Most Networks in Wagner's Model Are Cycling

In this paper we study a model of gene networks introduced by Andreas Wagner in the 1990s that has been used extensively to study the evolution of mutational robustness. We investigate a range of model features and parameters and evaluate the extent to which they influence the probability that a random gene network will produce a fixed point steady state expression pattern. There are many different types of models used in the literature, (discrete/continuous, sparse/dense, small/large network) and we attempt to put some order into this diversity, motivated by the fact that many properties are qualitatively the same in all the models. Our main result is that random networks in all models give rise to cyclic behavior more often than fixed points. And although periodic orbits seem to dominate network dynamics, they are usually considered unstable and not allowed to survive in previous evolutionary studies. Defining stability as the probability of fixed points, we show that the stability distribution of these networks is highly robust to changes in its parameters. We also find sparser networks to be more stable, which may help to explain why they seem to be favored by evolution. We have unified several disconnected previous studies of this class of models under the framework of stability, in a way that had not been systematically explored before

Breast cancer risk and drinking water contaminated by wastewater: a case control study

BACKGROUND: Drinking water contaminated by wastewater is a potential source of exposure to mammary carcinogens and endocrine disrupting compounds from commercial products and excreted natural and pharmaceutical hormones. These contaminants are hypothesized to increase breast cancer risk. Cape Cod, Massachusetts, has a history of wastewater contamination in many, but not all, of its public water supplies; and the region has a history of higher breast cancer incidence that is unexplained by the population's age, in-migration, mammography use, or established breast cancer risk factors. We conducted a case-control study to investigate whether exposure to drinking water contaminated by wastewater increases the risk of breast cancer. METHODS: Participants were 824 Cape Cod women diagnosed with breast cancer in 1988–1995 and 745 controls who lived in homes served by public drinking water supplies and never lived in a home served by a Cape Cod private well. We assessed each woman's exposure yearly since 1972 at each of her Cape Cod addresses, using nitrate nitrogen (nitrate-N) levels measured in public wells and pumping volumes for the wells. Nitrate-N is an established wastewater indicator in the region. As an alternative drinking water quality indicator, we calculated the fraction of recharge zones in residential, commercial, and pesticide land use areas. RESULTS: After controlling for established breast cancer risk factors, mammography, and length of residence on Cape Cod, results showed no consistent association between breast cancer and average annual nitrate-N (OR = 1.8; 95% CI 0.6 – 5.0 for ≥ 1.2 vs. < .3 mg/L), the sum of annual nitrate-N concentrations (OR = 0.9; 95% CI 0.6 – 1.5 for ≥ 10 vs. 1 to < 10 mg/L), or the number of years exposed to nitrate-N over 1 mg/L (OR = 0.9; 95% CI 0.5 – 1.5 for ≥ 8 vs. 0 years). Variation in exposure levels was limited, with 99% of women receiving some of their water from supplies with nitrate-N levels in excess of background. The total fraction of residential, commercial, and pesticide use land in recharge zones of public supply wells was associated with a small statistically unstable higher breast cancer incidence (OR = 1.4; 95% CI 0.8–2.4 for highest compared with lowest land use), but risk did not increase for increasing land use fractions. CONCLUSION: Results did not provide evidence of an association between breast cancer and drinking water contaminated by wastewater. The computer mapping methods used in this study to link routine measurements required by the Safe Drinking Water Act with interview data can enhance individual-level epidemiologic studies of multiple health outcomes, including diseases with substantial latency

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

All-sky search for continuous gravitational waves from isolated neutron stars in the early O3 LIGO data

We report on an all-sky search for continuous gravitational waves in the frequency band 20-2000 Hz and with a frequency time derivative in the range of [-1.0,+0.1]×10-8 Hz/s. Such a signal could be produced by a nearby, spinning and slightly nonaxisymmetric isolated neutron star in our Galaxy. This search uses the LIGO data from the first six months of Advanced LIGO's and Advanced Virgo's third observational run, O3. No periodic gravitational wave signals are observed, and 95% confidence-level (C.L.) frequentist upper limits are placed on their strengths. The lowest upper limits on worst-case (linearly polarized) strain amplitude h0 are ∼1.7×10-25 near 200 Hz. For a circularly polarized source (most favorable orientation), the lowest upper limits are ∼6.3×10-26. These strict frequentist upper limits refer to all sky locations and the entire range of frequency derivative values. For a population-averaged ensemble of sky locations and stellar orientations, the lowest 95% C.L. upper limits on the strain amplitude are ∼1.4×10-25. These upper limits improve upon our previously published all-sky results, with the greatest improvement (factor of ∼2) seen at higher frequencies, in part because quantum squeezing has dramatically improved the detector noise level relative to the second observational run, O2. These limits are the most constraining to date over most of the parameter space searched

Combination of searches for heavy spin-1 resonances using 139 fb−1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, , and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Search for resonant production of dark quarks in the dijet final state with the ATLAS detector

This paper presents a search for a new Z′ resonance decaying into a pair of dark quarks which hadronise into dark hadrons before promptly decaying back as Standard Model particles. This analysis is based on proton-proton collision data recorded at $$\sqrt{s}$$ s = 13 TeV with the ATLAS detector at the Large Hadron Collider between 2015 and 2018, corresponding to an integrated luminosity of 139 fb−1. After selecting events containing large-radius jets with high track multiplicity, the invariant mass distribution of the two highest-transverse-momentum jets is scanned to look for an excess above a data-driven estimate of the Standard Model multijet background. No significant excess of events is observed and the results are thus used to set 95% confidence-level upper limits on the production cross-section times branching ratio of the Z′ to dark quarks as a function of the Z′ mass for various dark-quark scenarios

Electron and photon energy calibration with the ATLAS detector using LHC Run 2 data

This paper presents the electron and photon energy calibration obtained with the ATLAS detector using 140 fb-1 of LHC proton-proton collision data recorded at √(s) = 13 TeV between 2015 and 2018. Methods for the measurement of electron and photon energies are outlined, along with the current knowledge of the passive material in front of the ATLAS electromagnetic calorimeter. The energy calibration steps are discussed in detail, with emphasis on the improvements introduced in this paper. The absolute energy scale is set using a large sample of Z-boson decays into electron-positron pairs, and its residual dependence on the electron energy is used for the first time to further constrain systematic uncertainties. The achieved calibration uncertainties are typically 0.05% for electrons from resonant Z-boson decays, 0.4% at ET ∼ 10 GeV, and 0.3% at ET ∼ 1 TeV; for photons at ET ∼ 60 GeV, they are 0.2% on average. This is more than twice as precise as the previous calibration. The new energy calibration is validated using J/ψ → ee and radiative Z-boson decays

Measurement of the inclusive and differential Higgs boson production cross sections in the decay mode to a pair of τ Leptons in pp collisions at sqrt[s]=13 TeV

Measurements of the inclusive and differential fiducial cross sections of the Higgs boson are presented, using the τ lepton decay channel. The differential cross sections are measured as functions of the Higgs boson transverse momentum, jet multiplicity, and transverse momentum of the leading jet in the event, if any. The analysis is performed using proton-proton collision data collected with the CMS detector at the LHC at a center-of-mass energy of 13  TeV and corresponding to an integrated luminosity of 138  fb^{-1}. These are the first differential measurements of the Higgs boson cross section in the final state of two τ leptons. In final states with a large jet multiplicity or with a Lorentz-boosted Higgs boson, these measurements constitute a significant improvement over measurements performed in other final states

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI 2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesity. Funding UK Medical Research Council, UK Research and Innovation (Research England), UK Research and Innovation (Innovate UK), and European Union