Ancient technology and punctuated change: Detecting the emergence of the Edomite Kingdom in the Southern Levant.

While the punctuated equilibrium model has been employed in paleontological and archaeological research, it has rarely been applied for technological and social evolution in the Holocene. Using metallurgical technologies from the Wadi Arabah (Jordan/Israel) as a case study, we demonstrate a gradual technological development (13th-10th c. BCE) followed by a human agency-triggered punctuated "leap" (late-10th c. BCE) simultaneously across the entire region (an area of ~2000 km2). Here, we present an unparalleled, diachronic archaeometallurgical dataset focusing on elemental analysis of dozens of well-dated slag samples. Based on the results, we suggest punctuated equilibrium provides an innovative theoretical model for exploring ancient technological changes in relation to larger sociopolitical conditions-in the case at hand the emergence of biblical Edom-, exemplifying its potential for more general cross-cultural applications

Recurrent sublethal warming reduces embryonic survival, inhibits juvenile growth, and alters species distribution projections under climate change

The capacity to tolerate climate change often varies across ontogeny in organisms with complex life cycles. Recently developed species distribution models incorporate traits across life stages; however, these life-cycle models primarily evaluate effects of lethal change. Here, we examine impacts of recurrent sublethal warming on development and survival in ecological projections of climate change. We reared lizard embryos in the laboratory under temperature cycles that simulated contemporary conditions and warming scenarios. We also artificially warmed natural nests to mimic laboratory treatments. In both cases, recurrent sublethal warming decreased embryonic survival and hatchling sizes. Incorporating survivorship results into a mechanistic species distribution model reduced annual survival by up to 24% compared to models that did not incorporate sublethal warming. Contrary to models without sublethal effects, our model suggests that modest increases in developmental temperatures influence species ranges due to effects on survivorship

Recreational cannabis legislation and binge drinking in U.S. adolescents and adults.

BACKGROUND: Recreational cannabis laws (RCLs) may have spillover effects on binge drinking. Our aims were to investigate binge drinking time trends and the association between RCLs and changes in binge drinking in the United States (U.S.). METHODS: We used restricted National Survey on Drug Use and Health data (2008-2019). We examined trends in the prevalence of past-month binge drinking by age groups (12-20, 21-30, 31-40, 41-50, 51+). Then, we compared model-based prevalences of past-month binge drinking before and after RCL by age group, using multi-level logistic regression with state random intercepts, an RCL by age group interaction term, and controlling for state alcohol policies. RESULTS: Binge drinking declined overall from 2008 to 2019 among people aged 12-20 (17.54% to 11.08%), and those aged 21-30 (43.66% to 40.22%). However, binge drinking increased among people aged 31+ (ages 31-40: 28.11% to 33.34%, ages 41-50: 25.48% to 28.32%, ages 51+: 13.28% to 16.75%). When investigating model-based prevalences after versus before RCL, binge drinking decreased among people aged 12-20 (prevalence difference=-4.8%; adjusted odds ratio (aOR)=0.77, [95% confidence interval (CI) 0.70-0.85]), and increased among participants aged 31-40 (+1.7%; 1.09[1.01-1.26]), 41-50 (+2.5; 1.15[1.05-1.26]) and 51+ (+1.8%; 1.17[1.06-1.30]). No RCL-related changes were noted in respondents ages 21-30. CONCLUSIONS: Implementation of RCLs was associated with increased past-month binge drinking in adults aged 31+ and decreased past-month binge drinking in those aged < 21. As the cannabis legislative landscape continues to change in the U.S., efforts to minimize harms related to binge drinking are critical

Approaches for advancing scientific understanding of macrosystems

The emergence of macrosystems ecology (MSE), which focuses on regional- to continental-scale ecological patterns and processes, builds upon a history of long-term and broad-scale studies in ecology. Scientists face the difficulty of integrating the many elements that make up macrosystems, which consist of hierarchical processes at interacting spatial and temporal scales. Researchers must also identify the most relevant scales and variables to be considered, the required data resources, and the appropriate study design to provide the proper inferences. The large volumes of multi-thematic data often associated with macrosystem studies typically require validation, standardization, and assimilation. Finally, analytical approaches need to describe how cross-scale and hierarchical dynamics and interactions relate to macroscale phenomena. Here, we elaborate on some key methodological challenges of MSE research and discuss existing and novel approaches to meet them

Approaches to advance scientific understanding of macrosystems ecology

The emergence of macrosystems ecology (MSE), which focuses on regional- to continental-scale ecological pat- terns and processes, builds upon a history of long-term and broad-scale studies in ecology. Scientists face the difficulty of integrating the many elements that make up macrosystems, which consist of hierarchical processes at interacting spatial and temporal scales. Researchers must also identify the most relevant scales and variables to be considered, the required data resources, and the appropriate study design to provide the proper inferences. The large volumes of multi-thematic data often associated with macrosystem studies typically require valida- tion, standardization, and assimilation. Finally, analytical approaches need to describe how cross-scale and hierarchical dynamics and interactions relate to macroscale phenomena. Here, we elaborate on some key methodological challenges of MSE research and discuss existing and novel approaches to meet them

Human histone H1 variants impact splicing outcome by controlling RNA polymerase II elongation

Histones shape chromatin structure and the epigenetic landscape. H1, the most diverse histone in the human genome, has 11 variants. Due to the high structural similarity between the H1s, their unique functions in transferring information from the chromatin to mRNA-processing machineries have remained elusive. Here, we generated human cell lines lacking up to five H1 subtypes, allowing us to characterize the genomic binding profiles of six H1 variants. Most H1s bind to specific sites, and binding depends on multiple factors, including GC content. The highly expressed H1.2 has a high affinity for exons, whereas H1.3 binds intronic sequences. H1s are major splicing regulators, especially of exon skipping and intron retention events, through their effects on the elongation of RNA polymerase II (RNAPII). Thus, H1 variants determine splicing fate by modulating RNAPII elongation.The research was funded by the Israel Science Foundation (ISF 671/18, ISF 142/13, and ISF 2417/20); the Israel Cancer Research Foundation (ICRF PG-18-105, PG-20-104); and the United States – Israel Binational Science Foundation (BSF 2017086). V.R.R. was supported by Edmond J. Safra Bioinformatics Center fellowship at Tel Aviv University.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding: Novo Nordisk