A large population sample of African HIV genomes from the 1980s reveals a reduction in subtype D over time associated with propensity for CXCR4 tropism

We present 109 near full-length HIV genomes amplified from blood serum samples obtained during early 1986 from across Uganda, which to our knowledge is the earliest and largest population sample from the initial phase of the HIV epidemic in Africa. Consensus sequences were made from paired-end Illumina reads with a target-capture approach to amplify HIV material following poor success with standard approaches. In comparisons with a smaller 'intermediate' genome dataset from 1998 to 1999 and a 'modern' genome dataset from 2007 to 2016, the proportion of subtype D was significantly higher initially, dropping from 67% (73/109), to 57% (26/46) to 17% (82/465) respectively (p < 0.0001). Subtype D has previously been shown to have a faster rate of disease progression than other subtypes in East African population studies, and to have a higher propensity to use the CXCR4 co-receptor ("X4 tropism"); associated with a decrease in time to AIDS. Here we find significant differences in predicted tropism between A1 and D subtypes in all three sample periods considered, which is particularly striking the 1986 sample: 66% (53/80) of subtype D env sequences were predicted to be X4 tropic compared with none of the 24 subtype A1. We also analysed the frequency of subtype in the envelope region of inter-subtype recombinants, and found that subtype A1 is over-represented in env, suggesting recombination and selection have acted to remove subtype D env from circulation. The reduction of subtype D frequency over three decades therefore appears to be a result of selective pressure against X4 tropism and its higher virulence. Lastly, we find a subtype D specific codon deletion at position 24 of the V3 loop, which may explain the higher propensity for subtype D to utilise X4 tropism

Perinatal Environmental Tobacco Smoke Exposure in Rhesus Monkeys: Critical Periods and Regional Selectivity for Effects on Brain Cell Development and Lipid Peroxidation

Perinatal environmental tobacco smoke (ETS) exposure in humans elicits neurobehavioral deficits. We exposed rhesus monkeys to ETS during gestation and through 13 months postnatally, or postnatally only (6–13 months). At the conclusion of exposure, we examined cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation. For perinatal ETS, two archetypal patterns were seen in the various regions, one characterized by cell loss (reduced DNA concentration) and corresponding increases in cell size (increased protein/DNA ratio), and a second pattern suggesting replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/DNA ratio). The membrane/total protein ratio, a biomarker of neurite formation, also indicated potential damage to neuronal projections, accompanied by reactive sprouting. When ETS exposure was restricted to the postnatal period, the effects were similar in regional selectivity, direction, and magnitude. These patterns resemble the effects of prenatal nicotine exposure in rodent and primate models. Surprisingly, perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not. The heart, a tissue that, like the brain, has high oxygen demand, displayed a similar but earlier decrease (2–3 months) in lipid peroxidation in the perinatal exposure model, whereas values were reduced at 13 months with the postnatal exposure paradigm. Our results provide a mechanistic connection between perinatal ETS exposure and neurobehavioral anomalies, reinforce the role of nicotine in these effects, and buttress the importance of restricting or eliminating ETS exposure in young children

Using Three-Dimensional Gait Data for Foot/Ankle Orthopaedic Surgery

We present the case of a forty year old male who sustained a torn carotid during strenuous physical activity. This was followed by a right hemispheric stroke due to a clot associated with the carotid. Upon recovery, the patient’s gait was characterized as hemiparetic with a stiff-knee pattern, a fixed flexion deformity of the toe flexors, and a hindfoot varus. Based on clinical exams and radiographs, the surgical treatment plan was established and consisted of correction of the forefoot deformities, possible hamstrings lengthening, and tendon transfer of the posterior tibial tendon to the dorsolateral foot. To aid in surgical planning, a three-dimensional gait analysis was conducted using a state-of-the-art motion capture system. Data from this analysis provided insight into the pathomechanics of the patient’s gait pattern. A forefoot driven hindfoot varus was evident from the presurgical data and the tendon transfer procedure was deemed unnecessary. A computer was used in the OR to provide surgeons with animations of the patient’s gait and graphical results as needed. A second gait analysis was conducted 6 weeks post surgery, shortly after cast removal. Post-surgical gait data showed improved foot segment orientation and position. Motion capture data provides clinicians with detailed information on the multisegment kinematics of foot motion during gait, before and during surgery. Further, treatment effectiveness can be evaluated by repeating gait analyses after recovery

Erratum: Hearing the Shape of the Ising Model with a Programmable Superconducting-Flux Annealer.

Erratum: Hearing the Shape of the Ising Model with a Programmable Superconducting-Flux Anneale

Interactions between the Nse3 and Nse4 Components of the SMC5-6 Complex Identify Evolutionarily Conserved Interactions between MAGE and EID Families

The SMC5-6 protein complex is involved in the cellular response to DNA damage. It is composed of 6-8 polypeptides, of which Nse1, Nse3 and Nse4 form a tight sub-complex. MAGEG1, the mammalian ortholog of Nse3, is the founding member of the MAGE (melanoma-associated antigen) protein family and Nse4 is related to the EID (E1A-like inhibitor of differentiation) family of transcriptional repressors.Using site-directed mutagenesis, protein-protein interaction analyses and molecular modelling, we have identified a conserved hydrophobic surface on the C-terminal domain of Nse3 that interacts with Nse4 and identified residues in its N-terminal domain that are essential for interaction with Nse1. We show that these interactions are conserved in the human orthologs. Furthermore, interaction of MAGEG1, the mammalian ortholog of Nse3, with NSE4b, one of the mammalian orthologs of Nse4, results in transcriptional co-activation of the nuclear receptor, steroidogenic factor 1 (SF1). In an examination of the evolutionary conservation of the Nse3-Nse4 interactions, we find that several MAGE proteins can interact with at least one of the NSE4/EID proteins.We have found that, despite the evolutionary diversification of the MAGE family, the characteristic hydrophobic surface shared by all MAGE proteins from yeast to humans mediates its binding to NSE4/EID proteins. Our work provides new insights into the interactions, evolution and functions of the enigmatic MAGE proteins

Manipulating the metal-to-insulator transition and magnetic properties in manganite thin films via epitaxial strain

Strain engineering of epitaxial transition metal oxide heterostructures offers an intriguing opportunity to control electronic structures by modifying the interplay between spin, charge, orbital, and lattice degrees of freedom. Here, we demonstrate that the electronic structure, magnetic and transport properties of La0.9Ba0.1MnO3 thin films can be effectively controlled by epitaxial strain. Spectroscopic studies and first-principles calculations reveal that the orbital occupancy in Mn eg orbitals can be switched from the d3z2-r2 orbital to the dx2-y2 orbital by varying the strain from compressive to tensile. The change of orbital occupancy associated with Mn 3d-O 2p hybridization leads to dramatic modulation of the magnetic and electronic properties of strained La0.9Ba0.1MnO3 thin films. Under moderate tensile strain, an emergent ferromagnetic insulating state with an enhanced ferromagnetic Curie temperature of 215 K is achieved. These findings not only deepen our understanding of electronic structures, magnetic and transport properties in the La0.9Ba0.1MnO3 system, but also demonstrate the use of epitaxial strain as an effective knob to tune the electronic structures and related physical properties for potential spintronic device applications

Ecological succession of a Jurassic shallow-water ichthyosaur fall.

After the discovery of whale fall communities in modern oceans, it has been hypothesized that during the Mesozoic the carcasses of marine reptiles created similar habitats supporting long-lived and specialized animal communities. Here, we report a fully documented ichthyosaur fall community, from a Late Jurassic shelf setting, and reconstruct the ecological succession of its micro- and macrofauna. The early 'mobile-scavenger' and 'enrichment-opportunist' stages were not succeeded by a 'sulphophilic stage' characterized by chemosynthetic molluscs, but instead the bones were colonized by microbial mats that attracted echinoids and other mat-grazing invertebrates. Abundant cemented suspension feeders indicate a well-developed 'reef stage' with prolonged exposure and colonization of the bones prior to final burial, unlike in modern whale falls where organisms such as the ubiquitous bone-eating worm Osedax rapidly destroy the skeleton. Shallow-water ichthyosaur falls thus fulfilled similar ecological roles to shallow whale falls, and did not support specialized chemosynthetic communities

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Pharmacokinetics and transcriptional effects of the anti-salmon lice drug emamectin benzoate in Atlantic salmon (Salmo salar L.)

Background Emamectin benzoate (EB) is a dominating pharmaceutical drug used for the treatment and control of infections by sea lice (Lepeophtheirus salmonis) on Atlantic salmon (Salmo salar L). Fish with an initial mean weight of 132 g were experimentally medicated by a standard seven-day EB treatment, and the concentrations of drug in liver, muscle and skin were examined. To investigate how EB affects Atlantic salmon transcription in liver, tissues were assessed by microarray and qPCR at 7, 14 and 35 days after the initiation of medication. Results The pharmacokinetic examination revealed highest EB concentrations in all three tissues at day 14, seven days after the end of the medication period. Only modest effects were seen on the transcriptional levels in liver, with small fold-change alterations in transcription throughout the experimental period. Gene set enrichment analysis (GSEA) indicated that EB treatment induced oxidative stress at day 7 and inflammation at day 14. The qPCR examinations showed that medication by EB significantly increased the transcription of both HSP70 and glutathione-S-transferase (GST) in liver during a period of 35 days, compared to un-treated fish, possibly via activation of enzymes involved in phase II conjugation of metabolism in the liver. Conclusion This study has shown that a standard seven-day EB treatment has only a modest effect on the transcription of genes in liver of Atlantic salmon. Based on GSEA, the medication seems to have produced a temporary oxidative stress response that might have affected protein stability and folding, followed by a secondary inflammatory response.publishedVersio