Grxcr1 promotes hair bundle development by destabilizing the physical interaction between Harmonin and Sans usher syndrome proteins

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Cell Reports 25 (2018): 1281–1291, doi:10.1016/j.celrep.2018.10.005.Morphogenesis and mechanoelectrical transduction of the hair cell mechanoreceptor depend on the correct assembly of Usher syndrome (USH) proteins into highly organized macromolecular complexes. Defects in these proteins lead to deafness and vestibular areflexia in USH patients. Mutations in a non-USH protein, glutaredoxin domain-containing cysteine-rich 1 (GRXCR1), cause non-syndromic sensorineural deafness. To understand the deglutathionylating enzyme function of GRXCR1 in deafness, we generated two grxcr1 zebrafish mutant alleles. We found that hair bundles are thinner in homozygous grxcr1 mutants, similar to the USH1 mutants ush1c (Harmonin) and ush1ga (Sans). In vitro assays showed that glutathionylation promotes the interaction between Ush1c and Ush1ga and that Grxcr1 regulates mechanoreceptor development by preventing physical interaction between these proteins without affecting the assembly of another USH1 protein complex, the Ush1c- Cadherin23-Myosin7aa tripartite complex. By elucidating the molecular mechanism through which Grxcr1 functions, we also identify a mechanism that dynamically regulates the formation of Usher protein complexes.This work was supported by grants from the NIH (DC004186, OD011195, and HD22486)

Reclaiming Futures and Organizing Justice for Drug-Using Youth

Reclaiming Futures is an organizational change initiative that supports coordinated and individualized responses for justice-involved youth with problematic substance use issues. The Research and Evaluation Center at John Jay College of Criminal Justice compared people\u27s perceptions currently working in Reclaiming Futures communities with similar colleagues from nearly ten years ago. The study suggested that communities with the strongest engagement in Reclaiming Futures tended to have more positive perceptions of their youth justice and substance abuse treatment systems, including key facets of administration, collaboration, and overall system quality

Coloration in different areas of facial skin is a cue to health: The role of cheek redness and periorbital luminance in health perception

Looking healthy is a desirable trait, and facial skin color is a predictor of perceived health. However, skin conditions that cause dissatisfaction with appearance are specific to particular facial areas. We investigated whether color variation in facial skin is related to perceived health. Study 1 defined three areas based on color differences between faces perceived as healthy or unhealthy: the forehead, periorbital areas, and the cheeks. Periorbital luminance and cheek redness predicted perceived health, as did global skin yellowness. In Study 2, increased luminance and redness caused faces to be perceived as healthier, but only when the increase was in the periorbital and cheek areas, respectively. Manipulating each area separately in Study 3 revealed cheek redness and periorbital luminance equally increased perceived health, with low periorbital luminance more negatively affecting perceptions. These findings show that color variation in facial skin is a cue for health perception in female faces

Transcranial Direct Current Stimulation Modulates Efficiency of Reading Processes

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that offers promise as an investigative method for understanding complex cognitive operations such as reading. This study explores the ability of a single session of tDCS to modulate reading efficiency and phonological processing performance within a group of healthy adults. Half the group received anodal or cathodal stimulation, on two separate days, of the left temporo-parietal junction while the other half received anodal or cathodal stimulation of the right homologue area. Pre- and post-stimulation assessment of reading efficiency and phonological processing was carried out. A larger pre-post difference in reading efficiency was found for participants who received right anodal stimulation compared to participants who received left anodal stimulation. Further, there was a significant post-stimulation increase in phonological processing speed following right hemisphere anodal stimulation. Implications for models of reading and reading impairment are discussed

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.This work is supported by the Wellcome strategic award (100574/Z/12/Z); MRC MDU: MC_UU_12012/2 and MC_UU_12012/5 (The Disease Model Core, Biochemistry Assay Lab, Histology Core, and the Genomics and Transcriptomics Core); the Wellcome grant 10953/Z/15/Z (I.S.); the Wellcome Cambridge Trust scholarship (E.F.-J.); the Spanish Ministry of Economy and Competitiveness (SAF2017-88908-R) and PT17/0009/0006 from the ISCIII (C.Ç. and J.D.B.); the Academy of Finland (grants 259926, 265204, 292839, 314456, and 335446), the Paulo Foundation, the Finnish Cultural Foundation Southwest Finland Regional Fund, the Turku University Hospital Research Funds, and the European Union (EUFP7 project 278373; DIABAT) (K.A.V. and M.U.-D.); the Fundación Ramón Areces (BEVP32P01S10090) and subsequently by a Sir Henry Wellcome postdoctoral fellowship (222748/Z/21/Z) (S.R.-F.); We thank the Wellcome-Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Pepd<tm1a[KOMP]Wtsi). Funding and associated primary phenotypic information may be found at www.sanger.ac.uk/mouseportal.Peer reviewe

Harmonic biases in child learners: In support of language universals

A fundamental question for cognitive science concerns the ways in which languages are shaped by the biases of language learners. Recent research using laboratory language learning paradigms, primarily with adults, has shown that structures or rules that are common in the languages of the world are learned or processed more easily than patterns that are rare or unattested. Here we target child learners, investigating a set of biases for word order learning in the noun phrase studied by Culbertson, Smolensky & Legendre (2012) in college-age adults. We provide the first evidence that child learners exhibit a preference for typologically common harmonic word order patterns—those which preserve the order of the head with respect to its complements—validating the psychological reality of a principle formalized in many different linguistic theories. We also discuss important differences between child and adult learners in terms of both the strength and content of the biases at play during language learning. In particular, the bias favoring harmonic patterns is markedly stronger in children than adults, and children (unlike adults) acquire adjective ordering more readily than numeral ordering. The results point to the importance of investigating learning biases across development in order to understand how these biases may shape the history and structure of natural languages

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists

Research design considerations for clinical studies of abuse-deterrent opioid analgesics: IMMPACT recommendations

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Due to the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs in order to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability; (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation; (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse; and (4) post-marketing epidemiological studies

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care