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Aging is a natural and continuous irreversible changing process. In this stage progressive generalized impairment of function occur which results in loss of adaptive response to stress. This study was conducted to assess the emotional problem and coping strategies among senior citizens, The research design used for this study was non experimental descriptive research design, The setting of the study was selected old-age home at Azahiamandapam in Kanyakumari district. The selected population for the study was senior citizens those who are (60yrs and above). Structured questionnaire was used to assess emotional problems and level of coping strategies. On the basis of the study findings, most of the senior citizens have adequate level of coping strategies regarding emotional problems.

Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases 1 – 3 . However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9 , a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse Pcsk9 . A single administration of lipid nanoparticles loaded with the editors’ mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing. Experiments in mice show that designed epigenome editors that contain domains of transcriptional repressors can enable stable epigenetic silencing of Pcsk9 , a gene with a role in cholesterol homeostasis, without inducing DNA breaks.

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1; c.835C>T; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28; c.708G>T; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes: STX1A, SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl4 gene. TMEM187 gene, like SYTL4, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4, the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1; TMLHE; MECP2; and GPHN. TMM187 is in linkage with MECP2, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism.

James Webb Space Telescope observations have spectroscopically confirmed the existence of galaxies as early as 300 Myr after the Big Bang and with a higher number density than what was expected based on galaxy formation models and Hubble Space Telescope observations. Yet, most sources confirmed spectroscopically so far in the first 500 Myr have rest-frame ultraviolet (UV) luminosities below the characteristic luminosity ( M UV * ), limiting the signal-to-noise ratio for investigating substructure. Here we present a high-resolution spectroscopic and spatially resolved study of a bright galaxy ( M UV  = −21.66 ± 0.03, ~ 2 M UV * ) at a redshift z  = 9.3127 ± 0.0002 (510 Myr after the Big Bang) with an estimated stellar mass of 1 . 6 − 0.4 + 0.5 × 1 0 9 M ⊙ , forming 1 9 − 6 + 5 solar masses per year and with a metallicity of about one tenth that of solar. The system has a morphology typically associated with two interacting galaxies, with a two-component main clump of very young stars (age less than 10 Myr) surrounded by an extended stellar population (120 ± 20 Myr old, identified from modelling the NIRSpec spectrum) and an elongated clumpy tidal tail. The observations acquired at high spectral resolution identify oxygen, neon and hydrogen emission lines, as well as the Lyman break, where there is evidence of substantial absorption of Lyα. The [O ii ] doublet is resolved spectrally, enabling an estimate of the electron number density and ionization parameter of the interstellar medium and showing higher densities and ionization than in analogues at lower redshifts. We identify evidence of absorption lines (silicon, carbon and iron), with low confidence individual detections but a signal-to-noise ratio larger than 6 when stacked. These absorption features suggest that Lyα is damped by the interstellar and circumgalactic media. Our observations provide evidence of a rapid and efficient build-up of mass and metals in the immediate aftermath of the Big Bang through mergers, demonstrating that there were massive galaxies with several billion stars at early times. JWST detections of Si, C and Fe absorption lines in a bright z  = 9.31 galaxy with a two-component clump structure suggest that mergers contributed to the rapid build-up of mass and chemical enrichment soon after the Big Bang.

To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (p = 0.016) and autism spectrum disorder (ASD; p = 0.02), while paternal deletions were associated with congenital heart disease (CHD; p = 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (p < 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (p < 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (p = 0.019) and paternal deletions associated with muscular phenotypes (p = 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions.

Bio-epoxy composites were fabricated by casting a resin–hardener–filler mixture into 3D-printed molds, using different sea-originated secondary raw materials: mussel shell powder (MSP) (63–83 μm) and Posidonia oceanica short fibers (POF) (1–2 mm). Monofiller composites were prepared with 5 or 10 wt.% MSP, or 5 or 10 wt.% POF. Hybrid formulations were also produced, containing both MSP and POF in two combinations, where the total amount of filler again summed up at 10 wt.%. A subset of the samples was conditioned by immersion in a 35 ‰ NaCl solution reproducing seawater composition until saturation was reached. Characterization was carried out on unconditioned and conditioned samples by Shore D hardness and Charpy impact tests while performing three-point flexural loading only on unconditioned ones. Fracture morphology was also investigated. Adding MSP slightly enhanced resin hardness, whereas impact absorption exhibited, to a variable extent, a two-phase behavior, reproducing crack initiation and propagation. The MSP6-POF4 hybrid configuration provided the greatest improvement in absorbed energy (25–30% higher), which was retained after conditioning. The introduction of fillers, first separately, then in combination, resulted in a reduction in flexural strength to a similar extent for all unconditioned configurations. Finally, composite panels containing 10 wt.% MSP, 10 wt.% POF, and a 6MSP–4POF hybrid formulation, intended for prospective boat deck applications, were fabricated and compared with neat bio-epoxy, showing satisfactory consolidation. Density and post-molding dimensional shrinkage were measured on the panels.

Abstract Context Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. Objective To evaluate safety and efficacy of intranasal carbetocin in PWS. Design Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. Setting Twenty-four ambulatory clinics at academic medical centers. Participants A total of 130 participants with PWS aged 7 to 18 years. Interventions Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. Main outcome measures Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). Results Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. Conclusions Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. Clinical Trials Registration Number NCT03649477

Gut commensal bacteria are known to have a significant role in regulating the innate and adaptive immune homeostasis. Alterations in the intestinal microbial composition have been associated with several disease states, including autoimmune and inflammatory conditions. However, it is not entirely clear how commensal gut microbiota modulate and contribute to the systemic immunity, and whether circulating elements of the host immune system could regulate the microbiome. Thus, we have studied the diversity and abundance of specific taxons in the gut microbiota of inbred GalT-KO mice during 7 months of animal life by metagenetic high-throughput sequencing (16S rRNA gene, variable regions V3-V5). The repertoire of glycan-specific natural antibodies, obtained by printed glycan array technology, was then associated with the microbial diversity for each animal by metagenome-wide association studies (MWAS). Our data show that the orders (most abundant), , and may be associated with the development of the final repertoire of natural anti-glycan antibodies in GalT-KO mice. The main changes in microbiota diversity (month-2 and month-3) were related to important changes in levels and repertoire of natural anti-glycan antibodies in these mice. Additionally, significant positive and negative associations were found between the gut microbiota and the pattern of specific anti-glycan antibodies. Regarding individual features, the gut microbiota and the corresponding repertoire of natural anti-glycan antibodies showed differences among the examined animals. We also found redundancy in different taxa associated with the development of specific anti-glycan antibodies. Differences in microbial diversity did not, therefore, necessarily influence the overall functional output of the gut microbiome of GalT-KO mice. In summary, the repertoire of natural anti-carbohydrate antibodies may be partially determined by the continuous antigenic stimulation produced by the gut bacterial population of each GalT-KO mouse. Small differences in gut microbiota diversity could determine different repertoire and levels of natural anti-glycan antibodies and consequently might induce different immune responses to pathogens or other potential threats.

Due to its structural and functional complexity the heart imposes immense physical, physiological and electromechanical challenges on the engineering of a biological replacement. Therefore, to come closer to clinical translation, the development of a simpler biological assist device is requested. Here, we demonstrate the fabrication of tubular cardiac constructs with substantial dimensions of 6 cm in length and 11 mm in diameter by combining human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and human foreskin fibroblast (hFFs) in human fibrin employing a rotating mold technology. By centrifugal forces employed in the process a cell-dense layer was generated enabling a timely functional coupling of iPSC-CMs demonstrated by a transgenic calcium sensor, rhythmic tissue contractions, and responsiveness to electrical pacing. Adjusting the degree of remodeling as a function of hFF-content and inhibition of fibrinolysis resulted in stable tissue integrity for up to 5 weeks. The rotating mold device developed in frame of this work enabled the production of tubes with clinically relevant dimensions of up to 10 cm in length and 22 mm in diameter which—in combination with advanced bioreactor technology for controlled production of functional iPSC-derivatives—paves the way towards the clinical translation of a biological cardiac assist device.

PurposeThis paper aims to investigate the cultural meanings of excessive drinking in three different countries with different levels of alcohol use chosen as case studies of wider geographies representing Northern (Denmark), Southern (Italy) and Eastern (Estonia) Europe.Design/methodology/approachData were collected according to the Reception Analytical Group Interview method, using video clips as stimuli to enhance comparability. Eight online focus groups were organized in each country for a total number of 128 participants. Symbolic boundaries defining what drinking patterns are socially acceptable were then analysed to look at cross-national variations.FindingsResults show how different conceptualizations of excessive drinking persist, although a convergence process among drinking patterns is also observed, which suggests that differences mainly depend on meanings and values attributed to intoxication. These are both rooted in the traditional drinking cultures and affected by ongoing social and economic change processes.Research limitations/implicationsBecause of the chosen research approach, the research results may lack generalizability, even at country level, as there are differences also within the same drinking culture; however, addressing these differences was beyond the scope of the present study, which aimed to contribute to understanding persisting differences in European drinking culture despite different drivers seem to act for globalization of drinking habits.Practical implicationsThe paper includes implications for the development of tailored and effective prevention messages, considering rooted attitudes and cultural values attached to drinking and drunkenness in different European geographies, which are also related to conceptualizations of risks and pleasure.Originality/valueThis paper fulfils an identified need to understand persisting differences in alcohol-related behaviours and outcome in different European countries emerging from quantitative data.