High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important ...variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a 'variants reduction' protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ~4 min to perform gene-based annotation and ~15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/.
As a class of brown carbon, organonitrogen compounds originating from the heterogeneous uptake of NH3 by secondary organic aerosol (SOA) have received significant attention recently. In the current ...work, particulate organonitrogen formation during the ozonolysis of α-pinene and the OH oxidation of m-xylene in the presence of ammonia (34–125 ppb) was studied in a smog chamber equipped with a high resolution time-of-flight aerosol mass spectrometer and a quantum cascade laser instrument. A large diversity of nitrogen-containing organic (NOC) fragments was observed which were consistent with the reactions between ammonia and carbonyl-containing SOA. Ammonia uptake coefficients onto SOA which led to organonitrogen compounds were reported for the first time, and were in the range of ∼ 10-3–10−2, decreasing significantly to < 10-5 after 6 h of reaction. At the end of experiments (~ 6 h) the NOC mass contributed 8.9 ± 1.7 and 31.5 ± 4.4 wt % to the total α-pinene- and m-xylene-derived SOA, respectively, and 4–15 wt % of the total nitrogen in the system. Uptake coefficients were also found to be positively correlated with particle acidity and negatively correlated with NH3 concentration, indicating that heterogeneous reactions were responsible for the observed NOC mass, possibly limited by liquid phase diffusion. Under these conditions, the data also indicate that the formation of NOC can compete kinetically with inorganic acid neutralization. The formation of NOC in this study suggests that a significant portion of the ambient particle associated N may be derived from NH3 heterogeneous reactions with SOA. NOC from such a mechanism may be an important and unaccounted for source of PM associated nitrogen. This mechanism may also contribute to the medium or long-range transport and wet/dry deposition of atmospheric nitrogen.
Objective
About half or more of treatment‐resistant depressed patients do not respond to ketamine, and few clinical predictors to gauge the most likely antidepressant response have been proposed. We ...explored whether depression subtypes are associated with response to ketamine.
Method
Ninety‐seven participants with depression were administered six repeated‐dose intravenous ketamine and assessed for depression (Montgomery–Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAMA), and suicidal ideation (Beck Scale for Suicidal Ideation, SSI) at baseline, 24 h after each infusion, and 2 weeks after the whole treatment. Participants were classified by melancholic/anxious subtype. Individuals who met criteria for neither or both subtypes were classified separately, resulting in four mutually exclusive groups.
Results
Patients with melancholic or melancholic–anxious features were less likely to respond (e.g., day 13, melancholic–anxious vs. anxious, OR 0.138, 95% CI 0.032–0.584, P = 0.007) or remit (e.g., day 26, melancholic vs. no subtype, OR 0.182, 95% CI 0.035–0.960, P = 0.045) and took longer to achieve response/remission than those with anxious or no subtype features. Faster HAMA score reductions were observed in patients with anxious or melancholic–anxious features, and faster SSI score reductions were observed among those with melancholic–anxious features.
Conclusion
Our study shows promising results for ketamine as a novel antidepressant preferentially for the treatment of non‐melancholic or anxious depression.
ZNF804A (zinc-finger protein 804A) has been recognized as a schizophrenia risk gene across multiple world populations. Its intronic single-nucleotide polymorphism (SNP) rs1344706 is among one of the ...strongest susceptibility variants that have achieved genome-wide significance in genome-wide association studies (GWAS) for schizophrenia and has been widely and intensively studied. To elucidate the biological mechanisms underlying the genetic risk conferred by rs1344706, we retrospectively analyzed the progresses in brain gene expression quantitative trait loci (eQTL) analyses, ZNF804A-induced pathway alterations in neural cells and changes in synaptic phenotypes associated with ZNF804A expression. Based on these data, we hypothesize a potential biological mechanism for a genetic risk allele of ZNF804A in schizophrenia pathogenesis. We also review the efforts being made to characterize the affected intermediate phenotypes using neuroimaging and neuropsychological approaches. We then discuss additional common and rare ZNF804A variants in schizophrenia susceptibility and the potential genetic heterogeneity of these genomic loci between Europeans and Asians. This review for we believe the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis. We believe that this work has summarized this information with a systemic and broad assessment of recent findings.
Revealing the microscopic structural and dynamic pictures of glasses is a long-standing challenge for scientists1,2. Extensive studies on the structure and relaxation dynamics of glasses have ...constructed the current classical picture3–5: glasses consist of some ‘soft zones’ of loosely bound atoms embedded in a tightly bound atomic matrix. Recent experiments have found an additional fast process in the relaxation spectra6–9, but the underlying physics of this process remains unclear. Here, combining extensive dynamic experiments and computer simulations, we reveal that this fast relaxation is associated with string-like diffusion of liquid-like atoms, which are inherited from the high-temperature liquids. Even at room temperature, some atoms in dense-packed metallic glasses can diffuse just as easily as they would in liquid states, with an experimentally determined viscosity as low as 107 Pa·s. This finding extends our current microscopic picture of glass solids and might help establish the dynamics–property relationship of glasses4.The existence of fast dynamics in glass solids at low temperatures is attributed to liquid-like atoms that are inherited from high-temperature liquids and exhibit behaviour similar to that of atoms in liquid states.
The mechanism in the β phase evolution during hot deformation of a near β titanium alloy Ti–5Al–2Sn–2Zr–4Mo–4Cr with a transformed microstructure was investigated in the present work by the ...high-resolution electron backscatter diffraction (EBSD) and transmission electron microscope (TEM) techniques. The β phase exhibits significant variation in orientation, local texture and grain boundary during hot deformation, which is highly related to the globularization of α platelets. Kinking of the α platelets promotes the continuous dynamic recrystallization (CDRX) of β phase by increasing the misorientation, and formation of the globular α grains assists in the recrystallization of β phase via grain boundary sliding. The strain rate plays an important role in the β phase evolution as well which is greatly affected by the α phase evolution. The recrystallization of β phase is more evident during kinking at a higher strain rate where a structure with more and finer β recrystallized grains occurs, while dynamic recovery (DRC) is the main mechanism in the β phase where the globularization of α phase is relatively low at a larger strain.
Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor ...therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.
Topological photonics offers enhanced control over electromagnetic fields by providing a platform for robust trapping and guiding of topological states of light. By combining the strong coupling ...between topological photons with phonons in hexagonal boron nitride (hBN), we demonstrate a platform to control and guide hybrid states of light and lattice vibrations. The observed topological edge states of phonon-polaritons are found to carry nonzero angular momentum locked to their propagation direction, which enables their robust transport. Thus, these topological quasiparticles enable the funneling of infrared phonons mediated by helical infrared photons along arbitrary pathways and across sharp bends, thereby offering opportunities for applications ranging from Raman and vibrational spectroscopy with structured phonon-polaritons to directional heat dissipation.
We present improved germanium-based constraints on sub-GeV dark matter via dark matter-electron (χ-e) scattering using the 205.4 kg·day dataset from the CDEX-10 experiment. Using a novel calculation ...technique, we attain predicted χ-e scattering spectra observable in high-purity germanium detectors. In the heavy mediator scenario, our results achieve 3 orders of magnitude of improvement for m_{χ} larger than 80 MeV/c^{2} compared to previous germanium-based χ-e results. We also present the most stringent χ-e cross-section limit to date among experiments using solid-state detectors for m_{χ} larger than 90 MeV/c^{2} with heavy mediators and m_{χ} larger than 100 MeV/c^{2} with electric dipole coupling. The result proves the feasibility and demonstrates the vast potential of a new χ-e detection method with high-purity germanium detectors in ultralow radioactive background.
PDF
