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To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at high imminent risk of developing symptoms due to Alzheimer's disease. This 5–8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30–60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1Glu280Ala autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test–Cueing Index (FCSRT–CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed. 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab–carrier, n=85; placebo–carrier, n=84; placebo–non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was –1·10 (SE 0·29) in the crenezumab group and –1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI –0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT–CI was –0·03 (0·00) in the crenezumab group and –0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5–8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.

To have maximal benefit, Alzheimer's disease-modifying treatments might need to be started before the onset of clinical symptoms. Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years. We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1 mutation at high imminent risk of developing symptoms due to Alzheimer's disease. This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia. Participants who were cognitively unimpaired and carried the PSEN1 autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks. Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating. Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control. Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment. Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors. Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed. 619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022. The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43). The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16). All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group. No fatalities occurred. Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes. Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid. This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials. US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.

Mortality concern is a frequent driver of care seeking in patients with irritable bowel syndrome (IBS). Data on mortality in IBS are scarce, and population-based studies have been limited in size. We examined mortality in IBS. A nationwide, matched, population-based cohort study was conducted in Sweden. We identified 45,524 patients undergoing a colorectal biopsy at any of Sweden's 28 pathology departments and with a diagnosis of IBS from 2002 to 2016 according to the National Patient Register, a nationwide registry of inpatient and outpatient specialty care. We compared the mortality risk between these individuals with IBS and age- and sex-matched reference individuals (n = 217,316) from the general population and siblings (n = 53,228). In separate analyses, we examined the role of mucosal appearance for mortality in IBS. Finally, we examined mortality in 41,427 patients with IBS not undergoing a colorectal biopsy. Cox regression estimated hazard ratios (HRs) for death. During follow-up, there were 3,290 deaths in individuals with IBS (9.4/1,000 person-years) compared with 13,255 deaths in reference individuals (7.9/1,000 person-years), resulting in an HR of 1.10 (95% confidence interval [CI] = 1.05-1.14). After adjustment for confounders, IBS was not linked to mortality (HR = 0.96; 95% CI = 0.92-1.00). The risk estimates were neutral when patients with IBS were compared with their siblings. The underlying mucosal appearance on biopsy had only a marginal impact on mortality, and patients with IBS not undergoing a colorectal biopsy were at no increased risk of death (HR = 1.02; 95% CI = 0.99-1.06). IBS does not seem to confer an increased risk of death.

Motivated by the recent experiment (Lopes et al. in Phys Rev Lett 119:190404, 2017) with a homogeneous Bose gas, we investigate a homogeneous dilute Bose gas to calculate the quantum depletion density. By means of the Cornwall–Jackiw–Tomboulis effective action approach within an improved Hartree–Fock approximation, the condensed fraction is recovered in an alternative theoretical approach and compared with corresponding findings in experimental data. A good agreement in the extremely small region of gas parameter is demonstrated. Furthermore, the ground state energy is also reattained and discussed.

The gold-standard method for reconstruction of segmental nerve defects, the autologous nerve graft, has several drawbacks in terms of tissue availability and donor site morbidity. Therefore, feasible alternatives to autologous nerve grafts are sought. Muscle-in-vein conduits have been proposed as an alternative to autologous nerve grafts almost three decades ago, given the abundance of both tissues throughout the body. Based on the anti-inflammatory effects of veins and the proregenerative environment established by muscle tissue, this approach has been studied in various preclinical and some clinical trials. There is still no comprehensive systematic summary to conclude efficacy and feasibility of muscle-in-vein conduits for reconstruction of segmental nerve defects. Given this lack of a conclusive summary, we performed a meta-analysis to evaluate the potential of muscle-in-vein conduits. This work’s main findings are profound discrepancies regarding the results following nerve repair by means of muscle-in-vein conduits in a preclinical or clinical setting. We identified differences in study methodology, inter-species neurobiology and the limited number of clinical studies to be the main reasons for the still inconclusive results. In conclusion, we advise for large animal studies to elucidate the feasibility of muscle-in-vein conduits for repair of segmental defects of critical size in mixed nerves.

The question of how genetic variation in a population influences phenotypic variation and evolution is of major importance in modern biology. Yet much is still unknown about the relative functional importance of different forms of genome variation and how they are shaped by evolutionary processes. Here we address these questions by population level sequencing of 42 strains from the budding yeast Saccharomyces cerevisiae and its closest relative S. paradoxus. We find that genome content variation, in the form of presence or absence as well as copy number of genetic material, is higher within S. cerevisiae than within S. paradoxus, despite genetic distances as measured in single-nucleotide polymorphisms being vastly smaller within the former species. This genome content variation, as well as loss-of-function variation in the form of premature stop codons and frameshifting indels, is heavily enriched in the subtelomeres, strongly reinforcing the relevance of these regions to functional evolution. Genes affected by these likely functional forms of variation are enriched for functions mediating interaction with the external environment (sugar transport and metabolism, flocculation, metal transport, and metabolism). Our results and analyses provide a comprehensive view of genomic diversity in budding yeast and expose surprising and pronounced differences between the variation within S. cerevisiae and that within S. paradoxus. We also believe that the sequence data and de novo assemblies will constitute a useful resource for further evolutionary and population genomics studies.

The pathogenesis of dengue is attributed to a complex interaction between the dengue virus (DENV) and the host immune system. The aim of this study is to investigate the clinical, virological, and Interleukin-10 (IL-10) profiles of dengue patients in Vietnam from two consecutive outbreaks in 2021 and 2022. A total of n=306 dengue patients were examined, who were clinically stratified according to dengue without warning signs (DF; n=178), dengue with warning signs (DWS; n=115) and severe dengue (SD; n=13). Patients were screened for dengue, Zika and chikungunya viruses. DENV were subjected to serotype specific real-time RT-PCR. Interleukin-10 (IL-10) levels were measured by ELISA, and IL-10 promoter variants (-1082G/A; -819C/T; -592C/A) were genotyped by direct Sanger sequencing to determine a possible association with susceptibility to dengue and disease severity. No chikungunya or Zika viruses were detected. Patients were infected by one of the three different DENV serotypes (DENV-1, -2, -4). Plasma IL-10 levels were significantly elevated in patients (DF vs. DWS, p=0.004; DF vs. SD, p=0.001; DWS vs. SD, p=0.015). While the IL-10 allele -819C contributed to an increased risk of dengue (OR = 1.5, 95% CI = 1.1-2.0, p=0.04), genotype -1082GA showed a protective role against the disease (OR = 0.45, 95% CI = 0.27-0.72, p=0.009), and allele -1082G showed a protective role against DWS (OR = 0.44, 95% CI = 0.22-0.81, p=0.049). Also, the IL-10 GTA (-1082G/-819T/-592A) haplotype was observed to confer protection (OR = 0.31, 95% CI = 0.14-0.67, p< 0.003). While DENV-1 and DENV-2 were the predominant serotypes in circulation, plasma IL-10 levels and IL-10 promoter variants were also significantly associated with dengue and its severity.

This study introduces a flexible, adhesive-integrated electrode array that was developed to enable non-invasive monitoring of cervical nerve activity. The device uses silver-silver chloride as the electrode material of choice and combines it with an electrode array consisting of a customized biopotential data acquisition unit and integrated graphical user interface (GUI) for visualization of real-time monitoring. Preliminary testing demonstrated this electrode design can achieve a high signal to noise ratio during cervical neural recordings. To demonstrate the capability of the surface electrodes to detect changes in cervical neuronal activity, the cold-pressor test (CPT) and a timed respiratory challenge were employed as stressors to the autonomic nervous system. This sensor system recording, a new technique, was termed Cervical Electroneurography (CEN). By applying a custom spike sorting algorithm to the electrode measurements, neural activity was classified in two ways: (1) pre-to-post CPT, and (2) during a timed respiratory challenge. Unique to this work: (1) rostral to caudal channel position-specific (cephalad to caudal) firing patterns and (2) cross challenge biotype-specific change in average CEN firing, were observed with both CPT and the timed respiratory challenge. Future work is planned to develop an ambulatory CEN recording device that could provide immediate notification of autonomic nervous system activity changes that might indicate autonomic dysregulation in healthy subjects and clinical disease states.

Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.

Stomata of plant leaves open to enable CO 2 entry for photosynthesis and close when CO 2 in the leaf is elevated. CO 2 is thought to promote stomatal closure in part by activating the SLAC1 anion channel at the guard cell plasma membrane. Carbonic anhydrases (CAs) contribute to this activation, but their contribution as distinct from CO 2 -H 2 CO 3 catalysis remains controversial. Here we show that the β-carbonic anhydrase CA4 binds selectively with the guard-cell anion channel SLAC1 to enhance channel current. The interaction is CO 2 -dependent, but binding is mediated by amino acids distal from the CO 2 -binding site of CA4 and is separable from carbonic-anhydrase activity. CA4 mutants impaired in channel binding eliminate the CO 2 -sensitivity of SLAC1 in vivo and slow stomatal kinetics with a commensurate loss in water use efficiency. The findings demonstrate that CA4 contributes directly to the CO 2 -response mechanics regulating SLAC1 at near-ambient CO 2 in guard cells and to stomatal kinetics in the plant. Separate from its catalytic activity, b-carbonic anhydrase 4 binds directly the Cl- channel SLAC1 in Arabidopsis guard cells, promoting SLAC1 activity and stomatal responsiveness to CO2, and facilitating plant growth.