Vestibular sensation is essential for gaze stabilization, balance, and perception of gravity. The vestibular receptors in mammals, Type I and Type II hair cells, are located in five small organs in ...the inner ear. Damage to hair cells and their innervating neurons can cause crippling symptoms such as vertigo, visual field oscillation, and imbalance. In adult rodents, some Type II hair cells are regenerated and become re-innervated after damage, presenting opportunities for restoring vestibular function after hair cell damage. This article reviews features of vestibular sensory cells in mammals, including their basic properties, how they develop, and how they are replaced after damage. We discuss molecules that control vestibular hair cell regeneration and highlight areas in which our understanding of development and regeneration needs to be deepened.
Malaria vectors have demonstrated resistance to pyrethroid-based insecticides used in insecticide-treated nets, diminishing their effectiveness. This systematic review and meta-analysis investigated ...two forms of dual active-ingredient (DAI) insecticide-treated nets (ITN(s)) for malaria prevention. A comprehensive search was conducted on July 6
th
2022. The databases searched included PubMed, Embase, CINAHL, amongst others. Trials were eligible if they were conducted in a region with ongoing malaria transmission. The first DAI ITN investigated were those that combined a pyrethroid with a non-pyrethroid insecticides. The second DAI ITN investigated were that combined a pyrethroid with an insect growth regulator. These interventions were compared against either a pyrethroid-only ITN, or ITNs treated with pyrethroid and piperonyl-butoxide. Assessment of risk of bias was conducted in duplicate using the Cochrane risk of bias 2 tool for cluster-randomised trials. Summary data was extracted using a custom data-extraction instrument. This was conducted by authors THB, JCS and SH. Malaria case incidence was the primary outcome and has been meta-analysed, adverse events were narratively synthesised. The review protocol is registered on PROSPERO (CRD42022333044). From 9494 records, 48 reports were screened and 13 reports for three studies were included. These studies contained data from 186 clusters and all reported a low risk of bias. Compared to pyrethroid-only ITNs, clusters that received pyrethroid-non-pyrethroid DAI ITNs were associated with 305 fewer cases per 1000-person years (from 380 fewer cases to 216 fewer cases) (IRR = 0.55, 95%CI: 0.44–0.68). However, this trend was not observed in clusters that received pyrethroid-insect growth regulator ITNs compared to pyrethroid-only ITNs (from 280 fewer cases to 135 more) (IRR = 0.90, 95%CI: 0.73–1.13). Pyrethroid-non-pyrethroid DAI ITNs demonstrated consistent reductions in malaria case incidence and other outcomes across multiple comparisons. Pyrethroid-non-pyrethroid DAI ITNs may present a novel intervention for the control of malaria.
•Supporting cells are required for cell patterning, planar cell polarity, and synaptogenesis in developing sensory epithelia.•In mature sensory epithelia, supporting cells preserve the structural ...integrity of the sensory organs, modulate ion and small molecule homeostasis, and maintain the accessory extracellular matrices that enable hair cell mechanotransduction.•Supporting cells clear damaged hair cells and regenerate hair cells in injured sensory epithelia.
Sensory epithelia of the inner ear contain two major cell types: hair cells and supporting cells. It has been clear for a long time that hair cells play critical roles in mechanoreception and synaptic transmission. In contrast, until recently the more abundant supporting cells were viewed as serving primarily structural and homeostatic functions. In this review, we discuss the growing information about the roles that supporting cells play in the development, function and maintenance of the inner ear, their activities in pathological states, their potential for hair cell regeneration, and the mechanisms underlying these processes.
The purpose of the study was to examine (1) how patient adherence and eye drop technique were associated with visual field defect severity and (2) how general glaucoma adherence self-efficacy and eye ...drop technique self-efficacy were related to visual field defect severity.
Cross-sectional study conducted at a single private practice site.
Patients using eye drops for their glaucoma.
Subject adherence to glaucoma medications through Medication Events Monitoring System (MEMS) devices were measured, and eye drop instillation technique was assessed by video recording. General glaucoma medication adherence self-efficacy was measured using a 10-item scale, and eye drop technique self-efficacy was measured using a 6-item scale. Multivariate logistic regression was used to analyze the data.
Visual field defect severity.
Patients who were less than 80% adherent according to the MEMS devices were significantly more likely to have worse defect severity. Patients with lower scores on the general glaucoma medication adherence self-efficacy scale also were significantly more likely to have worse defect severity. Eye drop technique and eye drop technique self-efficacy were not related significantly to visual field defect severity.
Eye care providers need to assess patient adherence and to work with those patients with poor adherence to find ways to improve their ability and self-efficacy in using their glaucoma medications.
Proprietary or commercial disclosure may be found after the references.
Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
JBI recently began the process of updating and revising its suite of critical appraisal tools to ensure that these tools remain compatible with recent developments within risk of bias science. ...Following a rigorous development process led by the JBI Effectiveness Methodology Group, this paper presents the revised critical appraisal tool for the assessment of risk of bias for randomized controlled trials. This paper also presents practical guidance on how the questions of this tool are to be interpreted and applied by systematic reviewers, while providing topical examples. We also discuss the major changes made to this tool compared to the previous version and justification for why these changes facilitate best-practice methodologies in this field.
Lack of translation and irreproducibility challenge preclinical animal research. Insufficient reporting methodologies to safeguard study quality is part of the reason. This nationwide study ...investigates the reporting prevalence of these methodologies and scrutinizes the reported information’s level of detail. Publications were from two time periods to convey any reporting progress and had at least one author affiliated to a Danish University. We retrieved all relevant animal experimental studies using a predefined research protocol and a systematic search. A random sampling of 250 studies from 2009 and 2018 led to 500 publications in total. Reporting of measures known to impact study results estimates were assessed. Part I discloses a simplified two-level scoring “yes/no” to identify the presence of reporting. Part II demonstrates an additional three-level scoring to analyze the reported information’s level of detail. Overall reporting prevalence is low, although minor improvements are noted. Reporting of randomization increased from 24.0% in 2009 to 40.8% in 2018, blinded experiment conduct from 2.4% to 4.4%, blinded outcome assessment from 23.6% to 38.0%, and sample size calculation from 3.2% to 14.0%. Poor reporting of details is striking with reporting of the random allocation method to groups being only 1.2% in 2009 and 6.0% in 2018. Reporting of sample size calculation method was 2.4% in 2009 and 7.6% in 2018. Only conflict-of-interest statements reporting increased from 37.6% in 2009 to 90.4%. Measures safeguarding study quality are poorly reported in publications affiliated with Danish research institutions. Only a modest improvement was noted during the period 2009–2018, and the lack of details urgently prompts institutional strategies to accelerate this. We suggest thorough teaching in designing, conducting and reporting animal studies. Education in systematic review methodology should be implemented in this training and will increase motivation and behavior working towards quality improvements in science.
Millions of people worldwide suffer from hearing and balance disorders caused by loss of the sensory hair cells that convert sound vibrations and head movements into electrical signals that are ...conveyed to the brain. In mammals, the great majority of hair cells are produced during embryogenesis. Hair cells that are lost after birth are virtually irreplaceable, leading to permanent disability. Other vertebrates, such as fish and amphibians, produce hair cells throughout life. However, hair cell replacement after damage to the mature inner ear was either not investigated or assumed to be impossible until studies in the late 1980s proved this to be false. Adult birds were shown to regenerate lost hair cells in the auditory sensory epithelium after noise- and ototoxic drug-induced damage. Since then, the field of hair cell regeneration has continued to investigate the capacity of the auditory and vestibular epithelia in vertebrates (fishes, birds, reptiles, and mammals) to regenerate hair cells and to recover function, the molecular mechanisms governing these regenerative capabilities, and the prospect of designing biologically-based treatments for hearing loss and balance disorders. Here, we review the major findings of the field during the past 25 years and speculate how future inner ear repair may one day be achieved.
► Discovery of hair cell regeneration was serendipitous. ► Not known or generally believed possible before 1986–87. ► The future is bright – “we've come a long way, baby”!.
Vibrio cholerae infects human hosts following ingestion of contaminated food or water, resulting in the severe diarrheal disease cholera. The watery diarrhea that is characteristic of the disease is ...directly caused by the production of cholera toxin (CT). A complex regulatory cascade controls the production of CT and other virulence factors. However, ultimately, a single protein, ToxT, directly binds to virulence gene promoters and activates their transcription. Previously, we identified two ToxT binding sites, or toxboxes, within the cholera toxin promoter (P
). The toxboxes overlap the two promoter-proximal GATTTTT heptad repeats found within P
in classical biotype V. cholerae strain O395. These heptad repeats were previously found to be located within a large DNA region bound by H-NS, a global transcriptional repressor present in Gram-negative bacteria. The current model for the control of P
transcription proposes complete H-NS displacement from the DNA by ToxT, followed by direct activation by ToxT-RNA polymerase (RNAP) contacts. The goal of this study was to determine more precisely where H-NS binds to P
and test the hypothesis that ToxT completely displaces H-NS from the P
promoter before activating transcription. The results suggest that H-NS binds only to the region of P
encompassing the heptad repeats and that ToxT displaces H-NS only from its most promoter-proximal binding sites, calling for a revision of the current model involving H-NS and ToxT at P
.
H-NS is a global negative regulator of transcription in Gram-negative bacteria, particularly in horizontally acquired genetic islands. Previous work in Vibrio cholerae suggested that H-NS represses the transcription of cholera toxin genes by binding to a large region upstream of its promoter and that the virulence activator ToxT derepresses transcription by removing H-NS from the promoter. Here, new data support a revised model in which ToxT displaces only H-NS bound to the most promoter-proximal DNA sites that overlap the ToxT binding sites, leaving the upstream sites occupied by H-NS. This introduces a higher-resolution mechanism for the antirepression of H-NS in the control of cholera toxin production.
PDF
