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Background The primary pathological alterations of Pendred syndrome are endolymphatic pH acidification and luminal enlargement of the inner ear. However, the molecular contributions of specific cell types remain poorly characterized. Therefore, we aimed to identify pH regulators in pendrin-expressing cells that may contribute to the homeostasis of endolymph pH and define the cellular pathogenic mechanisms that contribute to the dysregulation of cochlear endolymph pH in Slc26a4 −/− mice. Methods We used single-cell RNA sequencing to identify both Slc26a4 -expressing cells and Kcnj10 -expressing cells in wild-type (WT, Slc26a4 +/+ ) and Slc26a4 −/− mice. Bioinformatic analysis of expression data confirmed marker genes defining the different cell types of the stria vascularis. In addition, specific findings were confirmed at the protein level by immunofluorescence. Results We found that spindle cells, which express pendrin, contain extrinsic cellular components, a factor that enables cell-to-cell communication. In addition, the gene expression profile informed the pH of the spindle cells. Compared to WT, the transcriptional profiles in Slc26a4 −/− mice showed downregulation of extracellular exosome-related genes in spindle cells. Immunofluorescence studies in spindle cells of Slc26a4 −/− mice validated the increased expression of the exosome-related protein, annexin A1, and the clathrin-mediated endocytosis-related protein, adaptor protein 2. Conclusion Overall, cell isolation of stria vascularis from WT and Slc26a4 −/− samples combined with cell type-specific transcriptomic analyses revealed pH-dependent alternations in spindle cells and intermediate cells, inspiring further studies into the dysfunctional role of stria vascularis cells in SLC26A4 -related hearing loss.

Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in TMC1 , a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7/11, respectively, accounting for ∼2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness. However, application of such approaches is limited by the infeasibility of development and validation of novel constructs for each variant. We developed an allele-non-specific approach consisting of mutation-agnostic RNAi suppression of both mutant and WT alleles, co-delivered with a knockdown-resistant engineered WT allele with or without the use of woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to augment transgene expression. This therapeutic construct was delivered into the mature murine model of DFNA36 with an AAV vector and achieved robust hair cell and auditory brainstem response preservation. However, WPRE-enhanced Tmc1 expression resulted in inferior outcomes, suggesting a role for gene dosage optimization in future TMC1 gene therapy development.

Mini-screw Assisted Rapid Maxillary Expanders (MARME’s) have become a popular alternative to SARME in the treatment of maxillary constriction in adult patients. This study’s objective was to evaluate the effectiveness of a traditional RME appliance to achieve a successful separation of the maxillary midpalatal suture (MPS) at different ages, pubertal status, months past puberty, and gender. Additionally, we explored whether effectiveness can be improved by utilization of a mini-screw assisted RME appliance. 115 subjects (mean age of 13.6 years; range 7.6-29.2) were treated with traditional two or four banded traditional RME appliances, and 25 subjects (mean age of 16.9 years; range 13.1-22.6) were treated with MARME’s. 73% of the traditional RME subjects and 100% of the MARME subjects had a MPS split (p= 0.001). Post-pubertal patients ≥15 years of age treated with traditional RME had a 52.2% chance of achieving a MPS split, compared to 100% success rate seen with TAD RME treatment (p < 0.001). Utilizing a MARME rather than a traditional RME can greatly improve a clinician’s chances of achieving a MPS split if the patient is post-pubertal and/or ≥15 years of age.

Ascaris is a large roundworm parasite that infects humans and pigs throughout the world. Molecular markers have been used to study parasite transmission in Ascaris-endemic and -nonendemic regions of the world. In the United States, ascariasis still persists in commercial swine and has been designated a neglected disease of poverty in humans. However, relatively few data are available for evaluation of zoonotic transmission. In the present study, we obtained adult worms from abattoirs and characterized each worm on the basis of the gene encoding nuclear internal transcribed sequence (ITS) and mitochondrial cox1. Restriction fragment–length polymorphism analysis of ITS revealed swine, human, and hybrid genotypes. coxl sequences were compared to all complete sequences available in GenBank, and haplotype analysis demonstrated 92 haplotypes worldwide. Sequences from the parasites in this study represented 10 haplotypes, including 6 new haplotypes that have not been previously described. Our results indicate that anthropozoonotic transmission has occurred in the past, resulting in the presence of human genotypes in pigs and supporting further investigation of zoonotic Ascaris transmission in the United States.

It has been two years, five surgeries, and one prosthetic eye since [Joe Bogart] was wounded in action that October morning in 2006 during his first tour in Iraq. Today, he is legally blind with a prosthetic right eye and the most amazing, inspirational, and humbling part of this story is that he is now Captain Joe Bogart, back in the fight and selflessly serving his nation proudly in Iraq. He remains a member of the Fightin' Fifth Engineer Battalion and is currently serving as the Executive Officer of Headquarters Company. Joe credits the doctors at Walter Reed Army Medical Center for saving some of his eyesight. While legally blind, his \"good\" eye still sees 20/40 with glasses. When it came down to the final decision, it was Joe who would not accept defeat, Joe who never quit, and Joe who fought passionately to continue his service in the Army and to deploy with his Battalion once again. \"Don't forget what you learned. Wear the protective gear you are issued. Getting blown up and walking away isn't fun. It means you were lucky. Getting wounded isn't glorious or cool; it freaking hurts, and continues to hurt for the rest of your life. But you deal with the pain both physically and emotionally. A Purple Heart isn't an award to strive for but is something the military gives you when you get wounded and you pay a price that you didn't plan on paying or ever hope to pay. It's a price that you don't even know. We all sacrifice for the good of our nation. It's just that some of us have the scars on the outside.\"

Arrhenoidy of mosquitofish (Gambusia affinis) was examined in fish recovered from a river receiving kraft mill effluent after a reduction in the use of molecular chlorine and increased reclamation of tall oils. Fish were obtained by seine net, keeping within a standard length of 25-40 mm. Anal fin lengths were measured, their elongation being a sign of masculinization. Although extreme modification of the anal fin was rare, anal fin lengths were greater than for fish in unaffected streams. Most individuals were at an intermediate level of masculinization. Its degree was greater during summer, probably because the mill effluent was more concentrated. Some overall reduction in masculinization had occurred but the effluent improvements had not yet eliminated it, possibly through the continued presence of some tall oils. The mosquitofish appeared a sensitive bioindicator.

INTRODUCTION Plasma biomarkers sensitive to Alzheimer's disease (AD) proteinopathy prior to the onset of dementia have significant implications for early detection. METHODS In 304 individuals without dementia, we investigated whether C2N Diagnostics’ mass spectrometry (MS)‐based plasma biomarkers (amyloid beta 42/40, %phosphorylated tau [p‐tau]181, and %p‐tau217) and amyloid probability scores (APS, PrecivityAD and APS2, PrecivityAD2) are associated with brain amyloid, brain tau, or preclinical cognitive decline. RESULTS In this cohort study, %p‐tau217 and the APS2 had high discriminative accuracy (area under the curve > 0.93) for identifying elevated brain amyloid and tau and were associated with faster preclinical cognitive decline. Using %p‐tau217 or the APS2 in a theoretical AD trial screening scenario reduced amyloid positron emission tomography imaging costs up to 41% or 45%, respectively. DISCUSSION These findings suggest that C2N Diagnostics’ MS‐based plasma biomarkers can detect brain amyloid and tau with high accuracy prior to dementia and could aid in identifying candidates for clinical trials or therapeutic intervention. Highlights C2N plasma biomarkers differentiated Alzheimer's disease proteinopathy status prior to dementia. Plasma %phosphorylated tau (p‐tau)217 and the C2N Diagnostics PrecivityAD2 (APS2) were concordant with amyloid and tau positron emission tomography status. Plasma %p‐tau217 and the APS2 were associated with preclinical cognitive decline.

The first cetacean circovirus, beaked whale circovirus (BWCV), was recently reported in a Longman’s beaked whale ( Indopacetus pacificus ) stranded in Hawai‘i and represents an emergent disease with unknown population impacts. In other species, circovirus infection may cause mortality or opportunistic co-infection by other pathogens. We report on a targeted surveillance of stranded cetaceans in the Pacific basin, including archived beaked whale species, strandings where pathological findings suggested disease presence, mass stranded animals, and additional individuals to represent a broad range of Hawaiian cetacean species. Archived tissues primarily from the brain, kidney, liver, lung, spleen, and lymph nodes of individuals stranded between 2000 and 2020 (n=30) were tested by PCR for the presence of BWCV. Suspect positive tissue amplicons were confirmed as BWCV through sequencing. Of the screened individuals, 15 animals tested positive in one or more tissues, with a single striped dolphin ( Stenella coeruleoalba ) testing positive in all six tissues. The highest rate of detection among positive cases was found in the brain (69%), followed by lymph (67%) and lung tissues (64%). Additionally, co-infections of cetacean morbillivirus (n=3), Brucella ceti (n=1), and Toxoplasma gondii (n=1) were found among the positive cases. These results expand the potential host range for BWCV into ten additional odontocete species. New host species include a dwarf sperm whale ( Kogia sima ) that stranded on O‘ahu in 2000, predating the initial case of BWCV. The results broaden the known geographic range of BWCV to Saipan in the Western Pacific, and American Samoa in the South Pacific, where stranded Cuvier’s beaked whales ( Ziphius cavirostris ) tested positive. Although the clinical significance is currently unknown, this study demonstrates that BWCV has a high prevalence within targeted cetacean screening efforts. Infectious diseases pose a major threat to cetaceans and BWCV may represent an important emerging disease within populations spanning the central, Western, and South Pacific.

BackgroundTissue hypoxia is a pathological condition characterized by reducing oxygen supply. Hypoxia is a hallmark of tumor environment and is commonly observed in many solid tumors. Non-invasive imaging techniques like positron emission tomography (PET) are at the forefront of detecting and monitoring tissue hypoxia changes in vivo.ResultsWe have developed a novel 18F-labeled radiotracer for hypoxia PET imaging based on cytotoxic agent benznidazole. Radiotracer N-(4-[18F]fluorobenzyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide ([18F]FBNA) was synthesized through acylation chemistry with readily available 4-[18F]fluorobenzyl amine. Radiotracer [18F]FBNA was obtained in good radiochemical yields (47.4 ± 5.3%) and high radiochemical purity (> 95%). The total synthesis time was 100 min, including HPLC purification and the molar activity was greater than 40 GBq/µmol. Radiotracer [18F]FBNA was stable in saline and mouse serum for 6 h. [18F]FBNA partition coefficient (logP = 1.05) was found to be more lipophilic than [18F]EF-5 (logP = 0.75), [18F]FMISO (logP = 0.4) and [18F]FAZA (logP =  − 0.4). In vitro studies showed that [18F]FBNA accumulates in gastric cancer cell lines AGS and MKN45 under hypoxic conditions.ConclusionsHence, [18F]FBNA represents a novel and easy-to-prepare PET radioligand for imaging hypoxia.