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The Geological Orrery is a network of geological records of orbitally paced climate designed to address the inherent limitations of solutions for planetary orbits beyond 60 million years ago due to the chaotic nature of Solar System motion.We use results from two scientific coring experiments in Early Mesozoic continental strata: the Newark Basin Coring Project and the Colorado Plateau Coring Project.We precisely and accurately resolve the secular fundamental frequencies of precession of perihelion of the inner planets and Jupiter for the Late Triassic and Early Jurassic epochs (223–199 million years ago) using the lacustrine record of orbital pacing tuned only to one frequency (1/405,000 years) as a geological interferometer. Excepting Jupiter’s, these frequencies differ significantly from present values as determined using three independent techniques yielding practically the same results. Estimates for the precession of perihelion of the inner planets are robust, reflecting a zircon U–Pb-based age model and internal checks based on the overdetermined origins of the geologically measured frequencies. Furthermore, although not indicative of a correct solution, one numerical solution closely matches the Geological Orrery, with a very low probability of being due to chance. To determine the secular fundamental frequencies of the precession of the nodes of the planets and the important secular resonances with the precession of perihelion, a contemporaneous high-latitude geological archive recording obliquity pacing of climate is needed. These results form a proof of concept of the Geological Orrery and lay out an empirical framework to map the chaotic evolution of the Solar System.

\"Readers preparing to work in hospitality will enter a field that is quickly evolving. The rise of the global economy, ecotourism, internet commerce, and changing consumer demands are just some of the factors they will be dealing with in this exciting and dynamic industry. This new edition gives readers the foundation they need to thrive in today's hospitality industry, covering everything from finance to operational issues. The Eighth Edition of Introduction to the Hospitality Industry features both historical perspectives and discussions of new trends in a variety of sectors. This edition includes additional international examples of hospitality and tourism operations have been included throughout the text. This book covers all the latest trends, challenges, and opportunities in the hospitality industry. Readers will have a strong overview of the industry, where it fits into the broader world, the major issues and challenges in the field, and the many possible career paths that await them\"-- Provided by publisher.

Past studies have used various methods to assess perceived risk of HIV infection; however, few have included multiple items covering different dimensions of risk perception or have examined the characteristics of individual items. This study describes the use of Item Response Theory (IRT) to develop a short measure of perceived risk of HIV infection scale (PRHS). An item pool was administered by trained interviewers to 771 participants. Participants also completed the risk behavior assessment (RBA) which includes items measuring risky sexual behaviors, and 652 participants completed HIV testing. The final measure consisted of 8 items, including items assessing likelihood estimates, intuitive judgments and salience of risk. Higher scores on the PRHS were positively associated with a greater number of sex partners, episodes of unprotected sex and having sex while high. Participants who tested positive for HIV reported higher perceived risk. The PRHS demonstrated good reliability and concurrent criterion-related validity. Compared to single item measures of risk perception, the PRHS is more robust by examining multiple dimensions of perceived risk. Possible uses of the measure and directions for future research are discussed.

\"Readers seeking management careers in hospitality will enter a dynamic industry filled with opportunities. The rewards are many, but so are the challenges. Today's hospitality managers must deal with such complex factors as globalization, terrorism threats, ecotourism, internet commerce, new business and financial models, and rapidly changing consumer demands. Introduction to Management in the Hospitality Industry, 10th Edition gives readers the industry know-how and the management skills needed to thrive in all aspects of the field, from food service to lodging to tourism. The Tenth Edition of Introduction to Management in the Hospitality Industry features both historical perspectives and discussions of new trends in a variety of sectors. This book has the most thorough coverage of the hospitality industry, covering foodservice, lodging, and travel and tourism, hospitality careers, and hospitality management. Upon successful completion of this text, readers will have a strong grasp of the many facets of the hospitality industry\"-- Provided by publisher.

RNA sequencing of Burkitt lymphoma tumours allows identification of mutations affecting the transcription factor TCF3, its negative regulator ID3 and the cell cycle regulator CCND3; these pathways reveal new targets for potential therapeutic intervention. New drug targets in Burkitt’s lymphoma Although intensive chemotherapy can cure Burkitt’s lymphoma, the associated toxicity means that this treatment is not suitable for more vulnerable patients, such as the elderly or people in developing countries with the endemic form of the disease. This study identifies mutations of the transcription factor TCF3 or its negative regulator ID3 in a high percentage of sporadic cases of Burkitt’s lymphoma and suggests several novel drug targets, including PI(3) kinase and its downstream pathways, B-cell-receptor signalling and cyclin D3/CDK6. Burkitt’s lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL in developing countries, necessitating new strategies 1 . The normal germinal centre B cell is the presumed cell of origin for both BL and diffuse large B-cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may use different oncogenic pathways 2 . BL is subdivided into a sporadic subtype that is diagnosed in developed countries, the Epstein–Barr-virus-associated endemic subtype, and an HIV-associated subtype, but it is unclear whether these subtypes use similar or divergent oncogenic mechanisms. Here we used high-throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways in BL that cooperate with MYC , the defining oncogene of this cancer. In 70% of sporadic BL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival phosphatidylinositol-3-OH kinase pathway in BL, in part by augmenting tonic B-cell receptor signalling. In 38% of sporadic BL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.

The terminology for human papillomavirus (HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Background There is an urgent need to identify novel, accessible and affordable strategies to prevent cognitive decline and progression in the Alzheimer disease and related dementias (ADRD) continuum. Vitamin D3 and marine omega‐3 fatty acids (omega‐3s) supplements show promise for cognitive protection, with potential variations in their effects by sex or race. However, to date, no randomized clinical trials (RCTs) have tested their impact on emerging plasma‐based biomarkers with potential utility to predict ADRD pathogenesis. Methods Vitamin D and Omega‐3 Trial (VITAL) is a completed, nation‐wide, 2x2 factorial placebo‐controlled RCT testing vitamin D3 (2000 IU/d) and omega‐3s (1 g/d) for cancer and cardiovascular disease prevention. We included a Boston‐area sub‐cohort of 929 randomized VITAL participants who provided blood samples at baseline, 2‐year, and/or 4‐year follow‐up. Plasma ADRD biomarkers, including an N‐terminal tau fragment (NT1), amyloid‐β (Aβ)‐40, Aβ‐42, neurofilament‐light (NfL), and glial fibrillary acidic protein (GFAP), were measured. We used multivariable‐adjusted repeated measures models for data analysis; sex and race were pre‐specified effect modifiers. Results Among 929 participants, the mean age was 65 years; 49.2% were females; 17.3% were from racial and/or ethnic minority backgrounds, including 8.2% Black adults. Neither vitamin D3 nor omega‐3s, compared to placebo, significantly reduced ADRD biomarkers overall across 4 years of treatment; however, there was a trend for reduction in Aβ‐40:Aβ‐42 ratio over 4 years for vitamin D3 versus placebo [percent difference (95% confidence interval [CI]): ‐1.2 (‐2.7, 0.3)]. Subgroup analyses uncorrected for multiple‐testing suggested interactions by sex and race. Vitamin D3 versus placebo resulted in a reduction in NT1 among males (‐2.7%) but not females (p‐interaction=0.08). Among Black participants, vitamin D3 versus placebo resulted in a 16% reduction in NfL levels [95% CI, ‐30.5% to 1.1%; p‐interaction=0.06], while omega‐3s versus placebo showed a 12.4% reduction in GFAP levels [95% CI, ‐21.5% to ‐2.2%; p‐interaction=0.049]. Conclusion In this RCT sub‐cohort of 929 older adults, neither vitamin D3 nor omega‐3s supplements significantly reduced selected plasma ADRD biomarkers over 4 years. We observed potential differences by sex and race in reductions of some ADRD biomarkers in response to these supplements which warrant further investigation in a larger sample.

Between 2013 and 2015, a large part of the western United States, including the Central Valley of California, sustained an extreme drought. The Central Valley is recognized as a region of hemispheric importance for waterbirds, which use flooded agriculture and wetlands as habitat. Thus, the impact of drought on the distribution of surface water needed to be assessed to understand the effects on waterbird habitat availability. We used remote sensing data to quantify the impact of the recent extreme drought on the timing and extent of waterbird habitat during the non-breeding season (July-May) by examining open water in agriculture (rice, corn, and other crops) and managed wetlands across the Central Valley. We assessed the influence of habitat incentive programs, particularly The Nature Conservancy's BirdReturns and The Natural Resources Conservation Service's Waterbird Habitat Enhancement Program (WHEP), at offsetting habitat loss related to drought. Overall, we found statistically significant declines in open water in post-harvest agriculture (45-80% declines) and in managed wetlands (39-60% declines) during the 2013-2015 drought compared to non-drought years during the period of 2000-2011. Crops associated with the San Joaquin Basin, specifically corn, as well as wetlands in that part of the Central Valley exhibited larger reductions in open water than rice and wetlands in the Sacramento Valley. Semi-permanent wetlands on protected lands had significantly lower (39-49%) open water in the drought years than those on non-protected lands while seasonal wetlands on protected lands had higher amounts of open water. A large fraction of the daily open water in rice during certain times of the year, particularly in the fall for BirdReturns (61%) and the winter for WHEP (100%), may have been provided through incentive programs which underscores the contribution of these programs. However, further assessment is needed to know how much the incentive programs directly offset the impact of drought in post-harvest rice by influencing water management or simply supplemented funding for activities that might have been done regardless. Our landscape analysis documents the significant impacts of the recent extreme drought on freshwater wetland habitats in the Central Valley, the benefits of incentive programs, and the value of using satellite data to track surface water and waterbird habitats. More research is needed to understand subsequent impacts on the freshwater dependent species that rely on these systems and how incentive programs can most strategically support vulnerable species during future extreme drought.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria ( n  = 59 for molnupiravir and n  = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.