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\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.

Background Chronic diarrhea (CD) is common in cats, with unknown etiology in many cases. Objectives To establish the prevalence of feline coronavirus (FCoV) and other enteropathogens in cats with CD. Animals Veterinarians at a feline specialty practice examined 493 cats with CD. The breed of three (0.6%) was unknown; 373 (75.7%) were non‐purebred, and 117 (23.7%) purebred. Methods Retrospective database review of 586 fecal sample results of an RT‐PCR and PCR diarrheal panel. Results Feline coronavirus was found in 321 (65.1%) of 493 cats with CD. FCoV RNA and Clostridium perfringens toxin DNA were detected in 377 (64.3%) and 319 (54.4%) samples respectively: 206 (35.2%) samples were positive for both pathogens. Feline coronavirus was the sole pathogen detected in 118 (23.9%) cats. Samples from 203 cats under 1 year old were significantly (p = 0.0001) more frequently FCoV positive than samples from older cats (166/224 [74.1%] samples vs. 211/362 [58.3%]). FCoV RT‐PCR positivity peaked in February (p = 0.016) and March (p = 0.0064). Other detected pathogens included Giardia spp. (8.4%; 49/586 samples); Tritrichomonas blagburni (8.4%; 46/586); Cryptosporidium (5.1%; 30/586); Campylobacter jejuni (3.4%; 17/497); Campylobacter coli (1.6%; 8/497); Salmonella spp. (0.8%; 5/586); panleukopenia virus (0.8%; 5/586); and Toxoplasma gondii (0.5%; 3/586). Sixty‐nine cats gave 162 samples: 54/69 (78.3%) cats were FCoV positive, 39/54 (72.2%) persistently so. Conclusions If FCoV is non‐pathogenic, as often assumed, its having the highest rate of positivity in CD cases is difficult to explain. If pathogenic and overlooked, key diagnostic and therapeutic opportunities might be missed.

For the past two decades, microbial monitoring of the International Space Station (ISS) has relied on culture-dependent methods that require return to Earth for analysis. This has a number of limitations, with the most significant being bias towards the detection of culturable organisms and the inherent delay between sample collection and ground-based analysis. In recent years, portable and easy-to-use molecular-based tools, such as Oxford Nanopore Technologies’ MinION™ sequencer and miniPCR bio’s miniPCR™ thermal cycler, have been validated onboard the ISS. Here, we report on the development, validation, and implementation of a swab-to-sequencer method that provides a culture-independent solution to real-time microbial profiling onboard the ISS. Method development focused on analysis of swabs collected in a low-biomass environment with limited facility resources and stringent controls on allowed processes and reagents. ISS-optimized procedures included enzymatic DNA extraction from a swab tip, bead-based purifications, altered buffers, and the use of miniPCR and the MinION. Validation was conducted through extensive ground-based assessments comparing current standard culture-dependent and newly developed culture-independent methods. Similar microbial distributions were observed between the two methods; however, as expected, the culture-independent data revealed microbial profiles with greater diversity. Protocol optimization and verification was established during NASA Extreme Environment Mission Operations (NEEMO) analog missions 21 and 22, respectively. Unique microbial profiles obtained from analog testing validated the swab-to-sequencer method in an extreme environment. Finally, four independent swab-to-sequencer experiments were conducted onboard the ISS by two crewmembers. Microorganisms identified from ISS swabs were consistent with historical culture-based data, and primarily consisted of commonly observed human-associated microbes. This simplified method has been streamlined for high ease-of-use for a non-trained crew to complete in an extreme environment, thereby enabling environmental and human health diagnostics in real-time as future missions take us beyond low-Earth orbit.

Aim Introduced predators negatively impact biodiversity globally, with insular fauna often most severely affected. Here, we assess spatial variation in the number of terrestrial vertebrates (excluding amphibians) killed by two mammalian mesopredators introduced to Australia, the red fox (Vulpes vulpes) and feral cat (Felis catus). We aim to identify prey groups that suffer especially high rates of predation, and regions where losses to foxes and/or cats are most substantial. Location Australia. Methods We draw information on the spatial variation in tallies of reptiles, birds and mammals killed by cats in Australia from published studies. We derive tallies for fox predation by (i) modelling continental-scale spatial variation in fox density, (ii) modelling spatial variation in the frequency of occurrence of prey groups in fox diet, (iii) analysing the number of prey individuals within dietary samples and (iv) discounting animals taken as carrion. We derive point estimates of the numbers of individuals killed annually by foxes and by cats and map spatial variation in these tallies. Results Foxes kill more reptiles, birds and mammals (peaking at 1071 km−2 year−1) than cats (55 km−2 year−1) across most of the unmodified temperate and forested areas of mainland Australia, reflecting the generally higher density of foxes than cats in these environments. However, across most of the continent – mainly the arid central and tropical northern regions (and on most Australian islands) – cats kill more animals than foxes. We estimate that foxes and cats together kill 697 million reptiles annually in Australia, 510 million birds and 1435 million mammals. Main conclusions This continental-scale analysis demonstrates that predation by two introduced species takes a substantial and ongoing toll on Australian reptiles, birds and mammals. Continuing population declines and potential extinctions of some of these species threatens to further compound Australia's poor contemporary conservation record.

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal. SLEAP is a versatile deep learning-based multi-animal pose-tracking tool designed to work on videos of diverse animals, including during social behavior.

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19) 1 – 4 . However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories. A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Previous studies suggested that risk for Autism Spectrum Disorder (ASD) may be increased in children exposed to antidepressants during the prenatal period. The disease specificity of this risk has not been addressed and the possibility of confounding has not been excluded. Children with ASD or attention-deficit hyperactivity disorder (ADHD) delivered in a large New England health-care system were identified from electronic health records (EHR), and each diagnostic group was matched 1:3 with children without ASD or ADHD. All children were linked with maternal health data using birth certificates and EHRs to determine prenatal medication exposures. Multiple logistic regression was used to examine association between prenatal antidepressant exposures and ASD or ADHD risk. A total of 1377 children diagnosed with ASD and 2243 with ADHD were matched with healthy controls. In models adjusted for sociodemographic features, antidepressant exposure prior to and during pregnancy was associated with ASD risk, but risk associated with exposure during pregnancy was no longer significant after controlling for maternal major depression (odds ratio (OR) 1.10 (0.70–1.70)). Conversely, antidepressant exposure during but not prior to pregnancy was associated with ADHD risk, even after adjustment for maternal depression (OR 1.81 (1.22–2.70)). These results suggest that the risk of autism observed with prenatal antidepressant exposure is likely confounded by severity of maternal illness, but further indicate that such exposure may still be associated with ADHD risk. This risk, modest in absolute terms, may still be a result of residual confounding and must be balanced against the substantial consequences of untreated maternal depression.

Our aim was to understand how reviewers appraise mixed methods research by analyzing reviewer comments for grant applications submitted primarily to the National Institutes of Health. We requested scholars and consultants in the Mixed Methods Research Training Program (MMRTP) for the Health Sciences to send us summary statements from their mixed methods grant applications and obtained 40 summary statements of funded (40%) and unfunded (60%) mixed methods grant applications. We conducted a document analysis using a coding rubric based on the NIH Best Practices for Mixed Methods Research in the Health Sciences and allowed inductive codes to emerge. Reviewers favorably appraised mixed methods applications demonstrating coherence among aims and research design elements, detailed methods, plans for mixed methods integration, and the use of theoretical models. Reviewers identified weaknesses in mixed methods applications that lacked methodological details or rationales, had a high participant burden, and failed to delineate investigator roles. Successful mixed methods applications convey assumptions behind the methods chosen to accomplish specific aims and clearly detail the procedures to be taken. Investigators planning to use mixed methods should remember that reviewers are looking for both points of view.