Regulation of the length of neuronal primary cilia and its potential effects on signalling.

Primary cilia protrude from most vertebrate cell bodies and act as specialized 'signalling antennae' that can substantially lengthen or retract in minutes to hours in response to specific stimuli. Here, we review the conditions and mechanisms responsible for regulating primary cilia length (PCL) in mammalian nonsensory neurons, and propose four models of how they could affect ciliary signalling and alter cell state and suggest experiments to distinguish between them. These models include (i) the passive indicator model, where changes in PCL have no consequence; (ii) the rheostat model, in which a longer cilium enhances signalling; (iii) the local concentration model, where ciliary shortening increases the local protein concentration to facilitate signalling; and (iv) the altered composition model where changes in PCL skew signalling.

Factors Associated with Significant Weight Loss in Hospitalised Patients with COVID-19: A Retrospective Cohort Study in a Large Teaching Hospital.

SARS-CoV-2 infection (COVID-19) is associated with malnutrition risk in hospitalised individuals. COVID-19 and malnutrition studies in large European cohorts are limited, and post-discharge dietary characteristics are understudied. This study aimed to assess the rates of and risk factors for ≥10% weight loss in inpatients with COVID-19, and the need for post-discharge dietetic support and the General Practitioner (GP) prescription of oral nutritional supplements, during the first COVID-19 wave in a large teaching hospital in the UK. Hospitalised adult patients admitted between March and June 2020 with a confirmed COVID-19 diagnosis were included in this retrospective cohort study. Demographic, anthropometric, clinical, biochemical, and nutritional parameters associated with ≥10% weight loss and post-discharge characteristics were described. Logistic regression models were used to identify risk factors for ≥10% weight loss and post-discharge requirements for ongoing dietetic input and oral nutritional supplement prescription. From the total 288 patients analysed (40% females, 72 years median age), 19% lost ≥ 10% of their admission weight. The length of hospital stay was a significant risk factor for ≥10% weight loss in multivariable analysis (OR 1.22; 95% CI 1.08-1.38; p = 0.001). In addition, ≥10% weight loss was positively associated with higher admission weight and malnutrition screening scores, dysphagia, ICU admission, and artificial nutrition needs. The need for more than one dietetic input after discharge was associated with older age and ≥10% weight loss during admission. A large proportion of patients admitted to the hospital with COVID-19 experienced significant weight loss during admission. Longer hospital stay is a risk factor for ≥10% weight loss, independent of disease severity, reinforcing the importance of repeated malnutrition screening and timely referral to dietetics.

Ciliopathy genes are required for apical secretion of Cochlin, an otolith crystallization factor.

Here, we report that important regulators of cilia formation and ciliary compartment-directed protein transport function in secretion polarity. Mutations in cilia genes cep290 and bbs2, involved in human ciliopathies, affect apical secretion of Cochlin, a major otolith component and a determinant of calcium carbonate crystallization form. We show that Cochlin, defective in human auditory and vestibular disorder, DFNA9, is secreted from small specialized regions of vestibular system epithelia. Cells of these regions secrete Cochlin both apically into the ear lumen and basally into the basal lamina. Basally secreted Cochlin diffuses along the basal surface of vestibular epithelia, while apically secreted Cochlin is incorporated into the otolith. Mutations in a subset of ciliopathy genes lead to defects in Cochlin apical secretion, causing abnormal otolith crystallization and behavioral defects. This study reveals a class of ciliary proteins that are important for the polarity of secretion and delineate a secretory pathway that regulates biomineralization.

Is Breast Cancer Risk Associated with Menopausal Hormone Therapy Modified by Current or Early Adulthood BMI or Age of First Pregnancy?

Menopausal hormone therapy (MHT) has an attenuated effect on breast cancer (BC) risk amongst heavier women, but there are few data on a potential interaction with early adulthood body mass index (at age 20 years) and age of first pregnancy. We studied 56,489 women recruited to the PROCAS (Predicting Risk of Cancer at Screening) study in Manchester UK, 2009-15. Cox regression models estimated the effect of reported MHT use at entry on breast cancer (BC) risk, and potential interactions with a. self-reported current body mass index (BMI), b. BMI aged 20 and c. First pregnancy >30 years or nulliparity compared with first pregnancy <30 years. Analysis was adjusted for age, height, family history, age of menarche and menopause, menopausal status, oophorectomy, ethnicity, self-reported exercise and alcohol. With median follow up of 8 years, 1663 breast cancers occurred. BC risk was elevated amongst current users of combined MHT compared to never users (Hazard ratioHR 1.64, 95% CI 1.32-2.03), risk was higher than for oestrogen only users (HR 1.03, 95% CI 0.79-1.34). Risk of current MHT was attenuated by current BMI (interaction HR 0.80, 95% CI 0.65-0.99) per 5 unit increase in BMI. There was little evidence of an interaction between MHT use, breast cancer risk and early and current BMI or with age of first pregnancy.