Adaptive HIV-1 evolutionary trajectories are constrained by protein stability

Despite the use of combination antiretroviral drugs for the treatment of HIV-1 infection, the emergence of drug resistance remains a problem. Resistance may be conferred either by a single mutation or a concerted set of mutations. The involvement of multiple mutations can arise due to interactions between sites in the amino acid sequence as a consequence of the need to maintain protein structure. To better understand the nature of such epistatic interactions, we reconstructed the ancestral sequences of HIV-1’s Pol protein, and traced the evolutionary trajectories leading to mutations associated with drug resistance. Using contemporary and ancestral sequences we modelled the effects of mutations (i.e. amino acid replacements) on protein structure to understand the functional effects of residue changes. Although the majority of resistance-associated sequences tend to destabilise the protein structure, we find there is a general tendency for protein stability to decrease across HIV-1’s evolutionary history. That a similar pattern is observed in the non-drug resistance lineages indicates that non-resistant mutations, for example, associated with escape from the immune response, also impacts on protein stability. Maintenance of optimal protein structure therefore represents a major constraining factor to the evolution of HIV-1

Audit of surgical procedures in regional and central hospitals in Limpopo Province, South Africa

Background. There is a paucity of data on the functioning and surgical procedures performed in rural hospitals in South Africa.Objective. To determine the category of procedures performed at regional and tertiary hospitals in Limpopo Province, South Africa. Method. We conducted a retrospective analysis of surgical procedures performed in the regional and tertiary hospitals in Limpopo Province during a 1-year period from 1 March 2019 to 29 February 2020.Results. A total of 24 263 surgical procedures were performed during the study period. More than half of all cases (50.4%; n=12 252) were operated on at the tertiary hospitals while regional hospitals performed the remaining 12 011 operations.Conclusion. There is a great necessity to alleviate the central hospitals from the bulk of surgical procedures

Effects of treatment dosage of whole-body cryotherapy upon post-match recovery of endocrine and biochemical markers in elite rugby league players: An experimental study

Background and Aims: The use of whole-body cryotherapy (WBC) for athletic recovery is becoming increasingly popular despite the lack of evidence supporting the dosage parameters in its implementation. The aim of the current study was to investigate the dose–response effects of WBC following match-play in elite rugby league players. Methods: We observed endocrine (salivary cortisol and testosterone) and biochemical (creatine kinase) responses following three separate post-match recovery periods in elite rugby league players. Comparisons were made between a single exposure (3 min at −120°C to -−135°C) of WBC to two consecutive exposures (2 × 3 min), to a control (no exposure) during the recovery trials. Recovery characteristics were measured 36 h prematch, immediately postmatch, and 60 h postmatch. Results: Cortisol concentrations remained unchanged in its pattern of response during the postmatch recovery periods across all WBC doses. Testosterone concentrations increased significantly (p < 0.0005) at 60 h, in the WBC2 trial. The Testosterone:Cortisol ratio increased significantly (p < 0.0005) at 60 h in the WBC2 trial, while during the WBC0 trial it did not recover to baseline levels. No significant effect on creatine kinase concentration was observed, although a statistical trend was shown in WBC2 for improved reduction of this marker at 60 h. Conclusions: These findings suggest that two, consecutive exposures to WBC immediately following fatiguing rugby league competition appear to stimulate an increase to the anabolic endocrine profile of participants by 60 h post-match, and may reduce the CK concentration. Coaches and athletes should consider the treatment dosage of WBC when used to optimize the desired response following a high-stress environment

Scaling Separability Criterion: Application To Gaussian States

We introduce examples of three- and four-mode entangled Gaussian mixed states that are not detected by the scaling and Peres-Horodecki separability criteria. The presented modification of the scaling criterion resolves this problem. Also it is shown that the new criterion reproduces the main features of the scaling pictures for different cases of entangled states, while the previous versions lead to completely different outcomes. This property of the presented scheme is evidence of its higher generality.Comment: 7 pages, 4 figure

Book Reviews

Book Review 1Book Title: Megaherbivores: the influence of very large body size on ecologyBook Author: R.N. Owen-SmithCambridge University Press, Cambridge, 1988. 369 pages.Book Review 2Book Title: Comparative Physiology of the Vertebrate KidneyBook Author: W.H. Dantzler Springer-Verlag 1989.198 pp. (Hardcover).Book Review 3Book Title: Atlas on the Biology of Soil ArthropodsBook Authors: G. Esenbeis &amp; W. Wichard Springer-Verlag, Berlin 1987. 437 pp.Book Review 4Book Title: Primate Vocal CommunicationBook Authors: Edited by D. Todt, P. Goedeking &amp; D. SymmesSpringer Verlag, Berlin (1988)Book Review 5Book Title: The Honey BeeBook Authors: J.L. Gould &amp; C. G. GouldScientific American Ubrary, W.H.Freeman, New York. 239 pp.Book Review 6Book Title: Insect Development Photoperiodic and Temperature ControlBook Author: Victor A. ZaslavskiSpringer-Verlag, Berlin. 187 pp.Book Review 7Book Title: OrganellesBook Author: Mark CarrollMacmillan 1989. 202 pp.Book Review 8Book Title: Comparative Protozoology Ecology, Physiology, Life HistoryBook Author: O. Roger AndersonSpringer-Verlag, Berlin, 1988. 482pp.Book Review 9Book Title: Ecotoxicology: Problems and ApproachesBook Authors: Edited by S.A. Levin, M.A. Harwell, J.R. Kelly &amp; K.D. KimballSpringer Verlag, New York. 547 pp

Transferring an Analytical Technique from Ecology to the Sport Sciences

Background: Learning transfer is defined as an individual’s capability to apply prior learnt perceptual, motor or conceptual skills to a novel task or performance environment. In the sport sciences, learning transfers have been investigated from an athlete-specific perspective. However, sport scientists should also consider the benefits of cross-disciplinary learning to aid critical thinking and metacognitive skill gained through the interaction with similar quantitative scientific disciplines. Objective: Using team sports performance analysis as an example, this study aimed to demonstrate the utility of a common analytical technique in ecology to the sports sciences; namely, non-metric multidimensional scaling. Methods: To achieve this aim, three novel research examples using this technique are presented, each of which enables the analysis and visualisation of athlete (organism), team (aggregation of organisms) and competition (ecosystem) behaviours. Results: The first example reveals the technical behaviours of Australian Football League Brownlow medallists from the 2001 to 2016 seasons. The second example delineates dissimilarity in higher and lower ranked National Rugby League teams within the 2016 season. Lastly, the third example shows the evolution of game-play in the basketball tournaments between the 2004 to 2016 Olympic Games. Conclusions: In addition to the novel findings of each example, the collective results demonstrate that by embracing cross-disciplinary learning and drawing upon an analytical technique common to ecology, novel solutions to pertinent research questions within sports performance analysis could be addressed in a practically meaningful way. Cross-disciplinary learning may subsequently assist sport scientists in the analysis and visualisation of multivariate datasets

Investigating and learning lessons from early experiences of implementing ePrescribing systems into NHS hospitals:a questionnaire study

Background: ePrescribing systems have significant potential to improve the safety and efficiency of healthcare, but they need to be carefully selected and implemented to maximise benefits. Implementations in English hospitals are in the early stages and there is a lack of standards guiding the procurement, functional specifications, and expected benefits. We sought to provide an updated overview of the current picture in relation to implementation of ePrescribing systems, explore existing strategies, and identify early lessons learned.Methods: a descriptive questionnaire-based study, which included closed and free text questions and involved both quantitative and qualitative analysis of the data generated.Results: we obtained responses from 85 of 108 NHS staff (78.7% response rate). At least 6% (n = 10) of the 168 English NHS Trusts have already implemented ePrescribing systems, 2% (n = 4) have no plans of implementing, and 34% (n = 55) are planning to implement with intended rapid implementation timelines driven by high expectations surrounding improved safety and efficiency of care. The majority are unclear as to which system to choose, but integration with existing systems and sophisticated decision support functionality are important decisive factors. Participants highlighted the need for increased guidance in relation to implementation strategy, system choice and standards, as well as the need for top-level management support to adequately resource the project. Although some early benefits were reported by hospitals that had already implemented, the hoped for benefits relating to improved efficiency and cost-savings remain elusive due to a lack of system maturity.Conclusions: whilst few have begun implementation, there is considerable interest in ePrescribing systems with ambitious timelines amongst those hospitals that are planning implementations. In order to ensure maximum chances of realising benefits, there is a need for increased guidance in relation to implementation strategy, system choice and standards, as well as increased financial resources to fund local activitie

Differential expression analysis for sequence count data

*Motivation:* High-throughput nucleotide sequencing provides quantitative readouts in assays for RNA expression (RNA-Seq), protein-DNA binding (ChIP-Seq) or cell counting (barcode sequencing). Statistical inference of differential signal in such data requires estimation of their variability throughout the dynamic range. When the number of replicates is small, error modelling is needed to achieve statistical power.&#xd;&#xa;&#xd;&#xa;*Results:* We propose an error model that uses the negative binomial distribution, with variance and mean linked by local regression, to model the null distribution of the count data. The method controls type-I error and provides good detection power. &#xd;&#xa;&#xd;&#xa;*Availability:* A free open-source R software package, _DESeq_, is available from the Bioconductor project and from &#x22;http://www-huber.embl.de/users/anders/DESeq&#x22;:http://www-huber.embl.de/users/anders/DESeq

Linking dwarf galaxies to halo building blocks with the most metal-poor star in Sculptor

Current cosmological models indicate that the Milky Way's stellar halo was assembled from many smaller systems. Based on the apparent absence of the most metal-poor stars in present-day dwarf galaxies, recent studies claimed that the true Galactic building blocks must have been vastly different from the surviving dwarfs. The discovery of an extremely iron-poor star (S1020549) in the Sculptor dwarf galaxy based on a medium-resolution spectrum cast some doubt on this conclusion. However, verification of the iron-deficiency and measurements of additional elements, such as the alpha-element Mg, are mandatory for demonstrating that the same type of stars produced the metals found in dwarf galaxies and the Galactic halo. Only then can dwarf galaxy stars be conclusively linked to early stellar halo assembly. Here we report high-resolution spectroscopic abundances for 11 elements in S1020549, confirming the iron abundance of less than 1/4000th that of the Sun, and showing that the overall abundance pattern mirrors that seen in low-metallicity halo stars, including the alpha-elements. Such chemical similarity indicates that the systems destroyed to form the halo billions of years ago were not fundamentally different from the progenitors of present-day dwarfs, and suggests that the early chemical enrichment of all galaxies may be nearly identical.Comment: 16 pages, including 2 figures. Accepted for publication in Nature. It is embargoed for discussion in the press until formal publication in Natur

Detecting and predicting neutralization of alemtuzumab responses in MS

Objective: To test the hypothesis that anti-drug antibodies against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. Methods: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding anti-drug antibodies. Alemtuzumab IgG Alexa-Fluor 488 conjugate was used in a competitive-binding cell based assay to detect neutralizing anti-drug antibodies. The assays were used to retrospectively screen, blinded, banked-serum samples from people with multiple sclerosis (n=32) who had received three or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month post-infusion. Results: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. Anti-drug antibody responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred prior to the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Pre-infusion, anti-drug antibody levels predicted limited, post-infusion lymphocyte depletion. Conclusions: Although anti-drug antibodies to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of, lymphocyte depletion and the anti-drug response may be of practical value in patients requiring additional cycles of alemtuzumab. Anti-drug antibody detection may help to inform on re-treatment or switching to another treatment