Molecular and physiologic changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Accelerating ethics, empathy, and equity in geographic information science.

Science has traditionally been driven by curiosity and followed one goal: the pursuit of truth and the advancement of knowledge. Recently, ethics, empathy, and equity, which we term "the 3Es," are emerging as new drivers of research and disrupting established practices. Drawing on our own field of GIScience (geographic information science), our goal is to use the geographic approach to accelerate the response to the 3Es by identifying priority issues and research needs that, if addressed, will advance ethical, empathic, and equitable GIScience. We also aim to stimulate similar responses in other disciplines. Organized around the 3Es we discuss ethical issues arising from locational privacy and cartographic integrity, how our ability to build knowledge that will lead to empathy can be curbed by data that lack representativeness and by inadvertent inferential error, and how GIScientists can lead toward equity by supporting social justice efforts and democratizing access to spatial science and its tools. We conclude with a call to action and invite all scientists to join in a fundamentally different science that responds to the 3Es and mobilizes for change by engaging in humility, broadening measures of excellences and success, diversifying our networks, and creating pathways to inclusive education. Science united around the 3Es is the right response to this unique moment where society and the planet are facing a vast array of challenges that require knowledge, truth, and action.

Mutagenesis of human genomes by endogenous mobile elements on a population scale.

Several large-scale Illumina whole-genome sequencing (WGS) and whole-exome sequencing (WES) projects have emerged recently that have provided exceptional opportunities to discover mobile element insertions (MEIs) and study the impact of these MEIs on human genomes. However, these projects also have presented major challenges with respect to the scalability and computational costs associated with performing MEI discovery on tens or even hundreds of thousands of samples. To meet these challenges, we have developed a more efficient and scalable version of our mobile element locator tool (MELT) called CloudMELT. We then used MELT and CloudMELT to perform MEI discovery in 57,919 human genomes and exomes, leading to the discovery of 104,350 nonredundant MEIs. We leveraged this collection (1) to examine potentially active L1 source elements that drive the mobilization of new Alu, L1, and SVA MEIs in humans; (2) to examine the population distributions and subfamilies of these MEIs; and (3) to examine the mutagenesis of GENCODE genes, ENCODE-annotated features, and disease genes by these MEIs. Our study provides new insights on the L1 source elements that drive MEI mutagenesis and brings forth a better understanding of how this mutagenesis impacts human genomes.

A novel technique to identify midline during endoscopic thyroidectomy.

ABSTRACT: Endoscopic thyroidectomy is a minimally invasive surgical approach that has become popular due to its cosmetic advantages and reduced post-operative discomfort. Central to the success of this procedure is the accurate identification of the midline, which becomes a challenge in endoscopic surgeries. We propose a novel method of using methylene blue, a Food and Drug Administration-approved dye, which offers the ability to clearly mark the midline, enhancing orientation and reducing the potential for injury to critical anatomical structures. Although using methylene blue has many benefits, there are drawbacks, including the requirement for intraoperative ultrasonography. Continued research and clinical experience will be critical in improving and extending its use in the field of thyroid surgery.

Hive Transplantation Has Minimal Impact on the Core Gut Microbiome of the Australian Stingless Bee, Tetragonula carbonaria.

Bacteria residing in the guts of pollinating insects play a key role in nutrient acquisition, digestion, and resistance to pests and diseases. Imbalances in microbial flora in response to environmental change and stress can therefore impact insect health and resilience. This study is aimed at defining the core gut microbiome of the Australian native stingless bee, Tetragonula carbonaria, and exploring the impact of colony transplantation on gut health. The gut microbiomes of nine forager bees from natural (log) and manufactured (box) hives were examined via 16S rRNA gene amplicon sequencing. Some differences were observed at the ASV level between the microbiomes of log and box hive bees. However, a core microbiome, dominated by Lactobacillus spp., unclassified Acetobacteraceae spp., and Bombella spp., was maintained. Further, the inferred functional potential of the microbiomes was consistent across all individuals. This study highlights that although hive transplantation has an impact on the overall diversity of stingless bee gut microbiomes, it is unlikely to have a significant negative impact on the overall health and resilience of the colony.

Examining lung mechanical strains as influenced by breathing volumes and rates using experimental digital image correlation.

BACKGROUND: Mechanical ventilation is often employed to facilitate breathing in patients suffering from respiratory illnesses and disabilities. Despite the benefits, there are risks associated with ventilator-induced lung injuries and death, driving investigations for alternative ventilation techniques to improve mechanical ventilation, such as multi-oscillatory and high-frequency ventilation; however, few studies have evaluated fundamental lung mechanical local deformations under variable loading. METHODS: Porcine whole lung samples were analyzed using a novel application of digital image correlation interfaced with an electromechanical ventilation system to associate the local behavior to the global volume and pressure loading in response to various inflation volumes and breathing rates. Strains, anisotropy, tissue compliance, and the evolutionary response of the inflating lung were analyzed. RESULTS: Experiments demonstrated a direct and near one-to-one linear relationship between applied lung volumes and resulting local mean strain, and a nonlinear relationship between lung pressures and strains. As the applied air delivery volume was doubled, the tissue surface mean strains approximately increased from 20 to 40%, and average maximum strains measured 70-110%. The tissue strain anisotropic ratio ranged from 0.81 to 0.86 and decreased with greater inflation volumes. Local tissue compliance during the inflation cycle, associating evolutionary strains in response to inflation pressures, was also quantified. CONCLUSION: Ventilation frequencies were not found to influence the local stretch response. Strain measures significantly increased and the anisotropic ratio decreased between the smallest and greatest tidal volumes. Tissue compliance did not exhibit a unifying trend. The insights provided by the real-time continuous measures, and the kinetics to kinematics pulmonary linkage established by this study offers valuable characterizations for computational models and establishes a framework for future studies to compare healthy and diseased lung mechanics to further consider alternatives for effective ventilation strategies.

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology.

Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.

The vaginal metabolome and microbiota of cervical HPV-positive and HPV-negative women: a cross-sectional analysis.

OBJECTIVE: Characterise the vaginal metabolome of cervical HPV-infected and uninfected women. DESIGN: Cross-sectional. SETTING: The Center for Health Behavior Research at the University of Maryland School of Public Health. SAMPLE: Thirty-nine participants, 13 categorised as HPV-negative and 26 as HPV-positive (any genotype; HPV+ ), 14 of whom were positive with at least one high-risk HPV strain (hrHPV). METHOD: Self-collected mid-vaginal swabs were profiled for bacterial composition by 16S rRNA gene amplicon sequencing, metabolites by both gas and liquid chromatography mass spectrometry, and 37 types of HPV DNA. MAIN OUTCOME MEASURES: Metabolite abundances. RESULTS: Vaginal microbiota clustered into Community State Type (CST) I (Lactobacillus crispatus-dominated), CST III (Lactobacillus iners-dominated), and CST IV (low-Lactobacillus, 'molecular-BV'). HPV+ women had higher biogenic amine and phospholipid concentrations compared with HPV- women after adjustment for CST and cigarette smoking. Metabolomic profiles of HPV+ and HPV- women differed in strata of CST. In CST III, there were higher concentrations of biogenic amines and glycogen-related metabolites in HPV+ women than in HPV- women. In CST IV, there were lower concentrations of glutathione, glycogen, and phospholipid-related metabolites in HPV+ participants than in HPV- participants. Across all CSTs, women with hrHPV strains had lower concentrations of amino acids, lipids, and peptides compared with women who had only low-risk HPV (lrHPV). CONCLUSIONS: The vaginal metabolome of HPV+ women differed from HPV- women in terms of several metabolites, including biogenic amines, glutathione, and lipid-related metabolites. If the temporal relation between increased levels of reduced glutathione and oxidised glutathione and HPV incidence/persistence is confirmed in future studies, anti-oxidant therapies may be considered as a non-surgical HPV control intervention. TWEETABLE ABSTRACT: Metabolomics study: Vaginal microenvironment of HPV+ women may be informative for non-surgical interventions.

Cosmic-ray antinuclei as messengers of new physics: status and outlook for the new decade.

The precise measurement of cosmic-ray antinuclei serves as an important means for identifying the nature of dark matter and other new astrophysical phenomena, and could be used with other cosmic-ray species to understand cosmic-ray production and propagation in the Galaxy. For instance, low-energy antideuterons would provide a "smoking gun" signature of dark matter annihilation or decay, essentially free of astrophysical background. Studies in recent years have emphasized that models for cosmic-ray antideuterons must be considered together with the abundant cosmic antiprotons and any potential observation of antihelium. Therefore, a second dedicated Antideuteron Workshop was organized at UCLA in March 2019, bringing together a community of theorists and experimentalists to review the status of current observations of cosmic-ray antinuclei, the theoretical work towards understanding these signatures, and the potential of upcoming measurements to illuminate ongoing controversies. This review aims to synthesize this recent work and present implications for the upcoming decade of antinuclei observations and searches. This includes discussion of a possible dark matter signature in the AMS-02 antiproton spectrum, the most recent limits from BESS Polar-II on the cosmic antideuteron flux, and reports of candidate antihelium events by AMS-02; recent collider and cosmic-ray measurements relevant for antinuclei production models; the state of cosmic-ray transport models in light of AMS-02 and Voyager data; and the prospects for upcoming experiments, such as GAPS. This provides a roadmap for progress on cosmic antinuclei signatures of dark matter in the coming years.

A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer.

Although human LINE-1 (L1) elements are actively mobilized in many cancers, a role for somatic L1 retrotransposition in tumor initiation has not been conclusively demonstrated. Here, we identify a novel somatic L1 insertion in the APC tumor suppressor gene that provided us with a unique opportunity to determine whether such insertions can actually initiate colorectal cancer (CRC), and if so, how this might occur. Our data support a model whereby a hot L1 source element on Chromosome 17 of the patient's genome evaded somatic repression in normal colon tissues and thereby initiated CRC by mutating the APC gene. This insertion worked together with a point mutation in the second APC allele to initiate tumorigenesis through the classic two-hit CRC pathway. We also show that L1 source profiles vary considerably depending on the ancestry of an individual, and that population-specific hot L1 elements represent a novel form of cancer risk.

Incorporating a companion test into the noninferiority design of medical device trials.

Noninferiority trials are commonly utilized to evaluate the safety and effectiveness of medical devices. It could happen that the noninferiority hypothesis is rejected while the performance of the active control is clinically not satisfactory. This may pose a great challenge when making a regulatory decision. To avoid such a difficult situation, we propose to conduct a companion test to assess the performance of the active control when testing the main noninferiority hypothesis and to incorporate such a test into the study design. Under our proposal, the noninferiority of the investigational device to the active control can only be claimed when both hypotheses are rejected. The operating characteristics of the proposed study design based on these two tests can be fully evaluated at the design stage. This proposed approach is aimed to facilitate regulatory decision making in a more transparent manner.

EcoAnthromes of Alberta: An example of disturbance-informed ecological regionalization using remote sensing.

Humans influence ecosystems on magnitudes that often exceed that of natural forces such as climate and geology; however, frameworks rarely include anthropogenic disturbance when delineating unique ecological regions. A critical step toward understanding, managing and monitoring human-altered ecosystems is to incorporate disturbance into ecological regionalizations. Furthermore, quantitative regionalization approaches are desirable to provide cost-effective, repeatable and statistically sound stratification for environmental monitoring. We applied a two-stage multivariate clustering technique to identify 'EcoAnthromes' across a large area - the province of Alberta, Canada - at 30 m spatial resolution, and using primarily remotely sensed inputs. The EcoAnthrome clusters represent regions with unique ecological characteristics based on a combination of natural ecological potential (e.g., climatic and edaphic factors) and disturbance, both natural and anthropogenic. Compared to existing expert-derived Natural Subregions in Alberta, the model-based EcoAnthromes showed greater class separation and explained more variance for an assortment of variables related to land cover, disturbance and species intactness. The EcoAnthromes successfully separated important ecological regions that are defined by complex assemblages of topography, climate and disturbance, such as gravel-bed river valleys, boreal forests, grasslands, post-fire recovery areas and highly disturbed agricultural, industrial and urban landscapes. In addition to presenting a flexible method for EcoAnthrome regionalization, we group and describe the EcoAnthromes created for Alberta and discuss how they can complement expert-derived regionalizations to aid in environmental management efforts, such as species recovery planning and monitoring for threatened species.

Exposure to household air pollution from biomass-burning cookstoves and HbA1c and diabetic status among Honduran women.

Household air pollution from biomass cookstoves is estimated to be responsible for more than two and a half million premature deaths annually, primarily in low and middle-income countries where cardiometabolic disorders, such as Type II Diabetes, are increasing. Growing evidence supports a link between ambient air pollution and diabetes, but evidence for household air pollution is limited. This cross-sectional study of 142 women (72 with traditional stoves and 70 with cleaner-burning Justa stoves) in rural Honduras evaluated the association of exposure to household air pollution (stove type, 24-hour average kitchen and personal fine particulate matter [PM2.5 ] mass and black carbon) with glycated hemoglobin (HbA1c) levels and diabetic status based on HbA1c levels. The prevalence ratio (PR) per interquartile range increase in pollution concentration indicated higher prevalence of prediabetes/diabetes (vs normal HbA1c) for all pollutant measures (eg, PR per 84 µg/m3 increase in personal PM2.5 , 1.49; 95% confidence interval [CI], 1.11-2.01). Results for HbA1c as a continuous variable were generally in the hypothesized direction. These results provide some evidence linking household air pollution with the prevalence of prediabetes/diabetes, and, if confirmed, suggest that the global public health impact of household air pollution may be broader than currently estimated.

Correlates of atherosclerotic cardiovascular disease risk in older Colorado firefighters.

Background: It has been documented that cardiovascular disease is the leading cause of mortality in on-duty firefighters and little is known about the association between cardiorespiratory fitness and 10-year risk of atherosclerotic cardiovascular disease (ASCVD). Aims: To estimate the probability of 10-year ASCVD risk and its association with per cent body fat (%BF), metabolic syndrome (MetS) and physical fitness in Colorado firefighters. Methods: Ten-year ASCVD risk was calculated using the newly developed pooled cohort equations in firefighters. Logistic regression was conducted to examine the association of 10-year ASCVD risk (<5 versus ≥5%) with estimated maximum volume of oxygen (VO2 max), %BF and MetS. Results: Out of 294 firefighters, 9% had a 10-year ASCVD risk >5%. In the unadjusted models, %BF (odds ratio [OR] = 1.13, P < 0.01), VO2 max (OR = 2.87, P < 0.05) and MetS (OR = 2.66, P < 0.05) were significantly associated with 10-year ASCVD risk. In the adjusted model, only %BF (OR = 1.17, P < 0.01) was significantly associated with 10-year ASCVD risk. Conclusions: Among Colorado firefighters, %BF, but not cardiorespiratory fitness, was independently associated with 10-year ASCVD.

Cardiac health and fitness of Colorado male/female firefighters.

BACKGROUND: Cardiovascular disease (CVD) is documented as the leading cause of mortality in on-duty firefighters. AIMS: To examine the prevalence of metabolic syndrome (MetS) components, cardiorespiratory fitness levels and the association between them in firefighters in Colorado, USA. METHODS: This study included male and female Colorado firefighters. MetS was identified where three or more metabolic abnormalities were present, using Cholesterol Education Program/Adult Treatment Panel III guidelines. Cardiorespiratory fitness (indicated by VO2 max) was evaluated with the Bruce protocol. Poisson regression was conducted to examine the association between MetS components and VO2 max. RESULTS: Among the 947 male and 76 female study subjects, MetS was present in 9% of all firefighters, in 5% of females and 10% of males. The mean age was 37 ± 10 years. MetS prevalence increased with age (from 3% at age <30 to 17% at 50 and older, data not shown). In addition, 35% had one and 19% had two abnormal MetS components and 49% of participants did not meet the minimum recommended VO2 max of 42.0 ml/kg/min. VO2 max was negatively associated with abnormal MetS components (incident rate ratios = 0.95, 95% confidence interval 0.94-0.96, P < 0.001). CONCLUSIONS: About one in 10 of these Colorado firefighters had MetS and nearly half had insufficient cardiorespiratory fitness. Comprehensive CVD risk management and cardiorespiratory fitness improvement are essential for firefighter health and safety.

Cutaneous ulcers in a returning traveller: a rare case of imported diphtheria in the UK.

We describe a case of cutaneous diphtheria in the UK, presenting as lower leg ulcers in a returning traveller, and discuss the epidemiology, significance and public health implications of this disease and the therapeutic options available. A 65-year-old woman presented with a 6-week history of multiple ulcers appearing on her legs following a holiday in Kenya. Culture of biopsy tissue grew Corynebacterium diphtheriae. A cascade of therapeutic and public health interventions followed, many of which were terminated once the isolate was confirmed as nontoxigenic. Cutaneous diphtheria is a rare, notifiable disease in the UK, but is common in tropical countries, and is most often seen in the West as a traveller's disease. Corynebacteria are common skin commensals, and without appropriate clinical details, laboratories may not recognize C. diphtheriae/Corynebacterium ulcerans. This is likely to have led to under-reporting and under-recognition of the condition.

Neuroprotective versus tumorigenic protein kinase C activators.

Protein kinase C (PKC) activators possess potent neurotrophic and neuroprotective activity, thus indicating potential applications in treating neurodegenerative diseases, stroke and traumatic brain injury. Although some activators, such as bryostatin and gnidimacrin, have been tested as antitumor agents, others, such as phorbol esters, are potent tumor promoters. All PKC activators downregulate PKC at high concentrations and long application times. However, tumorigenic activators downregulate certain PKC isozymes, especially PKCdelta, more strongly. Tumorigenic activators possess unique structural features that could account for this difference. At concentrations that minimize PKC downregulation, PKC activators can improve long-term memory, reduce beta-amyloid levels, induce synaptogenesis, promote neuronal repair and inhibit cell proliferation. Intermittent, low concentrations of structurally specific, non-tumorigenic PKC activators, therefore, could offer therapeutic benefit for a variety of neurologic disorders.

A Comparative Study of Ex-Vivo Murine Pulmonary Mechanics Under Positive- and Negative-Pressure Ventilation.

Increased ventilator use during the COVID-19 pandemic resurrected persistent questions regarding mechanical ventilation including the difference between physiological and artificial breathing induced by ventilators (i.e., positive- versus negative-pressure ventilation, PPV vs NPV). To address this controversy, we compare murine specimens subjected to PPV and NPV in ex vivo quasi-static loading and quantify pulmonary mechanics via measures of quasi-static and dynamic compliances, transpulmonary pressure, and energetics when varying inflation frequency and volume. Each investigated mechanical parameter yields instance(s) of significant variability between ventilation modes. Most notably, inflation compliance, percent relaxation, and peak pressure are found to be consistently dependent on the ventilation mode. Maximum inflation volume and frequency note varied dependencies contingent on the ventilation mode. Contradictory to limited previous clinical investigations of oxygenation and end-inspiratory measures, the mechanics-focused comprehensive findings presented here indicate lung properties are dependent on loading mode, and importantly, these dependencies differ between smaller versus larger mammalian species despite identical custom-designed PPV/NPV ventilator usage. Results indicate that past contradictory findings regarding ventilation mode comparisons in the field may be linked to the chosen animal model. Understanding the differing fundamental mechanics between PPV and NPV may provide insights for improving ventilation strategies and design to prevent associated lung injuries.