The curious role of sarcomeric proteins in control of diverse processes in cardiac myocytes

Introduction Relatively recent developments in our understanding of sarcomeric proteins have expanded their role from the home of molecular motors generating force and shortening to a cellular organelle fully integrated in the control of structural, electrical, mechanical, chemical, and metabolic homeostasis. Even so, in some cases these diverse functions of sarcomeric proteins appear to remain a curiosity, not fully appreciated in the analysis of major controllers of cardiac function. This attitude toward the function of sarcomeric proteins in cardiac myocytes is summarized in the following definition of “curiosity,” which seems particularly apropos: “meddlesome; thrusting oneself into and taking an active part in others’ affairs.” We focus in this Perspective on how sarcomeric proteins function in integration with membrane channels and transporters in control of cardiac dynamics, especially in adrenergic control of cardiac function. Understanding these mechanisms at the level of cardiac sarcomeres took on special significance with the identification of mutations in sarcomeric proteins as the most common cause of familial hypertrophic and dilated cardiomyopathies. These mutations commonly lead to structural, electrical, and metabolic remodeling and to sudden death. These disorders indicate a critical role of processes at the level of the sarcomeres in homeostatic control of cardiac energetics, dynamics, and structure. Yet, control of Ca2+ delivery to and removal from the myofilaments has dominated discussions of mechanisms regulating cardiac contractility. We first provide an alternative perspective in which rate processes at the level of the sarcomeres appear to be dominant during the rise and maintenance of systolic elastance and of isovolumic relaxation. A discussion of established adrenergic mechanisms and newly understood anti-adrenergic mechanisms controlling sarcomere response to Ca2+ follows and expands on this perspective

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW ($\textit{P}$  < 5 × 10$^{-8}$). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure ($\textit{R}$ $_{g}$ = -0.22, $\textit{P}$  = 5.5 × 10$^{-13}$), T2D ($\textit{R}$ $_{g}$ = -0.27, $\textit{P}$  = 1.1 × 10$^{-6}$) and coronary artery disease ($\textit{R}$ $_{g}$ = -0.30, $\textit{P}$  = 6.5 × 10$^{-9}$). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions ($\textit{P}$ = 1.9 × 10$^{-4}$). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.For a full list of the funders pelase visit the publisher's website and look at the supplemetary material provided. Some of the funders are: British Heart Foundation, Cancer Research UK, Medical Research Council, National Institutes of Health, Royal Society and Wellcome Trust

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10$^{−8}$) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the estimated heritability. We implicate ~250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

The Comet Interceptor Mission

Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA’s F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum ΔV capability of 600 ms−1. Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes – B1, provided by the Japanese space agency, JAXA, and B2 – that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission’s science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule

Maximum Diversity Problem. A Multi-Objective Approach

The Maximum Diversity (MD) problem is the process of selecting a subset of elements where the diversity among selected elements is maximized. Several diversity measures were already studied in the literature, optimizing the problem considered in a pure mono-objective approach. This work presents for the first time multi-objective approaches for the MD problem, considering the simultaneous optimization of the following five diversity measures: (i) Max-Sum, (ii) Max-Min, (iii) Max-MinSum, (iv) Min-Diff and (v) Min-P-center. Two different optimization models are proposed: (i) Multi-Objective Maximum Diversity (MMD) model, where the number of elements to be selected is defined a-priori, and (ii) Multi-Objective Maximum Average Diversity (MMAD) model, where the number of elements to be selected is also a decision variable. To solve the formulated problems, a Multi-Objective Evolutionary Algorithm (MOEA) is presented. Experimental results demonstrate that the proposed MOEA found good quality solutions, i.e. between 98.85% and 100% of the optimal Pareto front when considering the hypervolume for comparison purposes

Cytotoxic granules house potent proapoptotic toxins critical for antiviral responses and immune homeostasis

General Introduction Cytotoxic lymphocytes and apoptosis The immune system of high-order organisms is a highly specialized compartment that eliminates transformed cells and cells infected with viruses or bacteria through a controlled process of cell-mediated cytotoxicity. The immune cells responsible for mediating cell death are collectively called cytotoxic lymphocytes (CLs) and are made up of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). CLs are distinguished primarily by their respective mechanism of antigen recognition. NK cells form part of the innate immune response, a generalized first line of defense. NK cells are generally CD3aeCD56+lymphocytes that recognize and respond to abnormal cells through an imbalance of facilitatory and inhibitory receptors (Bottino et al., 2004; Moretta et al., 2004). CTLs formpart of the adaptive immune response, a more specific response that is generated subsequent to and as a consequence of the innate response. These cells use their clonotypic T-cell receptors (TcRs) to recognize a peptide antigen presented on the major histocompatability complex (MHC) proteins on the surface of the target cell. CTLs can be identified on the basis of expression of CD3 and CD8 (CD3+CD8+) on their cell surface. In addition, some CD4+T cells (typically T-helper cells) can have limited cytotoxic capacity

Effect of Tinnitus on Sleep Quality and Insomnia

Introduction Tinnitus is a conscious perception of a sound resulting from abnormal activity within the nervous system. A relevant percentage of tinnitus patients report symptoms severe enough to significantly affect quality of life, including sleep disorders. Objective To analyze the sleep quality, insomnia, daytime sleepiness, and risk of obstructive sleep apnea (OSA) in participants with tinnitus. Methods The sample comprised 18 adults and older adults aged between 18 and 85 years old (mean age = 58.7 ± 17.5 years old), females and males, with complaint of continuous tinnitus for > 1 month. The instruments used were the Tinnitus Handicap Inventory (THI) questionnaire, the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, and the STOP-Bang questionnaire. Results By means of the THI questionnaire, the tinnitus severity degree reported by most participants was mild (27.8%) and moderate (27.8%), having a positive (r = 0.582) and significant (0.011) correlation to sleep quality, measured by means of the Pittsburgh questionnaire. There was a positive correlation between the Insomnia Severity Index and tinnitus handicap (r = 0.499; p = 0.035). A total of 72.2% of the participants self-assessed their sleep quality as poor, in addition to moderate insomnia (27.8%), although there is low risk of OSA (66.7%), without complaints of excessive daytime sleepiness (72.2%). Conclusion Subjects with tinnitus complaint self-rated their sleep quality as poor. Moreover, the higher the reported tinnitus handicap, the greater the symptoms of insomnia. There was no influence of tinnitus in relation to daytime sleepiness and no relationship between the severity of tinnitus and the risk of OSA

Competing mechanisms determine oxygen redox in doped Ni-Mn based layered oxides for Na-ion batteries

Cation doping is an effective strategy for improving the cyclability of layered oxide cathode materials through suppression of phase transitions in the high voltage region (>~4.0V). In this study we choose Mg and Sc as representative dopants in P2- Na0.67Ni0.33Mn0.67O2. While both dopants have a positive effect on the cycling stability, they are found to influence the properties in the high voltage regime in different ways. Through a combination of RIXS, XRD, XAS, PDF analysis, and DFT, we show that it is more than just suppression of the P2 to O2 phase transition that is critical for promoting the favorable properties, and that the interplay between Ni and O activity are also critical aspects that dictate the performance. With Mg doping, we could enhance the Ni activity while simultaneously suppressing the O activity. This is surprising because it is in contrast to what has been reported in other Mn-based layered oxides where Mg is known to trigger oxygen redox. We address this contradiction by proposing a competing mechanism between Ni and Mg that impacts differences in O activity in Na0.67MgxNi0.33-xMn0.67O2 (x<0<0.33). These findings provide a new direction in understanding the effects of cation doping on the electrochemical behavior of layered oxides