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An adeno-associated virus (AAV) receptor protein essential for AAV2 entry into cells is identified; AAV receptor binds directly to the virus, and its ablation renders a diverse range of mammalian cell types and mice resistant to infection by AAV of multiple serotypes. A receptor for adeno-associated virus infection The recent revival of interest in gene therapy has been fueled by the availability of safer and more effective viral gene delivery methods, most notably adeno-associated virus (AAV) vectors. Jan Carette and colleagues now identify a protein that is essential for AAV entry into cells, subsequent to cell attachment. This protein, which they call AAVR, rapidly traffics from the plasma membrane to the trans -Golgi network. The authors show that the virus directly binds to AAVR and that genetic ablation of AAVR renders a diverse range of mammalian cell types and mice resistant to AAV infection. Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity 1 . They have been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2 ), and have been approved for treatment of lipoprotein lipase deficiency in Europe 3 . Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration 1 , 4 , yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans -Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr −/− (also known as Au040320 −/− and Kiaa0319l −/− ) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.

Nature 530, 108–112 (2016); doi:10.1038/nature16465 In this Letter, there is an error in Extended Data Fig. 1b. During preparation of the figure, an error was introduced while copying the flow cytometry plot for ‘HAP1 WT+isotype’ and the y-axis label was incorrectly shown as ‘SSC’ instead of ‘PE’. As a result, the plot for ‘FGFR1KO+FGFR1 Ab.

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11–34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7–16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9–25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14–29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15–23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17–48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20–41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20–34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20–33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21–46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.

Centralized water treatment has dominated in developed urban areas over the past century, although increasing challenges with this model demand a shift to a more decentralized approach wherein advanced oxidation processes (AOPs) can be appealing treatment options. Efforts to overcome the fundamental obstacles that have thus far limited the practical use of traditional AOPs, such as reducing their chemical and energy input demands, target the utilization of heterogeneous catalysts. Specifically, recent advances in nanotechnology have stimulated extensive research investigating engineered nanomaterial (ENM) applications to AOPs. In this Perspective, we critically evaluate previously studied ENM catalysts and the next-generation treatment technologies they seek to enable. Opportunities for improvement exist at the intersection of materials science and treatment process engineering, as future research should aim to enhance catalyst properties while considering the unique roadblocks to practical ENM implementation in water treatment.

Background. Transgender individuals have a gender identity that differs from the sex they were assigned at birth. The population size of transgender individuals in the United States is not well-known, in part because official records, including the US Census, do not include data on gender identity. Population surveys today more often collect transgender-inclusive gender-identity data, and secular trends in culture and the media have created a somewhat more favorable environment for transgender people. Objectives. To estimate the current population size of transgender individuals in the United States and evaluate any trend over time. Search methods. In June and July 2016, we searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Web of Science for national surveys, as well as “gray” literature, through an Internet search. We limited the search to 2006 through 2016. Selection criteria. We selected population-based surveys that used probability sampling and included self-reported transgender-identity data. Data collection and analysis. We used random-effects meta-analysis to pool eligible surveys and used meta-regression to address our hypothesis that the transgender population size estimate would increase over time. We used subsample and leave-one-out analysis to assess for bias. Main results. Our meta-regression model, based on 12 surveys covering 2007 to 2015, explained 62.5% of model heterogeneity, with a significant effect for each unit increase in survey year (F = 17.122; df = 1,10; b = 0.026%; P = .002). Extrapolating these results to 2016 suggested a current US population size of 390 adults per 100 000, or almost 1 million adults nationally. This estimate may be more indicative for younger adults, who represented more than 50% of the respondents in our analysis. Authors’ conclusions. Future national surveys are likely to observe higher numbers of transgender people. The large variety in questions used to ask about transgender identity may account for residual heterogeneity in our models. Public health implications. Under- or nonrepresentation of transgender individuals in population surveys is a barrier to understanding social determinants and health disparities faced by this population. We recommend using standardized questions to identify respondents with transgender and nonbinary gender identities, which will allow a more accurate population size estimate.

Spin-triplet supercurrent spin valves are of practical importance for the realization of superconducting spintronic logic circuits. In ferromagnetic Josephson junctions, the magnetic-field-controlled non-collinearity between the spin-mixer and spin-rotator magnetizations switches the spin-polarized triplet supercurrents on and off. Here we report an antiferromagnetic equivalent of such spin-triplet supercurrent spin valves in chiral antiferromagnetic Josephson junctions as well as a direct-current superconducting quantum interference device. We employ the topological chiral antiferromagnet Mn 3 Ge, in which the Berry curvature of the band structure produces fictitious magnetic fields, and the non-collinear atomic-scale spin arrangement accommodates triplet Cooper pairing over long distances (>150 nm). We theoretically verify the observed supercurrent spin-valve behaviours under a small magnetic field of <2 mT for current-biased junctions and the direct-current superconducting quantum interference device functionality. Our calculations reproduce the observed hysteretic field interference of the Josephson critical current and link these to the magnetic-field-modulated antiferromagnetic texture that alters the Berry curvature. Our work employs band topology to control the pairing amplitude of spin-triplet Cooper pairs in a single chiral antiferromagnet. A Josephson junction with a weak link made from the chiral antiferromagnet Mn 3 Ge can act as a spin-triplet supercurrent spin valve.

Background To maintain adequate oxygenation is of utmost importance in intraoperative care. However, clinical evidence supporting specific oxygen levels in distinct surgical settings is lacking. This study aimed to compare the effects of 30% and 80% oxygen in off-pump coronary artery bypass grafting (OPCAB). Methods This multicenter trial was conducted in three tertiary hospitals from August 2019 to August 2021. Patients undergoing OPCAB were cluster-randomized to receive either 30% or 80% oxygen intraoperatively, based on the month when the surgery was performed. The primary endpoint was the length of hospital stay. Intraoperative hemodynamic data were also compared. Results A total of 414 patients were cluster-randomized. Length of hospital stay was not different in the 30% oxygen group compared to the 80% oxygen group (median, 7.0 days vs 7.0 days; the sub-distribution hazard ratio, 0.98; 95% confidence interval [CI] 0.83–1.16; P  = 0.808). The incidence of postoperative acute kidney injury was significantly higher in the 30% oxygen group than in the 80% oxygen group (30.7% vs 19.4%; odds ratio, 1.94; 95% CI 1.18–3.17; P  = 0.036). Intraoperative time-weighted average mixed venous oxygen saturation was significantly higher in the 80% oxygen group (74% vs 64%; P  < 0.001). The 80% oxygen group also had a significantly greater intraoperative time-weighted average cerebral regional oxygen saturation than the 30% oxygen group (56% vs 52%; P  = 0.002). Conclusions In patients undergoing OPCAB, intraoperative administration of 80% oxygen did not decrease the length of hospital stay, compared to 30% oxygen, but may reduce postoperative acute kidney injury. Moreover, compared to 30% oxygen, intraoperative use of 80% oxygen improved oxygen delivery in patients undergoing OPCAB. Trial registration ClinicalTrials.gov (NCT03945565; April 8, 2019).

Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.