Dynamic Electrochemistry of Anthanthrone.

In this investigation, we present a “nanographene” based on the low-cost commercially available 4,10-dibromoanthanthrone building block, where the anthanthrone core can be viewed as a fusion of two anthracene moieties with lateral functionalization. The chemical and physical properties of this molecule stand in sharp contrast with the present anthracene subunit. We have studied the dynamic electrochemistry from two derivates of anthanthrone where the research depends on the radical of peripheral phenyl groups. In this case, we compared the changes that produce a donor group and acceptor group respectively. In both cases, the neutral molecule has a butterfly shape due to the steric congestion between the protons at the peri position of the quinoidal anthanthrone core, which possess a nonplanar folded geometry, and the protons from the peripheral phenyl groups. However, when two electrons are subtracted, exist a core aromatization and planarization, this provides a stable flat shape. We show the existence of two conformational states through cyclic voltammetry, electrochemistry and variable temperature chemistry oxidation. We demonstrate the fast or slow equilibrium between both geometries depending on the radical of peripheral phenyl groups (donor or acceptor).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

CDG: an online server proposing biologically closest disease-causing genes and pathologies and its application to primary immunodeficiency

Summary: In analyses of exome data, candidate gene selection can be challenging in the absence of variants in known disease-causing genes. We calculated the putative biologically closest known disease-causing genes for 13,005 human genes not currently reported to be disease-causing. We used these data to construct the Closest Disease-Causing Genes (CDG) server, which can be used to infer the closest associated disease-causing genes and phenotypes for lists of candidate genes. This resource will be a considerable asset for ascertaining the poten-tial relevance of lists of genes to specific diseases of interest

Review Essay : The Family and Migration: News From the Frencn

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67023/2/10.1177_036319908601100205.pd

SeqTailor: a user-friendly webserver for the extraction of DNA or protein sequences from next-generation sequencing data

Human whole-genome-sequencing reveals about 4 000 000 genomic variants per individual. These data are mostly stored as VCF-format files. Although many variant analysis methods accept VCF as input, many other tools require DNA or protein sequences, particularly for splicing prediction, sequence alignment, phylogenetic analysis, and structure prediction. However, there is no existing webserver capable of extracting DNA/protein sequences for genomic variants from VCF files in a user-friendly and efficient manner. We developed the SeqTailor webserver to bridge this gap, by enabling rapid extraction of (i) DNA sequences around genomic variants, with customizable window sizes and options to annotate the splice sites closest to the variants and to consider the neighboring variants within the window; and (ii) protein sequences encoded by the DNA sequences around genomic variants, with built-in SnpEff annotator and customizable window sizes. SeqTailor supports 11 species, including: human (GRCh37/GRCh38), chimpanzee, mouse, rat, cow, chicken, lizard, zebrafish, fruitfly, Arabidopsis and rice. Standalone programs are provided for command-line-based needs. SeqTailor streamlines the sequence extraction process, and accelerates the analysis of genomic variants with software requiring DNA/protein sequences. It will facilitate the study of genomic variation, by increasing the feasibility of sequence-based analysis and prediction. The SeqTailor webserver is freely available at http://shiva.rockefeller.edu/SeqTailor/

A common TMPRSS2 variant has a protective effect against severe COVID-19

Background : The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection. Methods : We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry. Results : We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3 × 10−3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. Conclusion : TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this

Central African Field Epidemiology and Laboratory Training Program: building and strengthening regional workforce capacity in public health

The Central African Field Epidemiology and Laboratory Training Program (CAFELTP) is a 2-year public health leadership capacity building training program. It was established in October 2010 to enhance capacity for applied epidemiology and public health laboratory services in three countries: Cameroon, Central African Republic, and the Democratic Republic of Congo. The aim of the program is to develop a trained public health workforce to assure that acute public health events are detected, investigated, and responded to quickly and effectively. The program consists of 25% didactic and 75% practical training (field based activities). Although the program is still in its infancy, the residents have already responded to six outbreak investigations in the region, evaluated 18 public health surveillance systems and public health programs, and completed 18 management projects. Through these various activities, information is shared to understand similarities and differences in the region leading to new and innovative approaches in public health. The program provides opportunities for regional and international networking in field epidemiology and laboratory activities, and is particularly beneficial for countries that may not have the immediate resources to host an individual country program. Several of the trainees from the first cohort already hold leadership positions within the ministries of health and national laboratories, and will return to their assignments better equipped to face the public health challenges in the region. They bring with them knowledge, practical training, and experiences gained through the program to shape the future of the public health landscape in their countries

Genome-wide detection of human variants that disrupt intronic branchpoints

The search for candidate variants underlying human disease in massive parallel sequencing data typically focuses on coding regions and essential splice sites, mostly ignoring noncoding variants. The RNA spliceosome recognizes intronic branchpoint (BP) motifs at the beginning of splicing and operates mostly within introns to define the exon-intron boundaries; however, BP variants have been paid little attention. We established a comprehensive genome-wide database and knowledgebase of BP and developed BPHunter for systematic and informative genome-wide detection of intronic variants that may disrupt BP and splicing, together with an effective strategy for prioritizing BP variant candidates. BPHunter not only constitutes an important resource for understanding BP, but should also drive discovery of BP variants in human genetic diseases and traits. Pre-messenger RNA splicing is initiated with the recognition of a single-nucleotide intronic branchpoint (BP) within a BP motif by spliceosome elements. Forty-eight rare variants in 43 human genes have been reported to alter splicing and cause disease by disrupting BP. However, until now, no computational approach was available to efficiently detect such variants in massively parallel sequencing data. We established a comprehensive human genome-wide BP database by integrating existing BP data and generating new BP data from RNA sequencing of lariat debranching enzyme DBR1-mutated patients and from machine-learning predictions. We characterized multiple features of BP in major and minor introns and found that BP and BP-2 (two nucleotides upstream of BP) positions exhibit a lower rate of variation in human populations and higher evolutionary conservation than the intronic background, while being comparable to the exonic background. We developed BPHunter as a genome-wide computational approach to systematically and efficiently detect intronic variants that may disrupt BP recognition. BPHunter retrospectively identified 40 of the 48 known pathogenic BP variants, in which we summarized a strategy for prioritizing BP variant candidates. The remaining eight variants all create AG-dinucleotides between the BP and acceptor site, which is the likely reason for missplicing. We demonstrated the practical utility of BPHunter prospectively by using it to identify a novel germline heterozygous BP variant of STAT2 in a patient with critical COVID-19 pneumonia and a novel somatic intronic 59-nucleotide deletion of ITPKB in a lymphoma patient, both of which were validated experimentally. BPHunter is publicly available from an

Different paths to the modern state in Europe: the interaction between domestic political economy and interstate competition

Theoretical work on state formation and capacity has focused mostly on early modern Europe and on the experience of western European states during this period. While a number of European states monopolized domestic tax collection and achieved gains in state capacity during the early modern era, for others revenues stagnated or even declined, and these variations motivated alternative hypotheses for determinants of fiscal and state capacity. In this study we test the basic hypotheses in the existing literature making use of the large date set we have compiled for all of the leading states across the continent. We find strong empirical support for two prevailing threads in the literature, arguing respectively that interstate wars and changes in economic structure towards an urbanized economy had positive fiscal impact. Regarding the main point of contention in the theoretical literature, whether it was representative or authoritarian political regimes that facilitated the gains in fiscal capacity, we do not find conclusive evidence that one performed better than the other. Instead, the empirical evidence we have gathered lends supports to the hypothesis that when under pressure of war, the fiscal performance of representative regimes was better in the more urbanized-commercial economies and the fiscal performance of authoritarian regimes was better in rural-agrarian economie

Towards an Intelligent Tutor for Mathematical Proofs

Computer-supported learning is an increasingly important form of study since it allows for independent learning and individualized instruction. In this paper, we discuss a novel approach to developing an intelligent tutoring system for teaching textbook-style mathematical proofs. We characterize the particularities of the domain and discuss common ITS design models. Our approach is motivated by phenomena found in a corpus of tutorial dialogs that were collected in a Wizard-of-Oz experiment. We show how an intelligent tutor for textbook-style mathematical proofs can be built on top of an adapted assertion-level proof assistant by reusing representations and proof search strategies originally developed for automated and interactive theorem proving. The resulting prototype was successfully evaluated on a corpus of tutorial dialogs and yields good results.Comment: In Proceedings THedu'11, arXiv:1202.453