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Three loose housing systems for lactating cows (compost bedded pack, CBP; conventional bedded pack, BP; and freestalls, FS) were assessed on one farm in terms of cow behavior and welfare. An on-farm welfare assessment based on the Welfare Quality protocols was used four times every three months on 757 cows. Video recordings taken twice over four days were used to assess behavior patterns at resting areas. Cows in CBP and BP were dirtier than those in FS (p < 0.0001). Fewer integument alterations were recorded for CBP and BP than FS (p < 0.001). Cows in BP were quicker to lie down and stand up compared to those in CBP or FS (p < 0.001). Percentages of cows needing more attempts before rising were higher for FS (p < 0.01). However, a higher frequency of kneeling was observed in CBP (p = 0.033). A lower percentage of cows lying in the resting area was recorded for FS (56%) than CBP or BP (97 or 84%, respectively, p < 0.05). Overall, in this study, cows kept in bedded pack barns were dirtier but had fewer integument alterations and spent more time lying down in the resting area than cows housed in freestalls.

The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5' AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance.

Background Housing is a social determinant of health. Extensive research has highlighted its adverse effects on health. However, less is known about the effects of cohousing typology on health, which has the potential to create lively social networks and healthy communities and environments. We report the findings of a scoping study designed to gather and synthesise all known evidence on the relationship between cohousing and wellbeing and health. Method Using the scoping review method, we conducted a literature review in PubMed, ProQuest, Scopus, Web of Science, Science Direct and JSTOR in May 2019 and selected articles published from 1960 onwards, with no geographical limit and no design restrictions. Retrieved articles underwent three sequential screening phases. The results were described through a narrative synthesis of the evidence. Results Of the 2560 articles identified, we selected 25 full-text articles analysing 77 experiences. All of them were conducted in high-income countries. Ten studies analysed the impact of cohousing on physical and mental health or quality of life and wellbeing. Eight of the 10 studies found a positive association. In addition, 22 studies analysed one or more psychosocial determinants of health (such as social support, sense of community and physical, emotional and economic security) and most found a positive association. Through these determinants, quality of life, wellbeing and health could be improved. However, the quality of the evidence was low. Discussion The cohousing model could enhance health and wellbeing mediated by psychosocial determinants of health. However, extreme caution should be exercised in drawing any conclusions due to the dearth of data identified and the designs used in the included studies, with most being cross-sectional or qualitative studies, which precluded causal-based interpretations. Because housing is a major social determinant of health, more evidence is needed on the impact of this model on health through both psychosocial and material pathways.

Inherited cardiovascular diseases are rare diseases that are difficult to diagnose by non-expert professionals. Genetic analyses play a key role in the diagnosis of these diseases, in which the identification of a pathogenic genetic variant is often a diagnostic criterion. Therefore, genetic variant classification and routine reinterpretation as data become available represent one of the main challenges associated with genetic analyses. Using the genetic variants identified in an inherited cardiovascular diseases unit during a 10-year period, the objectives of this study were: 1) to evaluate the impact of genetic variant reinterpretation, 2) to compare the reclassification rates between different cohorts of cardiac channelopathies and cardiomyopathies, and 3) to establish the most appropriate periodicity for genetic variant reinterpretation. All the evaluated cohorts (full cohort of inherited cardiovascular diseases, cardiomyopathies, cardiac channelopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, Brugada syndrome, long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) showed reclassification rates above 25%, showing even higher reclassification rates when there is definitive evidence of the association between the gene and the disease in the cardiac channelopathies. Evaluation of genetic variant reclassification rates based on the year of the initial classification showed that the most appropriate frequency for the reinterpretation would be 2 years, with the possibility of a more frequent reinterpretation if deemed convenient. To keep genetic variant classifications up to date, genetic counsellors play a critical role in the reinterpretation process, providing clinical evidence that genetic diagnostic laboratories often do not have at their disposal and communicating changes in classification and the potential implications of these reclassifications to patients and relatives.

Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age‐related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass‐spectrometry‐based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether‐PC and ether‐LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether‐linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity. Mass spectrometry analysis of 569 lipid species showed that ceramide‐to‐hexosylceramide conversion and the preservation of ether‐linked PC levels are key phenotypic traits ensuring extreme longevity. This lipidomic signature is shaped by an intrinsic adaptive program that maintains protective mechanisms and cellular identity.

We reviewed the definitions and methods of assessment of gastro-oesophageal reflux (GOR) in anaesthetized dogs. Three databases were used. Titles and abstracts were screened by two of the authors independently. A total of 22 studies was included in the analysis. The definition of GOR implied the presence of fluids not reaching the mouth or nose in the oesophagus in all studies. Most studies considered a change in pH using oesophageal pH meters as the sole method of assessment. Calibration of the pH probe was inconsistently reported. The position of the tip of the oesophageal probe was inconsistent and not always precisely described. The correct positioning in the intended location was verified in a limited number of studies. Some studies considered that GOR had happened for changes in pH below 4.0 or above 7.5 while others considered that GOR had happened when the pH dropped below 4.0 only. Some studies stated that the pH change had to be sustained for a minimum period of time (20 or 30 s) whereas others did not mention any duration. The variability of definitions and methods of assessment of GOR in anaesthetized dogs precludes meaningful comparison of the findings. Re-evaluation and uniformization of the methods appear necessary.

IntroductionLynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.Materials and methodsBlood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.ResultsThe hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).ConclusionsThe hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Previous evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.

Advancements in genetic screening have generated massive amounts of data on genetic variation; however, a lack of clear pathogenic stratification has left most variants classified as being of unknown significance. This is a critical limitation for translating genetic data into clinical practice. Genetic screening is currently recommended in the guidelines for diagnosis and treatment of cardiac channelopathies, which are major contributors to sudden cardiac death in young people. We propose to characterize the pathogenicity of genetic variants associated with cardiac channelopathies using a stratified scoring system. The development of this system was considered by using all of the tools currently available to define pathogenicity. The use of this scoring system could help clinicians to understand the limitations of genetic associations with a disease and help them better define the role that genetics can have in their clinical routine.

BackgroundConstitutional MLH1 epimutationsare characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied byallele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim ofthis study was to perform an in-depth characterisation of constitutionalMLH1 epimutations targeting theaberrantly methylated region around MLH1 andother genomic loci.MethodsTwelve MLH1 epimutation carriers,61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium450 K array. Targeted molecular techniques were used to characterise theMLH1 epimutation carriers and theirinheritance pattern.ResultsNo nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, inwhich inter-generational methylation erasure was demonstrated in two, suggestingprimary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the soledifferentially methylated region in MLH1epimutation carriers compared to controls.ConclusionPrimary constitutional MLH1epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecularcharacterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and theirheritability/reversibility.