Deep Learning for Population Genetic Inference

Given genomic variation data from multiple individuals, computing the likelihood of complex population genetic models is often infeasible. To circumvent this problem, we introduce a novel likelihood-free inference framework by applying deep learning, a powerful modern technique in machine learning. Deep learning makes use of multilayer neural networks to learn a feature-based function from the input (e.g., hundreds of correlated summary statistics of data) to the output (e.g., population genetic parameters of interest). We demonstrate that deep learning can be effectively employed for population genetic inference and learning informative features of data. As a concrete application, we focus on the challenging problem of jointly inferring natural selection and demography (in the form of a population size change history). Our method is able to separate the global nature of demography from the local nature of selection, without sequential steps for these two factors. Studying demography and selection jointly is motivated by Drosophila, where pervasive selection confounds demographic analysis. We apply our method to 197 African Drosophila melanogaster genomes from Zambia to infer both their overall demography, and regions of their genome under selection. We find many regions of the genome that have experienced hard sweeps, and fewer under selection on standing variation (soft sweep) or balancing selection. Interestingly, we find that soft sweeps and balancing selection occur more frequently closer to the centromere of each chromosome. In addition, our demographic inference suggests that previously estimated bottlenecks for African Drosophila melanogaster are too extreme.     

Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3β Signaling Pathways in HT22 Hippocampal Neurons

Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer’s disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.     

Variation of Soil Organic Carbon and Its Major Constraints in East Central Asia

Variation of soil organic carbon (SOC) and its major constraints in large spatial scale are critical for estimating global SOC inventory and projecting its future at environmental changes. By analyzing SOC and its environment at 210 sites in uncultivated land along a 3020km latitudinal transect in East Central Asia, we examined the effect of environmental factors on the dynamics of SOC. We found that SOC changes dramatically with the difference as high as 5 times in north China and 17 times in Mongolia. Regardless, C:N remains consistent about 12. Path analysis indicated that temperature is the dominant factor in the variation of SOC with a direct effect much higher than the indirect one, the former breaks SOC down the year round while the latter results in its growth mainly via precipitation in the winter half year. Precipitation helps accumulate SOC, a large part of the effect, however, is taken via temperature. NH₄⁺-N and topography also affect SOC, their roles are played primarily via climatic factors. pH correlates significantly with SOC, the effect, however, is taken only in the winter months, contributing to the decay of SOC primarily via temperature. These factors explained as much as 79% of SOC variations, especially in the summer months, representing the major constraints on the SOC stock. Soil texture gets increasingly fine southward, it does not, however, constitute an apparent factor. Our results suggested that recent global warming should have been adversely affecting SOC stock in the mid-latitude as temperature dominates other factors as the constraint.     

Acceptability of Voluntary Medical Male Circumcision (VMMC) among Male Sexually Transmitted Diseases Patients (MSTDP) in China

Voluntary Medical Male circumcision (VMMC) is an evidence-based, yet under-utilized biomedical HIV intervention in China. No study has investigated acceptability of VMMC among male sexually transmitted diseases patients (MSTDP) who are at high risk of HIV transmission. A cross-sectional survey interviewed 350 HIV negative heterosexual MSTDP in Shenzhen, China; 12.0% (n = 42) of them were circumcised at the time of survey. When the uncircumcised participants (n = 308) were informed that VMMC could reduce the risk of HIV infection via heterosexual intercourse by 50%, the prevalence of acceptability of VMMC in the next six months was 46.1%. Adjusted for significant background variables, significant factors of acceptability of VMMC included: 1) emotional variables: the Emotional Representation Subscale (adjusted odds ratios, AOR = 1.13, 95%CI: 1.06–1.18), 2) cognitive variables derived from Health Belief Model (HBM): perceived some chance of having sex with HIV positive women in the next 12 months (AOR = 2.48, 95%CI: 1.15–5.33) (perceived susceptibility), perceived severity of STD infection (AOR = 1.06, 95%CI: 1.02–1.10), perceived benefit of VMMC in risk reduction (AOR = 1.29, 95%CI: 1.16–1.42) and sexual performance (AOR = 1.45, 95%CI: 1.26–1.71), perceived barriers against taking up VMMC (AOR = 0.88, 95%CI: 0.81–0.95), and perceived cue to action (AOR = 1.41, 95%CI: 1.23–1.61) and self-efficacy (AOR = 1.38, 95%CI: 1.26–1.35) related to taking up VMMC. The association between perceived severity of STD infection and acceptability was fully mediated by emotional representation of STD infection. The relatively low prevalence of circumcision and high acceptability suggested that the situation was favorable for implementing VMMC as a means of HIV intervention among MSTDP in China. HBM is a potential suitable framework to guide the design of future VMMC promotion. Future implementation programs should be conducted in STD clinic settings, taking the important findings of this study into account.     

Association of PON1, P2Y12 and COX1 with Recurrent Ischemic Events in Patients with Extracranial or Intracranial Stenting

Background and Purpose

Short-term combined use of clopidogrel and aspirin improves cerebrovascular outcomes in patients with symptomatic extracranial or intracranial stenosis. Antiplatelet non-responsiveness is related to recurrent ischemic events, but the culprit genetic variants responsible for the non-responsiveness have not been well studied. We aimed to identify the genetic variants associated with poor clinical outcomes.

Methods

Patients with symptomatic extracranial or intracranial stenosis scheduled for stenting and receiving dual antiplatelets (clopidogrel 75 mg and aspirin 100 mg daily) for at least 5 days before intervention were enrolled. Ischemic events including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality within 12 months follow-up were recorded. We examined the influence of genetic polymorphisms on treatment outcome in our patients.

Results

A total of 268 patients were enrolled into our study and ischemic events were observed in 39 patients. For rs662 of paraoxonase 1 (PON1), allele C was associated with an increased risk of ischemic events (OR = 1.64, 95%CI = 1.03–2.62, P = 0.029). The A-allele carriers of rs2046934 of P2Y12 had a significant association with adverse events (OR = 2.01, 95%CI = 1.10–3.67, P = 0.041). The variant T-allele of cyclooxygenase-1 (COX1) rs1330344 significantly increased the risk of recurrent clinical events (OR = 1.85, 95%CI = 1.12–3.03, P = 0.017). The other single nucleotide polymorphism (SNP) had no association with ischemic events.

Conclusions

PON1, P2Y12 and COX1 polymorphisms were associated with poorer vascular outcomes. Testing for these polymorphisms may be valuable in the identification of patients at risk for recurrent ischemic events.     

Role of Gemcitabine and Pemetrexed as Maintenance Therapy in Advanced NSCLC: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background

Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC).

Methods

We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration’s risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software.

Results

Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW".

Conclusions

Gemcitabine or pemetrexed compared with BSC/observation/placebo significantly improved PFS or OS. Whether pemetrexed + bevacizumab compared with bevacizumab alone significantly improves PFS requires further investigation.