Our results reveal a novel ATR-mediated anti-necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.Withanolides constitute a well-known family of plant-based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.The cochlear efferent feedback system plays important roles in auditory processing, including regulation of the dynamic range of hearing, and provides protection against acoustic trauma. These functions are performed through medial olivocochlear (MOC) neurons. However, the underlying cellular and molecular mechanisms are not fully understood. The serotonin type 3A (5-HT3A) receptor is widely expressed throughout the nervous system, which suggests important roles in various neural functions. However, involvement of the 5-HT3A receptor in the MOC system remains unclear. We used mice in this study and found that the 5-HT3A receptor was expressed in MOC neurons that innervated outer hair cells in the cochlea and was involved in the activation of MOC neurons by noise exposure. 5-HT3A receptor knockout impaired MOC functions, potentiated noise-induced hearing loss, and increased loss of ribbon synapses following noise exposure. Furthermore, 5-HT3 receptor agonist treatment alleviated the noise-induced hearing loss and loss of ribbon synapses, which enhanced cochlear protection provided by the MOC system. Our findings demonstrate that the 5-HT3A receptor plays fundamental roles in the MOC system and critically contributes to protection from noise-induced hearing impairment.Cocaine addiction is a complex pathology induced by long-term brain changes. Understanding the neurochemical changes underlying the reinforcing effects of this drug of abuse is critical for reducing the societal burden of drug addiction. The mu opioid receptor plays a major role in drug reward. This receptor is modulated by chronic cocaine treatment in specific brain structures, but few studies investigated neurochemical adaptations induced by voluntary cocaine intake. In this study, we investigated whether intravenous cocaine-self administration (0.33 mg/kg/injection, fixed-ratio 1 [FR1], 10 days) in rats induces transcriptional and functional changes of the mu opioid receptor in reward-related brain regions. Epigenetic processes with histone modifications were examined for two activating marks, H3K4Me3, and H3K27Ac. We found an increase of mu opioid receptor gene expression along with a potentiation of its functionality in hippocampus of cocaine self-administering animals compared to saline controls. Chromatin immunoprecipitation followed by qPCR revealed no modifications of the histone mark H3K4Me3 and H3K27Ac levels at mu opioid receptor promoter. Our study highlights the hippocampus as an important target to further investigate neuroadaptive processes leading to cocaine addiction. The origin of cough in dogs with heart murmurs is controversial, because the cough could be primary cardiac (eg, pulmonary edema, bronchi compression by left-sided cardiomegaly) or respiratory (eg, bronchomalacia, other bronchial or bronchiolar disease, interstitial lung disease) in origin. To study the association between left atrium (LA) dilatation and cardiomegaly and bronchial narrowing in coughing dogs with heart murmurs using computed tomography (CT). Twenty-one client-owned coughing dogs with heart murmurs and 14 historical control dogs. Dogs with cough and murmur were prospectively recruited over 4 months. Cervical and thoracic radiography, echocardiography, and thoracic CT were performed in enrolled dogs. Control dogs, with no disease on thoracic CT and no records of heart murmur and coughing, were gathered from the institution's computerized database. Degree of bronchial narrowing was assessed using the bronchial-to-aorta (Ao) ratio, measured by 3 radiologists blinded to the clinical findings. After identifying bronchi that were significantly narrowed in dogs with murmur compared to controls, the relationship between degree of narrowing and LA/Ao ratio (measured echocardiographically) and vertebral heart scale (VHS) measured radiographically was studied in dogs with murmur using mixed-effects regression. Significant narrowing was identified for all left-sided bronchi and the right principal, middle, and caudal bronchi in the coughing dogs, compared with controls. DMH1 Increasing LA size and VHS were significantly inversely associated with diameter for all left-sided and right-sided bronchi indicated above. Results indicate an association between LA enlargement and cardiomegaly and bronchial narrowing and support heart size-associated exacerbation of cough in dogs with murmurs.Results indicate an association between LA enlargement and cardiomegaly and bronchial narrowing and support heart size-associated exacerbation of cough in dogs with murmurs.The microvasculature is important for both health and exercise tolerance in a range of populations. However, methodological limitations have meant changes in microvascular blood flow are rarely assessed in humans during interventions designed to affect skeletal muscle blood flow such as the wearing of compression garments. The aim of this study is, for the first time, to use contrast-enhanced ultrasound to directly measure the effects of compression on muscle microvascular blood flow alongside measures of femoral artery blood flow and muscle oxygenation following intense exercise in healthy adults. It was hypothesized that both muscle microvascular and femoral artery blood flows would be augmented with compression garments as compared with a control condition. Ten recreationally active participants completed two repeated-sprint exercise sessions, with and without lower-limb compression tights. Muscle microvascular blood flow, femoral arterial blood flow (2D and Doppler ultrasound), muscle oxygenation (near-infrared spectroscopy), cycling performance, and venous blood samples were measured/taken throughout exercise and the 1-hour post-exercise recovery period.

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