Assignment of the lattice modes in TCNQ0 single crystals

A complete assignment of the six librational modes of the TCNQ0 crystal has been made employing both polarized Raman spectroscopic measurements and lattice dynamical calculations. Agreement between theory and experiment is good and modes at 40.5, 74.5, and 96 cm-1 are assigned as Ag active and those at 63, 75.5, and 104 cm-1 are Bg active. The lattice modes are found to be clearly separated from the molecular modes. The study emphasizes the importance of crystal optics and quality in the measurement of the polarized Raman spectra of biaxial crystals. The Journal of Chemical Physics is copyrighted by The American Institute of Physics

Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregu- lated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV priming protein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR, reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotrans- mission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand

De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy Due to Impaired GABAergic Neurotransmission

Objective:Rare inherited missense variants inSLC32A1, the gene that encodes the vesicular gamma-aminobutyric acid(GABA) transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarifyif de novo missense variants inSLC32A1can also cause epilepsy with impaired neurodevelopment.Methods:Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathyand de novo missense variants inSLC32A1. To assess causality, we performed functional evaluation of the identifiedvariants in a murine neuronal cell culture model.Results:The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset epilepsy within thefirst 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functionalanalyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway,result in reduced quantal size, consistent with impairedfilling of synaptic vesicles with GABA. The fourth variant,located in the vesicular gamma-aminobutyric acid N-terminus, does not affect quantal size, but increases presynapticrelease probability, leading to more severe synaptic depression during high-frequency stimulation. Thus, variants invesicular gamma-aminobutyric acid can impair GABAergic neurotransmission through at least two mechanisms, byaffecting synaptic vesiclefilling and by altering synaptic short-term plasticity.Interpretation:This work establishes de novo missense variants inSLC32A1as a novel cause of a developmental andepileptic encephalopathy

Genetic markers of Munc13 protein family member, BAIAP3, are gender-specifically associated with anxiety and benzodiazepine abuse in mouse and man

Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders

Quantification of SLIT-ROBO transcripts in hepatocellular carcinoma reveals two groups of genes with coordinate expression

<p>Abstract</p> <p>Background</p> <p>SLIT-ROBO families of proteins mediate axon pathfinding and their expression is not solely confined to nervous system. Aberrant expression of <it>SLIT-ROBO </it>genes was repeatedly shown in a wide variety of cancers, yet data about their collective behavior in hepatocellular carcinoma (HCC) is missing. Hence, we quantified <it>SLIT-ROBO </it>transcripts in HCC cell lines, and in normal and tumor tissues from liver.</p> <p>Methods</p> <p>Expression of <it>SLIT-ROBO </it>family members was quantified by real-time qRT-PCR in 14 HCC cell lines, 8 normal and 35 tumor tissues from the liver. ANOVA and Pearson's correlation analyses were performed in R environment, and different clinicopathological subgroups were pairwise compared in Minitab. Gene expression matrices of cell lines and tissues were analyzed by Mantel's association test.</p> <p>Results</p> <p>Genewise hierarchical clustering revealed two subgroups with coordinate expression pattern in both the HCC cell lines and tissues: <it>ROBO1</it>, <it>ROBO2</it>, <it>SLIT1 </it>in one cluster, and <it>ROBO4</it>, <it>SLIT2</it>, <it>SLIT3 </it>in the other, respectively. Moreover, <it>SLIT-ROBO </it>expression predicted <it>AFP</it>-dependent subgrouping of HCC cell lines, but not that of liver tissues. <it>ROBO1 </it>and <it>ROBO2 </it>were significantly up-regulated, whereas <it>SLIT3 </it>was significantly down-regulated in cell lines with high-<it>AFP </it>background. When compared to normal liver tissue, <it>ROBO1 </it>was found to be significantly overexpressed, while <it>ROBO4 </it>was down-regulated in HCC. We also observed that <it>ROBO1 </it>and <it>SLIT2 </it>differentiated histopathological subgroups of liver tissues depending on both tumor staging and differentiation status. However, <it>ROBO4 </it>could discriminate poorly differentiated HCC from other subgroups.</p> <p>Conclusion</p> <p>The present study is the first in comprehensive and quantitative evaluation of <it>SLIT-ROBO </it>family gene expression in HCC, and suggests that the expression of <it>SLIT-ROBO </it>genes is regulated in hepatocarcinogenesis. Our results implicate that <it>SLIT-ROBO </it>transcription profile is bi-modular in nature, and that each module shows intrinsic variability. We also provide quantitative evidence for potential use of <it>ROBO1</it>, <it>ROBO4 </it>and <it>SLIT2 </it>for prediction of tumor stage and differentiation status.</p

Evidence for proton acceleration up to TeV energies based on VERITAS and Fermi-LAT observations of the Cas A SNR

We present a study of $\gamma$-ray emission from the core-collapse supernova remnant Cas~A in the energy range from 0.1GeV to 10TeV. We used 65 hours of VERITAS data to cover 200 GeV - 10 TeV, and 10.8 years of \textit{Fermi}-LAT data to cover 0.1-500 GeV. The spectral analysis of \textit{Fermi}-LAT data shows a significant spectral curvature around $1.3 \pm 0.4_{stat}$ GeV that is consistent with the expected spectrum from pion decay. Above this energy, the joint spectrum from \textit{Fermi}-LAT and VERITAS deviates significantly from a simple power-law, and is best described by a power-law with spectral index of $2.17\pm 0.02_{stat}$ with a cut-off energy of $2.3 \pm 0.5_{stat}$ TeV. These results, along with radio, X-ray and $\gamma$-ray data, are interpreted in the context of leptonic and hadronic models. Assuming a one-zone model, we exclude a purely leptonic scenario and conclude that proton acceleration up to at least 6 TeV is required to explain the observed $\gamma$-ray spectrum. From modeling of the entire multi-wavelength spectrum, a minimum magnetic field inside the remnant of $B_{\mathrm{min}}\approx150\,\mathrm{\mu G}$ is deduced.Comment: 33 pages, 9 Figures, 6 Table

Direct measurement of stellar angular diameters by the VERITAS Cherenkov Telescopes

The angular size of a star is a critical factor in determining its basic properties. Direct measurement of stellar angular diameters is difficult: at interstellar distances stars are generally too small to resolve by any individual imaging telescope. This fundamental limitation can be overcome by studying the diffraction pattern in the shadow cast when an asteroid occults a star, but only when the photometric uncertainty is smaller than the noise added by atmospheric scintillation. Atmospheric Cherenkov telescopes used for particle astrophysics observations have not generally been exploited for optical astronomy due to the modest optical quality of the mirror surface. However, their large mirror area makes them well suited for such high-time-resolution precision photometry measurements. Here we report two occultations of stars observed by the VERITAS Cherenkov telescopes with millisecond sampling, from which we are able to provide a direct measurement of the occulted stars' angular diameter at the $\leq0.1$ milliarcsecond scale. This is a resolution never achieved before with optical measurements and represents an order of magnitude improvement over the equivalent lunar occultation method. We compare the resulting stellar radius with empirically derived estimates from temperature and brightness measurements, confirming the latter can be biased for stars with ambiguous stellar classifications.Comment: Accepted for publication in Nature Astronom