Miracle-dz/UniFAR-FTUs huggingface dataset:
International Differences in the Frequency of Chronic Obstructive Pulmonary Disease Exacerbations Reported in Three Clinical Trials

Rationale Exacerbations of chronic obstructive pulmonary disease (COPD) are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries. Objectives We investigated whether systematic differences in national exacerbation rates might explain this observed variation. Methods We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of COPD, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution. Measurements and Main Results For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was two- to threefold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrollment. Of the 18 countries contributing to all trials, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across trials. Severe exacerbations showed a different rank order internationally. Conclusions Countries contributing to COPD trials differ consistently in their reporting of healthcare–defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.
Mucus concentration–dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis

Cystic fibrosis (CF) is characterized by abnormal transepithelial ion transport. However, a description of CF lung disease pathophysiology unifying superficial epithelial and submucosal gland (SMG) dysfunctions has remained elusive. We hypothesized that biophysical abnormalities associated with CF mucus hyperconcentration provide a unifying mechanism. Studies of the anion secretion–inhibited pig airway model of CF revealed elevated SMG mucus concentrations, osmotic pressures, and SMG mucus accumulation. Human airway studies revealed hyperconcentrated CF SMG mucus with raised osmotic pressures and cohesive forces predicted to limit SMG mucus secretion/release. Using proline-rich protein 4 (PRR4) as a biomarker of SMG secretion, CF sputum proteomics analyses revealed markedly lower PRR4 levels compared to healthy and bronchiectasis controls, consistent with a failure of CF SMGs to secrete mucus onto airway surfaces. Raised mucus osmotic/cohesive forces, reflecting mucus hyperconcentration, provide a unifying mechanism that describes disease-initiating mucus accumulation on airway surfaces and in SMGs of the CF lung.
Investigation of Neural Substrates of Erroneous Behavior in a Delayed-Response Task

Abstract Motor cortical neurons exhibit persistent selective activities (selectivity) during motor planning. Experimental perturbation of selectivity results in the failure of short-term memory retention and consequent behavioral biases, demonstrating selectivity as a neural characteristic of encoding previous sensory input or future action. However, even without experimental manipulation, animals occasionally fail to maintain short-term memory leading to erroneous choice. Here, we investigated neural substrates that lead to the incorrect formation of selectivity during short-term memory. We analyzed neuronal activities in anterior lateral motor cortex (ALM) of mice, a region known to be engaged in motor planning while mice performed the tactile delayed-response task. We found that highly selective neurons lost their selectivity while originally nonselective neurons showed selectivity during the error trials where mice licked toward incorrect direction. We assumed that those alternations would reflect changes in intrinsic properties of population activity. Thus, we estimated an intrinsic manifold shared by neuronal population (shared space), using factor analysis (FA) and measured the association of individual neurons with the shared space by communality, the variance of neuronal activity accounted for by the shared space. We found a positive correlation between selectivity and communality over ALM neurons, which disappeared in erroneous behavior. Notably, neurons showing selectivity alternations between correct and incorrect licking also underwent proportional changes in communality. Our results demonstrated that the extent to which an ALM neuron is associated with the intrinsic manifolds of population activity may elucidate its selectivity and that disruption of this association may alter selectivity, likely leading to erroneous behavior.
Heteroplasmic mitochondrial DNA variants in cardiovascular diseases

Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5–10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10–95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs play a role in the pathophysiology of hypertension.
Microbial communities in sandy beaches from the three domains of life differ by microhabitat and intertidal location

The microbial communities of sandy beaches are poorly described despite the biogeochemical importance and ubiquity of these ecosystems. Using metabarcoding of the 16S and 18S rRNA genes, we investigated the diversity, microhabitats (with or between sand grains) and intertidal distributions of microorganisms (including meiofauna) from pristine sandy beaches in British Columbia, Canada, and hypothesized that abiotic variations due to microhabitat or intertidal gradients influence the distribution of microorganisms on local scales. Bacterial, archaeal and protistan communities of the sand were clearly distinct from interstitial communities, and from planktonic communities of the overlying seawater, which correlated with differences in function and lifestyle (e.g., sulphur reduction and gliding motility). In contrast, meiofaunal communities could not be distinguished by sample type, suggesting that they are more frequently mobilized between these microhabitats. Across intertidal zones, high intertidal, mid intertidal and low intertidal/swash communities were distinct and correlated with moisture, organic carbon and phosphate content, implying that the distribution of microorganisms is influenced by intertidal abiotic gradients. However, few taxa at the genus or species level individually contributed to this zonation pattern; rather, a unique combination of multiple microbial taxa was probably responsible. Although significant differences in microbial community composition on sandy beaches can be attributed to microhabitat and intertidal gradients, further investigations are needed to assess community assembly processes, the consistency of these distributions, and the functions of the majority of the microorganisms observed in the sand and their effects on the biogeochemistry and ecology of sandy beaches.
GABAB‐ and GABAA‐receptor‐mediated regulation of Up and Down states across development

Slow oscillations, the hallmark of non‐REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect the intrinsic network organization. Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age‐dependent alterations. To elucidate the developmental impact of GABAB and GABAA receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings ex vivo, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non‐saturating concentration of gabazine, respectively. Blockade of both GABAB and GABAA signalling showed age‐differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABAA receptors in young vs. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by α1‐subunit‐containing GABAA receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders.
Addressing Suicide Risk in Patients Living With Dementia During the COVID-19 Pandemic and Beyond

Abstract Alzheimer’s disease and related dementias (ADRD) are progressive illnesses characterized by decline in cognitive function that impairs performing daily activities. People with ADRD are at an increased risk of suicide, especially those who have comorbid mental health conditions, have specific types of ADRD, or have been recently diagnosed. The coronavirus disease 2019 (COVID-19) pandemic has increased the distress of people with ADRD, a population also at increased risk of contracting the COVID-19 virus. In this article, we draw on a case study and use the Interpersonal Theory of Suicide to help describe the association between ADRD and suicide risk. Secondly, we call for new strategies to mitigate suicide risk in people living with ADRD during and beyond the current pandemic by using lessons learned from cancer care. Our goal is not to dictate solutions but rather to start the conversation by outlining a framework for future research aimed at preventing death by suicide in people with ADRD. Specifically, we draw on the updated Framework for Developing and Evaluating Complex Interventions to reflect on the complexity of the issue and to break it down into achievable parts to reduce the risk of suicidal behavior (ideation, plans, attempts) in those living with ADRD.
Population genomics supports multiple hybrid zone origins of socially hybridogenetic lineages of Pogonomyrmex harvester ants

Reproductive division of labor in the social insects is typically determined by environmental cues; however, genetic effects on caste have been discovered in a growing set of ant taxa. An extreme form of genetic caste determination is “social hybridogenesis,” in which co‐occurring genetic lineages obligately interbreed to produce workers, whereas daughter queens are of pure‐lineage ancestry. In this study, we tested the hypothesis that social hybridogenesis in the genus Pogonomyrmex resulted from one or more interspecific hybridization events, and if so, whether individual lineages were of hybrid ancestry. We reconstructed evolutionary relationships of four lineage pairs to populations of two closely related non‐hybridogenetic species, Pogonomyrmex barbatus and Pogonomyrmex rugosus, using nuclear SNP loci and mitochondrial sequencing. The nuclear phylogeny supported a hybridization hypothesis, with one member of each pair nested within P. rugosus, whereas the other was nested within P. barbatus. The source populations corresponded with two distinct geographic areas at the eastern and western edges of a zone of contact. Relatively little gene flow was detected between interbreeding lineages, either historically or currently. This suggests that shifts in reproductive caste determination may reinforce reproductive incompatibility, in a manner similar to the evolution of hybridogenesis in nonsocial systems.
Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Abstract New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair–deficient or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell–dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB–mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.
Silicon Nitride MIM Capacitor Reliability for Multiple Dielectric Thicknesses

−A single GaAs MMIC fabrication flow produces three different types of silicon nitride capacitors, with 50 nm, 200 nm, and 250 nm nominal dielectric thickness. Ramped voltage data indicates that all three types are reliable. The results are compared to predictions of the linear field and Frenkel-Poole conduction models for capacitor lifetime at fixed voltages.
The life cycle of Puccinia digitariae on Digitaria eriantha and Solanum species in South Africa

ABSTRACT Rust fungi are important plant pathogens and have been extensively studied on crops and other host plants worldwide. This study describes the heterecious life cycle of a rust fungus on Digitaria eriantha (finger grass) and the Solanum species S. lichtensteinii (large yellow bitter apple), S. campylacanthum (bitter apple), and S. melongena (eggplant) in South Africa. Following field observations, inoculation studies involving telial isolates collected from Digitaria plants produced spermogonia and aecia on S. lichtensteinii, S. campylacanthum, and S. melongena. Likewise, inoculation of finger grass with aeciospores collected from the aforementioned Solanum species produced uredinia on D. eriantha. Pennisetum glaucum (pearl millet varieties Milkstar and Okashana, as well as 17 experimental lines) and S. elaeagnifolium (silverleaf nightshade or bitter apple) were resistant to the rust isolates. Morphological descriptions and molecular phylogenetic data confirmed the identity of the rust on Digitaria as P. digitariae, herein reinstated as a species and closely related to P. penicillariae the pearl millet rust, also reinstated. Puccinia digitariae has a macrocyclic, heterecious life cycle in which teliospores overwinter on dormant D. eriantha plants. Aecia sporulate on species of Solanum during spring and early summer to provide inocula that infect new growth of Digitaria.
Design and qualification of a bench-scale model for municipal waste-to-energy combustion

ABSTRACT This paper reports the design and qualification of the first purpose-built, bench-scale reactor system to model the municipal waste-to-energy combustion of fluorinated polymers. Using the principle of similarity, the gas-phase combustion zone of a typical municipal waste-to-energy plant has been scaled down to the bench with a focus on chemical similarity. Chemical similarity is achieved in large part through the use of methanol as a surrogate for municipal solid waste (MSW). Review of prior research shows that methanol is one of the major volatile products expected during MSW thermal conversion in the fuel bed of waste-to-energy plants. Like full-scale waste-energy plants, the design of the bench-scale model includes a flame zone and a post-flame zone. Maintaining steady methanol vapor flow premixed with air to the model reactor system ensures stable combustion resulting in bench-scale CO emission levels comparable to those of full-scale waste-to-energy plants. Since investigation of fluorinated polymer combustion includes trace analysis of exhaust gas for perfluorooctanoic acid (PFOA), qualification testing focused on PFOA collection efficiency. High PFOA collection efficiency (>90%) demonstrated the capability of the reactor system in transporting and absorbing PFOA that may be generated during high-temperature combustion testing of fluorinated polymers. Overall, the bench-scale system is qualified for its intended use to investigate potential generation of PFOA from combustion of fluorinated polymers under conditions representative of waste-to-energy combustion. Implications: Decision-makers depend on environmental researchers to provide reliable predictions of pollutant emissions from waste combustion of polymers at end of product life. Reliable predictions are especially important with regard to questions about potential PFOA emissions from municipal waste combustion of fluorinated polymers. Results from qualification testing confirm that the novel bench-scale model reactor system is capable of representing gas-phase municipal waste combustion behavior upstream of air pollution control and generating representative exhaust gas samples for off-line trace-level analysis of PFOA.
Passenger Traffic Volume Forecasting Based on Support Vector Machine Optimized by Genetic Algorithm

Forecasting highway passenger transport volume is one of the most important jobs to construct the road layout.In view of the difficulty to build a precise prediction model,combined with genetic algorithm and support vector machines,the paper presents a new method to forecast highway passenger transport volume.Because the accuracy of forecasting support vector machine depends largely on the selection of parameters,thus the paper uses genetic algorithm to optimize the training parameters,in order to obtain the optimized support vector machine model.The paper uses Beijing city's data as an application example,and analyzes the comparison between the data with the prediction results of BP neural network and RBF neural network.The experimental results show that,based on genetic algorithm,support vector machine model predicts more accurate with less errors,and is more effective on highway passenger transport volume forecast;also notes that the use of genetic algorithm support vector machine SVM parameters optimization method is feasible and effective.
Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low‐dose methotrexate in patients recently diagnosed with rheumatoid arthritis

Low‐dose methotrexate can be challenging to treat rheumatoid arthritis due to side effects, lack of adherence and risk of medication errors. The aim of this study was to explore the safety and efficacy of low‐dose methotrexate administered daily or weekly in patients with rheumatoid arthritis. Patients were randomized according to a total oral dose of 12.5 mg of methotrexate administered: (A) divided in 5 days/week and (B) once per week. Patients were assessed along 24 weeks after starting treatment. Polyglutamates of methotrexate were quantified by ultrahigh‐performance liquid chromatography coupled to tandem mass spectrometer. Patients from groups A and B showed a good response to methotrexate treatment in 29% and 25.5%, respectively, and a global frequency of adverse events of 37%. Methotrexate polyglutamate 3 concentrations were higher in normal weight (body mass index 18.5–24.9 kg/m2) than in obese (body mass index 30 kg/m2) patients with a median (interquartile range) of 28 (17.95–45.15) and 10.35 (5.22–30.88) nM without differences between dosage groups. Daily dosage regimen represents a therapeutic alternative without compromising the efficacy and safety of methotrexate treatment and with similar adherence patterns than weekly dosage regimen; further, methotrexate polyglutamate 3 concentrations could be a useful tool for therapeutic drug monitoring purposes.
Do Housing Values Respond to Underground Storage Tank Releases? Evidence from High-Profile Cases across the United States

Underground storage tanks (USTs) containing petroleum and hazardous substances are ubiquitous. Accidental releases of these substances can present risks to local residents and the environment. The purpose of this paper is to develop monetized estimates of the benefits of preventing and cleaning up UST releases, as reflected in house values. We focus on 17 of the most high-profile UST releases in the United States with release discovery and other milestone events occurring at different points between 1985 and 2013. These data are the broadest analyzed for property value impacts of UST releases, as previous hedonic studies of USTs focused only on a single county, city, or subset of counties within a state. We employ a two-step methodology in which (i) site specific hedonic regressions are estimated using a difference-in-differences approach, and then (ii) an internal meta-analysis of the resulting estimates is conducted. The spatial and temporal variation among the 17 sites improves our identification of the treatment effects by reducing local idiosyncratic biases; thus providing greater confidence to a causal interpretation of the estimated average price effects. The results suggest significant heterogeneity in the price effects across sites, but on average reveal a 3% to 6% depreciation upon the discovery of a high profile release, and a similar appreciation after cleanup. These average effects diminish with distance, extending out to 2 or 3km from the site.