Icing: Large-scale inference of immunoglobulin clonotypes

Immunoglobulin (IG) clonotype identification is a fundamental open question in modern immunology. An accurate description of the IG repertoire is crucial to understand the variety within the immune system of an individual, potentially shedding light on the pathogenetic process. Intrinsic IG heterogeneity makes clonotype inference an extremely challenging task, both from a computational and a biological point of view. Here we present icing, a framework that allows to reconstruct clonal families also in case of highly mutated sequences. icing has a modular structure, and it is designed to be used with large next generation sequencing (NGS) datasets, a technology which allows the characterisation of large-scale IG repertoires. We extensively validated the framework with clustering performance metrics on the results in a simulated case. icing is implemented in Python, and it is publicly available under FreeBSD licence at https://github.com/slipguru/icing

Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

Ethnic Variations in the Prevalence of Diabetic Retinopathy in People with Diabetes Attending Screening in the United Kingdom (DRIVE UK)

AIMS: To compare the prevalence of diabetic retinopathy (DR) in people of various ethnic groups with diabetes in the United Kingdom (UK). METHODS: The Diabetic Retinopathy In Various Ethnic groups in UK (DRIVE UK) Study is a cross-sectional study on the ethnic variations of the prevalence of DR and visual impairment in two multi-racial cohorts in the UK. People on the diabetes register in West Yorkshire and South East London who were screened, treated or monitored between April 2008 to July 2009 (London) or August 2009 (West Yorkshire) were included in the study. Data included age, sex, ethnic group, type of diabetes, presenting visual acuity and the results of grading of diabetic retinopathy. Prevalence estimates for the ethnic groups were age-standardised to the white European population for comparison purposes. RESULTS: Out of 57,144 people on the two diabetic registers, data were available on 50,285 individuals (88.0%), of these 3,323 had type 1 and 46,962 had type 2 diabetes. In type 2 diabetes, the prevalence of any DR was 38.0% (95% confidence interval (CI) 37.4% to 38.5%) in white Europeans compared to 52.4% (51.2% to 53.6%) in African/Afro-Caribbeans and 42.3% (40.3% to 44.2%) in South Asians. Similarly, sight threatening DR was also significantly more prevalent in Afro-Caribbeans (11.5%, 95% CI 10.7% to 12.3%) and South Asians (10.3%, 9.0% to 11.5%) compared to white Europeans (5.5%, 5.3% to 5.8%). Differences observed in Type 1 diabetes did not achieve conventional levels of statistical significance, but there were lower numbers for these analyses. CONCLUSIONS: Minority ethnic communities with type 2 diabetes in the UK are more prone to diabetic retinopathy, including sight-threatening retinopathy and maculopathy compared to white Europeans

Current research in biotechnology: Exploring the biotech forefront

Biotechnology is an evolving research field that covers a broad range of topics. Here we aimed to evaluate the latest research literature, to identify prominent research themes, major contributors in terms of institutions, countries/regions, and journals. The Web of Science Core Collection online database was searched to retrieve biotechnology articles published since 2017. In total, 12,351 publications were identified and analyzed. Over 8500 institutions contributed to these biotechnology publications, with the top 5 most productive ones scattered over France, China, the United States of America, Spain, and Brazil. Over 140 countries/regions contributed to the biotechnology research literature, led by the United States of America, China, Germany, Brazil, and India. Journal of Bioscience and Bioengineering was the most productive journal in terms of number of publications. Metabolic engineering was among the most prevalent biotechnology study themes, and Escherichia coli and Saccharomyces cerevisiae were frequently used in biotechnology investigations, including the biosynthesis of useful biomolecules, such as myo-inositol (vitamin B8), monoterpenes, adipic acid, astaxanthin, and ethanol. Nanoparticles and nanotechnology were identified too as emerging biotechnology research themes of great significance. Biotechnology continues to evolve and will remain a major driver of societal innovation and development

High risk for occupational exposure to HIV and utilization of post-exposure prophylaxis in a teaching hospital in Pune, India

<p>Abstract</p> <p>Background</p> <p>The risk for occupational exposure to HIV has been well characterized in the developed world, but limited information is available about this transmission risk in resource-constrained settings facing the largest burden of HIV infection. In addition, the feasibility and utilization of post-exposure prophylaxis (PEP) programs in these settings are unclear. Therefore, we examined the rate and characteristics of occupational exposure to HIV and the utilization of PEP among health care workers (HCW) in a large, urban government teaching hospital in Pune, India.</p> <p>Methods</p> <p>Demographic and clinical data on occupational exposures and their management were prospectively collected from January 2003–December 2005. US Centers for Diseases Control guidelines were utilized to define risk exposures, for which PEP was recommended. Incidence rates of reported exposures and trends in PEP utilization were examined using logistic regression.</p> <p>Results</p> <p>Of 1955 HCW, 557 exposures were reported by 484 HCW with an incidence of 9.5 exposures per 100 person-years (PY). Housestaff, particularly interns, reported the greatest number of exposures with an annual incidence of 47.0 per 100 PY. Personal protective equipment (PPE) was used in only 55.1% of these exposures. The incidence of high-risk exposures was 6.8/100 PY (n = 339); 49.1% occurred during a procedure or disposing of equipment and 265 (80.0%) received a stat dose of PEP. After excluding cases in which the source tested HIV negative, 48.4% of high-risk cases began an extended PEP regimen, of whom only 49.5% completed it. There were no HIV or Hepatitis B seroconversions identified. Extended PEP was continued unnecessarily in 7 (35%) of 20 cases who were confirmed to be HIV-negative. Over time, there was a significant reduction in proportion of percutaneous exposures and high-risk exposures (p < 0.01) and an increase in PEP utilization for high risk exposures (44% in 2003 to 100% in 2005, p = 0.002).</p> <p>Conclusion</p> <p>Housestaff are a vulnerable population at high risk for bloodborne exposures in teaching hospital settings in India. With implementation of a hospital-wide PEP program, there was an encouraging decrease of high-risk exposures over time and appropriate use of PEP. However, overall use of PPE was low, suggesting further measures are needed to prevent occupational exposures in India.</p

Exaggerated CpH methylation in the autism-affected brain

BACKGROUND: The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue. METHODS: Reduced representation bisulfite sequencing (RRBS) was completed, and analysis was carried out in 63 post-mortem cortical brain samples (Brodmann area 19) from 29 autism-affected and 34 control individuals. Analyses to identify single sites that were differentially methylated and to identify any global methylation alterations at either CpG or CpH sites throughout the genome were carried out. RESULTS: We report that while no individual site or region of methylation was significantly associated with autism after multi-test correction, methylated CpH dinucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p < 0.05 cutoff, p = 0.002). CONCLUSIONS: These results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13229-017-0119-y) contains supplementary material, which is available to authorized users

A redox state-dictated signalling pathway deciphers the malignant cell specificity of CD40-mediated apoptosis

CD40, a member of the tumour necrosis factor receptor (TNFR) superfamily, has the capacity to cause extensive apoptosis in carcinoma cells, while sparing normal epithelial cells. Yet, apoptosis is only achieved by membrane-presented CD40 ligand (mCD40L), as soluble receptor agonists are but weakly pro-apoptotic. Here, for the first time we have identified the precise signalling cascade underpinning mCD40L-mediated death as involving sequential TRAF3 stabilisation, ASK1 phosphorylation, MKK4 (but not MKK7) activation and JNK/AP-1 induction, leading to a Bak- and Bax-dependent mitochondrial apoptosis pathway. TRAF3 is central in the activation of the NADPH oxidase (Nox)-2 component p40phox and the elevation of reactive oxygen species (ROS) is essential in apoptosis. Strikingly, CD40 activation resulted in down-regulation of Thioredoxin (Trx)-1 to permit ASK1 activation and apoptosis. Although soluble receptor agonist alone could not induce death, combinatorial treatment incorporating soluble CD40 agonist and pharmacological inhibition of Trx-1 was functionally equivalent to the signal triggered by mCD40L. Finally, we demonstrate using normal, ‘para-malignant’ and tumour-derived cells that progression to malignant transformation is associated with increase in oxidative stress in epithelial cells, which coincides with increased susceptibility to CD40 killing, while in normal cells CD40 signalling is cytoprotective. Our studies have revealed the molecular nature of the tumour specificity of CD40 signalling and explained the differences in pro-apoptotic potential between soluble and membrane-bound CD40 agonists. Equally importantly, by exploiting a unique epithelial culture system that allowed us to monitor alterations in the redox-state of epithelial cells at different stages of malignant transformation, our study reveals how pro-apoptotic signals can elevate ROS past a previously hypothesised ‘lethal pro-apoptotic threshold’ to induce death; an observation that is both of fundamental importance and carries implications for cancer therap

An informatics model for tissue banks – Lessons learned from the Cooperative Prostate Cancer Tissue Resource

BACKGROUND: Advances in molecular biology and growing requirements from biomarker validation studies have generated a need for tissue banks to provide quality-controlled tissue samples with standardized clinical annotation. The NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) is a distributed tissue bank that comprises four academic centers and provides thousands of clinically annotated prostate cancer specimens to researchers. Here we describe the CPCTR information management system architecture, common data element (CDE) development, query interfaces, data curation, and quality control. METHODS: Data managers review the medical records to collect and continuously update information for the 145 clinical, pathological and inventorial CDEs that the Resource maintains for each case. An Access-based data entry tool provides de-identification and a standard communication mechanism between each group and a central CPCTR database. Standardized automated quality control audits have been implemented. Centrally, an Oracle database has web interfaces allowing multiple user-types, including the general public, to mine de-identified information from all of the sites with three levels of specificity and granularity as well as to request tissues through a formal letter of intent. RESULTS: Since July 2003, CPCTR has offered over 6,000 cases (38,000 blocks) of highly characterized prostate cancer biospecimens, including several tissue microarrays (TMA). The Resource developed a website with interfaces for the general public as well as researchers and internal members. These user groups have utilized the web-tools for public query of summary data on the cases that were available, to prepare requests, and to receive tissues. As of December 2005, the Resource received over 130 tissue requests, of which 45 have been reviewed, approved and filled. Additionally, the Resource implemented the TMA Data Exchange Specification in its TMA program and created a computer program for calculating PSA recurrence. CONCLUSION: Building a biorepository infrastructure that meets today's research needs involves time and input of many individuals from diverse disciplines. The CPCTR can provide large volumes of carefully annotated prostate tissue for research initiatives such as Specialized Programs of Research Excellence (SPOREs) and for biomarker validation studies and its experience can help development of collaborative, large scale, virtual tissue banks in other organ systems

Early postural blood pressure response and cause-specific mortality among middle-aged adults

Orthostatic hypotension (OH) is associated with increased total mortality but contribution of specific death causes has not been thoroughly explored. In this prospective study, authors followed up 32,068 individuals without baseline history of cancer or cardiovascular disease (69% men; mean age, 46 years; range, 26–61 years) over a period of 24 years. Hazard ratios (HRs) for total and cause-specific mortality associated with presence of OH and by quartiles of postural systolic blood pressure response (∆SBP) were assessed using multivariate adjusted Cox regression model. A total of 7,145 deaths (22.3%, 9.4 deaths/1,000 person-years) occurred during follow-up. Those with OH (n = 1,943) had higher risk of death due to injury (HR, 1.88; 1.37–2.57) and neurological disease (HR, 2.21; 1.39–3.51). Analogically, risk of death caused by injury and neurological disease increased across the quartiles of ∆SBP from hyper- (Q1SBP, +8.5 ± 4.7 mmHg) to hypotensive response (Q4SBP, −13.7 ± 5.7 mmHg; HR, 1.32; 1.00–1.72, and 1.84; 1.20–2.82, respectively) as did also risk of death due to respiratory disease (Q4SBP vs. Q1SBP: HR, 1.53; 1.14–2.04). In contrast, risk curve for cerebrovascular death was U-shaped with nadir in the mildly hypotensive 3rd quartile of ∆SBP (−5.0 ± 0.1 mmHg, Q3SBP vs. Q1SBP: HR, 0.75; 0.54–1.03; P for linear trend = 0.021). Additionally, cardiovascular mortality was increased among 5,805 rescreened participants (mean age, 53 years; 9.8% OH positive: HR, 1.54; 1.24–1.89, and Q4SBP vs. Q1SBP: 1.27; 1.02–1.57, respectively). In summary, increased mortality predicted by blood pressure fall on standing is associated with injuries, neurodegenerative, and respiratory diseases, as well as with cardiovascular disease in older adults. Moreover, both increase and pronounced decrease of SBP during early orthostasis indicate higher risk of cerebrovascular death