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ABSTRACT Development of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.

Severe alpha-1-antitrypsin deficiency (AATD) is an established risk factor for chronic obstructive pulmonary disease (COPD) and liver disease, but the effect on the incidence of ischemic heart disease (IHD) is not well known. The aim was to evaluate the risk of incident IHD in patients with severe AATD compared with a random sample of the general population, with known smoking habits.AAT-deficient individuals, phenotype PiZZ (n=1545), were included in the Swedish National AATD Register. Controls (n=5883) were selected from population-based cohorts in Northern Sweden. Data on IHD and comorbidities were obtained by nationwide cross-linkage with the Swedish National Patient Register. Risk factors for incident IHD were analyzed using Cox regression, adjusted for age, gender, smoking status and the presence of COPD, hypertension, hyperlipidemia and diabetes.At inclusion, 46% of the PiZZ individuals and 53% of the controls were never-smokers. During follow-up (median 16 years; range 0.2-23), 8% (n=123) of PiZZ individuals and 12% (n=690) of controls developed IHD. The controls had a significantly higher risk for incident IHD than the PiZZ individuals, with adjusted hazard ratio (HR) of 1.8 (95% CI 1.4-2.3). The risk was higher for controls in both ever-smokers (HR 2.1; 95% CI 1.5-2.9) and never-smokers (HR 1.5; 95% CI 1.1-2.2).PiZZ individuals have a lower risk of developing incident ischemic heart disease than the control subjects with known smoking habits, who had been randomly selected from population-based cohorts.

High-strength concrete (HSC) is highly applicable to the construction of heavy structures. However, shear strength (Ss) determination of HSC is a crucial concern for structure designers and decision makers. The current research proposes the novel models based on the combination of adaptive neuro-fuzzy inference system (ANFIS) with several meta-heuristic optimization algorithms, including ant colony optimizer (ACO), differential evolution (DE), genetic algorithm (GA), and particle swarm optimization (PSO), to predict the Ss of HSC slender beam. The proposed models were constructed using several input combinations incorporating several related dimensional parameters such as effective depth of beam (d), shear span (a), maximum size of aggregate (ag), compressive strength of concrete (fc), and percentage of tension reinforcement (ρ). To assess the impact of the non-homogeneity of the dataset on the prediction result accuracy, two possible modeling scenarios, (i) non-processed (initial) dataset (NP) and (ii) pre-processed dataset (PP), are inspected by several performance indices. The modeling results demonstrated that ANFIS-PSO hybrid model attained the best prediction accuracy over the other models and for the pre-processed input parameters. Several uncertainty analyses were examined (i.e., model, variables, and data), and results indicated predicting the HSC shear strength was more sensitive to the model structure uncertainty than the input parameters.

QC 20221219

AbstractBackgroundLecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia.MethodsBAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.ResultsA total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.ConclusionsBAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway.Trial registrationClinicalTrials.govNCT01767311.

Objective: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis due to excessive bone erosion causing joint destruction and decreased functional capacity. The aim of this study was to investigate the prevalence of comorbidities among patients with PAM and the association between comorbidities and joint involvement.Methods: A total of 66 patients aged ≥18 years from the Nordic countries with past or present psoriasis along with at least one mutilated joint were included in the present study.Results: The median number of comorbid conditions per patient was 1 [interquartile range (IQR) 0–2] and 16.7% reported three or more comorbidities. The most frequent comorbidity was hypertension (36.4%). The median number of mutilated joints per patient was 3 (IQR 1–8.3; range 1–38).Conclusion: Two thirds of the patients with PAM reported comorbid conditions and the most frequent was hypertension which affected more than a third of the patients. However, this study was unable to detect any association between comorbidities and the severity of PAM.

This paper estimates family spillovers in high school major choice in Sweden, where admission to oversubscribed majors is determined based on GPA. Using a regression discontinuity design, we find large sibling and intergenerational spillovers that depend on the gender mix of a dyad. Same-gender siblings copy one another, while younger brothers recoil from older sister's choices. Fathers and mothers influence sons, but not their daughters, except when a mother majors in the male-dominated program of Engineering. Back of the envelope calculations reveal these within family spillovers have sizable implications for the gender composition of majors.