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Taste buds are maintained via continuous turnover of taste bud cells derived from local epithelial stem cells. A transcription factor Skn-1a (also known as Pou2f3) is required for the generation of sweet, umami (savory), and bitter taste cells that commonly express TRPM5 and CALHM ion channels. Here, we demonstrate that sodium-taste cells distributed only in the anterior oral epithelia and involved in evoking salty taste also require Skn-1a for their generation. We discovered taste cells in fungiform papillae and soft palate that show similar but not identical molecular feature with sweet, umami, and bitter taste-mediated Type II cells. This novel cell population expresses Plcb2, Itpr3, Calhm3, Skn-1a, and ENaCα (also known as Scnn1a) encoding the putative amiloride-sensitive (AS) salty taste receptor but lacks Trpm5 and Gnat3Skn-1a-deficient taste buds are predominantly composed of putative non-sensory Type I cells and sour-sensing Type III cells, whereas wild-type taste buds include Type II (i.e., sweet, umami, and bitter taste) cells and sodium-taste cells. Both Skn-1a and Calhm3-deficient mice have markedly decreased chorda tympani nerve responses to sodium chloride, and those decreased responses are attributed to the loss of the AS salty taste response. Thus, AS salty taste is mediated by Skn-1a-dependent taste cells, whereas amiloride-insensitive salty taste is mediated largely by Type III sour taste cells and partly by bitter taste cells. Our results demonstrate that Skn-1a regulates differentiation toward all types of taste cells except sour taste cells.Numerous immunomodulating agents are currently being studied in clinical trials for the treatment of COVID-19, including interferon therapies. Interferons are naturally occurring host antiviral proteins upstream of the inflammatory pathway that are released by host cells in response to the presence of viral pathogens. It is known that beta coronaviruses deploy anti-interferon defenses to escape host innate immunity early in the infection course, and thus interferons have become attractive candidates for treatment of COVID-19. Questions surrounding timing, type of interferon, and route of administration all remain unanswered. Here we discuss the role of interferons in host antiviral immunity, and review the current data surrounding use of interferons in COVID-19.
Dysregulated cellular metabolism is a distinct hallmark of human colorectal cancer (CRC). However, metabolic programme rewiring during tumour progression has yet to be fully understood.
We analysed altered gene signatures during colorectal tumour progression, and used a complex of molecular and metabolic assays to study the regulation of metabolism in CRC cell lines, human patient-derived xenograft mouse models and tumour organoid models.
We identified a novel RNA-binding protein, RALY (also known as hnRNPCL2), that is highly associated with colorectal tumour aggressiveness. RALY acts as a key regulatory component in the Drosha complex, and promotes the post-transcriptional processing of a specific subset of miRNAs (miR-483, miR-676 and miR-877). These miRNAs systematically downregulate the expression of the metabolism-associated genes (ATP5I, ATP5G1, ATP5G3 and CYC1) and thereby reprogramme mitochondrial metabolism in the cancer cell. Analysis of The Cancer Genome Atlas (TCGA) reveals that increased levels of RALY are associated with poor prognosis in the patients with CRC expressing low levels of mitochondrion-associated genes. Mechanistically, induced processing of these miRNAs is facilitated by their N6-methyladenosine switch under reactive oxygen species (ROS) stress. Inhibition of the m
A methylation abolishes the RALY recognition of the terminal loop of the pri-miRNAs. Knockdown of RALY inhibits colorectal tumour growth and progression in vivo and in organoid models.
Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.
Collectively, our results reveal a critical metabolism-centric role of RALY in tumour progression, which may lead to cancer therapeutics targeting RALY for treating CRC.The field of immunology is rapidly evolving and has significant relevance to understanding human health, particularly in light of the threat from infectious diseases and the ability to harness the immune system to treat cancer, autoimmune diseases, and allergies. Providing opportunities to explore the field of immunology is relevant to undergraduate students interested in pursuing careers in health professions and biomedical research. selleck kinase inhibitor There are calls for greater emphasis on interdisciplinary science education at the undergraduate level and the acquisition of transferrable competencies that will prepare undergraduates for success in a range of careers. The study of immunology provides an ideal platform to expose students to interdisciplinary science, both at the foundational and applied level. We describe the organization of an immunology curriculum, development of program learning objectives, selection and mapping of content objectives across courses, and programmatic assessment with the intent to meet calls for reform in undergraduate biology education.
To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting.
Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy.
10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83) age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These oncephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.
Recent years have seen an almost sevenfold rise in referrals to specialist memory clinics. This has been associated with an increased proportion of patients referred with functional cognitive disorder (FCD), that is, non-progressive cognitive complaints. These patients are likely to benefit from a range of interventions (eg, psychotherapy) distinct from the requirements of patients with neurodegenerative cognitive disorders. We have developed a fully automated system, 'CognoSpeak', which enables risk stratification at the primary-secondary care interface and ongoing monitoring of patients with memory concerns.
We recruited 15 participants to each of four groups Alzheimer's disease (AD), mild cognitive impairment (MCI), FCD and healthy controls. Participants responded to 12 questions posed by a computer-presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification.
CognoSpeak could distinguish betweeat assessments. The current data supports CognoSpeak's promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.Brain death, or death by neurological criteria (BD/DNC), has been accepted conceptually, medically and legally for decades. Nevertheless, some areas remain controversial or understudied, pointing to a need for focused research to advance the field. Multiple recent contributions have increased our understanding of BD/DNC, solidified our practice and provided guidance where previously lacking. There have also been important developments on a global scale, including in low-to-middle income countries such as in South America. Although variability in protocols and practice still exists, new efforts are underway to reduce inconsistencies and better train practitioners in accurate and sound BD/DNC determination. Various legal challenges have required formal responses from national societies, and the American Academy of Neurology has filled this void with much needed guidance. Questions remain regarding concepts such as 'whole brain' versus 'brainstem' death, and the intersection of BD/DNC and rubrics of medical futility. These concepts are the subject of this review.
To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD) and to identify risk factors that predict pregnancy-related attack.
From January 2015 to April 2019, 418 female patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records and identified 110 patients with 136 informative pregnancies, of whom 83 were aquaporin-4 antibody (AQP4-ab)-positive and 21 were myelin oligodendrocyte glycoprotein-antibody-positive. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1 year after delivery/abortion. We compared annualised relapse rate (ARR) during 12 months before pregnancy with that during every trimester of pregnancy and after delivery/abortion. Multivariate analyses were used to explore the independent risk factors involved and a nomogram was generated for the prediction of pregnancy-related attack. Thirty-five female patients from 3 other centres formed an external cohort to validate this nomogram.
ARR increased significantly during the first trimester after delivery (p<0.001) or abortion (p=0.019) compared with that before pregnancy. Independent risk factors predicting pregnancy-related attack included age at delivery/abortion (20-26.5, p=0.018; 26.5-33, p=0.001), AQP4-ab titre (≥1100, p=0.049) and inadequate treatment during pregnancy and postpartum period (p=0.004). The concordance index of nomogram was 0.87 and 0.77 using bootstrap resampling in internal and external validation.
The first trimester post partum is a high-risk period for NMOSD recurrence. Patients with younger age, higher AQP4-ab titre and inadequate treatment are at higher risk for pregnancy-related attack.
The first trimester post partum is a high-risk period for NMOSD recurrence. Patients with younger age, higher AQP4-ab titre and inadequate treatment are at higher risk for pregnancy-related attack.
Responsiveness to direct verbal suggestions (suggestibility) has long been hypothesised to represent a predisposing factor for functional neurological disorder (FND) but previous research has yielded conflicting results. The aim of this study was to quantitatively evaluate whether patients with FND display elevated suggestibility relative to controls via meta-analysis.
Four electronic databases were searched in November 2019, with the search updated in April 2020, for original studies assessing suggestibility using standardised behavioural scales or suggestive symptom induction protocols in patients with FND (including somatisation disorder) and controls. The meta-analysis followed Cochrane, Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Data extraction and study quality coding were performed by two independent reviewers. Standardised suggestibility scores and responsiveness to symptom induction protocols were used to calculate standardised mean differences (SMDs) between groups.
