Neural networks for self-adjusting mutation rate estimation when the recombination rate is unknown

Estimating the mutation rate, or equivalently effective population size, is a common task in population genetics. If recombination is low or high, optimal linear estimation methods are known and well understood. For intermediate recombination rates, the calculation of optimal estimators is more challenging. As an alternative to model-based estimation, neural networks and other machine learning tools could help to develop good estimators in these involved scenarios. However, if no benchmark is available it is difficult to assess how well suited these tools are for different applications in population genetics.Here we investigate feedforward neural networks for the estimation of the mutation rate based on the site frequency spectrum and compare their performance with model-based estimators. For this we use the model-based estimators introduced by Fu, Futschik et al., and Watterson that minimize the variance or mean squared error for no and free recombination. We find that neural networks reproduce these estimators if provided with the appropriate features and training sets. Remarkably, using the model-based estimators to adjust the weights of the training data, only one hidden layer is necessary to obtain a single estimator that performs almost as well as model-based estimators for low and high recombination rates, and at the same time provides a superior estimation method for intermediate recombination rates. We apply the method to simulated data based on the human chromosome 2 recombination map, highlighting its robustness in a realistic setting where local recombination rates vary and/or are unknown.     

Continuous Theta Burst Stimulation over the Left Dorsolateral Prefrontal Cortex Decreases Medium Load Working Memory Performance in Healthy Humans

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load.     

Synthesis and biological activity of heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone derivatives as hepatitis C virus NS5B polymerase inhibitors

Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.     

Mandibular shape variation in mainland and insular hylobatids

Although hylobatids are the most speciose of the living apes, their morphological interspecies and intraspecies variation remains poorly understood. Here, we assess mandibular shape variation in two species of Hylobates, white-handed (Hylobates lar) and black-handed (Hylobates agilis) gibbons. Using 71 three-dimensional landmarks to quantify mandibular shape, interspecies and intraspecies variation and geographic patterns of mandibular shape are examined in a mixed sex sample of adult H. lar and H. agilis through generalized Procrustes analysis, Procrustes analysis of variance, and principal components analysis. We find that relative to H. agilis, H. lar exhibits a higher amount of variation in mandibular shape. Both species demonstrate similar allometric patterns in mandibular shape. We also highlight a geographic pattern in mandibular shape variation. Compared to mainland hylobatids, insular hylobatids have relatively lower, more posteriorly oriented, and anteroposteriorly wider mandibular condyles, with an increased distance between the condyles and the coronoid processes. This geographic pattern could reflect differences in functional demands on the mandible during mastication and/or could be driven by factors often associated with evolutionary pressures of island populations relative to mainland populations. The findings of this study highlight how little is known about Hylobates morphological variation and how important this is for using Hylobates to help interpret the primate fossil record. Understanding interspecific and intraspecific variation in extant primates is vital to interpreting variation in the primate fossil record.     

Observations of two deep-sea chimaeroids in Icelandic waters

Long-term survey time series repeated occurrence of the deep-sea chimaeroid species small-eyed rabbitfish Hydrolagus affinis and large-eyed rabbitfish H. mirabilis have been observed at same but few locations in Icelandic waters over 23 years. For H. affinis the catch at one specific station has consisted almost exclusively of mature males over the time period. Identification of potential aggregation locations is of vital importance to natural resource management because such aggregation may render these species vulnerable to potential fishing activities.     

Prokaryotic SPHINX replication sequences are conserved in mammalian brain and participate in neurodegeneration

A new class of viral mammalian Slow Progressive Hidden INfections of variable (X) latency (“SPHINX”) DNAs, represented by the 1.8 and 2.4 kb nuclease-protected circular elements, were discovered in highly infectious cytoplasmic particles isolated from Creutzfeldt-Jakob Disease (CJD) and scrapie samples. These DNAs contained replication initiation sequences (REPs) with approximately 70% homology to those of environmental Acinetobacter phage. Antibodies against REP peptides from the 1.8 kb DNA highlighted a 41 kDa protein (spx) on Western blots, and in situ studies previously revealed its peripheral tissue expression, for example, in pancreatic islet cells, keratinocytes, kidney tubules, and oocytes but not pancreatic exocrine cells, alveoli, and striated muscle. To determine if spx concentrated in specific neurons and synapses, and also maintained a conserved pattern of architectural organization in mammalian brains, we evaluated mouse, rat, hamster, guinea pig (GP), and human samples. Most outstanding was the cross-species concentration of spx in huge excitatory synapses of mossy fibers and small internal granule neuron synapses, the only excitatory neuron within the cerebellum. Spx also localized to excitatory glutamate type synapses in the hippocampus, and both cerebellar and hippocampal synaptic spx was demonstrable ultrastructurally. Studies of two well-characterized models of sporadic CJD (sCJD) revealed novel spx pathology. Vacuolar loss of cerebellar synaptic complexes, thinning of the internal granule cell layer, and fibrillar spx accumulations within Purkinje neurons were prominent in sCJD GP brains. In rats, comparable spx fibrillar changes appeared in hippocampal pyramidal neurons, and they preceded prion protein misfolding. Hence, spx is an integral player in progressive neurodegeneration. The evolutionary origin, spread, and neuropathology of SPHINX 1.8 REP sequences opens another unanticipated chapter for mammalian symbiotic interactions with environmental microbes.     

Feasibility and Safety of Cervical Biopsy Sampling for Mucosal Immune Studies in Female Sex Workers from Nairobi,Kenya

Background

There is an urgent need to improve our understanding of the mucosal immuno-pathogenesis of HIV acquisition in the female genital tract, particularly in high-risk women such as female sex workers (FSWs). Cervical biopsy samples offer technical advantages over cytobrush sampling, but there are concerns that this might increase HIV acquisition, particularly if healing is slow and/or women do not abstain from sex during healing.

Methodology/Principal Findings

Cervical biopsy samples and cervico-vaginal swabs for co-infection diagnostics, prostate specific antigen (PSA) and immune studies were collected from 59 women, including HIV seropositive and HIV-exposed seronegative (HESN) FSWs as well as lower risk women from Nairobi, Kenya. A clinical-demographic questionnaire was administered and women were instructed to avoid sexual intercourse, douching and the insertion of tampons for 14 days. All participants underwent a repeat exam to assess healing within the 14 days, and had HIV diagnostics at six months. Cervical sampling was well tolerated, and 82% of participants had healed macroscopically by 5 days. Both self-report and PSA screening suggested high levels of compliance with pre- and post-procedure abstinence. Delayed healing was associated with vulvovaginal candidiasis (VVC) and HESN status. At six-month follow up all low-risk and HESN participants remained HIV seronegative.

Conclusion

Cervical biopsy sampling is a safe and well-tolerated method to obtain cervical biopsies in this context, particularly if participants with VVC are excluded. As healing could be delayed up to 11 days, it is important to support (both financially and with rigorous counseling) a period of post-procedure abstinence to minimize HIV risk.