Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations

The conformation of HIV-1 envelope (Env) glycoprotein trimers is key in ensuring protection against waves of neutralizing antibodies generated during infection, while maintaining sufficient exposure of the CD4 binding site (CD4bs) for viral entry. The CD4 binding loop on Env is an early contact site for CD4 while penetration of a proximal cavity by CD4 triggers Env conformational changes for entry. The role of residues in the CD4 binding loop in regulating the conformation of the trimer and trimer association domain (TAD) was investigated using a novel saturation mutagenesis approach. Single mutations identified, resulted in distinct trimer conformations affecting CD4bs exposure, the glycan shield and the TAD across diverse HIV-1 clades. Importantly, mutations that improve access to the CD4bs without exposing the immunodominant V3 loop were identified. The different trimer conformations identified will affect the specificity and breadth of nabs elicited in vivo and are important to consider in design of Env immunogens for vaccines

Influence Diffusion in Social Networks under Time Window Constraints

We study a combinatorial model of the spread of influence in networks that generalizes existing schemata recently proposed in the literature. In our model, agents change behaviors/opinions on the basis of information collected from their neighbors in a time interval of bounded size whereas agents are assumed to have unbounded memory in previously studied scenarios. In our mathematical framework, one is given a network $G=(V,E)$, an integer value $t(v)$ for each node $v\in V$, and a time window size $\lambda$. The goal is to determine a small set of nodes (target set) that influences the whole graph. The spread of influence proceeds in rounds as follows: initially all nodes in the target set are influenced; subsequently, in each round, any uninfluenced node $v$ becomes influenced if the number of its neighbors that have been influenced in the previous $\lambda$ rounds is greater than or equal to $t(v)$. We prove that the problem of finding a minimum cardinality target set that influences the whole network $G$ is hard to approximate within a polylogarithmic factor. On the positive side, we design exact polynomial time algorithms for paths, rings, trees, and complete graphs.Comment: An extended abstract of a preliminary version of this paper appeared in: Proceedings of 20th International Colloquium on Structural Information and Communication Complexity (Sirocco 2013), Lectures Notes in Computer Science vol. 8179, T. Moscibroda and A.A. Rescigno (Eds.), pp. 141-152, 201

Direct medical costs related to COVID-19 in Colombia

We studied 113 patients hospitalized by COVID-19, 51.3% men. On average, the hospital length of stay for COVID-19 hospitalized patient was 7,3 (± 6,2) days with a median cost of $1,688 (IQR 788-2,523). In women, the median direct medical cost of hospitalization was$1,328 (IQR $463-$2,098), while in men was 1.4 times greater. Being 60 years of age or older triggers hospitalization costs almost twice as high as those under this age ($1,813 vs.$2,994), and when the cost is compared by type of hospitalization, this difference is more than three times (ICU: 4,118; general ward: $1,312)

Do trees in UK-relevant river catchments influence fluvial flood peaks?: a systematic review

This report describes a systematic review of the evidence in support of the primary question “Do trees in UK-relevant river catchments influence fluvial flood peaks?

Energy measurement and fragment identification using digital signals from partially depleted Si detectors

A study of identification properties of a Si-Si DE-E telescope exploiting an underdepleted residual-energy detector has been performed. Five different bias voltages have been used, one corresponding to full depletion, the others associated with a depleted layer ranging from 90% to 60% of the detector thickness. Fragment identification has been performed using either the DE-E technique or Pulse Shape Analysis (PSA). Both detectors are reverse mounted: particles enter from the low field side, to enhance the PSA performance. The achieved charge and mass resolution has been quantitatively expressed using a Figure of Merit (FoM). Charge collection efficiency has been evaluated and the possibility of energy calibration corrections has been considered. We find that the DE-E performance is not affected by incomplete depletion even when only 60% of the wafer is depleted. Isotopic separation capability improves at lower bias voltages with respect to full depletion, though charge identification thresholds are higher than at full depletion. Good isotopic identification via PSA has been obtained from a partially depleted detector whose doping uniformity is not good enough for isotopic identification at full depletion.Comment: 13 pages, 10 figures 5 tables; submitted to European Physical Journal

Associations Between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress

Holographic phase diagram of quark-gluon plasma formed in heavy-ions collisions

The phase diagram of quark gluon plasma (QGP) formed at a very early stage just after the heavy ion collision is obtained by using a holographic dual model for the heavy ion collision. In this dual model colliding ions are described by the charged shock gravitational waves. Points on the phase diagram correspond to the QGP or hadronic matter with given temperatures and chemical potentials. The phase of QGP in dual terms is related to the case when the collision of shock waves leads to formation of trapped surface. Hadronic matter and other confined states correspond to the absence of trapped surface after collision. Multiplicity of the ion collision process is estimated in the dual language as area of the trapped surface. We show that a non-zero chemical potential reduces the multiplicity. To plot the phase diagram we use two different dual models of colliding ions, the point and the wall shock waves, and find qualitative agreement of the results.Comment: 33 pages, 14 figures, typos correcte

Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi

DNA phylogenetic comparisons have shown that morphology-based species recognition often underestimates fungal diversity. Therefore, the need for accurate DNA sequence data, tied to both correct taxonomic names and clearly annotated specimen data, has never been greater. Furthermore, the growing number of molecular ecology and microbiome projects using high-throughput sequencing require fast and effective methods for en masse species assignments. In this article, we focus on selecting and re-annotating a set of marker reference sequences that represent each currently accepted order of Fungi. The particular focus is on sequences from the internal transcribed spacer region in the nuclear ribosomal cistron, derived from type specimens and/or ex-type cultures. Re-annotated and verified sequences were deposited in a curated public database at the National Center for Biotechnology Information (NCBI), namely the RefSeq Targeted Loci (RTL) database, and will be visible during routine sequence similarity searches with NR_prefixed accession numbers. A set of standards and protocols is proposed to improve the data quality of new sequences, and we suggest how type and other reference sequences can be used to improve identification of Fungi

Factors associated with outcomes for looked-after children and young people: a correlates review of the literature.

In 2008, the Department of Health made a referral to the National Institute for Health and Clinical Excellence and the Social Care Institute for Excellence to develop joint public health guidance on improving the physical and emotional health and well-being of children and young people looked after by the local authority/state. To help inform the decision-making process by identifying potential research questions pertinent to the outcomes of looked-after children and young people (LACYP), a correlates review was undertaken. Iterative searches of health and social science databases were undertaken; searches of reference lists and citation searches were conducted and all included studies were critically appraised. The correlates review is a mapping review conducted using systematic and transparent methodology. Interventions and factors that are associated (or correlated) with outcomes for LACYP were identified and presented as conceptual maps. This review maps the breadth (rather than depth) of the evidence and represents an attempt to use the existing evidence base to map associations between potential risk factors, protective factors, interventions and outcomes for LACYP. Ninety-two studies were included: four systematic reviews, five non-systematic reviews, eight randomized controlled trials, 66 cohort studies and nine cross-sectional studies. The conceptual maps provide an overview of the key relationships addressed in the current literature, in particular, placement stability and emotional and behavioural factors in mediating outcomes. From the maps, there appear to be some key factors that are associated with a range of outcomes, in particular, number of placements, behavioural problems and age at first placement. Placement stability seems to be a key mediator of directional associations. The correlates review identified key areas where sufficient evidence to conduct a systematic review might exist. These were: transition support, training and support for carers and access to services