bacterironstad) , and dystzoglou) . Lastly, reviews/


Gracilibacteria (formerly GN02) and Saccharibacteria (formerly TM7) of the recently described Candidate Phyla Radiation  and not to Gracilibacteria as reported by Espinoza et al. (Saccharibacteria genomes showed a 7-fold increase in the number of single-copy core genes (To briefly demonstrate their composite nature, we refined some of the key Espinoza et al. MAGs through a previously described approach  and the a et al. . A pangere genes . These fre genes . Composire genes  recruiteCo-assembly of a large number of metagenomes that contain very closely related populations often hinders confident assignments of shared contigs into individual bins. Nevertheless, even when proper refinement is not possible, reporting composite MAGs as single genomes should be avoided. As of today, highly composite Espinoza et al. MAGs (The rapidly increasing number of MAGs in public databases already competes with the total number of microbial isolate genomes , and inc7–


Ad-HBV is a product T101) aiming to treat chronic HBV firstly developed by Transgene S.A., France then by Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China in China. So, in the originally published article [01 aimingAdditionally, in the “Acknowledgements” section in the originally published article, “The Ad-HBV were a kind gift from Xia Meng (Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China). We want to thank Zhiming Wang and Xiaomin Wang (Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., Tianjin, China) for teaching neutralization activity detection of anti-Ad antibodies” should be replaced by “We want to thank Transgene Tasly (Tianjin) Biopharmaceutical Co., Ltd., to provide us the opportunity to participate in the non-clinical safety assessment of T101, and most of the research work appeared in this paper came from the non-clinical safety assessment of T101”.


Protein kinases represent a large and diverse multi-gene family of enzymes, which catalyze the transfer of the γ-phosphate group from its natural co-substrate adenosine triphosphate (ATP) to a free hydroxyl group of an amino acid side chain. They are involved in numerous cell signaling pathways. Diseases might arise when deregulation or mutation of a kinase takes place. Therefore, kinases are promising drug targets for the treatment of several disorders ranging from cancer, autoimmune pathologies, inflammation, or neurodegenerative diseases. After the approval of imatinib in 2001, 38 kinase inhibitors were introduced to the market by the beginning of 2018. Numerous kinase inhibitors are currently in clinical trials.Structural data—e.g., from the structural genomics consortium (SGC)—as well as the high-quality kinase probe programs from the Chemical Probe Portal and the SGC kept pushing forward both the identification of new kinase targets and the design of novel kinase inhibitors within the last years. The numbers of reported type I½, type III, and type V kinase inhibitors as well as covalent kinase inhibitors have continuously increased in the last few years.This Special Issue deals with the design and development of novel inhibitors addressing different kinases as well as with strategies to inhibit kinases. The Special Issue consists of eight original research articles and four reviews, as briefed below.Brenner et al. described the efficacy of six inhibitors of CDC25, dual-specificity phosphatases that activate cyclin-dependent kinases, on acute myeloid leukemia cells isolated from patients . The resIn their study, Halekotte et al. designed and synthesized optimized 4,5-diarylimidazoles as ATP-competitive inhibitors of CK1δ and discussed their structural relation to the p38α mitogen-activated protein (MAP) kinase . The resb]pyrazine-based FGFR inhibitors starting from a c-Met inhibitor [Zhang et al. described the ligand-based design of pyrrolo2,3--bpyrazinAn analysis of kinase inhibitors and their specificity with respect to their scaffold diversity is described by Dimova and Bajorath . Yang et al. reported the synthesis of novel pyrrolidone-fused methylpyrrole derivatives and their biological evaluation as potential multi-target tyrosine kinase receptor inhibitors . An exteIn their study, Tegethoff et al. showed that 1-methylisoindigo is a Stat3-related inhibitor of various tyrosine kinases . The autThe metabolic stability of two potent pyridinylimidazole-based p38α mitogen-activated protein (MAP) kinase inhibitors ML3403 and LN950 was improved by Heider et al. . The novThe number of both approved kinase inhibitors and kinase inhibitors in clinical trials increases continuously. In their research article, Carles et al. presented an extensive analysis of their monthly-updated Protein Kinase Inhibitor Database (PKID) . The PKIIn their review, Lee at al. summarized recent advances in the targeting of the p38α MAP kinase as a potential strategy for the treatment of Alzheimer’s disease . InhibitLee et al. discuss the pro- and anti-tumorigenesis functions of senescence as well as the roles of kinase modulators in these processes . An overIn their comprehensive review, Cheng et al. summarized the recent progress of MEK inhibitors and focused on marketed MEK inhibitors and inhibitors in clinical trials . ClinicaSchmidt et al. presented a timely review on the two members of the WEE kinase family, WEE1 and PKMYT1 . Both ki


This research describes how Department of Veterans Affairs (VA) and non-VA home-based long-term care (LTC) environments prepared for and secured the safety and wellbeing of elderly and disabled persons in the wake of Hurricane Maria, which struck Puerto Rico on September 20, 2017. In-person interviews, home visits, and field observations were conducted in Puerto Rico from January-March 2019. Staff from three of the VA’s Caribbean Healthcare System’s home-based LTC programs were interviewed, as well as caregivers in non-VA LTC environments. Veterans, family members of Veterans, family members of VA caregivers, and community members with expertise in disaster recovery were also interviewed for a total of N = 58 interviews and N = 12 home visits. Preliminary results of qualitative content analysis show VA and non-VA LTC environments prepared residents and caregivers for Hurricane Maria through providing education and recommendations in advance, including having enough medications and food on hand. Participants described Hurricane Maria not simply as a disaster but a “crisis” and a storm unlike any they had ever experienced. The interconnected nature of the VA seemed to provide a stronger support network compared to non-VA environments that were often independently run. Health of Veterans and non-Veterans was reported to be mostly stable during recovery. Perspectives from VA and non-VA entities allowed for a fuller picture to emerge around how Hurricane Maria impacted home-based LTC environments in Puerto Rico. This research can inform policies and procedures for such environments caring for elderly and disabled populations in areas prone to disasters.


The tumor microenvironment (TME) constitutes an important component of any cancer. The histology of TME consists of a series of normal resident cells and a variety of recruited cells, which are involved in complex and dynamic interactions with cancer cells . These iSachs et al., describe a novel method for overcoming this problem by demonstrating, in different cancer models, the ability of new small molecules to reverse chemotherapy resistance. Munoz et al., address the problem of chemoresistance of glioblastoma multiforme (GBM), a fatal malignancy of the central nervous system. They show that MiR-93 and−193 are specifically expressed in temozolomide (TMZ) resistant glioblastoma cells (GBM), including resistant neurospheres from a patient with TMZ resistance. Part of the resistance occurs by miR-93 and−193 decreasing Cyclin D1 to reduce GBM cycling. This may open up avenues for new therapeutic approaches to reverse such chemoresistance . Besides chemoresistance in GBM, expansion of residual glioma cells is also a challenge in the context of chemotherapy. Work by Tsidulko et al., indicates that conventional anti-glioblastoma therapy such as TMZ affects proteoglycan structure and composition of normal brain tissue. Proteoglycan alteration may be involved in brain extracellular matrix (ECM) deterioration and the development of residual glioma cells .In this Research Topic, diverse facets of the TME are addressed, including different tumor types and tissue specificity of TME . RecentlLadomersky et al., demonstrate a significant association between advanced age of patients and immunosuppression in the circulation and central nervous system. Based on their findings, the authors propose that normal human aging suppresses immune surveillance and immunotherapeutic efficacy against glioma, and thus, contributes to GBM initiation and progression .Although immune checkpoint blockade therapy has afforded new hope for the durable treatment of many cancers, it has not provided yet substantial benefit to patients with glioblastoma. Utilizing a series of epidemiological, genome expression, and immunome databases, Yang et al., focus their study on bronchoalveolar lavage fluid-derived exosomes, released in the TME and demonstrate their role in fueling inflammation and tumor invasiveness via mast cells/neutrophils activation and cytokines release in TME. In a gastric cancer study, Zhao et al., analyze the role of NEDD9 in cancer cell migration under hypoxia. They demonstrate that NEDD9 regulates MICAL1, which facilitates hypoxia-induced gastric cancer cell migration in a Rac1-dependent manner .Using a lung cancer model, Tuo et al., address the role of the cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1) in the progression of hepatocellular carcinoma (HCC). PCK1 is a rate-limiting enzyme in gluconeogenesis which occurs mainly in the liver. The authors find that the expression of PCK1 is down regulated in HCC and associated with poor outcome. In hepatoma cells, the authors demonstrate that reactive oxygen species (ROS) production and nuclear translocation of Nrf2 and thioredoxin reductase 1 (TXNRD1) are suppressed during PCK1 overexpression. Furthermore, the authors show that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro .Hu et al., investigate the effect of berberine (BBR) in gastric cancer (GC). BBR is a natural isoquinoline alkaloid, presumably involved in lipid metabolism and glucose homeostasis by regulating the expression of HNF4α. The authors show that BBR inhibits the proliferation, invasion, and migration of GC cell lines, and thus reduces GC tumor growth in vivo. The antitumor effect of BBR shown appears to involve the AMPK-HNF4α-WNT5A signaling pathway . Using scutellarin, an active flavone extracted from Erigeron breviscapus Hand-Mazz (EBHM), Sun et al., investigate cisplatin resistance in non-small cell lung cancer (NSCLC). The authors find that scutellarin sensitizes tumor cells to cisplatin by enhancing apoptosis and autophagy via downregulation of p-AKT and c-Met in autophagy and caspase-3-dependent apoptosis. They suggest that the combination of cisplatin and scutellarin may be a novel therapeutic strategy for patients with NSCLC .The role of natural products in the modulation of the TME is likewise addressed in this Research Topic. Tirado-Hurtado et al., highlight the role of DNA Damage Inducible Transcript 4 (DDIT4) in cancer. The DDIT4 gene is expressed under stress situations, turning off the metabolic activity triggered by the mammalian target of rapamycin (mTOR). The authors propose targeting DDIT4 for the development of novel drugs that could be more specific and efficient than current mTOR inhibitors .The impact of DNA damage on TME is also investigated. Chulpanova et al., address the use of MCSs for drug delivery in oncology. The authors focus on MSC and tumor interactions, which are crucial for cancer control. They also describe novel therapeutic strategies using MSCs and MSC-derived membrane microvesicles for cancer therapy .Mesenchymal stem cells (MCSs) play important role in the TME . ChulpanIn conclusion, investigation of TME continues to be a vital focus toward the elaboration of novel strategies that produce more effective treatments for localized cancers and metastases. Findings presented in this Research Topic have the potential to make a major impact on this field and to inspire further discoveries.AL drafted the manuscript. AL, MB, KC-S, and AZ critically reviewed the manuscript for important intellectual content and approved it for publication.AL and KC-S are Founders and Shareholders of Lambda Pharmaceuticals. The remaining 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.


To identify which patient-related effect modifiers influence the outcomes of integrated care programs for type 2 diabetes in primary care.Integrated care is a widespread management strategy for the treatment of type 2 diabetes. However, most integrated care programs are not tailored to patients’ needs, preferences and abilities. There is increasing consensus that such a patient-centered approach could improve the management of type 2 diabetes. Thus far, it remains unclear which patient-related effect modifiers should guide such an approach.PubMed, CINAHL and EMBASE were searched for empirical studies published after 1998. A systematic literature review was conducted according to the PRISMA guidelines.In total, 23 out of 1015 studies were included. A total of 21 studies measured the effects of integrated diabetes care programs on hemoglobin A1c (HbA1c) and three on low-density lipoprotein cholesterol, systolic blood pressure and health-care utilization. In total, 49 patient characteristics were assessed as potential effect modifiers with HbA1c as an outcome, of which 46 were person or health-related and only three were context-related. Younger age, insulin therapy and longer disease duration were associated with higher HbA1c levels in cross-sectional and longitudinal studies. Higher baseline HbA1c was associated with higher HbA1c at follow-up in longitudinal studies. Information on context- and person-related characteristics was limited, but is necessary to help identify the care needs of individual patients and implement an effective integrated type 2 diabetes tailored care program. More than 90% agreement was reached. Therefore, the remainder of the titles and abstracts were screened by 1 reviewer (D.H.). Second, the first 20 full texts were screened independently by two reviewers (D.H. and A.E.). Again, more than 90% agreement was reached and therefore, each reviewer independently screened half of the full texts. Third, the reference lists of the included studies were screened to obtain additional studies. Steps 1 and 2 of the study selection process were then repeated.Descriptive data on studies were extracted by 1 reviewer (D.H.) between August and October 2015. Studies were coded for author names, year of publication, country, study design, length of follow-up, population size, age, percentage of males and CCM components. In case of uncertainties, a group discussion was held with two other authors (A.E. and M.B.).et al., The Effective Public Health Practice Project Quality Assessment Tool (EPHPP) was used to assess the quality of the included studies (Armijo-Olivo Two reviewers (D.H. and M.B.) independently performed the quality assessment for each study. Disagreements were resolved via discussion conform EPHPP guidelines.The included studies were categorized according to: (1) the reported outcome(s) of interest ; and (2) the type of patient characteristic(s) investigated in subgroup analyses. Characteristics were classified as person-related (predisposing), context-related (enabling) or health-related (illness level) characteristics according to Andersen and Newman’s  Behaviorn=453), and/or type of care was not integrated (n=257). After the title, abstract and full text screening, 27 studies were included , blinding (n=9) and selection bias (n=9). Almost all studies (n=25) scored high on the domain data collection. The overall study quality was strong for four studies, moderate for 11 studies and low for 12 studies. Most studies with low quality had a cross-sectional study design and did not report on or adjust for possible confounders.The methodological quality of the included studies can be found in Supplementary Table 1. The domains with the most ‘weak’ ratings were confounders (n=20) was 15 months (range 6–112). The median sample size consisted of 376 individuals (range 80–105 056) with an average age of 60.0 years (range 50.5–70.9); the percentage of male subjects ranged from 31.3 to 68.0.Of the included studies, nine (33.3%) were retrospective cohort studies, seven (25.9%) cross-sectional studies, seven (25.9%) (randomized) controlled studies and four (14.8%) prospective cohort studies. n=25), followed by self-management support (n=20). Of the studies that included the components delivery system design, most introduced a care team (n=13), followed by regular follow-up visits (n=8). Self-management support was mostly realized through individual educational sessions on diabetes, health and nutrition (n=14).In total, 18 uncontrolled studies – including prospective, retrospective and cross-sectional cohort designs – measured the effects of integrated care programs on HbA1c. In addition, seven studies compared the influence of patient characteristics on the effectiveness of integrated diabetes care programs between intervention and control groups. In total, 51 patient characteristics were assessed as potential effect modifiers of the relationship between integrated care and HbA1c. The results will be presented according to study design. For RCTs all characteristics assessed by this study design will be discussed. Due to the high number of characteristics assessed by the cross-sectional, retrospective and prospective cohort studies, only characteristics assessed by three or more studies will be presented.(Randomized) controlled trials: Five RCTs and two controlled trials (CTs) compared the influence of patient characteristics on the effectiveness of integrated diabetes care programs on the HbA1c level between intervention and control groups . In totaet al., et al., et al., et al., et al., Sex and age were the person-related characteristics evaluated as potential effect modifiers. Three studies assessed sex as a potential modifier, of which two found that women in the intervention group had statistically significant lower HbA1c values at follow-up compared to women in the control group , depression and diabetes mellitus (DM) duration. Each characteristic was assessed by one study. Patients with high FBG (>10 mmol/L) at baseline receiving integrated diabetes care had significantly lower HbA1c levels at follow-up compared to patients receiving usual care  and sex (n=9). In seven studies the effect of integrated diabetes care programs on HbA1c differed significantly across ranges of age: younger patients had higher HbA1c levels at follow-up compared to older patients (n=5) and experienced greater change from baseline in HbA1c (n=2) , baseline HbA1c (n=7) and duration of type 2 diabetes (n=6). The effect of integrated diabetes care programs on HbA1c was different for people on insulin therapy. These patients had higher HbA1c levels at follow-up compared with patients on diet and/or oral therapy in five studies   , body mass index (BMI) (n=6) and sex (n=5). Four studies of integrated care programs found non-significant associations between age and HbA1c  and medication use (n=4). The effect of integrated care programs on HbA1c differed significantly across ranges of diabetes duration in four studies (De Alba Garcia et al., et al., et al., et al., et al., et al., et al., et al., Most examined health-related characteristics were duration of type 2 diabetes (No context-related characteristics were assessed by three or more studies.Three prospective and retrospective cohort studies measured the effect of integrated diabetes care programs on LDL-c. The RCTs and cross-sectional studies included in this review did not measure this effect. In total, 11 patient characteristics were assessed by the studies. Only those results that were assessed by at least two studies will be discussed.et al., et al., Prospective and retrospective cohort studies: The person-related characteristic age was examined by three studies (Sperl-Hillen and O’Connor, et al., The modifying effect of baseline LDL-c on the relationship between integrated diabetes care programs and changes in LDL-c over baseline was assessed by two studies (Sperl-Hillen and O’Connor, No context-related characteristics were assessed by the included studies.Four retrospective and prospective cohort studies measured the effect of integrated diabetes care programs on SBP. In total, nine patient characteristics were assessed by the studies. Only those results that were assessed by at least two studies will be discussed.et al., et al., et al., et al., et al., et al., et al., et al., Retrospective cohort and prospective cohort studies: Age was measured by three studies (Mold et al., et al., et al., et al., et al., et al. (et al., et al. found that the effect of integrated diabetes care programs on health-care utilization was different between males and females (Liu et al., Health-care utilization was assessed by three studies: one RCT (Nielsen , et al.  found th et al., . For malThis paper presents a literature review on relevant patient characteristics for guiding tailored integrated type 2 diabetes care in primary care. HbA1c was considered an outcome in 93% of the 27 studies identified. Many different patient characteristics were investigated by these studies. Findings indicate that the effect of integrated primary care programs on HbA1c differs significantly according to a number of person and health-related characteristics. Younger age, longer disease duration, higher baseline HbA1c and insulin therapy were associated with higher HbA1c levels. Health insurance status, living situation and income were the only context-related characteristics in the included studies and were not frequently assessed.Compared to HbA1c, LDL-c, SBP and health-care utilization were included far less. It was found that higher baseline LDL-c lead to greater LDL-c improvement. Patients with higher age had higher SBP levels at follow-up as well as greater improvements in SBP compared to younger patients. The relationship between integrated care and health-care utilization seemed to be modified by sex: women had more consultations per year compared to men.et al., et al., β cell function and pancreatic insulin secretion, resulting in the need for a more complex and intensive drug therapy (Al Omari et al., et al., et al., et al., et al., et al., et al., Several factors might explain the elevated HbA1c levels in a subset of patients with type 2 diabetes. Younger patients tend be more non-adherent to oral medication therapy and experience less profound diabetes-related health problems than older patients (Pyatak et al., β-cell dysfunction (Heianza et al., et al., et al., High HbA1c at baseline also seemed to be predictive of later HbA1c. First, type 2 diabetes is a heterogeneous disease in both pathogenesis and clinical manifestation (Inzucchi et al., et al., et al., Several factors could explain the differences in levels of LDL-c, SBP and health-care utilization between levels of patient characteristics. Prescription of statins usually follows when LDL-c level is 2.5 mmol/L or higher, possibly leading to greater improvements in LDL-c for those patients with high baseline LDL-c levels (The Dutch college of general practitioners, et al., et al., et al., et al., Overall, our results indicate the need to implement integrated diabetes care programs specifically tailored to the needs, values and preferences of younger patients and to those on insulin therapy, with longer disease duration and/or higher HbA1c levels and older patients with high SBP levels. These effect modifiers can help to provide the right care to the right person at the right time. At this moment, not every patient with these characteristics receives such care. Current practice might therefore not be suitable for all patients. Lack of motivation, family support and feeling burned-out from managing diabetes are reported barriers to optimal self-management (Browne et al., et al., et al., et al., This review has several limitations that should be taken into account. First, given the scarceness of studies assessing the differences in the effect of integrated diabetes care programs on diabetes control measures by levels of patient characteristics, it was decided to include RCTs, prospective and retrospective cohort studies. However, this introduced significant heterogeneity and made it impossible to conduct a meta-analysis. Second, quality of the studies was weak for most studies. This was mainly due to the cross-sectional study design of more than one-third of the studies and the use of less robust statistical methods. Fortunately, it is unlikely that these studies altered the results, as their findings were similar to those of the other, more robust studies. Third, very few context- and person-related characteristics were analyzed. Studies performed in a non-integrated diabetes care setting, found that context-related characteristics, such as socio-economic status and social network, are associated with measures of diabetes control and are likely to be strong predictors of diabetes control (Jotkowitz et al., The current review provides a good understanding of which characteristics can help to identify patients with different health-care needs and preferences. However, to implement an effective integrated type 2 diabetes tailored care program, it is necessary to know which context- and person-related characteristics are important to identify patients. Furthermore, implementation of an effective tailored diabetes care program is only possible by taking into account the care preferences of patients and caregivers. In the next phase of the PROFILe project (Elissen