Incorporating Distant Sequence Features and Radial Basis Function Networks to Identify Ubiquitin Conjugation Sites

Ubiquitin (Ub) is a small protein that consists of 76 amino acids about 8.5 kDa. In ubiquitin conjugation, the ubiquitin is majorly conjugated on the lysine residue of protein by Ub-ligating (E3) enzymes. Three major enzymes participate in ubiquitin conjugation. They are – E1, E2 and E3 which are responsible for activating, conjugating and ligating ubiquitin, respectively. Ubiquitin conjugation in eukaryotes is an important mechanism of the proteasome-mediated degradation of a protein and regulating the activity of transcription factors. Motivated by the importance of ubiquitin conjugation in biological processes, this investigation develops a method, UbSite, which uses utilizes an efficient radial basis function (RBF) network to identify protein ubiquitin conjugation (ubiquitylation) sites. This work not only investigates the amino acid composition but also the structural characteristics, physicochemical properties, and evolutionary information of amino acids around ubiquitylation (Ub) sites. With reference to the pathway of ubiquitin conjugation, the substrate sites for E3 recognition, which are distant from ubiquitylation sites, are investigated. The measurement of F-score in a large window size (−20∼+20) revealed a statistically significant amino acid composition and position-specific scoring matrix (evolutionary information), which are mainly located distant from Ub sites. The distant information can be used effectively to differentiate Ub sites from non-Ub sites. As determined by five-fold cross-validation, the model that was trained using the combination of amino acid composition and evolutionary information performs best in identifying ubiquitin conjugation sites. The prediction sensitivity, specificity, and accuracy are 65.5%, 74.8%, and 74.5%, respectively. Although the amino acid sequences around the ubiquitin conjugation sites do not contain conserved motifs, the cross-validation result indicates that the integration of distant sequence features of Ub sites can improve predictive performance. Additionally, the independent test demonstrates that the proposed method can outperform other ubiquitylation prediction tools

Improving physical health and reducing substance use in psychosis - randomised control trial (IMPACT RCT): study protocol for a cluster randomised controlled trial

The National Institute for Health Research funds the IMPACT programme at King’s College London and South London and Maudsley NHS Foundation Trust (ref: RP-PG-0606-1049)

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness.

Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P<0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness

Understanding the rise of faculty-student coaching: an academic capitalism perspective

We examine the rise of coaching within management education to support student learning. We question the assumption that faculty-student coaching (FSC) is beneficial and propose that there may be some limitations in the use of FSC that have yet to be adequately acknowledged and discussed in the literature. In particular, we propose that there is currently insufficient evidence to conclude that coaching can produce knowledge acquisition and therefore ask why we persist in the use of FSC when we have limited evidence of its efficacy in delivering a core education outcome. We suggest that the theory of academic capitalism provides a useful, critical lens through which to view the growing trend in FSC, identifying that FSC may be utilized as a method of increasing student satisfaction, perceptions of value for money and as a useful marketing tool for business schools competing for students. However, academic capitalism may also explain the use of coaching via its ability to enhance the skills and attitudes of students, providing outcomes that are valued by students, employers and governments. We conclude our essay by providing recommendations to mitigate these proposed dangers and consequently maximise the effectiveness of coaching as a development tool in management education

Sex Differences in Avoidance Behavior and Neuroinflammation in a Comorbid Model of Posttraumatic Stress Disorder and Alcohol Use Disorder

Post-traumatic stress disorder (PTSD) is a debilitating disorder with a prevalence rate of approximately 6%. PTSD is commonly associated with alcohol use disorder (AUD). Of those diagnosed with PTSD, 30%-59% also suffer from AUD. Currently, there are limited effective treatment options for those suffering from comorbid PTSD/AUD. Previous research suggests that biological sex differentially impacts comorbid PTSD/AUD, however, the underlying mechanisms are enigmatic. Those with PTSD and AUD also tend to avoid environmental cues associated with the disorders. Avoidance and freezing are two distinct defensive responses to threats that display sex differences as well. Active avoidance behavior involves actively taking steps to prevent or mitigate a perceived threat, such as moving away from a source of danger, like avoiding the location of the trauma. Freezing behavior, on the other hand, is a passive defensive response characterized by immobility, which is thought to reduce the likelihood of detection by predators, such as freezing in place when someone hears a sound associated with the trauma. The underlying mechanisms of avoidance and the apparent sex differences, however, are unknown. While some studies have investigated the neural mechanisms associated with avoidance fear responses, the impact that stress and chronic alcohol exposure have on avoidance behavior needs further investigation. Our lab recently found that in an animal model of comorbid PTSD/AUD, there are significant increases in neuroinflammation in the prelimbic (PrL), and infralimbic (IfL) cortices, and the hippocampus (HPC), all brain regions that are significantly involved in learning and memory. Both PTSD and AUD have been associated with increased proinflammatory markers in humans and animals, including tumor necrosis factor (TNF)- and interleukin (IL)-1 in plasma and the HPC and PrL. The purpose of this set of experiments was to utilize our rat model of PTSD/AUD comorbidity to assess changes in avoidance behaviors using the platform-mediated avoidance (PMA) paradigm and investigate brain region specific neuroinflammation. A comorbid PTSD/AUD rodent model was implemented in our lab using restraint stress (RS) and chronic intermittent ethanol exposure (CIE) in both male and female Wistar rats. This was followed by the PMA task to assess avoidance behavior where the rodents learned to avoid a tone-signaled footshock by stepping onto a nearby platform. In the experiments described, freezing was initially a common response to the tone that signaled a footshock, but as rats learned the avoidance task, freezing decreased. Importantly, a sex difference found that females displayed more active avoidance while the males displayed more passive avoidance by freezing. The neuroinflammation data was collected from the PrL, IfL and HPC of the brain tissue. TNF- and IL-1 enzyme linked-immunosorbent assays (ELISAs) were used to analyze the tissue. The neuroinflammation data indicated that males not exposed to RS or CIE showed higher levels of IL-1 than any other group. These results reveal that avoidance behavior strategies in comorbid PTSD/AUD are sex-dependent and neuroinflammation could be part of the pathology of comorbid PTSD/AUD

Behavioral and Neuroinflammatory Sex Differences in Comorbid Posttraumatic Stress Disorder and Alcohol Use Disorder

Post-traumatic stress disorder (PTSD) is a debilitating disorder with a prevalence rate of approximately 5%. Unfortunately, this disorder is commonly associated with another debilitating disorder, alcohol use disorder (AUD). Of the 5% of people diagnosed with PTSD, 30%-59% also suffer from AUD. Currently, there are limited effective treatment options for those suffering from comorbid PTSD/AUD. Previous research has suggested that biological sex differentially impacts PTSD comorbid with AUD, however, the underlying mechanisms are enigmatic. The goal of this study was to better understand the underlying mechanisms that mediate sex differences in a rodent model of comorbid PTSD/AUD by analyzing specific behavioral tasks and changes in neuronal function of specific brain regions. Chronic inflammation has been implicated in PTSD and AUD respectively, with differences between sexes being observed. Females tend to express elevated levels of inflammation in both disorders compared to males in brain regions such as, the hippocampus, amygdala, and prefrontal cortex. Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that is released during neuronal inflammation. To further examine these sex differences, a comorbid PTSD/AUD rodent model was implemented using restraint stress (RS) and chronic intermittent ethanol use (CIE). Following the exposure to RS and CIE a fear conditioning procedure was implemented to assess changes in future stress sensitivity. The fear conditioning paradigm was accomplished by conditioning the animal to pair a tone with a foot shock, followed by extinction of that behavior in a different context where the animal received the tone but no foot shock. Thereafter, the animal was placed back in the context they received the foot shock, known as context renewal, but acquired no tone or foot shock. The behavior in these different contexts was analyzed to test memory and stress sensitivity. Brain tissue was collected to analyze TNF-α protein expression in regions associated with learning, memory, and addiction such as, the prelimbic cortex (PrL), infralimbic cortex (IfL), and the hippocampus. The results of the fear conditioning revealed that the females froze more altogether compared to the males, and there was more freezing of the females with RS and CIE during context renewal. It is expected that TNF-α protein expression will be significantly elevated in females when compared to males, regardless of treatment group. Females exposed to RS and CIE will have significantly higher TNF-α levels when compared to all other treatment groups. Finally, increases in TNF-α protein expression will be region specific with the PrL and IfL regions exhibiting significantly greater expression than the hippocampus. This study will aid in better understanding the sex differences and lead to better treatment options that are sex-dependent for those diagnosed with comorbid PTSD/AUD

CDPPB attenuates risky behavior in a rodent model of PTSD/AUD comorbidity

Alcohol use disorder (AUD) is the leading cause of substance use disorders among Veterans and 55 to 75% of the population that are diagnosed with PTSD also receive a comorbid diagnosis of AUD. The co-diagnosis of PTSD/AUD is associated with neurocognitive changes such as increased impulsivity and risk-taking behavior, especially among individuals with combat-related trauma. Furthermore, increased neuroinflammation in subregions of the prefrontal cortex (PFC) are suggested to contribute to these neurocognitive changes. To better understand the cognitive deficits associated with co-occurring PTSD/AUD we incorporated a probabilistic discounting task (PDT) to model risk-based decision-making in male and female Wistar rats that were exposed to restraint stress (RS) and chronic intermittent ethanol exposure (CIE). Following RS and CIE, rats underwent lever press training through a series of different training phases, in which one lever delivered a small reward 100% of the time, and the other a large reward, delivered with descending probability each trial block. Pressing the large-reward lever during the final two trial blocks when it is disadvantageous to do so is considered “risky” behavior. A week prior to PDT, rats were treated prophylactically with CDPPB, a positive allosteric modulator of the metabotropic glutamate type 5 (mGlu5) receptor, to determine if the cognitive deficits caused by stress and alcohol exposure could be prevented. Additionally, to determine if our model mimicked the neuroinflammatory mechanism seen in the human condition and the therapeutic effects of CDPPB, we assessed TNF-⍺ protein expression in a subset of rats. Our results indicated that male rats exposed to RS and CIE had significantly greater responding during the 3rd, 4th, and 5th risk blocks compared to all other groups. However, the administration of CDPPB reversed this effect. Females exposed to RS and CIE only displayed increased risky behavior at the highest risk block and this was also blocked with the administration of CDPPB. We also determined that RS and CIE significantly increased TNF-⍺ levels in the IfL cortex compared to either RS or CIE alone and the prophylactic administration of CDPPB reduced TNF-⍺ protein expression to control animal levels. In the present study, we demonstrate that exposure to stress and chronic alcohol leads to significant neurocognitive deficits resulting in increased risky decision-making, but these deficits can be attenuated through modulation of the mGlu5 receptor prior to behavioral testing. Additionally, these deficits could be due to deleterious neuroinflammation in subregions of the PFC

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.Puya Gharahkhani ... Shiwani Sharma ... Robert J Casson, Mark Chehade ... Wellcome Trust Case Control Consortium, NEIGHBORHOOD Consortium ... et.al