The rockefeller university

Our sense of hearing boasts exquisite sensitivity to periodic signals. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. As a result, small changes in these values could compromise the ability of the mechanosensory hair cells to detect stimuli. We propose that, rather than exerting tight control over parameters, the auditory system employs a homeostatic mechanism that ensures the robustness of its operation to variation in parameter values. Through analytical techniques and computer simulations we investigate whether a homeostatic mechanism renders the hair bundle's signal-detection ability more robust to alterations in experimentally accessible parameters. When homeostasis is enforced, the range of values for which the bundle's sensitivity exceeds a threshold can increase by more than an order of magnitude. The robustness of cochlear function based on somatic motility or hair bundle motility may be achieved by employing the approach we describe here.

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.

Background Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X-linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. Methods We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next-gen sequencing for defining the duplication breakpoint, PacBio sequencing of full-length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB-null cells with lentiviral FANCBWT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. Results We describe here an FA-B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology-mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild-type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. Conclusion Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA-B patient described here.

Purpose: The purpose of this study is to assess the impact of duration of energy delivery on adverse events (AEs) and heat sink effects during high power microwave ablation (MWA) of normal swine lung.Materials and methods: High power (100 W) MWA was performed with short (2min, 18 ablations) or long (10min, nine ablations) duration of energy delivery in unilateral lung of swine (n=10). CT imaging was done prior to sacrifice at 2 or 28d post-treatment, with additional imaging at 7 and 14d for the latter cohort. Ablation zones were assessed with CT imaging and histopathology analysis. Differences in AEs and ablation characteristics between groups were compared with Fisher's exact test and Student's t-test, respectively.Results: There were no significant differences in formation of air-filled needle tract, cavitation, and pneumonia (p>0.5) between the treatment groups. Intra-procedural pneumothorax requiring chest tube placement occurred in three animals. Substantial (>20%, p=0.01) intra-procedural ablation zone distortion was observed in both groups. The presence of large airways or blood vessels did not result in heat sink effect within the ablation zones and was not indicative of reduced ablation size. Increased energy delivery yielded larger (8.93.1cm(3) vs. 3.4 +/- 1.7cm(3), p<0.001) spherical ablations (sphericity: 0.70 +/- 0.10 vs. 0.56 +/- 0.13, p=0.01).Conclusions: High power MWA of normal lung with longer duration of energy delivery can create larger spherical ablations, without significant differences in post-procedure AEs when compared with shorter energy delivery time.

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.

The similar to 9.5 kilobase HIV-1 genome contains RNA sequences and structures that control many aspects of viral replication, including transcription, splicing, nuclear export, translation, packaging and reverse transcription. Nonetheless, chemical probing and other approaches suggest that the HIV-1 genome may contain many more RNA secondary structures of unknown importance and function. To determine whether there are additional, undiscovered cis-acting RNA elements in the HIV-1 genome that are important for viral replication, we undertook a global silent mutagenesis experiment. Sixteen mutant proviruses containing clusters of similar to 50 to similar to 200 synonymous mutations covering nearly the entire HIV-1 protein coding sequence were designed and synthesized. Analyses of these mutant viruses resulted in their division into three phenotypic groups. Group 1 mutants exhibited near wild-type replication, Group 2 mutants exhibited replication defects accompanied by perturbed RNA splicing, and Group 3 mutants had replication defects in the absence of obvious splicing perturbation. The three phenotypes were caused by mutations that exhibited a clear regional bias in their distribution along the viral genome, and those that caused replication defects all caused reductions in the level of unspliced RNA. We characterized in detail the underlying defects for Group 2 mutants. Second-site revertants that enabled viral replication could be derived for Group 2 mutants, and generally contained point mutations that reduced the utilization of proximal splice sites. Mapping of the changes responsible for splicing perturbations in Group 2 viruses revealed the presence of several RNA sequences that apparently suppressed the use of cryptic or canonical splice sites. Some sequences that affected splicing were diffusely distributed, while others could be mapped to discrete elements, proximal or distal to the affected splice site(s). Overall, our data indicate complex negative regulation of HIV-1 splicing by RNA elements in various regions of the HIV-1 genome that enable balanced splicing and viral replication.

Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking toRNAdecay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylationdependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins. Further examination of ZC3H18 function, by genome-wide analyses, demonstrated its impact on transcription of a subset of protein-coding genes. This activity requires the CBC-interacting domain of the protein, with some genes being also dependent on the NEXT-and/or histone-interacting domains. Our data shed light on the domain requirements of a protein positioned centrally in nuclear RNA metabolism, and they suggest that post-translational modification may modulate its function.

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.

Spontaneous otoacoustic emissions (SOAEs) are a universal feature of all classes of tetrapods. Although the generation mechanism of SOAEs are incompletely understood, these emissions are undoubtedly associated with the active process of the inner ear. In most lizards, unlike mammals and amphibians, robust SOAEs can ordinarily be detected from both ears. In this work, we investigated the interactions between emissions recorded simultaneously from the two ears of tokay geckos. We found that the frequency spectra of SOAEs from both ears of an individual animal are partially correlated: the peaks of several emissions occur at identical frequencies. To investigate the underlying mechanisms of these identical-frequency SOAEs, we perturbed the emissions from one or both ears by manipulating the pressure in the ear canals or by decreasing the local temperature in the vicinity of one inner ear. Suppression of SOAEs due to large positive pressures revealed that some identical-frequency emissions were generated unilaterally, whereas others were contributed by both ears at identical or slightly different frequencies. These bilaterally generated SOAEs became desynchronized as their frequency detuning grew sufficiently large, a phenomenon consistent with the synchronization of two active oscillators. Finally, we found that manipulations of the volume of the oral cavity or altering the impedance of the tympanum strongly affected the synchronization of SOAEs. These findings agreed with previous studies suggesting that the tokay gecko, like other lizards, exhibits strong acoustic coupling between its tympani through the oral cavity.

The recent development of DNA sequencing technology has given rise to many statistical methods for Rare Variant Association Studies (RVASs), such as burden and sequence kernel association tests. However, these methods, which usually require large samples, can lose power in association studies with small samples. In this study, we propose two statistical approaches applicable for RVASs when the sample size is not large. Our approaches are based on the Hamming distance, which compares the dissimilarity of Single Nucleotide Polymorphisms (SNPs) components between cases and controls. Existing Hamming distance-based methods mainly analyse common variants. For rare variant data with a small sample size, we extended two existing methods by using the weight based on minor allele frequency. Through simulation studies, we show that our proposed approaches control type 1 error rates and are more powerful even when given very small sample sizes. They also work well regardless of the direction of causal SNP effects. Applying these methods to real data, we confirmed that they identified true causal genes well. Based on the results of this study, we firmly believe that our proposed methods are powerful for small sample data.