To better understand the type and range of health issues initiated by patients and providers in ‘high-quality’ primary-care for adults with diabetes and low socio-economic status (SES).Although quality of care guidelines are straightforward, diabetes visits in primary care are often more complex than adhering to guidelines, especially in adults with low SES who experience many financial and environmental barriers to good care.We conducted a qualitative study using direct observation of primary-care diabetes visits at an exemplar safety net practice in 2009–2010.In a mainly African American (93%) low-income population with fair cardiovascular control , visits addressed a variety of bio-psychosocial health issues [median: 25 problems/visit (range 13–32)]. Physicians most frequently initiated discussions about chronic diseases, prevention, and health behavior. Patients most frequently initiated discussions about social environment and acute symptoms followed by prevention and health behavior.Primary-care visits by diabetes patients with low SES address a surprising number and diversity of problems. Emerging new models of primary-care delivery and quality measurement should allow adequate time and resources to address the range of tasks necessary for integrating biomedical and psychosocial concerns to improve the health of socio-economically disadvantaged patients. Africanet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Previous research has shown patient, provider, or system factors associated with improved diabetes outcomes, such as better medication adherence, greater medication intensification, fewer competing demands at the office visit, greater access to care, greater patient motivation, and better continuity of care  from a county hospital in Northeast Ohio, performing in the top quartile on their biomedical quality of care scores for their patients with diabetes in 2009–2010 after obtaining institutional review board approval. The biomedical quality of care scores are locally adapted National Council of Quality Assurance measures for adults with diabetes, and included the percent of diabetes patients with blood pressure (BP) <140/90 mmHg, hemoglobin A1c<7%, and low-density lipoprotein cholesterol (LDL-c) <100 mg/dL. We purposively selected adult patients with diabetes who were scheduled for routine follow-up visits with their primary-care provider at the practice site.We used participant/direct observation for data collection, as we were interested in the observed number, range, and types of health issues brought up at the primary-care visit for adults with diabetes and as the primary author was a provider at the practice site. For each of the practices’ four primary-care physicians, we audio taped, observed, and transcribed three to four routine follow-up visits with diabetes patients after obtaining informed consent from patients and physicians. We excluded the primary-care provider who authored this paper due to potential biases; however, all the other providers participated in the study. Providers were told that we were observing the visit to evaluate current primary-care practice. We continued the enrollment of patients until we reached saturation of themes . The research assistant and internal medicine physician developed and piloted an observation form, environmental checklist, performed key informant interviews of providers and patients, wrote daily field notes, and composed reflective memos. For this analysis, we focused on analyzing the transcribed office visits, as these were felt to be most pertinent to our objective of evaluating the range and types of health issues that arose at the visit. The research assistant (a PhD sociology candidate) audio-recorded and observed most of the patient visits, whereas a primary-care provider/health services researcher audio-recorded and observed the remaining patient visits.et al., et al., A multidisciplinary team used a purposeful, constant comparative approach to count and categorize health issues, raised by the patient or the physician at the primary-care visit (Bradley n=5) were more likely to be men but were otherwise similar to participants in terms of age and race. The providers were all family practice physicians, Caucasian, and married. Three providers were women and one provider was a man.The safety net clinic serves a mainly low-income African American population . Out of the 20 patients asked to enroll, 15 patients consented to participate. The 15 patients were mainly African American (93%) with fair cardiovascular risk factor control . The patients had a mixture of insurance categories: private (33%), private plus medicare (20%), medicare alone (7%), medicaid (7%), and uninsured (33%). These numbers were similar to the numbers of the overall clinic population outlined above. Patients who refused to participate , prevention , changes in sexual partners, her spiritual beliefs as they relate to her health, and two acute issues.In-depth study reveals a rich subtext of the attitudes, beliefs, knowledge, and behaviors, as well as the role of popular culture underpinning patients’ attempts to manage their diabetes. It is instructive for ‘Dr Smith’ to know that ‘Ms Jones’ ‘ate at Subway for a whole month’ (because Jared lost weight doing so) and decided that because the contestants on the Biggest Losers maintained their weight loss ‘at home, after the show,’ she could do so as well. Ms Jones acknowledges that she allows herself ‘wiggle room’ in trying to manage her diabetes: ‘I ate only half the foot long for lunch and the other half for dinner.’ Ms Jones’ expression of the belief that ‘my body feels better when my sugar is higher’ initiated a lengthy discussion about how to manage low as well as high blood sugar.Her physician resourcefully integrates both the physician-directed health priorities such as chronic disease management of her diabetes and the patient-directed priorities such as her social environment into the overall plan of care. For instance, the physician incorporates the patient’s concerns about potential job loss and concern for medication costs when writing prescriptions, and the provider and patient work together with the social worker to derive the most appropriate regimen that will minimize costs while maximizing adherence. In the end, the provider prescribes some expensive medications such as insulin, which will be obtained through the help of the social worker via a free pharmaceutical company program that will mail the patient her medications. Other generic medications were prescribed that cost four dollars a month, such as her cholesterol medicine. Furthermore, the physician incorporates the patient-directed comments about her social environment regarding diet into the plan for weight loss by encouraging recent weight loss while modifying the ‘subway’ diet to have less bread.Patients and providers discussed a wide range of issues at these primary-care visits . Importaet al., et al., Although we expected the primary-care visit for adults with diabetes and low SES to be diverse in the range of health issues, the surprisingly large number of health issues (median 25) and the inter-relationship with the social environment of patients’ lives was remarkable. Similar to our study, one previous observational study reported that primary-care physicians deal with an average of 17 topics, questions, and symptoms at the primary-care diabetic visit (Parchman et al., Quantitative studies often fail to capture other issues such as the social environment (Samuels et al., et al., et al., These findings show what is possible in dedicated primary care – possibilities that provide hope for overcoming the chasms of fragmentation and poor quality that characterize much of the US healthcare system IOM, . Study fSeveral limitations to our study deserve mention. As this was a qualitative study that was carried out at one clinic, the conclusions may not be generalizable to the overall population. However, we were not trying to generalize findings but explore the range of health issues discussed in a primary-care visit to inform future potential interventions to improve care. Second, although we tried to combat bias in our analysis by including sociologists and primary-care physicians along with third-party physician review to confirm or refute findings, we recognize that some biases are hard to fully address. For instance, providers are more likely to conclude that they need more time with patients as we have suggested in this study. However, we also note that patients are more likely to bring up psychosocial issues than providers during an office visit; therefore, not all of our findings are biased toward positive provider performance.et al., et al., et al., et al., This study also has several important implications. First, the study raises questions about how ‘productivity’ is assessed in primary care. From bio-psychosocial and patient-centered points of view, the observed visits were highly productive. However, most of the present productivity measures and financial incentives emphasize ‘throughput’ (Morrison and Smith, Systems that incentivize quality and care integration over quantity may have the benefit of allowing scheduling of complex patients at more appropriate intervals and allow for more adequate resources for caring for biomedical and psychosocial aspects of patient health. In this time of tumultuous change in care organization and payment, we should support models of primary-care delivery and quality measurement, which allow adequate time and resources to address the range and complexity of tasks that are necessary for improving the health of socio-economically disadvantaged patients.


In 2014, Schlichting and co-workers  have opened up new opportunities to collect damage-free diffraction data from randomly oriented sub-micron-sized crystals using serial femtosecond crystallography (SFX) (Chapman  al. 2015 demonstrIUCrJ, Schlichting and co-workers (Nass et al., 2016et al., 2014In this issue of They then applied the same methodology to a thaumatin data set collected at the LCLS using the native sulfur as a source of anomalous scatterering Fig. 1. A photoet al., 2015de novo phasing of SFX data, particularly with only native crystals, is still far from trivial. Millions of crystals and many hours of beamtime are usually required to collect a sufficient amount of data for structure determination. Nass et al.’s study has demonstrated that with optimized data processing technology, single-wavelength anomalous diffraction data from the native sulfur atoms can allow protein structures to be solved ab initio. Improvements in XFEL instrumentation and processing software should further reduce the number of images required to phase SFX data.X-ray free-electron lasers have provided a new way to obtain SFX data that is advantageous over traditional synchrotron sources in terms of better data resolution, smaller sample size and minimal radiation damage (Kang


Pseudomonas aeruginosa biofilm (Costerton et al., Bacillus subtilis can choose between a variety of lifestyles such as sporulation, motility as an explorative lifestyle, biofilm formation, and the acquisition of genetic competence for the uptake of foreign DNA (López and Kolter, In their endless struggle to survive in harsh and rapidly changing environments, many bacteria depend on their ability to live together as multicellular communities, also known as biofilms. In these communities cells are embedded within a self-produced slimy matrix that is mainly composed out of extracellular polysaccharides and proteins (Hall-Stoodley et al., B. subtilis biofilm communities, different groups of cells fulfill distinct functions, which are important for the well-being of the whole community of clonal identical bacteria. Some bacteria produce extracellular polysaccharides and proteins and thereby provide the matrix for the community. Other cells secrete exoproteases for degradation of protein as an alternative energy source (Marlow et al., In the B. subtilis suggest that tyrosine phosphorylation plays an important role in the regulation of biofilm formation and cell differentiation, in addition to the known mechanisms of transcriptional regulation and protein-protein interactions (for review see Vlamakis et al., B. subtilis encodes two protein tyrosine kinase/ modulator couples, PtkA/ TkmA, and EpsB/ EpsA. Interestingly, the simultaneous deletion of either both kinase or modulator genes totally abolished extracellular polysaccharide production causing a biofilm defect. The single mutants did not phenocopy the kinase or modulator double mutant and were still able to produce exopolysaccharides. However, colony structure and pellicle formation was affected in the single mutants (Gerwig et al., B. subtilis at different levels: EpsB acts downstream of the central regulator of cell differentiation, Spo0A, whereas PtkA is likely to act upstream of Spo0A (see Figure Recent studies in In principle, the stochastic phosphorylation state of the Spo0A protein determines to which promoters the protein binds and consequently if cells differentiate into a spore or become a matrix producer. High levels of phosphorylated Spo0A induce spore development, whereas medium levels lead to matrix production (Fujita and Losick, In order to influence sporulation efficiency as shown by Kiley and Stanley-Wall , PtkA moptkA mutant, Kiley and Stanley-Wall (In order to explain altered biofilm formation and the sporulation defect of the ley-Wall  conducteley-Wall  were notley-Wall , except ley-Wall . ClearlyA more obvious problem for the identification of tyrosine phosphorylated proteins with the potential to control biofilm formation and sporulation is that most published data relates to cells harvested from exponentially growing cultures rather than from biofilms. Moreover, the studies were performed with strains derived from a domesticated strain that does not produce robust bofilms. Thus, it is reasonable to assume that not all of the proteins that might be relevant for biofilm formation and sporulation are expressed under these conditions. Furthermore, regulatory phosphorylation is a rapid method for adapting cellular processes to environmental changes. Thus, it seems safe to assume that not all phosphorylations are present permanently. Interestingly, all currently identified tyrosine phosphorylation reactions with functional relevance have been found by attempts other than large-scale phosphoproteomics analyses. Examples include the regulator of unsaturated fatty acid synthesis FatR (Derouiche et al., eps operon for exopolysaccharide production. Hence, the regulation of the two corresponding genes is similar. The eps operon is only strongly expressed if the SinR anti-activator protein is inhibited by either of its antagonists SinI and SlrR under biofilm forming conditions (Kearns et al., epsB gene only affects exopolysaccharide production but leaves sporulation unaffected (Gerwig et al., The second level of regulatory tyrosine phosphorylation is provided by the EpsB kinase that phosphorylates the glycosyltransferase EpsE (Elsholz et al., Straight signal transduction is an important issue for many conserved multi-component signal transduction system families and has been extensively studied for two-component regulatory systems and phosphotransferase system-controlled RNA-binding antitermination proteins. These systems have evolved to avoid non-cognate interactions either by restricting the interactions with non-cognate proteins partners, ligands, and target molecules. Moreover, differential gene expression of the non-cognate components has been observed to prevent non-productive cross-talk (Schilling et al., Staphylococcus aureus that also contains two similar tyrosine kinase/ modulator couples. In this case, the Cap5A1 modulator protein of one couple and the Cap5B2 protein tyrosine kinase of the other couple show functional cross-talk suggesting that interplay between different tyrosine/ modulator couples might not be limited to B. subtilis (Soulat et al., However, this might be different for regulatory tyrosine phosphorylation, as suggested for the interplay between EpsB and PtkA. In yeast (Shi et al., B. subtilis is one of the most exciting results of recent studies. This is underlined by the observation of extensive links between the different signal transduction systems that involve post-translational modifications (van Noort et al., ptkA deletion mutant. Furthermore, large-scale phosphoproteomics under biofilm-promoting conditions could help to identify potential tyrosine phosphorylated targets. Additional tasks are the identification of substances that can be sensed by the PtkA modulator protein TkmA and to further dissect the potential cross-talk between the two known tyrosine kinase/ modulator couples EpsB/ EpsA and PtkA/ TkmA in B. subtilis.The detection of a regulatory interplay between protein tyrosine phosphorylation and classical sensing via the phosphorelay in the control of cell differentiation in 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.


Microarray technologies facilitate high-throughput gene expression analysis. However, the diversity of platforms for rice gene expression analysis hinders efficient analysis. Tools to broadly integrate microarray data from different platforms are needed.http://www.ricearray.org) to explore gene expression across 1,867 publicly available rice microarray hybridizations. The ROAD’s user-friendly web interface and variety of visualization tools facilitate the extraction of gene expression profiles using gene and microarray element identifications. The ROAD supports meta-analysis of genes expressed in different tissues and at developmental stages. Co-expression analysis tool provides information on co-regulation between genes under general, abiotic and biotic stress conditions. Additionally, functional analysis tools, such as Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) Orthology, are embedded in the ROAD. These tools facilitate the identification of meaningful biological patterns in a list of query genes.In this study, we developed the Rice Oligonucleotide Array Database  contains supplementary material, which is available to authorized users. Oryza sativa) is a staple food for more than 50% of the human population. Because of the high level of genomic colinearity and conservation of gene function among grass species, rice serves as a useful research model in other grass studies . The co and Gale), has br and Gale; Itoh et and Gale; Tanaka  and Gale). Despit and Gale).japonica and indica) have been reported and their characteristics are summarized in Table japonica and indica cultivars, respectively. Agilent has constructed a 22K Rice Oligo Microarray Kit based on rice FLcDNAs and recently announced a 44K version  was designed by the Beijing Genomics Institute and Yale University  and based on the draft indica and japonica sequences. The University of California, Davis, led a National Science Foundation (NSF) supported effort to design, print and validate 22K and 45K oligonucleotide arrays based on gene model predictions from TIGR’s osa1 version 3.0 release.Microarray technologies are an important strategy for genome-wide expression pattern analysis and is becoming increasingly important for gene functional analysis . Severano et al.). The Orhttp://ricexpro.dna.affrc.go.jp/), which is based on the Agilent 44K microarray, provides an overview of the spatiotemporal gene expression profiles of various organs and tissues  provides a meta-analysis toolbox to explore gene expressions across a wide variety of biological contexts for rice and other species, but it is commercial and not completely publicly available , which integrates the most comprehensive public microarray datasets and provides several functional analysis tools. With a user-friendly web interface, the ROAD is a useful reference for elucidating rice gene expression and function.These rice microarray platforms have been successfully used in characterizing gene expression profiles from different tissues and organs , differto et al.). Geneveuz et al.). Other uz et al.), RicePLuz et al.), Bio-Aruz et al.) and Yaluz et al.) are usend Fobert). This sWe collected information from six rice microarray platforms, including the Affymetrix, Agilent 22K and 44K, BGI/Yale, and the NSF 20K and 45K, to construct the ROAD. Probe sequences from each platform were extracted and mapped onto cDNAs to match the probes to the expressed genes; the cDNAs were drawn from the Rice Genome Annotation Project  V6 , Rice A2(Cy3/Cy5)) were used and the color-swap hybridizations were manually corrected to make them comparable among other samples. Normalized data were integrated into the ROAD, thus simplifying the retrieval process of their gene expression profiles. After entering a list of genes or microarray element IDs into the ROAD, the user can then select the microarray platform and specific experiment to search against  to assemble microarray data from different experiments into context-related profiles (meta-profiles). This large-scale combination and analysis of expression data from a single organism using a single platform allows the identification of biologically meaningful expression patterns of individual genes . One drSimilarity of gene expression profiles (co-expression) can provide powerful information to identify new genes functionally related. The rapid accumulation of microarray data in past decade allows the creation of co-expression networks by examining the co-expression patterns of genes over a large number of experimental conditions. Several online co-expression analysis tools have been developed for rice, including OryzaExpress , RiceArp value is calculated for each GO/KO term, whose value is based on comparisons of the observed number from the queried gene list and the expected number from the genome scale.Gene Ontologies (GO) provide controlled vocabulary to describe the biological process, molecular function, and component of the cell to which a gene product putatively contributes , R package marray in Bioconductor was used to do the normalization with within-array Lowess and between-array MAD scale normalization methods  were collected from NCBI GEO , EBI ArCleveland; Wang etCleveland). The coad et al.). The sead et al.). Regardhttp://www.ricearray.org. Heatmap and classic line plots were generated by the PHP library JpGraph (http://jpgraph.net/).The ROAD database was constructed with PHP (Hypertext Preprocessor) and MySQL, run on a Windows 2003 server. The http address isAfter MAS normalization of all Affymetrix microarray samples, outliers were detected using the arrayQualityMetricsBioconductor package, which uses three different statistical tests to identify outliers     and KO sa et al.). The RAka et al.). Then hTable S1. Detailed information of rice microarray experiments available in ROAD. (XLS 204 KB)Additional file 1: Figure S1. Screenshots of meta-analysis in ROAD queried with 19 root-preferential genes for anatomy (a) and developmental stages (b) of Affymetrix array platform, and anatomy (c) and developmental stages  of Agilent 44K array platform. (JPEG 5 MB)Additional file 2: Authors’ original file for figure 1Authors’ original file for figure 2Below are the links to the authors’ original submitted files for images.


This Research Topic aims to cover recent progress in research studying how genetic make-up and environmental factors can contribute to the development of mental disorders such as anxiety, depression, schizophrenia, and psychoactive substances abuse. It has brought together leading experts in the field to address these questions from different angles in eleven reviews, seven original research articles and two theoretic/opinion papers.1A receptor KO mice compared to WT animals. Then, by performing loose-seal cell-attached electrophysiological recordings in 5-HT transporter knockout (Sert−/−) and tryptophan hydroxylase-2 knockout (Tph2−/−) mice, Araragi et al.  in the pathophysiology and the treatment of psychiatric disorders. First, Prof. Gardier  nicely si et al.  demonstret al.'s  results The following eleven articles provide excellent insights into the interaction between gene and environment in mental disorders as well as the role of several transmitters/neuropeptides and the different therapeutic strategies. El-Hage et al.  elegantlin vivo. They present novel methods using [11C]-(+)-PHNO and PET which could provide insights into the function of D3 receptors in addiction.The last five articles cover neuroscience research on drug of abuse. In order to better understand the processes by which peer influences take effect in prairie voles, Anacker and Ryabinin  measure In summary, these studies illustrate how mental disorders can arise from multiple sources. It even seems that the entire body can impact on mental state and psychiatric health (Renoir et al., 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.


Most individuals experience these threats at least once during their lives, and some individuals experience them daily  and other forms of interpersonal rejection threaten individuals' physical and psychological well-being  because these behaviors are more likely to achieve re-inclusion; anti-social behaviors should be more likely to fortify power/provocation needs (control and meaningful existence) because these behaviors will likely provoke acknowledgement from the ostracizers . Thus, participants who give a small amount could be interpreted as either being less aggressive or potentially more pro-social because they are obeying the experimenter nominally but also not subjecting the target to unnecessary discomfort. Further, how do researchers categorize participants who actively choose not to allocate any hot sauce at all? Is this simply lack of aggression or also an independent pro-social behavior toward the target?Future research needs to address directly these two conflicting behavioral responses. Often, researchers only give participants one behavioral option. Because of this, it is hard to rule out the possibility that ostracized participants are simply responding more extremely than included participants using whatever option they are given because it is the only option they have to fortify some of their basic needs. Some behavioral measures can be interpreted as pro- or anti-social depending on how participants respond  and devaluate the same target  simultaneously (Sommer and Bernieri, Other threat-focused models [e.g., rejection-based threats, Smart Richman and Leary , or threResearchers could also measure theoretically meaningful individual difference variables to test potential moderation of the anti-social/pro-social paradox. For example, ostracized participants who have a higher dispositional need to belong (Leary et al., future expectations argument. Wesselmann et al. (Some individual differences should moderate anti-social responses. Individuals higher in rejection sensitivity (i.e., the tendency to expect and easily perceive rejection; Ayduk et al., n et al.  offer ann et al. , but theflight response (compared with fight responses, i.e., pro- and anti-social behaviors; Williams, freeze response (Williams, flight and freeze responses.Williams  developemeaning/significance (also Jonas et al., control (Kruglanski, Chronically ostracized individuals may also be susceptible to recruitment by predatory/extreme groups because these groups may offer a last bastion of inclusion (Wesselmann and Williams, 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.


Epichloë, Bacon et al., Balansia, Porter et al., Claviceps purpurea where the alkaloids, typically ergotamine and ergocristine, are responsible for the resultant ergotism associated with C. purpurea. The presence of these toxins can compound livestock issues with the concomitant consumption of ergovaline produced by the endophyte. In terms of livestock production systems, associated ergot alkaloid toxicities are not limited to pasture or feeding pasture products. While Claviceps Africana is widespread throughout Africa and Asia, the first reported case of toxicity was in Australian sorghum in 1996 (Ryley et al., C. Africana-infested sorghum has been demonstrated to be detrimental to steer performance in Australian feedlots that utilize this feedstuff (Blaney et al., Ergot alkaloids have been associated with endophyte-infected grasses (e.g., the While ergot alkaloid incidences are rare in humans resulting from increased regulation of grain processing (Flieger et al., If fungi that synthesize ergot alkaloids pre-date the human race, and knowledge of ergot properties has been recorded as far back as 1100 BC Schiff, , why havA multi-disciplinary approach will be needed to solve most ergot alkaloid related issues. This research topic, Recent Investigations of Ergot Alkaloids Incorporated into Plant and/or Animal Systems, epitomizes that reality through diverse scientific approaches addressing the core issue of ergot alkaloids in agriculture. Innovative research articles highlight the numerous effects that ergot alkaloids can have on livestock (Aiken and Flythe, 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.


Chandelier cells  are a specialized GABAergic interneuron subtype that selectively innervates pyramidal neurons at the axon initial segment (AIS), the site of action potential generation. ChC connectivity allows for powerful yet precise modulation of large populations of pyramidal cells, suggesting ChCs have a critical role in brain functions. Dysfunctions in ChC connectivity are associated with brain disorders such as epilepsy and schizophrenia; however, whether this is causative, contributory or compensatory is not known. A likely stumbling block toward mechanistic discoveries and uncovering potential therapeutic targets is the apparent lack of rudimentary understanding of ChCs. For example, whether cortical ChCs are inhibitory or excitatory remains unresolved, and thus whether altered ChC activity results in altered inhibition or excitation is not clear. Recent studies have shed some light onto this excitation-inhibition controversy. In addition, new findings have identified preferential cell-type connectivities established by cortical ChCs, greatly expanding our understanding of the role of ChCs in the cortical microcircuit. Here we aim to bring more attention to ChC connectivity to better understand its role in neural circuits, address whether ChCs are inhibitory or excitatory in light of recent findings and discuss ChC dysfunctions in brain disorders. Discovered in the 1970s, ChCs quickly gained intrigue as a unique and potentially powerful subtype of GABAergic interneurons that selectively innervates pyramidal neurons at the axon initial segment (AIS), directly regulating the site of action potential generation , L3, L5a and L5b , ChC axons can vary in their complexity and localization in different cortical areas and layers, and depends on the type and age of the animal  mice (Kirmse et al., Whether ChCs are inhibitory or excitatory is not currently agreed upon. ChCs activate GABAd Kaila, . However− regulation at the postsynaptic AIS (Szabadics et al., − concentrations, Szabadics et al. used the gramicidin perforated patch technique (Szabadics et al., in vivo. Nevertheless, a possibility for ChC excitation is hypothesized to occur during “down” states, when pyramidal neurons are hyperpolarized and sodium channels are deinactivated (Szabadics et al., ChCs in L2/3, on the other hand, have been shown to be capable of mediating excitatory activity in brain slices from animals well past the developmental period when GABA-mediated excitation is thought to occur (Szabadics et al., in vivo conditions indicated that L2/3 ChCs were predominately inhibitory (Woodruff et al.,  In vivo studies that clearly demonstrate whether ChCs are inhibitory or excitatory are lacking, but some results suggest that ChCs are not excitatory (Klausberger et al., Because the perforated patch technique may still alter GABAergic activity, concerns with this technique and the results obtained were raised (Glickfeld et al., in vivo data, suggest that ChCs are inhibitory, as originally assumed (Somogyi, ChC-mediated excitation is an enigmatic issue. This is largely due to the complications when recording GABAergic responses. Nevertheless, currently those experiments using the least invasive techniques, along with Somogyi,  and demoSomogyi, .A receptor α2 subunit is increased in pyramidal neurons in schizophrenia (Volk et al., ChC dysfunctions are well associated with schizophrenia (Lewis et al., Schizophrenia is associated with significant changes in neural activity. These changes are shown with both structural and functional alterations and result in abnormal neural network oscillations and synchrony (Meyer-Lindenberg et al., in vivo recordings show that ChCs fire more robustly than other types of cortical neurons when overall cortical excitation increases (Zhu et al., ChC dysfunction is also implicated in epilepsy (DeFelipe, A significant impediment that prevents elucidating the link between ChC dysfunctions and brain disorders is the uncertainties in the role of ChCs in the cortical microcircuit, including whether ChCs are inhibitory or excitatory. Ideally, the ability to specifically target ChCs with the identification of specific markers will greatly aid in resolving the role of ChCs in brain functions. One such undertaking is the creation of the Nkx2.1CreERT2 mouse line that can label a portion of interneurons, the majority of which are ChCs (Taniguchi et al., 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 reviewer GGB and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Autism spectrum disorder (ASD) is an umbrella term for a heterogeneous group of developmental disorders that present with persistent deficits in social communication/interaction and repetitive/restricted patterns of behavior, interests, or activities that cannot be better explained by intellectual disability or global developmental delay   could directly affect the enteric nervous system (ENS), a nervous tissue within the gut wall often called “the second brain” due to its size, structure, complexity, and autonomic regulation of gut functions, such as bowel motility, secretion/absorption and local blood flow Furness, , 2012. FS-nitrosoglutathione (GSNO) , traditionally considered as only supportive cells of the ENS, are emerging as local GI regulators. They are strategically located at the interface between the neurons and other non-neuronal cells in the gut, such as enterocytes or immune cells, and participate in the regulation of gut motility, intestinal epithelial barrier, and inflammatory processes  in Rett Syndrome (Yasui et al., Recent study showed the role of EGCs' Cx43 hemichannels in the regulation of the GI motility (McClain et al., Concurrently, Cx43 on EGCs is taking part in the inflammatory process. Neuronal loss is one of the characteristics of intestinal inflammation and is driven by the activation of neuronal purinergic receptor (Gulbransen et al., 2+oscillations that can consequently regulate gene transcription (Dolmetsch et al., Animals with ablated Cx43 in EGCs also exhibited an increased fluid content in stools, indicating disabled water reabsorption/secretion (McClain et al., EGCs are also in proximity of capillaries within the gut wall (Fu et al., In summary, we presented a hypothetical link between the Cx43 of EGCs and GI related symptoms in patients with autism Figure . EGCs inThe 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.


Literature indicates that racism, sexism, homophobia and HIV-related stigma have adverse impacts on health, well-being, and quality of life among HIV-positive women of African descent (African/Black diaspora). However, limited evidence exists on the effectiveness of interventions aimed at reducing stigma tailored for these women. This study systematically reviewed randomized controlled trials (RCTs), non-randomized observational and quasi-experimental studies evaluating the effectiveness of interventions aimed at reducing stigma experienced by this population.The Cochrane methodology was used to develop a search strategy in consultation with a librarian scientist. Databases searched included the Cochrane Library, Ovid EMBASE, PsycInfo, and 10 others. Two reviewers independently assessed the studies for potential relevance and conducted the Cochrane grading of RCTs to assess risk of bias and the Newcastle–Ottawa scale to assess the quality of non-randomized studies. Eligible papers were selected if they employed an intervention design with African/Black diasporic women living with HIV as the target population and had a primary outcome of stigma reduction.Of the five studies that met all of the eligibility criteria, four demonstrated the effectiveness of interventions in reducing HIV-related stigma. Only two of the five studies were designed specifically for HIV-positive African/Black diasporic women. Limitations included the absence of interventions addressing other forms of stigma and discrimination .Our findings suggest that there are limited interventions designed to address multiple forms of stigma, including gender and racial discrimination, experienced by HIV-positive African/Black diasporic women. Both in the global South and the global North, the HIV epidemic has disproportionately impacted people of African descent. Disproportionate rates of HIV in women of African descent have been reported in Western countries including Canada, the United States and the United Kingdom ,2. For tThe demographic profile in Canada signifies that a high proportion of HIV-positive women were born outside of Canada, particularly in Africa and the Caribbean . CurrentA preponderance of research has documented negative associations between singular forms of marginalization – HIV-related stigma, racism, sexism – and the health and well-being of people with HIV . For HIVThe term intersectional stigma was coined to describe the co-occurrence of stigma based on multiple identities of women living with HIV, including ethnoracial identity, gender and gender identity, national identity, sexual orientation and HIV serostatus . InterseAs recent HIV research recommends interventions that address stigma/discrimination at the micro, mesa and macro levels, there is limited evidence of interventions that address intersecting forms of marginalization ,43. Neveet al. [et al. [While evidence syntheses have been conducted evaluating the effectiveness of interventions designed to reduce HIV-related stigma ,54, theret al.  evaluate [et al.  examinedTo identify interventions designed for African/Black diasporic women with HIV and to examine their effectiveness at reducing stigma, we reviewed randomized controlled trials (RCTs), non-randomized quasi-experimental and observational studies that reported on the efficacy of stigma reducing interventions compared to treatment as usual in reducing the multiple forms of stigma and discrimination experienced by HIV-positive African/Black diasporic women. For the purposes of this review, we define African/Black diaspora as people of African ancestry who are living outside of the African continent  with a sFor our systematic review of stigma reducing interventions for African/Black diasporic women, we identified intervention research that targeted any level  or form  of stigma and discrimination experienced by this population. As applicable, we also evaluated the effectiveness of stigma reducing interventions at addressing well-being and self-efficacy among African/Black diasporic women living with HIV.This project was not prospectively registered. A protocol was developed during the planning process (Grant# CIHR No. 97106 U of T Fund No. 487453 sub-grant 11).This systematic review adheres to guidelines outlined by the Cochrane Collaboration . The PRIIn June 2013 (current end date of electronic search), we conducted a search of 13 electronic databases that covered national and international literature in medical/health sciences, psychology, and social sciences. The search strategy was applied to Ovid MEDLINE (1946–current) and Ovid EMBASE (1980–current), then adapted for AgeLine Database (1978 – current), ASSIA: Applied Social Sciences Index and Abstract database (1987 – current), CINAHL (1980 – current), Clinicaltrials.gov (1999 – current), the Cochrane Library, a collection of six databases including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA) Database, and NHS Economic Evaluation Database (NHS EED) (1898 – current), Dissertation Abstract International (1637 – Current), PsycINFO (1806 – present), Social Services Abstracts database (1979 – current), Social Science Abstracts (1972 – current), Sociological Abstracts (1952 – current), Social Sciences Citation Index (1900 – current). Keywords searched included: (1) HIV/AIDS keywords ; (2) stigma/discrimination keywords  intervention search terms ). We also undertook a hand search of 19 journals (Supplementary Appendix) from 1995 to August 2013 to identify articles missed by our search, and conducted a citation search of the reference list of included studies. As only published manuscripts were included, authors were contacted by email to ascertain if a complete manuscript or publication was available. If any additional information or clarification were required, authors were also contacted.Two reviewers  divided and screened all titles from the literature search for obvious exclusions. The remaining abstracts were independently assessed by two reviewers , with disagreements resolved by a third reviewer (LAC). We included published intervention studies if: (1) study population included HIV-positive women of African ancestry ; (2) the intervention aimed to reduce stigma and discrimination; (3) the study provided quantitative outcome data for: (a) stigma and discrimination , and (b) well-being , or (4) self-efficacy . Only RCTs and observational study designs were included.Three reviewers  designed and independently piloted a data extraction form. The following items were extracted: (1) study information ; (2) participant information ; (3) intervention information ; (4) outcomes and measures used. Two investigators  independently extracted data from relevant research. The definition of stigma reduction intervention is any intervention for which the reduction of stigma or discrimination was considered an outcome of the intervention. Our definition of stigma included HIV-related stigma as well as other forms of stigmatization or discrimination identified . The datasets were compared for each study, and a third party settled disagreements (LAC). Our review did not have any jurisdiction restrictions; though we were only able to extract data from papers published in English.The risk of bias of each eligible study was assessed by two investigators  using the eight-item Newcastle–Ottawa Scale for non-random and observational studies  and the An a priori decision was made to conduct a meta-analysis; however, due to the heterogeneity of the study findings, including type and measurement of health outcomes, it prevented us from pooling the results using meta-analysis. Instead, we reported on study findings and conducted a descriptive analysis based on reported outcomes.Our study selection process is described in Supplementary Fig. 2 using an adapted version of the PRISMA flow diagram . After rThe details of the study characteristics of the included studies are reported in Supplementary Table 1. Of the five studies that met criteria for inclusion, three reported findings from RCTs ,62,64, aThe review sample totalled 238 participants of which 188 participants (79%) identified as African–American women with HIV. Sample size ranged from 11 to 109 per study. Although all of the included studies focused on HIV-positive populations and considered cultural differences such as gender and ethnoracial identity in their analysis, only two of the five studies designed their interventions specifically for African–American women ,65. The et al. [et al. [et al. [et al. [All five of the included studies reported on the effectiveness of interventions where stigma reduction was an expected outcome. Abel et al.  and Abelet al.  evaluate [et al.  evaluate [et al.  evaluate [et al.  evaluateet al. [et al. [The results of the risk of bias assessments are reported in Supplementary Table 2 for the included RCTs and Supplementary Table 3 for observational studies. Overall, the three RCTs had a moderate risk of bias. Of the two prospective cohort studies Hosek et al.  had a lo [et al.  had an uWe conducted a descriptive synthesis of findings based on stigma reduction outcomes and reported on the effectiveness of the interventions for reducing stigma and discrimination. We also summarized findings on physical and mental well-being as reported in each study. The resulting data from each included study are presented in Supplementary Table 4.All five included studies reported stigma outcomes. Four studies measured perceived HIV stigma  –64. One et al.’s [et al. [Findings from four of the included studies indicated that the specified interventions demonstrated promise in reducing stigma. Both of the studies with an exclusively African/Black diasporic female sample reported reductions in stigma post-intervention. Rao et al.’s  evaluati [et al.  reportedet al. [The two studies with a mixed ethnoracial female sample also demonstrated reductions in stigma post-intervention. Findings from Abel et al.  and Abelet al.  indicateet al. , and 12 et al. .et al. [The one study with a gender and ethnoracially diverse sample demonstrated mixed results in regards to stigma reduction. The Project ACCEPT intervention evaluated by Hosek et al.  reportedet al. .et al. [et al. [et al. [Findings on physical and mental well-being post-intervention were mixed. Abel et al.  reported [et al.  reported [et al.  noted siWe performed a comprehensive systematic review of the literature to evaluate the efficacy of current HIV-interventions in reducing stigma and discrimination experienced by African/Black diasporic women with HIV. We identified five studies that met our inclusion criteria, of which four studies demonstrated that their interventions had a positive effect on reducing HIV-related stigma in women living with HIV. These findings indicate that stigma reducing interventions can be of benefit for African/Black diasporic women with HIV. These findings could be useful for practitioners wishing to identify interventions that are effective in addressing HIV-related stigma in this population and the subsequent health benefits of such interventions.et al. [et al. [Of these studies, two exclusively sampled African/Black diasporic women with HIV and developed interventions that were culturally appropriate for this population. Rao et al.  adapted  [et al.  develope [et al. ; oral an [et al. ), peer fet al. [et al. [The included studies identified interventions that showed promise in reducing the effects of stigma on African/Black diasporic women with HIV; however, only two studies were designed specifically for this population. While Abel et al.  and Abelet al.  conducteet al. . Althoug [et al.  revealedet al.’s [et al. [et al. [Furthermore, only one of these interventions was specifically designed to address both internal and perceived experiences of stigma. Rao et al.’s  interven [et al. , the aim [et al.  addresse [et al. ,61. Over [et al.  integratThis review also shows limited evidence of the long-term effectiveness of stigma reducing interventions for African/Black diasporic women with HIV. The follow-up duration ranged from four weeks to six months, with only two studies having a follow-up period of three months or longer ,64. WhilAdditionally, while all of these studies reported HIV-related stigma outcomes using similar measures, there is a lack of data demonstrating the effectiveness of stigma reducing interventions addressing other forms of stigma experienced by HIV-positive African/Black diasporic women including sexism and racism. These interventions were also focused on addressing stigma at the interpersonal or intrapersonal level; there is little evidence of interventions addressing stigma and discrimination at community, institutional or structural levels, which has been identified in the literature as essential to combating stigma . MoreoveSeveral limitations in our review merit discussion. First, although our study did not exclude based on language, in our analysis we were unable to include studies published in languages other than English. Our search strategy did not include an electronic database search for grey literature, though we did conduct manual searches that could capture non-peer reviewed or unpublished literature. Our study definitions of stigma/discrimination and health derived from Westernized concepts and may not have captured non-Westernized conceptualizations of these terms. Lastly, we were unable to pool the data for meta-analysis because of the significant heterogeneity in many study features.In summary, our systematic review contributes to the emerging body of literature on stigma reducing interventions for people with HIV ,53,54. NClick here for additional data file.Click here for additional data file.


Increasing distress about climate change consequences is noticeable in daily press releases and science news articles. In the last 5 years more than 3 hundred thousand scientific articles included the terms “climate change,” “drought stress” and/or “climate adaptation” as a main topic. This build-up of energy devoted to understand climate change significance parallels the fact that any living organism must be able to cope with environmental changes to survive. Plant's sessile condition reinforces even more the need of an efficient adaptive response to counteract a suboptimal environment. Such adaptive strategies synchronize growth and development adjustments, as well as cellular and molecular activities, aimed at an efficient use of scarce resources, e.g., water.Arabidopsis HD-Zip I transcription factors, named ATHB7 and ATHB12, down-regulating a number of genes encoding ABA-receptor proteins, in addition to up-regulating protein phosphatases type 2C. Both ABA receptors and protein phosphatases 2C are well established components of the ABA signaling pathway  accumulation upon drought perception serves as an initial signal for long-term acclimation reactions, which eventually involve the differential expression of genes leading to changes in transcript and protein patterns (Valdés et al., As previously mentioned, developmental changes and morphological alterations are part of the plant adaptation and, besides controlling stress responses, HD-Zip I genes have additional roles in controlling development (Ariel et al., in silico interactions between genes early regulated in the shade-avoidance response and, ATHB7 and ATHB12 that highlight their potential participation also in light signaling pathways (Ciolfi et al., Besides water availability, the plant environmental context is defined by additional, simultaneous external factors, e.g., light and temperature, and should these factors influence the transcript levels of HD-Zip proteins the dynamic behavior of the ABA-driven stress response becomes automatically dependent on such factors. This implies that cross-communication between different signaling systems should be mediated by the same HD-Zip proteins. In this sense, available genomic and proteomic data have predicted The intricate network established within this superfamily of transcription factors suggest that the plant-specific and evolutionary highly conserved HD-Zip proteins are crucial players modulating stress responses and may be linking patterning and adaptation by acting to adjust developmental programs to specific environmental situations.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 exponential growth in generation of large amounts of genomic data from biological samples has driven the emerging field of systems medicine. This field is promising because it improves our understanding of disease processes at the systems level. However, the field is still in its young stage. There exists a great need for novel computational methods and approaches to effectively utilize and integrate various -omics data.Systems medicine has been growing rapidly in part due to the emerging technologies to gather high-volume measurements from biological samples. One of the first such technologies, the mRNA microarray, is being replaced by next generation sequencing (NGS), which provides a much higher resolution  of genetic information . Array and NGS-based methods to characterize genetic variation , DNA methylation changes, microRNAs (miRNAs) differential expression, and other types of biological information have dramatically expanded the generation of biological data. Other sources of data from mass spectrometry-based proteomics and metabolomics to high-throughput determination of protein-protein interactions and regulatory relationships provide further information for a systems-level understanding of disease. Finally, collection of clinical data and electronic medical records (EMRs) has made modern biomedical research possible on the full scale of data integration, that is, an integration scenario of using genomic, transcriptomic, proteomic, metabolomic, and phenotypic data.The rationale of discovery-based high-throughput investigation of disease is that there are molecular signatures  that can be identified for better diagnosis, prognosis, and/or treatment of disease. However, challenges arise in the analysis of high-throughput data because of the large number of possible variables raising the very real potential for false-positive predictions and overfitting of data, as well as many other potential problems . To ameliorate these problems, computational approaches have been developed that utilize existing knowledge, such as overlaying high-throughput observations on regulatory or protein-protein interaction networks or canonical biological pathways.For this special issue we solicited manuscripts in several different subject areas including data integration from multiple high-throughput sources, NGS data analysis and applications, personalized medicine and translational bioinformatics, modeling of pathways and networks, and data mining and pattern recognition in biomedical applications. We briefly describe the accepted papers in this special issue in the remainder of this editorial.MultiRankSeq: multi-perspective approach for RNAseq differential expression analysis and quality control” by Y. Guo et al. and “QPLOT: a quality assessment tool for next generation sequencing data” by B. Li et al., describe algorithms for analysis of NGS data. Y. Guo et al. introduce a novel tool, namely, MultiRankSeq, which combines the output of three independent programs to determine differential expression from RNAseq data to provide a single improved output. QPLOT is a tool for assessing the quality of NGS runs by providing both summary quality metrics and graphical representations of these metrics. In another paper, entitled “Comparative study of exome copy number variation estimation tools using array comparative genomic hybridization as control,” Y. Guo et al. systematically compare four different tools for detecting copy number variations (CNVs) from whole exome sequencing (WES) against a standard array-based method for CNV evaluation.Two papers, “Computational analysis of transcriptional circuitries in human embryonic stem cells reveals multiple and independent networks,” X. Wang and C. Guda assess the role of core transcription factors in the pluripotency of embryonic stem (ES) cells. Their computational analyses identified several additional transcriptional regulatory networks that might be involved in this complex regulatory process, providing interesting hypotheses about mechanisms of fate determination in ES cells. The paper “Network-assisted prediction of potential drugs for addiction” by J. Sun et al. describes computational analyses of drug-target networks for addictive and nonaddictive drugs. The authors analyzed the topology of these networks and found that drugs with similar effects could cluster together and identified a set of nonaddictive drugs that might have therapeutic benefits for treatment of addiction. This paper was called out in the recent “Translational Bioinformatics Year-in-Review” in 2014 Joint Summits on Translational Science (http://www.amia.org/jointsummits2014). In “DeGNServer: deciphering genome-scale gene networks through high performance reverse engineering analysis,” J. Li et al. describe their webserver to infer transcriptional regulatory networks from large-scale datasets. The server makes use of a computer cluster to run a number of network inference algorithms and return the results to the user very quickly, thus facilitating genome-scale network reconstruction.In “Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking” and “Novel natural structure corrector of ApoE4 for checking Alzheimer's disease: benefits from high throughput screening and molecular dynamics simulations,” deal with molecular docking simulations to determine small-molecule inhibitors targeting Alzheimer's disease. In the first paper, M. Goyal et al. used a fragment-based quantitative structure activity relationship (QSAR) analysis to identify lead compounds that might inhibit interaction of proteins that drive Alzheimer's disease pathogenesis. In the second paper, the authors describe large-scale docking simulations to screen for inhibitors of the conformational change of apolipoprotein E4 (ApoE4) that is thought to drive Alzheimer's pathogenesis. They further show the value of molecular dynamics simulations to screen candidates to eliminate molecules that do not have stable binding properties with targets. In “HGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through β1-integrin/ILK pathway,” J.-F. Li et al. experimentally investigate the contribution of hepatocyte growth factor (HGF) to wound healing. They showed that treatment of diabetic mice promoted proliferation and migration of epithelial cells and that this effect could be blocked by silencing the β1-integrin signaling pathway.Two papers from M. Goyal et al., “Integrative analysis of miRNA-mRNA and miRNA-miRNA interactions,” the authors first generated RNAseq data for normal and tumor cell lines and then identified aberrantly expressed mRNAs and miRNAs. Groups of similarly expressed miRNAs and mRNAs were analyzed to highlight examples of flexible and selective regulatory networks underlying these interactions. In “A diverse stochastic search algorithm for combination therapeutics,” M. U. Caglar and R. Pal show how the use of a stochastic search algorithm can be useful in identification of optimal combinations of drugs for therapy, the so-called drug cocktails. Their novel method greatly reduces the number of experimental steps needed to assess the optimal combination of drugs for a particular therapy. In “Evaluating word representation features in biomedical named entity recognition tasks” by B. Tang et al., the authors present a comparative analysis of three different methods for word representation in recognition of named entities from biomedical literature. Their findings indicate that a combination of the complementary approaches can improve results on benchmark recognition tasks.In the paper “Multiple biomarker panels for early detection of breast cancer in peripheral blood,” the authors describe the use of machine-learning approaches to identify a five-gene panel that can identify breast cancer from peripheral blood samples. In the paper by Jiang et al., “New aQTL SNPs for the CYP2D6 identified by a novel mediation analysis of genome-wide SNP arrays, gene expression arrays, and CYP2D6 activity,” the authors develop a novel approach for the detection of transexpression quantitative trait loci (eQTLs) from genome-wide association studies by considering indirect effects introduced by a mediator gene. They apply their method to analyze indirect regulatory effects on the important liver enzyme, CYP2D6. Finally, in “Expression sensitivity analysis of human disease related genes,” L.-X. Ma et al. examine the expression of genes implicated in a range of diseases. They report that genes that are robustly expressed under different perturbations are more likely to be associated with lethal diseases, whereas less robustly expressed genes are associated with nonlethal diseases.In the paper by F. Zhang et al., “


Although 3D cell cultures better mimic in vivo microenvironments of human tissues and provide an in-depth understanding of the morphological and functional features of tissues, they are also limited by having relatively low throughput and thus are not amenable to high-throughput screening (HTS). One attempt of making 3D cell culture amenable for HTS is to utilize miniaturized cell culture platforms. This review aims to highlight miniaturized 3D cell culture platforms compatible with current HCI technology.High content imaging (HCI) is a multiplexed cell staining assay developed for better understanding of complex biological functions and mechanisms of drug action, and it has become an important tool for toxicity and efficacy screening of drug candidates. Conventional HCI assays have been carried out on two-dimensional (2D) cell monolayer cultures, which in turn limit predictability of drug toxicity/efficacy  To address this issue, high content imaging (HCI) or high content screening (HCS) technology—which refers to a high-throughput, automated microscope-based assay that provides information on multiple properties or features of individual cells simultaneously with several fluorescent dyes—has been adapted to a more systematic and accurate evaluation of drug candidates ,9998,99]G2 cells . Similarll lines . Apart fll lines . Cheong  [et al. . Additio [et al. ,105,106  [et al. . One of  [et al. ,109. High-throughput HCI on miniaturized 3D cell culture has a potential to decipher toxicodynamic and toxicokinetic traits of drugs and helps us to understand complicated toxicology pathways and related adverse responses in early stages of drug discovery. Simplifying steps for miniaturized 3D cell culture and integrating the cell culture platforms with automation systems for liquid handling and image acquisition/analysis are critical to implement 3D HCI. Microwell and cellular microarray platforms are more compatible with automated liquid dispensing robots such as microarray spotters than microfluidic devices, resulting in increased throughput of HCI, whereas microfluidic devices are inherently low throughput in HCI due to the sample loading processes and large pumping units . In addi


Studies over the last decade have provided insights on the molecular and structural determinants of Gag-membrane binding. The human immunodeficiency virus type-1 (HIV-1) Gag polyprotein adopts a compact “folded over” conformation and exists in the monomeric or low-order oligomeric states prior to targeting to the PM  in the pericentriolar region of the infected cell and therefore. Structural details of M-PMV MA binding to single phospholipids are discussed. Dick et al. describe the principles that govern Gag interactions with membranes, focusing on RSV and HIV-1 Gag , a channel mediating release of Ca2+ from ER stores, as a cellular factor differentially associated with HIV-1 Gag that might facilitate ESCRT function in virus budding. In a research article, Ehrlich et al. show that Gag modulates ER store gating and refilling  and how various membrane components facilitate these events. It is well established that assembly of most of retroviral Gag proteins occurs on the plasma membrane (PM) (Ono et al., 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.


Streptomyces, which includes several hundred species, many of which produce biotechnologically useful secondary metabolites. The last 2 years have seen numerous publications describing Streptomyces genome sequences . Our blastn searches (using these two cluster sequences as queries) failed to detect a complete streptomycin gene cluster in the S. gancidicus genome, but there were some regions of sequence similarity on a 111 kb contig (GenBank: AOHP01000057). An antiSMASH 2.0 search failed to find any aminoglycoside biosynthetic cluster in this genome. We are not aware of any experimental evidence that this strain produces the aminoglycoside streptomycin and conclude that these seven genes highlighted by the authors  and relatively high error rates associated with these platforms can lead to rather fragmented and/or incomplete genome assemblies. The situation is not helped by the biased sequence composition (approximately 70% G + C) of Streptomyces DNA. Furthermore, non-ribosomal peptide synthases (NRPS) and polyketide synthetases (PK) are long, modular proteins made up of many repeated domain units. This means that the genes encoding these key enzymes can be particularly difficult to assemble accurately from short sequence reads. To overcome this issue, the authors of the Mg1 genome project  and which is notable for its production of the antibiotic moenomycin A , which has an 11.14 Mbp genome. Rather, strains SPC6 and DSM 40736 are closely related and fall within a clade with several other strains for which draft genomes are available and with Streptomyces venezuelae for which a complete finished genome sequence is available (Pullan et al., S. venezuelae reference sequence. Evidently, genome reduction has also occurred in S. albus strain J1074 (Zaburannyi et al., S. somaliensis (Kirby et al., Among bacteria, streptomycetes have some of the largest genomes, typically within the range of 8.7 Mbp to 11.9 Mbp (Zhou Streptomyces and related species [e.g. (Liu et al., Streptomyces sp. strain OH-4156, revealing an unusual class of post-translationally modified ribosomally synthesized peptides (Claesen and Bibb, et al., Streptomyces genome comes from strain PRh5, an endophyte of wild rice that produces nigericin, an antibiotic effective against mycobacteria (Yang et al., The availability of cheap sequencing has led to the generation of numerous genome sequences for


Escherichia coli is a heterogeneous species that can be part of the normal flora of humans but also include strains of medical importance. Among pathogenic members, Shiga-toxin producing E. coli (STEC) are some of the more prominent pathogenic E. coli within the public sphere. STEC disease outbreaks are typically associated with contaminated beef, contaminated drinking water, and contaminated fresh produce. These water- and food-borne pathogens usually colonize cattle asymptomatically; cows will shed STEC in their feces and the subsequent fecal contamination of the environment and processing plants is a major concern for food and public safety. This is especially important because STEC can survive for prolonged periods of time outside its host in environments such as water, produce, and farm soil. Biofilms are hypothesized to be important for survival in the environment especially on produce, in rivers, and in processing plants. Several factors involved in biofilm formation such as curli, cellulose, poly-N-acetyl glucosamine, and colanic acid are involved in plant colonization and adherence to different surfaces often found in meat processing plants. In food processing plants, contamination of beef carcasses occurs at different stages of processing and this is often caused by the formation of STEC biofilms on the surface of several pieces of equipment associated with slaughtering and processing. Biofilms protect bacteria against several challenges, including biocides used in industrial processes. STEC biofilms are less sensitive than planktonic cells to several chemical sanitizers such as quaternary ammonium compounds, peroxyacetic acid, and chlorine compounds. Increased resistance to sanitizers by STEC growing in a biofilm is likely to be a source of contamination in the processing plant. This review focuses on the role of biofilm formation by STEC as a means of persistence outside their animal host and factors associated with biofilm formation. Escherichia coli is a diverse species of bacterium that includes members of the normal commensal flora of humans and animals but also pathogenic strains of veterinary and medical importance. Pathogenic members are usually classified in two major groups: intestinal E. coli (InPEC) and extraintestinal E. coli (ExPEC). The latter group is typically responsible for urinary tract infections [uropathogenic E. coli (UPEC)], neonatal sepsis, and meningitis in humans and various infectious diseases in animals including mastitis  associated with Crohn's disease, diffusely adherent E. coli (DAEC), enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC), Shiga-toxin producing E. coli (STEC) that includes enterohemorrhagic E. coli (EHEC), and enteroinvasive E. coli (including Shigella) (EIEC)  strain will not be covered in this review because it does not fit within the classic STEC pathotype.The predominant STEC serotype associated with outbreaks is O157:H7. Since it was one of the first serotypes identified as causing hemolytic uremic syndrome (HUS) and the most severe illness, EHEC O157:H7 is the most commonly reported STEC serotype in the media , but in complex communities called biofilms. Biofilms are aggregates of microorganisms  enclosed in a self-produced extracellular polymeric matrix that are attached to a biotic or abiotic surface , several of which encode fimbrial adhesins  for the matrix architecture  among 51 STEC strains found that the presence of autotransporter genes within the genome was variable among STEC serotypes , colanic acid, and/or cellulose. The genes encoding proteins that are involved in the synthesis of these polysaccharides are present in the genomes of STEC strains EDL933 and Sakai  and capsules, which are surface structures, have been implicated in biofilm formation by E. coli group 4 capsule, which is composed of the same sugar repeats as the LPS O-antigen and acetamido sugars in their repeat-unit structures  and the export machinery (CsgE-G) , the signal molecule for AI-1, secreted by others bacterial species. In Sharma et al.  systems  in EPEC and aggregative adherence fimbriae (AAFs) in EAEC, results in the detachment of bacteria from the biofilm and surface  are also significantly up-regulated when E. coli O157:H7 interacts with lettuce roots , expel vesicles containing viable E. coli O157:H7, whereas Colpoda steinii and Acanthamoeba palestinensis (flagellates) do not . The persistence of STEC in the presence of disinfectants gives rise to the probability that STEC survive and grow within a biofilm in processing plants  and 4°C (production hours temperature) (Dourou et al., E. coli O157:H7 attachment increased at 4°C over time in the presence of a fat-lean tissue homogenate (Dourou et al., E. coli O157:H7 EDL933 is able to adhere and produce a dense biofilm on surfaces that are not favorable for its attachment when collagen I is present, which is a muscle fibrous extracellular matrix protein (Chagnot et al., E. coli O157:H7 is also able to form biofilms on stainless steel when grown in spinach leaf lysates (Carter et al., E. coli O157:H7 biofilms produce large amounts of AI-2 when cultured in pork, beef or spinach broth (Silagyi et al., In the processing plant environment, temperatures are normally controlled and maintained between 4 and 15°C. Many studies have shown that STEC are able to grow in a biofilm within this temperature range (Dourou et al., E. coli O157:H7 biofilms were more resistant to sanitizers than at lower RH (Bae et al., E. coli O157:H7 that were able to regrow as a biofilm on polyurethane (Marouani-Gadri et al., Fouladkhah et al. showed that the use of quaternary ammonium compound-based and peroxyacetic-based chemical sanitizers on biofilms that had matured for 1 week were more effective at 4°C than 25°C. However, these commercial sanitizers used at concentrations recommended to kill planktonic STEC were not able to kill or remove STEC biofilms from stainless steel surfaces (Fouladkhah et al., Comamonas testosterone, Acinetobacter calcoaceticus, Burkholderia caryphylli, and Ralstonia insidiosa, can initiate biofilm formation and may allow E. coli O157:H7 to integrate within a pre-formed biofilm, resulting in a mixed biofilm (Marouani-Gadri et al., C. testosteroni can enhance the ability of E. coli O157:H7 to form biofilms (Marouani-Gadri et al., C. testosteroni within the biofilm did, however, decrease the number of colony forming units of E. coli O157:H7 following chemical treatment when compared to chemical treatment of a single species E. coli O157:H7 biofilm (Marouani-Gadri et al., Interestingly, non-pathogenic bacteria isolated from processing plants, such as E. coli O157:H7 (Ryu et al., E. coli O157:H7 from sanitizer treatments (Ryu et al., E. coli O157:H7 could colonize a mature biofilm formed by EPS-producing bacteria (Castonguay et al., The ability to secrete EPS is related to biofilm formation on stainless steel surfaces, but it was shown that overproduction of the EPS inhibits the initial attachment of E. coli in general, a slow-growing and dormant subpopulations are highly tolerant to antibacterial treatments (Lewis, In addition to the protection offered by the biofilm matrix against sanitizers, it is well established that for s Lewis, . Cells fs Lewis, . The emes Lewis, . This noIt is known that STEC biofilms are more resistant to sanitizers than their planktonic counterparts (Wang et al., E. coli O157:H7 inside a biofilm. However, the biofilm matrix remains attached to the surface (Perez-Conesa et al., E. coli O157:H7 biofilms from processing plants. Others strategies such as bacteriophage treatments of E. coli O157:H7 biofilms have also been investigated. The KH1 bacteriophage reduces the population of O157:H7 cells attached to stainless steel, but not those incased within a biofilm matrix (Sharma et al., E. coli O157:H7 within the biofilm and remove the biofilm matrix from the contaminated surface. For example, a combination of steam and lactic acid were able to kill E. coli O157:H7 and remove the biofilm matrix from stainless steel surfaces (Ban et al., Many essential oils have been shown to have good antibiofilm activity against food-borne pathogens (Giaouris et al., Contamination of the environment and processing plants with cow feces containing STEC is a major concern for food and public safety, especially since STEC can survive for prolonged periods of time outside its host. Biofilm formation appears to contribute significantly to STEC survival on produce, in rivers, and in processing plants. Several factors involved in biofilm formation such as curli, cellulose, PGA, and colanic acid are involved in plant colonization and attachment to different surfaces often found in meat processing plants. However, the factors involved in STEC survival within biofilms in rivers remain unknown. Furthermore, STEC biofilm formation on farms, in manure, and in soil has not been thoroughly explored despite the presence and persistence of STEC in these environments. The Stx toxin, which is a key factor in human host pathology, also appears to be an important factor for STEC survival against protozoan predation. In the food industry, resistance to sanitizers improves the ability of STEC to persist in the processing plant. Despite the development of new strategies to eradicate biofilms formed by food-borne pathogens, no effective solutions to remove STEC biofilms from surfaces have been identified. Therefore, future research should focus on the identification of factors promoting STEC survival, especially non-O157 STEC, and the persistence of STEC in environmental biofilms on the farm.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 = 106)  , a recently developed therapy for resistant hypertension, is generally regarded as a safe procedure  renal artery stenosis causes recurrent hypertension in denervated patients (Kaltenbach et al., Long-term randomized trials are needed. Two major randomized trials on RDN, i.e., the Symplicity HTN-2 and HTN-3 trials (Esler et al., Imaging methods monitoring renal artery stenosis need to be standardized. Symplicity HTN trials did not standardize renal artery imaging methods during follow ups. Ultrasonography, magnetic resonance angiography, and computerized tomographic angiography were used (Krum et al., It is likely that improved catheters for RDN using lower power radiofrequency over a shorter time will reduce the local tissue injury at the ablation site compared with that caused by the first generation RDN systems (Versaci et al., 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.


We appreciate Lioy et al.’s interest in our recent article  documentn-butyl phthalate (DnBP) and di(2-ethylhexyl) phthalate (DEHP) is encouraging, but the rising trend in other phthalates, such as diisobutyl phthalate (DiBP) and diisononyl phthalate (DiNP), is worrisome. Lioy et al. note that DiNP is less potent as an antiandrogen than the other phthalates. However, its increasing presence in the U.S. general population warrants public health concern: The U.S. Environmental Protection Agency (EPA) has expressed concern about DiNP’s use [Phthalates Action Plan  and other large environmental health studies to evaluate the presence of potential “substitute” chemicals not only of phthalates but also of other environmental chemicals to provide the best human exposure information. In fact, for the most recent NHANES survey (2011–2012), scientists at the Centers for Disease Control and Prevention are beginning to release population-level data for the urinary metabolite of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a nonphthalate plasticizer that is used as a replacement for some of the high-molecular-weight phthalates . Indeed,


Growth factors such as transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) have been associated with the tendon healing process  as a novel method for treating tendon and ligament injuries is also discussed.Human tendon healing process is classified into five phases as follows: immediate post injury phase, inflammatory phase, proliferation phase, reparative phase, and remodeling phase  consist of MSCs and HSCs, which can further differentiate into various cell types that secrete growth factors  is impeded by the lack of soft tissue around it. However, partially ruptured ACL can regenerate with growth factor administration and after cell transplantation. Intra-articular transplantation therapies using MSCs have been used for treating torn ACLs (Agung et al., Recently, we showed that partially transected rodent ACL can be repaired by injection of BMCs or cultured MSCs into the articular cavity at 1 week after transection (Oe et al., Stem cell therapies use several stem cell sources such as human embryonic stem cells, MSCs, BMCs, and bone marrow mononucleated cells have been reported (Chen et al., Few clinical trials have been performed using stem cells transplantations for treating tendon and ligament injuries in humans. Ahmad et al have reviewed 5 clinical studies that used stem cell therapy for treating tendon injuries and concluded that stem cells can have positive effect on tendon healing (Ahmad et al., 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.


Our earlier studies showed that lactational exposure to lead (Pb) caused irreversible neurochemical alterations in rats. The present study was carried out to examine whether gestational exposure to Pb can cause long-term changes in the brain cholinergic system and behavior of rats. The protective effect of calcium (Ca) supplementation against Pb toxicity was also examined. Pregnant rats were exposed to 0.2% Pb (Pb acetate in drinking water) from gestational day (GD) 6 to GD 21. The results showed decrease in body weight gain (GD 6–21) of dams, whereas no changes were observed in offspring body weight at different postnatal days following Pb exposure. Male offspring treated with Pb showed marginal alterations in developmental landmarks such as unfolding of pinnae, lower and upper incisor eruption, fur development, eye slit formation and eye opening on postnatal day (PND) 1, whereas significant alterations were found in the righting reflex (PNDs 4–7), slant board behavior (PNDs 8–10) and forelimb hang performance (PNDs 12–16). Biochemical analysis showed decrease in synaptosomal acetylcholinesterase (AChE) activity and an increase in acetylcholine (ACh) levels in the cortex, cerebellum and hippocampus on PND 14, PND 21, PND 28 and in the four-month age group of rats following Pb exposure. Significant deficits were also observed in total locomotor activity, exploratory behavior and open field behavior in selected age groups of Pb-exposed rats. These alterations were found to be maximal on PND 28, corresponding with the greater blood lead levels observed on PND 28. Addition of 0.02% Ca to Pb reversed the Pb-induced impairments in the cholinergic system as well as in behavioral parameters of rats. In conclusion, these data suggest that gestational exposure to Pb is able to induce long-term changes in neurological functions of offspring. Maternal Ca administration reversed these neurological effects of Pb later in life, suggesting a protective effect of calcium in Pb-exposed animals. Developmental exposure to Pb has become an important public health concern because of the possible toxic impact on sensitive development and programing of organ functions  is an essential mineral for the newborn infant and alteration in Ca signaling may have life-long consequences in brain functions (Bass Lead acetate (99.99% purity) was purchased from Sigma Chemicals  and all other chemicals from Merck, India.et al.,et al.,et al.,et al.,Female and male albino rats (Wistar) were acclimatized for one week before mating. Two females and one male were placed overnight in a cage and the presence of a vaginal sperm plug was recorded. Pregnancies determined by the presence of sperm in the vaginal smear were considered gestational day (GD) 1. On GD 6, the dams were randomly assigned to three experimental groups  exposed rats and Group III – animals exposed to 0.02% calcium supplement together with Pb. The animals were housed individually. Pregnant animals were exposed to low level Pb (0.2%) by intake of Pb-acetate dissolved in deionized water from gestational day 6 (GD 6) until the birth of pups (GD 21) . Calciumet al.,et al.,Starting with PND 1, the number of pups  was counted and gender differences were recorded. The male pups were weighed and observed for developmental signs, such as fur development (the appearance of fur sufficient to cover skin), incisor teeth eruption (the first appearance of the upper and lower incisors), pinnae detachment (both ears completely unfolded from the head), eye slit formation, eye opening (both eyes fully open) and crown rump length  stretched between two wooden blocks was then permitted to grasp the string with its forepaws, where the point was released, so that it was suspended from the string by its forepaws. The latency to fall from the string (maximum 60 s) was measured and each pup was tested for a single trial on each of the five test days  at the designated time periods (PNDs) for a period of two hours in the morning (08.00–10.00AM). The activity was presented as counts/min.Open field behavior: The open field behavior was measured in a chamber measuring 90×90×90 cm. The floor of the arena was divided into 36 equal squares. The number of squares crossed with all paws (crossing), standing on the hind legs (rearing), standing on the hind legs and placing the forelimbs on the wall , placing the nose against the wall or floor (sniffing), and wiping, licking or combing of any part of the body (grooming) were recorded. The sum of all tasks in open field was considered the total behavior  containing three equally spaced holes (3 cm in diameter) in the floor. Each rat was placed in the center of the arena for 5 min., the time during which the number of head dips and head-dipping duration (in seconds) were recorded. A head dip was scored if both eyes disappeared into the hole.et al.,For the determination of Pb levels, 5.0 ml of whole blood was taken by heart puncture. After digestion with concentrated nitric acid using a microwave digestion system followed by addition of 30% hydrogen peroxide, the samples were brought to a constant volume. Blood Pb levels were determined with an atomic absorption spectrophotometer (AAS-Shimadzu-AA 6300) with graphite furnace (GFA-EX7i)  followed by Student-Newman-Keuls (SNK) post hoc test using statistical package for social sciences (SPSS 16) to compare the effects among various groups. The 0.05 level of probability was used as the criterion for significance. All the data in this study were analyzed using the dam or litter as the experimental unit. For some behavioral measures, two pups from each litter were tested, but the values were averaged and only one value from each litter was considered for statistical analysis. The variation within the litter was less than 5%.p<0.05), while the body weight of male offspring from Pb-exposed mothers showed no significant changes on PND 7, PND 14, PND 21, PND 28 and in 4-month-old rats compared to controls (p<0.01) was observed in the latency to turn in the righting reflex and slant board behavior of Pb-exposed offspring (p<0.01) recorded from PND 12 to PND 16  and levels of acetylcholine (ACh) were determined in the cortex, cerebellum and hippocampus on PND 14, PND 21, PND 28 and in the 4-month age groups of control and Pb exposed rats  and 7. Ap<0.001) increased the Pb levels  in all selected age groups of rats  levels at any age induce neuro-degeneration that leads to impairment of neurobehavioral functions (Schwartz et al.,  observed et al., also obset al.,et al., (et al.,et al.,et al.,et al.,et al.,et al.,et al.,Dietary Ca intake can support normal fetal growth and development during pregnancy in animals and humans (Han et al.,  have sugConsistent with the published work and results from our laboratory, it is clear that gestational exposure to Pb is sufficient to induce late life alterations in neurobehavioral functions in rats. These neurobehavioral changes continue even long after the Pb exposure was stopped. Although Ca supplement reversed the Pb-induced neurotoxicity, longterm protection by Ca is partial, suggesting that adequate calcium intake would be beneficial in treating Pb-induced toxicity during pregnancy in rats.


Recent advances in modern molecular technology and next-generation sequencing platform have brought in enormous insights into evolution. Although challenges remain, evolutionary research now enters a new era and becomes a hybrid discipline encompassing the fields of molecular biology, genetics and genomics, metabolomics, neuroscience, structural and chemical biology, bioinformatics, proteomics, pharmacology, statistics, and computational biology. The common bond or theme that unifies the various fields is the need to reveal complex genotype-phenotype relationships and their mechanistic regulations, attempting to understand the diversifying functionality in life and ultimately find the underlying causes and effective means of treating disease.Articles in this special issue cover a broad range of topics related to the evolution of genomes, transcriptomes, proteomes, and interactomes in diverse organisms, including humans.Signal transduction networks are dynamic and constantly under environmental selection in evolution. This topic is covered in the long review article “Multi-OMICs and Genome Editing Perspectives on Liver Cancer Signaling Networks” by S. Lin et al. This review covers multiple advances in the multi-OMICs and genome editing technologies, now available for use in biomedical and cancer research, and provides new perspectives in targeted therapy and precision medicine. Proteome and interactome networks are also investigated in an accompanying research paper “Positive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks.” S. Chakraborty and D. Alvarez-Ponce study the selective pressures of yeast and fly proteome and show that long-term positive selection has preferentially targeted the periphery of the yeast interactome, while interestingly in flies genes under positive selection encode significantly more connected and central proteins.Transcriptional and functional regulation and conservation during evolution are touched upon in two other reviews in this special issue. In “Circadian Control of Global Transcription,” S. Li and L. Zhang discuss circadian rhythms through investigating expression of clock-controlled genes (CCGs). They summarize the circadian control of CCG transcription in five model organisms, including cyanobacterium, fungus, plant, fruit fly, and mouse, providing an overview to the function of the circadian clock, as well as its output mechanisms adapted to meet the demands of diverse environmental conditions. In “Roles of Hsp70s in Stress Responses of Microorganisms, Plants, and Animals,” A. Yu et al. review the heat shock protein 70s family members, a class of molecular chaperones that are highly conserved and ubiquitous in organisms ranging from microorganisms to plants and humans. This review provides an overview of the specific roles of Hsp70s in response to stress, particularly abiotic stress, in diverse taxa. Mycobacterium tuberculosis and Lung Cancer: Implications into Host-Pathogen Interaction and Coevolution,” Y. Tian et al. study the cross-link between pathogens and cancer. They examined the association between the Mycobacterium tuberculosis (MTB) and lung cancer and found that 62% of the lung cancer samples are MTB-L positive, suggesting a link between MTB infection and lung cancer development. In another paper “Lost Polarization of Aquaporin4 and Dystroglycan in the Core Lesion after Traumatic Brain Injury Suggests Functional Divergence in Evolution,” H. Liu et al. study the roles of aquaporin4 and dystroglycan in brain edema formation after traumatic brain injury. They found that at an early stage of traumatic brain injury aquaporin4 and dystroglycan maintained the polarized distribution, which were subsequently lost from perivascular end-feet and induced cytotoxic brain edema. In addition, in the study entitled “Identification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder,” U. Sabbagh et al. set out to find genes linked with eating disorders and associated with both metabolic and neural systems . Through a text-based analysis, they identified a number of potential candidate genes including VGF. VGF human polymorphism studies contribute to eating disorders and obesity, suggesting a new approach to connect eGWAS and GWAS in NES patients.Evolutionary principles and adaptation lessons learned from research have been successfully applied to human disease studies, revealing important insights into potential targets for therapy. In the paper “Clinical End-Points Associated with flfl Triggers JNK-Dependent Cell Death in Drosophila,” J. Huang and L. Xue study a gene, falafel (flfl), that encodes a fruit fly Drosophila homolog of human SMEK. They performed both gain-of-function and loss-of-function analysis in Drosophila and identified flfl as a negative regulator of JNK pathway-mediated cell death. In another study “Neurotrophin, p75, and Trk Signaling Module in the Developing Nervous System of the Marine Annelid Platynereis dumerilii,” A. Lauri et al. study the evolution of neurotrophic signaling in neuronal development, neural circuit formation, and neuronal plasticity using the worm Platynereis system. They discovered and validated nucleotide sequences encoding putative neurotrophic ligands and receptors in two annelids, suggesting roles of these molecules in nervous system and circuit development, as well as their involvement in shaping neural networks during protostome-deuterostome evolution.Model systems have been instrumental in elucidating signaling mechanisms underlying biological function, providing interesting cues in evolutionary research areas. In the article “Loss ofThe great leap in evolutionary research would not be possible without the development of modern molecular technologies. CRISPR/Cas9 system is a powerful technology to perform genome editing in a variety of cell types. In the paper “A CRISPR-Based Toolbox for Studying T Cell Signal Transduction,” S. Chi et al. adapted CRISPR/Cas9-based tools to study human Jurkat cells. They showed that distinct Cas9 variants, including wild-type Cas9, dCas9-KRAB, and sunCas9 function as expected in different Jurkat cell lines.With the advent of next-generation sequencing platforms, a large number of genomewide sequencing data become available, which greatly facilitate the evolution research field to promote to a new height. In the paper “Computational Analysis of the Binding Specificities of PH Domains,” Z. Jiang et al. study Pleckstrin homology domain proteins with significant insights into binding specificity and abnormal regulation in disease. In addition, in another report “SimFuse: A Novel Fusion Simulator for RNA Sequencing (RNA-Seq) Data,” Y. Tan et al. developed the SimFuse pipeline to accelerate fusion discovery from RNAseq data. SimFuse utilizes real sequencing data as the fusions' background to closely approximate the distribution of reads from a real sequencing library and uses a reference genome as the template from which to simulate fusions' supporting reads, improving the performance metrics, rigor, and control.The future evolution researchers will need to be well versed in interdisciplinary fields and have the appropriate background to leverage the biological, clinical, and computational resources necessary to understand their data and track dynamic evolution. The communication among these specialty disciplines, acting in unison, will be critical as we strive to uncover answers underlying the complex and often puzzling molecular events in evolution.We hope that this special issue would shed light on major advances in the broad area of signal transduction with evolutionary insights and engender novel hypotheses and research innovations to investigate deeper mechanisms and further to engineer signaling circuits for personalized therapeutics in human disease.