Modifiers of Hearing Impairment in Humans and Mice

Lack of penetrance and variability of expression are common findings in nonsyndromic hearing loss with autosomal dominant mode of inheritance, but are also seen with recessive inheritance. Now we know that genotype cannot necessarily predict phenotype due to the complexity of the genome, the proteome interacting with the transcriptome, and the dynamically coupled systems that are involved. The contribution of genetic background to phenotypic diversity reflects the additive and interactive (epistasis) effects of multiple genes. Because, individual genes do not act alone but rather in concert with many other genes, it is not surprising that, modifier genes are common source of phenotypic variation in human populations. They can affect the phenotypic outcome of a given genotype by interacting in the same or in a parallel biological pathway as the disease gene. These modifier genes modulate penetrance, dominance, pleiotropy or expressivity in individuals with Mendelian traits and can also be exerted by influencing the severity, the penetrance, the age of onset and the progression of a disease. In this review, we focus on modifier genes that specifically affect hearing loss phenotypes in humans as well as those described in mice. We also include examples of digenic inheritance of deafness, because additive or interactive effects can also result from interaction between two mutant genes

Otopathogenic Staphylococcus aureus Invades Human Middle Ear Epithelial Cells Primarily through Cholesterol Dependent Pathway

Chronic suppurative otitis media (CSOM) is one of the most common infectious diseases of the middle ear especially affecting children, leading to delay in language development and communication. Although Staphylococcus aureus is the most common pathogen associated with CSOM, its interaction with middle ear epithelial cells is not well known. In the present study, we observed that otopathogenic S. aureus has the ability to invade human middle ear epithelial cells (HMEECs) in a dose and time dependent manner. Scanning electron microscopy demonstrated time dependent increase in the number of S. aureus on the surface of HMEECs. We observed that otopathogenic S. aureus primarily employs a cholesterol dependent pathway to colonize HMEECs. In agreement with these findings, confocal microscopy showed that S. aureus colocalized with lipid rafts in HMEECs. The results of the present study provide new insights into the pathogenesis of S. aureus induced CSOM. The availability of in vitro cell culture model will pave the way to develop novel effective treatment modalities for CSOM beyond antibiotic therapy

Diversity in Honors: Understanding Systemic Biases through Student Narratives

Centered on superiority over a certain group or individual, discrimination becomes predominant in prestigious institutions that pride themselves on exclusivity. Collegiate honors programs tend to deepen this practice by creating highly elite spaces accessible only to a select few. This rigidity can lead to an underrepresentation of historically marginalized groups, students who often lack the necessary resources for achieving academic excellence. This case study examines the ways honors programs inadvertently perpetuate discrimination among different social identities. Using inductive interviewing of honors students (n = 12) to gauge individual perceptions of program diversity, researchers rely on content analysis to generate four themes (relationship, discrimination, exclusion, conformity). By cross-analyzing participant responses with social identities, key programmatic components that may have led to covert systemic bias are uncovered. Results further indicate a possible link between a student’s racial identity and their sense of belonging within the program, with people of color reporting more instances of “othering” and discrimination. This study reveals a pressing need for increasing access to honors for minority students and improving the level of integration and retention among students currently enrolled

Expression of HIV transgene aggravates kidney injury in diabetic mice

With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wild-type mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease

Elucidation of repeat motifs R1- and R2-related TRIOBP variants in autosomal recessive nonsyndromic hearing loss DFNB28 among indigenous South African individuals

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request.BACKGROUND : DFNB28, a recessively inherited nonsyndromic form of deafness in humans, is caused by mutations in the TRIOBP gene (MIM #609761) on chromosome 22q13. Its protein TRIOBP helps to tightly bundle F-actin filaments, forming a rootlet that penetrates through the cuticular plate into the cochlear hair cell body. Repeat motifs R1 and R2, located in exon 7 of the TRIOBP-5 isoform, are the actin-binding domains. Deletion of both repeat motifs R1 and R2 results in complete disruption of both actin-binding and bundling activities, whereas deletion of the R2 motif alone retains F-actin bundling ability in stereocilia rootlets. METHODS : Target sequencing, using a custom capture panel of 180 known and candidate genes associated with sensorineural hearing loss, bioinformatics processing, and data analysis were performed. Genesis 2.0 was used for variant filtering based on quality/score read depth and minor allele frequency (MAF) thresholds of 0.005 for recessive NSHL, as reported in population-based sequencing databases. All variants were reclassified based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines together with other variant interpretation guidelines for genetic hearing loss . Candidate variants were confirmed via Sanger sequencing according to standard protocols, using the ABIPRISM 3730 DNA Analyzer. DNA sequence analysis was performed with DNASTAR Lasergene software. RESULTS : Candidate TRIOBP variants identified among 94 indigenous sub-Saharan African individuals were characterized through segregation analysis. Family TS005 carrying variants c.572delC, p.Pro191Argfs*50, and c.3510_3513dupTGCA, p.Pro1172Cysfs*13, demonstrated perfect cosegregation with the deafness phenotype. On the other hand, variants c.505C > A p.Asp168Glu and c.3636 T > A p.Leu1212Gln in the same family did not segregate with deafness and we have classified these variants as benign. A control family, TS067, carrying variants c.2532G > T p.Leu844Arg, c.2590C > A p.Asn867Lys, c.3484C > T p.Pro1161Leu, and c.3621 T > C p.Phe1187Leu demonstrated no cosegregation allowing us to classify these variants as benign. Together with published TRIOBP variants, the results showed that genotypes combining two truncating TRIOBP variants affecting repeat motifs R1 and R2 or R2 alone lead to a deafness phenotype, while a truncating variant affecting repeat motifs R1 and R2 or R2 alone combined with a missense variant does not. Homozygous truncating variants affecting repeat motif R2 cosegregate with the deafness phenotype. CONCLUSION : While a single intact R1 motif may be adequate for actin-binding and bundling in the stereocilia of cochlear hair cells, our findings indicate that a truncated R2 motif in cis seems to be incompatible with normal hearing, either by interfering with the function of an intact R1 motif or through another as yet unknown mechanism. Our study also suggests that most heterozygous missense variants involving exon 7 are likely to be tolerated.Fulbright Senior Research Scholar Award; R01 DC05575 and R01 DC012115 National institutes of Health/ National Institute on Deafness and other Communication Disorders; South African Medical Research Council; University of Pretoria RDP Fund.http://www.wileyonlinelibrary.com/journal/mgg3hj2023BiochemistryGeneticsImmunologyMicrobiology and Plant PathologyOtorhinolaryngolog

An iPS-derived in vitro model of human atrial conduction

Atrial fibrillation (AF) is the most common arrhythmia in the United States, affecting approximately 1 in 10 adults, and its prevalence is expected to rise as the population ages. Treatment options for AF are limited; moreover, the development of new treatments is hindered by limited (1) knowledge regarding human atrial electrophysiological endpoints (e.g., conduction velocity [CV]) and (2) accurate experimental models. Here, we measured the CV and refractory period, and subsequently calculated the conduction wavelength, in vivo (four subjects with AF and four controls), and ex vivo (atrial slices from human hearts). Then, we created an in vitro model of human atrial conduction using induced pluripotent stem (iPS) cells. This model consisted of iPS-derived human atrial cardiomyocytes plated onto a micropatterned linear 1D spiral design of Matrigel. The CV (34-41 cm/s) of the in vitro model was nearly five times faster than 2D controls (7-9 cm/s) and similar to in vivo (40-64 cm/s) and ex vivo (28-51 cm/s) measurements. Our iPS-derived in vitro model recapitulates key features of in vivo atrial conduction and may be a useful methodology to enhance our understanding of AF and model patient-specific disease

The genetic basis of deafness in populations of African descent

Hearing loss is the most common sensorineural disorder worldwide and is associated with more than 1000 mutations in more than 90 genes. While mutations in genes such as GJB2 (gap-junction protein β 2) and GJB6 (gap-junction protein β 6) are highly prevalent in Caucasian, Asian, and Middle Eastern populations, they are rare in both native African populations and those of African descent. The objective of this paper is to review the current knowledge regarding the epidemiology and genetics of hearing loss in African populations with a focus on native sub-Saharan African populations. Environmental etiologies related to poor access to healthcare and perinatal care account for the majority of cases. Syndromic etiologies including Waardenburg, Pendred and Usher syndromes are uncommon causes of hearing loss in these populations. Of the non-syndromic causes, common mutations in GJB2 and GJB6 are rarely implicated in populations of African descent. Recent use of next-generation sequencing (NGS) has identified several candidate deafness genes in African populations from Nigeria and South Africa that are unique when compared to common causative mutations worldwide. Researchers also recently described a dominant mutation in MYO3a in an African American family with non-syndromic hearing loss. The use of NGS and specialized panels will aid in identifying rare and novel mutations in a more cost- and time-effective manner. The identification of common hearing loss mutations in indigenous African populations will pave the way for translation into genetic deafness research in populations of African descent worldwide.The National Institutes of Health/National Institute on Deafness and Other Communication Disorders to Xuezhong Liu (R01 DC05575, R01 DC01246, 2P50DC000422-Sub-Project 6432, and R01 DC012115), and the University of Pretoria RDP grant and the South African ENT Society Research Grant to RI Kabahuma.http://www.journals.elsevier.com/journal-of-genetics-and-genomics2018-06-20hj2017Otorhinolaryngolog

The IRAC point response function in the warm Spitzer mission

The Infrared Array Camera (IRAC) is now the only science instrument in operation on the Spitzer Space Telescope. The 3.6 and 4.5 µm channels are temperature-stabilized at ~28.7K, and the sensitivity of IRAC is nearly identical to what it was in the cryogenic mission. The instrument point response function (PRF) is a set of values from which one can determine the point spread function (PSF) for a source at any position in the field, and is dependent on the optical characteristics of the telescope and instrument as well as the detector sampling and pixel response. These data are necessary when performing PSF-fitting photometry of sources, for deconvolving an IRAC image, subtracting out a bright source in a field, or for estimating the flux of a source that saturates the detector. Since the telescope and instrument are operating at a higher temperature in the post-cryogenic mission, we re-derive the PRFs for IRAC from measurements obtained after the warm mission temperature set point and detector biases were finalized and compare them to the 3.6 and 4.5 µm PRFs determined during the cryogenic mission to assess any changes

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Developing a research strategy to better understand, observe, and simulate urban atmospheric processes at kilometer to subkilometer scales

A Met Office/Natural Environment Research Council Joint Weather and Climate Research Programme workshop brought together 50 key international scientists from the UK and international community to formulate the key requirements for an Urban Meteorological Research strategy. The workshop was jointly organised by University of Reading and the Met Office