HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

BACKGROUND: Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. METHODS: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. RESULTS: After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. CONCLUSIONS: These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy

A human Dectin-2 deficiency associated with invasive aspergillosis

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. PBMCs from this patient were unable to mount a cytokine (TNF, IL-6) response to A. fumigatus and this first identified Dectin-2-deficient patient succumbed to invasive aspergillosis

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Understanding how ABI3 contributes to the aetiology of Alzheimer’s Disease

Neuroinflammation in Alzheimer’s Disease (AD) is not a simple by-product of β-amyloidosis and neurofibrillary tangles, but it rather plays a crucial role in AD pathogenesis. However, we are still far from understanding how exactly microglia influence disease progression. A rare missense variant, S209F, associated to an increased risk of AD has been identified in Abi3 (Abl-interactor-3), a poorly investigated member of the Abi family, which is involved in Rac-dependent regulation of the actin cytoskeleton. Within the brain, Abi3 is considered a core human microglial signature gene. Given that a flexible actin cytoskeleton is key to many microglia – and more broadly, macrophages – functions, the precise role of Abi3 in these cells in health and pathology, such as AD, needs to be clarified. In order to investigate Abi3 biological functions, a combination of cellular assays, histology, live imaging and behavioural paradigms was employed. In an actin-mediated spreading assay, Abi3 knock-out (KO) BMDM-like cells – derived from conditionally-immortalized macrophage precursors – showed increased cellular surface and solidity. These findings have been validated by histological analyses of brains of healthy Abi3-WT and -KO mice as well as in the APPNL-G-F AD model. Microglial cells lacking Abi3 present reduced ramifications accompanied by an increase in cell density and CD68 expression. Young Abi3-KO mice also show impaired surveyance activity in vivo. In addition, Abi3 ablation leads to an elevated astrocytic density from a young age, as well as a reduction in Amyloid β deposition in the hippocampus, but not in the prefrontal cortex, of 16-week-old mice. Behavioural assays highlighted a potential impact of Abi3 ablation on the emotional domain but not on cognitive ability. These results support the hypothesis of a critical role of Abi3 in microglial homeostasis, and suggest that its rare variant may promote AD development by altering microglia homeostatic functions

Biología y Pesquería de la merluza (Merluccius hubbsi)

Argentine hake (Merluccius hubbsi) is a demersal, eurythermic and euryhaline species associated to subantarctic waters of the continental shelf and slope. The species, considered the main fishery resource of Argentina that in 2011 reached the maximum catch and export levels, distributes from Southern Brazil to 55° S in a 50-400 m depth range. The three stocks identified, located between 34° S-41° S, south of said latitude and in the San Matías Gulf, show differences as regards reproduction and nursery areas and time, meristic and morphometric characters, abundance level and growth parameters. At the Instituto Nacional de Investigación y Desarrollo Pesquero (INIDEP) annual assessments of the exploitation status of the stocks north and south of 41° S are carried out and management recommendations made. In this chapter, the biology, fishery characteristics, population abundance and structure and management recommendations for the two main Argentine hake stocks are described.Fil: Irusta, Gabriela. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Macchi, Gustavo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Louge, Elena. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Rodrigues, Karina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: D´Atri, Luciana. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Villarino, Fernanda. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Santos, Betina. Instituto Nacional de Investigaciones y Desarrollo Pesquero; ArgentinaFil: Simonazzi, Mario Arturo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Investigaciones y Desarrollo Pesquero; Argentin

Preliminary evaluation of aqueous tear production in dogs after sedation with intramuscular dexmedetomidine-butorphanol combination

Objective. The aims of the study are to evaluate the effect of dexmedetomidine-butorphanol combination on aqueous tear production assessed with Schirmer tear test I (STT I) in dogs and to evaluate the influence of gender, weight, duration of sedation and right or left eye on STT I values after the sedation. Materials and Methods. One hundred forty-one client-owned dogs undergoing clinic visit, radiologic or ultrasonographic assessments, aged > 12 months, without previous ocular disease and with no drug therapy or sedation or anesthesia in the previous three months are included. Ocular examination consists of STT I and an exam with a slit lamp executed before sedation. The same experienced veterinarian performed ocular examination. Dogs with STT I lower than 15 mm/min or higher than 25 mm/min or with abnormalities of the ocular surface were withdrawn from the study. The dogs were sedated with dexmedetomidine 5 μg/kg combined with butorphanol 0.2 mg/kg inoculated intramuscularly (IM). Dexmedetomidine was completely reversed by administering atipamezole IM. The STT I was detected for each dog before sedation, at 15 minutes after the administration of the dexmedetomidine-butorphanol combination and at 15 minutes after the injection of atipamezole at the end of procedure. The data were analysed using ANOVA by means of the general linear model (GLM). STT I values were reported as least-squares means (LSMeans) ± standard error (SE). Age, weight and duration of sedation were expressed as mean ± standard deviation (SD). P values < 0.05 were considered significant. Results. Forty-three dogs are withdrawn from the study because of ocular surface abnormalities or STT I 25 mm/min. The 98 dogs included in the study (16 entire females, 31 spayed females, 28 entire males and 23 neutered males) belonged to thirty-three breeds, had a mean age of 5.2 ± 2.8 years with a range of 1-11 years and a mean weight of 18.21 ± 9.66 kg with a range of 6-66 kg. STT I before sedation was 21.53 ± 0.24. Mean duration of sedation was 52.57 ± 11.41 minutes with a range of 30-87 minutes. All dogs recovered the walking ability at 15 minutes after the administration of atipamezole. STT I significantly decreased at 15 minutes after sedation (10.03 ± 0.24). At 15 minutes after injection of atipamezole, STT I was significantly higher (14.05 ± 0.24) compared to STT I at 15 minutes after sedation, but it was significantly lower compared to values before sedation. No differences related to breed, sex, right or left eye and body weight are recorded. Conclusions and clinical significance. Dexmedetomidine-butorphanol combination significantly reduces aqueous tear production in dogs. The administration of atipamezole increases tear production, but STT I values stay below 15 mm/min even if dogs are able to walk. Therefore, the use of tear substitutes are recommended just before the sedation and in the hours following the recovery

midwives’ physiological approach at the third stage of labour: a protocol for a scoping review

This scoping review aims to identify and describe the kind of midwifery practices and care that midwives usually use to keep third stage normal and physiological