Initiation codon mutation in βB1-crystallin (CRYBB1) associated with autosomal recessive nuclear pulverulent cataract

PurposeTo identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children.MethodsAn autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing.ResultsThe SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys).ConclusionsTo our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract

Development of a low-aspect ratio fin for flight research experiments

A second-generation flight test fixture, developed at NASA Dryden Flight Research Center, offers a generic testbed for aerodynamic and fluid mechanics research. The new fixture, a low-aspect ratio vertical fin shape mounted on the centerline of an F-15B aircraft lower fuselage, is designed for flight research at Mach numbers up to 2.0. The new fixture is a composite structure with a modular configuration and removable components for functional flexibility. This report describes the multidisciplinary design and analysis approach used to develop the fixture. The approach integrates conservative assumptions with simple analysis techniques to minimize the time and cost associated with its development. Presented are the principal disciplines required for this effort, which include aerodynamics, structures, stability, and operational considerations. In addition, preliminary results from the first phase of flight testing are presented. Acceptable directional stability and flow quality are documented and show agreement with predictions. Future envelope expansion activities will minimize current limitations so that the fixture can be used for a wide variety of high-speed aerodynamic and fluid mechanics research experiments

JWST Reveals Excess Cool Water near the Snow Line in Compact Disks, Consistent with Pebble Drift

Previous analyses of mid-infrared water spectra from young protoplanetary disks observed with the Spitzer-IRS found an anticorrelation between water luminosity and the millimeter dust disk radius observed with ALMA. This trend was suggested to be evidence for a fundamental process of inner disk water enrichment proposed decades ago to explain some properties of the solar system, in which icy pebbles drift inward from the outer disk and sublimate after crossing the snow line. Previous analyses of IRS water spectra, however, were uncertain due to the low spectral resolution that blended lines together. We present new JWST-MIRI spectra of four disks, two compact and two large with multiple radial gaps, selected to test the scenario that water vapor inside the snow line is regulated by pebble drift. The higher spectral resolving power of MIRI-MRS now yields water spectra that separate individual lines, tracing upper level energies from 900 to 10,000 K. These spectra clearly reveal excess emission in the low-energy lines in compact disks compared to large disks, demonstrating an enhanced cool component with T ≈ 170–400 K and equivalent emitting radius R eq ≈ 1–10 au. We interpret the cool water emission as ice sublimation and vapor diffusion near the snow line, suggesting that there is indeed a higher inward mass flux of icy pebbles in compact disks. Observation of this process opens up multiple exciting prospects to study planet formation chemistry in inner disks with JWST

Nepali migrant workers and the need for pre-departure training on mental health: a qualitative study

Every year around 1,000 Nepali migrant workers die abroad. Every one in three females and one in ten males commit suicide, reflecting a high mental health risk among Nepali migrant workers. This study aims to identify triggers of mental ill-health among Nepali migrant workers and their perception on need of mental health components in the pre-departure orientation programme. We conducted five focus group discussions (FGD) and seven in-depth interviews with Nepali migrant workers and eight semi-structured interviews with stakeholders working for migrants. Participants were invited at Kathmandu’s international airport on return from abroad, at hotels or bus stations near the airport, through organisations working for migrants, and participants’ network. All FGD and interviews were conducted in Kathmandu and audio recorded, transcribed and translated into English. Data were analyzed thematically. High expectations from families back home, an unfair treatment at work, poor arrangements of accommodation, loneliness and poor social life abroad were frequently reported factors for poor mental health. Access to mental health services abroad by Nepali migrant was also poor. We found little on mental health in the pre-departure orientation. We need to improve our knowledge of mental health risks to provide better, more focused and more up-to-date pre-departure training to new migrant workers leaving Nepal

Lessons Learned Developing a Diagnostic Tool for HIV-Associated Dementia Feasible to Implement in Resource-Limited Settings: Pilot Testing in Kenya

Objective: To conduct a preliminary evaluation of the utility and reliability of a diagnostic tool for HIV-associated dementia (HAD) for use by primary health care workers (HCW) which would be feasible to implement in resource-limited settings. Background: In resource-limited settings, HAD is an indication for anti-retroviral therapy regardless of CD4 T-cell count. Anti-retroviral therapy, the treatment for HAD, is now increasingly available in resource-limited settings. Nonetheless, HAD remains under-diagnosed likely because of limited clinical expertise and availability of diagnostic tests. Thus, a simple diagnostic tool which is practical to implement in resource-limited settings is an urgent need. Methods: A convenience sample of 30 HIV-infected outpatients was enrolled in Western Kenya. We assessed the sensitivity and specificity of a diagnostic tool for HAD as administered by a primary HCW. This was compared to an expert clinical assessment which included examination by a physician, neuropsychological testing, and in selected cases, brain imaging. Agreement between HCW and an expert examiner on certain tool components was measured using Kappa statistic. Results: The sample was 57 % male, mean age was 38.6 years, mean CD4 T-cell count was 323 cells/mL, and 54 % had less than a secondary school education. Six (20%) of the subjects were diagnosed with HAD by expert clinical assessment. The diagnostic tool was 63 % sensitive and 67 % specific for HAD. Agreement between HCW and expert examiners was poor for many individual items of the diagnostic tool (K =.03–.65). This diagnostic tool had moderate sensitivity and specificity fo

Enhanced prefrontal serotonin 5-HT1A currents in a mouse model of Williams-Beuren syndrome with low innate anxiety

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously (Gtf2ird1+/−) or homozygously (Gtf2ird1−/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1−/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1−/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1−/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1−/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines

NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker

Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies

Exploring CRM effectiveness: an institutional theory perspective

This study identifies the potential contribution that institutional theory can make to understanding the success of marketing practices. Based on institutional theory, we argue that the effectiveness of marketing practices decreases when firms are motivated to adopt such practices under the influence of institutional pressures originating in firms' environments. However, alignment between a practice and a firm's marketing strategy may buffer against these negative effects. We apply these insights to the case of customer relationship management (CRM). CRM is considered an important way to enhance customer loyalty and firm performance, but it has also been criticized for being expensive and for not living up to expectations. Empirical data from 107 organizations confirm that, in general, adopting CRM for mimetic motives is likely to result in fewer customer insights as a result of using this practice. Our study suggests that institutional theory has much to offer to the investigation of the effectiveness of marketing practices

Mediator Acts Upstream of the Transcriptional Activator Gal4

We show that Mediator, a protein originally isolated on the basis of its ability to respond to transcriptional activators, and thought to be regulated by an activator, can also be the master that controls the activator