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Gene duplication is an important process of molecular evolutionary change, though identifying these events and their functional implications remains challenging. Studies on gene duplication more often focus on the presence of paralogous genes within the genomes and less frequently explore shifts in expression. We investigated the evolutionary history of calsequestrin (CASQ), a crucial calcium-binding protein in the junctional sarcoplasmic reticulum of muscle tissues. CASQ exists in jawed vertebrates as subfunctionalized paralogs CASQ1 and CASQ2 expressed primarily in skeletal and cardiac muscles, respectively. We used an enhanced sequence dataset to support initial duplication of CASQl in a jawed fish ancestor prior to the divergence of cartilaginous fishes. Surprisingly, we find CASQ2 is the predominant skeletal muscle paralog in birds, while CASQ1 is either absent or effectively nonfunctional. Changes in the amino acid composition and electronegativity of avian CASQ2 suggest enhancement to calcium-binding properties that preceded the loss of CASQ1. We identify this phenomenon as CASQ2 “synfunctionalization,” where one paralog functionally replaces another. While additional studies are needed to fully understand the dynamics of CASQ1 and CASQ2 in bird muscles, the long and consistent history of CASQ subfunctions outside of birds indicate a substantial evolutionary pressure on calcium-cycling processes in muscle tissues, likely connected to increased avian cardiovascular and metabolic demands. Our study provides an important insight into the molecular evolution of birds and shows how gene expression patterns can be comparatively studied across phylum-scale deep time to reveal key evolutionary events.

Myosin heavy chain proteins are essential for muscle contraction and nearly every physiological function in animals, but their diversity and evolution outside mammals is largely unknown. Here, we analyze over 1,000 myosin protein sequences and dozens of skeletal muscle expression profiles to comprehensively model the evolutionary history of heavy-chain myosins and understand common themes of their tissue-specific expression. We show that even though skeletal muscle myosins are located in the same tandem gene cluster across vertebrate species, repeated gene duplication-loss turnover has resulted in each major vertebrate group now having an independently evolved set of core skeletal muscle myosins. Despite these separate derivations of skeletal myosins, each major vertebrate group exhibits tissue-specific patterns of expression, includes diverse myosin molecular properties, and employs different myosins in extreme muscles. Our results suggest that muscle evolution across vertebrates involves a repeated and multifaceted process of gene family diversification of sarcomeric myosin proteins, with shifting expression of myosins in different muscle types as a general theme of their evolution across vertebrates.

The microbiome of the respiratory tract, including the nasopharyngeal and oropharyngeal microbiota, is a dynamic community of microorganisms that is highly diverse. The cystic fibrosis (CF) airway microbiome refers to the polymicrobial communities present in the lower airways of CF patients. It is comprised of chronic opportunistic pathogens (such as Pseudomonas aeruginosa) and a variety of organisms derived mostly from the normal microbiota of the upper respiratory tract. The complexity of these communities has been inferred primarily from culture independent molecular profiling. As with most microbial communities it is generally assumed that most of the organisms present are not readily cultured. Our culture collection generated using more extensive cultivation approaches, reveals a more complex microbial community than that obtained by conventional CF culture methods. To directly evaluate the cultivability of the airway microbiome, we examined six samples in depth using culture-enriched molecular profiling which combines culture-based methods with the molecular profiling methods of terminal restriction fragment length polymorphisms and 16S rRNA gene sequencing. We demonstrate that combining culture-dependent and culture-independent approaches enhances the sensitivity of either approach alone. Our techniques were able to cultivate 43 of the 48 families detected by deep sequencing; the five families recovered solely by culture-independent approaches were all present at very low abundance (<0.002% total reads). 46% of the molecular signatures detected by culture from the six patients were only identified in an anaerobic environment, suggesting that a large proportion of the cultured airway community is composed of obligate anaerobes. Most significantly, using 20 growth conditions per specimen, half of which included anaerobic cultivation and extended incubation times we demonstrate that the majority of bacteria present can be cultured.

Ambient concentrations of ice-forming particles measured during ship expeditions are collected and summarised with the aim of determining the spatial distribution and variability in ice nuclei in oceanic regions. The presented data from literature and previously unpublished data from over 23 months of ship-based measurements stretch from the Arctic to the Southern Ocean and include a circumnavigation of Antarctica. In comparison to continental observations, ship-based measurements of ambient ice nuclei show 1 to 2 orders of magnitude lower mean concentrations. To quantify the geographical variability in oceanic areas, the concentration range of potential ice nuclei in different climate zones is analysed by meridionally dividing the expedition tracks into tropical, temperate and polar climate zones. We find that concentrations of ice nuclei in these meridional zones follow temperature spectra with similar slopes but vary in absolute concentration. Typically, the frequency with which specific concentrations of ice nuclei are observed at a certain temperature follows a log-normal distribution. A consequence of the log-normal distribution is that the mean concentration is higher than the most frequently measured concentration. Finally, the potential contribution of ship exhaust to the measured ice nuclei concentration on board research vessels is analysed as function of temperature. We find a sharp onset of the influence at approximately −36 ∘C but none at warmer temperatures that could bias ship-based measurements.

Weather and climate models are challenged by uncertainties and biases in simulating Southern Ocean (SO) radiative fluxes that trace to a poor understanding of cloud, aerosol, precipitation, and radiative processes, and their interactions. Projects between 2016 and 2018 used in situ probes, radar, lidar, and other instruments to make comprehensive measurements of thermodynamics, surface radiation, cloud, precipitation, aerosol, cloud condensation nuclei (CCN), and ice nucleating particles over the SO cold waters, and in ubiquitous liquid and mixed-phase clouds common to this pristine environment. Data including soundings were collected from the NSF–NCAR G-V aircraft flying north–south gradients south of Tasmania, at Macquarie Island, and on the R/V Investigator and RSV Aurora Australis. Synergistically these data characterize boundary layer and free troposphere environmental properties, and represent the most comprehensive data of this type available south of the oceanic polar front, in the cold sector of SO cyclones, and across seasons. Results show largely pristine environments with numerous small and few large aerosols above cloud, suggesting new particle formation and limited long-range transport from continents, high variability in CCN and cloud droplet concentrations, and ubiquitous supercooled water in thin, multilayered clouds, often with small-scale generating cells near cloud top. These observations demonstrate how cloud properties depend on aerosols while highlighting the importance of dynamics and turbulence that likely drive heterogeneity of cloud phase. Satellite retrievals confirmed low clouds were responsible for radiation biases. The combination of models and observations is examining how aerosols and meteorology couple to control SO water and energy budgets.

The Southampton PRegnancy Intervention for the Next Generation (SPRING) aimed to assess the efficacy of vitamin D supplementation and the behaviour change intervention 'Healthy Conversation Skills' (HCS) in improving the nutritional status of pregnant women. This paper describes the implementation of these interventions. Efficacy of HCS in improving diet quality and physical activity was evaluated in subgroups of women who discussed ways to improve these behaviours. In total, 717 pregnant women were recruited from a maternity hospital in Southampton, England. Quantitative data were collected using questionnaires, case report forms, and audio recordings. Following Medical Research Council guidance, fidelity, dose, and reach were evaluated descriptively. Multiple linear regression models were produced for subgroup analyses. Research nurses demonstrated high competence in using HCS. Compliance with intervention protocols for delivering and receiving both interventions was high. Participants took a median of 96% of the supplements and most women (85%) attended all four Healthy Conversations sessions. Women of lower socioeconomic status and from ethnic minorities were under-represented amongst participants. Findings were not sufficient to suggest an effect of HCS on diet quality among those who discussed diet but indicated a marginally beneficial effect on physical activity among those who discussed physical activity. Results suggested a weak dose-dependent effect, with the most pronounced difference in physical activity between the control group and the intervention sub-group with the highest exposure (adjusted difference 0.16 SD (95%-CI -0.03; 0.34)). This process evaluation confirms that the intervention components were delivered with high fidelity and rates of compliance. Altering dietary behaviours proved more challenging than altering physical activity behaviours. Research is needed to explore barriers to healthy eating faced by women during pregnancy and how these can be overcome. This paper also highlights the difficulty of engaging people from ethnic minorities and disadvantaged backgrounds in research.

Background Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. Methods We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. Results The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node ( n  =  58 ), liver ( n  =  40 ), lung ( n  =  37 ), bone ( n  =  24 ), and brain ( n  =  8 ). Most patients (80.7%) were RMH good risk. Most patients ( n = 62 ) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p  = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p  = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p  = 0.0048). Conclusions Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated. This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib. The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for Cmax, AUC0–t, and AUC0–∞ were within the 0.80 to 1.25 BE limits. In the FE stage, Cmax, AUC0–t, and AUC0–∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified. Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability. ClinicalTrials.gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX–XXX) © 2024 Elsevier HS Journals, Inc.

Overview The etiology of Parkinson disease (PD) involves both genetic susceptibility and environmental exposures. In particular, coffee consumption is inversely associated with PD but the mechanisms underlying this intriguing association are unknown. According to a recent genome-wide gene–environment interaction study, the inverse coffee–PD association was two times stronger among carriers of the T allele of SNP rs4998386 in gene GRIN2A than in homozygotes for the C allele. We attempted to replicate this result in a similarly sized pooled analysis of 2,289 cases and 2,809 controls from four independent studies (Denmark, France, Seattle-United States (US), and Rochester-US) with detailed caffeinated coffee consumption data and rs4998386 genotypes. Using a variety of definitions of coffee drinking and statistical modeling techniques , we failed to replicate this interaction. Notably, whereas in the original study there was an association between rs4998386 and coffee consumption among controls, but not among cases, none of the datasets analyzed here indicated an association between rs4998386 and coffee consumption among controls. Based on large, well-characterized datasets independent from the original study, our results are not in favor of an interaction between caffeinated coffee consumption and rs4998386 for PD risk and suggest that the original finding may have been driven by an association of coffee consumption with rs4998386 in controls. The next years will likely see an increasing number of papers examining gene–environment interactions at the genome-wide level, which poses important methodological challenges. Our findings underline the need for a careful assessment of the findings of such studies.

Background Feed intake and body weight gain are economically important inputs and outputs of beef production systems. The purpose of this study was to discover differentially expressed genes that will be robust for feed intake and gain across a large segment of the cattle industry. Transcriptomic studies often suffer from issues with reproducibility and cross-validation. One way to improve reproducibility is by integrating multiple datasets via meta-analysis. RNA sequencing (RNA-Seq) was performed on longissimus dorsi muscle from 80 steers (5 cohorts, each with 16 animals) selected from the outside fringe of a bivariate gain and feed intake distribution to understand the genes and pathways involved in feed efficiency. In each cohort, 16 steers were selected from one of four gain and feed intake phenotypes ( n  = 4 per phenotype) in a 2 × 2 factorial arrangement with gain and feed intake as main effect variables. Each cohort was analyzed as a single experiment using a generalized linear model and results from the 5 cohort analyses were combined in a meta-analysis to identify differentially expressed genes (DEG) across the cohorts. Results A total of 51 genes were differentially expressed for the main effect of gain, 109 genes for the intake main effect, and 11 genes for the gain x intake interaction (P corrected  < 0.05). A jackknife sensitivity analysis showed that, in general, the meta-analysis produced robust DEGs for the two main effects and their interaction. Pathways identified from over-represented genes included mitochondrial energy production and oxidative stress pathways for the main effect of gain due to DEG including GPD1 , NDUFA6 , UQCRQ , ACTC1 , and MGST3 . For intake, metabolic pathways including amino acid biosynthesis and degradation were identified, and for the interaction analysis the pathways identified included GADD45, pyridoxal 5’phosphate salvage, and caveolar mediated endocytosis signaling. Conclusions Variation among DEG identified by cohort suggests that environment and breed may play large roles in the expression of genes associated with feed efficiency in the muscle of beef cattle. Meta-analyses of transcriptome data from groups of animals over multiple cohorts may be necessary to elucidate the genetics contributing these types of biological phenotypes.