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Studying the neurological, genetic, and evolutionary basis of human vocal communication mechanisms using animal vocalization models is an important field of neuroscience. The datasets typically comprise structured sequences of syllables or songs produced by animals from different genotypes under different social contexts. It has been difficult to come up with sophisticated statistical methods that appropriately model animal vocal communication syntax. We address this need by developing a novel Bayesian semiparametric framework for inference in such datasets. Our approach is built on a novel class of mixed effects Markov transition models for the songs that accommodate exogenous influences of genotype and context as well as animal-specific heterogeneity. Crucial advantages of the proposed approach include its ability to provide insights into key scientific queries related to global and local influences of the exogenous predictors on the transition dynamics via automated tests of hypotheses. The methodology is illustrated using simulation experiments and the aforementioned motivating application in neuroscience. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

Background: Preimplantation genetic screening (PGS) is increasingly utilized as an adjunct procedure to IVF. Recently healthy euploid live birth were reported following transfer of mosaic embryos. Several recent publications have surmised that the degree of trophectoderm (TE) mosaicism in transferred embryos is predictive of ongoing pregnancy and miscarriage rates. Methods: This is a corrected analysis of previously published retrospective data on vitro fertilization (IVF) cycle outcomes involving replacement of 143 mosaic and 1045 euploid embryos tested by PGS, utilizing high-resolution next-generation sequencing (NGS) of TE and determination of percentages of mosaicism. Receiver operating curves (ROCs) and measurement of area under the curve (AUC) were used to evaluated the accuracy of the predictor variable, proportion of aneuploid cells in a TE biopsy specimen, with IVF outcomes, ongoing pregnancy and miscarriage rates. Results: Confirming findings of the previously published report we also found higher ongoing pregnancy rates (63.3% vs. 39.2%) and lower miscarriage rates (10.2% vs. 24.3%) with euploid embryo transfers than with mosaic embryo transfer. There, however, were no significant differences in ongoing pregnancy or miscarriage rates among mosaic embryo transfers at any threshold of aneuploidy. Based on AUC, TE biopsies predicted ongoing pregnancy for euploid, as well as mosaic embryos, in a range of 0.50 to 0.59 and miscarriage in a range from 0.50 to 0.66 Conclusions: Degree of TE mosaicism was a poor predictor of ongoing pregnancy and miscarriage.

Interleukin (IL)-12 is composed of p35 and p40 subunits; in this case, IL-12p40 deficiency is a rare genetic etiology of Mendelian susceptibility to mycobacterial disease. Salmonellosis has been reported in almost half of these patients and mostly present in recurrent extraintestinal form. In this report, we described an 18-month-old boy with absence of IL-12p40 production suffering from chronic disseminated nontyphoidal salmonellosis. To the best of our knowledge, this is the first-reported case.

Engineering biomolecular motors can provide direct tests of structure-function relationships and customized components for controlling molecular transport in artificial systems(1) or in living cells(2). Previously, synthetic nucleic acid motors(3-5) and modified natural protein motors(6-10) have been developed in separate complementary strategies to achieve tunable and controllable motor function. Integrating protein and nucleic-acid components to form engineered nucleoprotein motors may enable additional sophisticated functionalities. However, this potential has only begun to be explored in pioneering work harnessing DNA scaffolds to dictate the spacing, number and composition of tethered protein motors(11-15). Here, we describe myosin motors that incorporate RNA lever arms, forming hybrid assemblies in which conformational changes in the protein motor domain are amplified and redirected by nucleic acid structures. The RNA lever arm geometry determines the speed and direction of motor transport and can be dynamically controlled using programmed transitions in the lever arm structure(7,9). We have characterized the hybrid motors using in vitro motility assays, single-molecule tracking, cryo-electron microscopy and structural probing(16). Our designs include nucleoprotein motors that reversibly change direction in response to oligonucleotides that drive strand-displacement(17) reactions. In multimeric assemblies, the controllable motors walk processively along actin filaments at speeds of 10-20 nm s(-1). Finally, to illustrate the potential for multiplexed addressable control, we demonstrate sequence-specific responses of RNA variants to oligonucleotide signals.

Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 x 10(6) mRNA-electroporated LCs, based on absolute number of CD83(+)CD86(bright)HLA-DR(bright)CD14(neg) LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-, IL-2, and TNF-), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V- CDR3 documented fold-increases in clonality of 2.11 (range 0.85-3.22) for CD4 and 2.94 (range 0.98-9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes.

For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3 overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

Background Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. Objective We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. Methods Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. Results We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. Conclusion This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.

The clonal complexity of adult stem cell pools is progressively lost during homeostatic turnover in several tissues, suggesting a decrease in the number of stem cells with distinct clonal origins. The functional impact of reduced complexity on stem cell pools, and how different tissue microenvironments may contribute to such a reduction, are poorly understood. Here, we performed clonal multicolor lineage tracing of skeletal muscle stem cells (MuSCs) to address these questions. We found that MuSC clonal complexity is maintained during aging despite heterogenous reductions in proliferative capacity, allowing aged muscle to mount a clonally diverse, albeit diminished, response to injury. In contrast, repeated bouts of tissue repair cause a progressive reduction in MuSC clonal complexity indicative of neutral drift. Consistently, biostatistical modeling suggests that MuSCs undergo symmetric expansions with stochastic fate acquisition during tissue repair. These findings establish distinct principles that underlie stem cell dynamics during homeostatic aging and muscle regeneration.

Isolated photons with high transverse energy have been studied in deep in-elastic ep scattering with the ZEUS detector at HERA, using an integrated luminosity of 326 pb(-1) in the range of exchanged-photon virtuality 10-350 GeV2. Outgoing isolated photons with transverse energy 4 < E-T(gamma) < 15 GeV and pseudorapidity -0.7 < eta(gamma) < 0.9 were measured with accompanying jets having transverse energy and pseudorapidity 2 : 5 < E-T(jet) < 35 GeV and -1.5 < eta(jet) < 1.8, respectively. Differential cross sections are presented for the following variables: the fraction of the incoming photon energy and momentum that is transferred to the outgoing photon and the leading jet; the fraction of the incoming proton energy transferred to the photon and leading jet; the differences in azimuthal angle and pseudorapidity between the outgoing photon and the leading jet and between the outgoing photon and the scattered electron. Comparisons are made with theoretical predictions: a leading-logarithm Monte Carlo simulation, a next-to-leading-order QCD prediction, and a prediction using the k(T)-factorisation approach.

A search for narrow vector resonances decaying into quark-antiquark pairs is presented. The analysis is based on data collected in proton-proton collisions at root s = 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1). The hypothetical resonance is produced with sufficiently high transverse momentum that its decay products are merged into a single jet with two-prong substructure. A signal would be identified as a peak over a smoothly falling background in the distribution of the invariant mass of the jet, using novel jet substructure techniques. No evidence for such a resonance is observed within the mass range of 50-300 GeV. Upper limits at 95% confidence level are set on the production cross section, and presented in a mass-coupling parameter space. The limits further constrain simplified models of dark matter production involving a mediator interacting between quarks and dark matter particles through a vector or axial-vector current. In the framework of these models, the results are the most sensitive to date, extending for the first time the search region to masses below 100 GeV.