Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight ...junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.
High-fidelity single-shot readout of spin qubits requires distinguishing states much faster than the T
time of the spin state. One approach to improving readout fidelity and bandwidth (BW) is ...cryogenic amplification, where the signal from the qubit is amplified before noise sources are introduced and room-temperature amplifiers can operate at lower gain and higher BW. We compare the performance of two cryogenic amplification circuits: a current-biased heterojunction bipolar transistor circuit (CB-HBT), and an AC-coupled HBT circuit (AC-HBT). Both circuits are mounted on the mixing-chamber stage of a dilution refrigerator and are connected to silicon metal oxide semiconductor (Si-MOS) quantum dot devices on a printed circuit board (PCB). The power dissipated by the CB-HBT ranges from 0.1 to 1 μW whereas the power of the AC-HBT ranges from 1 to 20 μW. Referred to the input, the noise spectral density is low for both circuits, in the 15 to 30 fA/Formula: see text range. The charge sensitivity for the CB-HBT and AC-HBT is 330 μe/Formula: see text and 400 μe/Formula: see text, respectively. For the single-shot readout performed, less than 10 μs is required for both circuits to achieve bit error rates below 10
, which is a putative threshold for quantum error correction.
Background Anaphylaxis is a potentially life-threatening systemic allergic reaction. Objective We aimed to determine the incidence rate and causes of anaphylaxis during a 10-year period in Olmsted ...County, Minnesota. Methods Using the resources of the Rochester Epidemiology Project, a comprehensive records linkage system, we performed a population-based incidence study in Olmsted County, Minnesota, from 2001 through 2010. All cases with a diagnosis of anaphylactic shock and 20% of cases with related diagnoses were manually reviewed. The relationships of age group, sex, and year of anaphylaxis with incidence rates were assessed by fitting Poisson regression models. Results Six hundred thirty-one cases of anaphylaxis were identified. The median age was 31 years (interquartile range, 19-44 years). The overall age- and sex-adjusted incidence rate was 42 (95% CI, 38.7-45.3) per 100,000 person-years. There was a significant increase in the overall incidence of anaphylaxis during the study period, with an average increase of 4.3% per year ( P < .001). In addition, there was a 9.8% increase per year in the incidence rate of food-related anaphylaxis. Food-related anaphylaxis was most common in children aged 0 to 9 years, venom-related anaphylaxis was most common in those 20 to 39 years of age, and medication-related anaphylaxis was most common in those 30 to 39 years of age. Conclusion The overall incidence rate of anaphylaxis was 42 per 100,000 person-years from 2001-2010 in Olmsted County, Minnesota. The incidence of anaphylaxis increased over time, and several inciting triggers were uniquely associated with different age groups.
Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis
. The ...understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited
. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2
). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
Summary Background Oral human papillomavirus (HPV) infection causes a subset of oropharyngeal cancers. These cancers disproportionately affect men, are increasing in incidence, and have no proven ...prevention methods. We aimed to establish the natural history of oral HPV infection in men. Methods To estimate incidence and clearance of HPV infections, men residing in Brazil, Mexico, and the USA who were HIV negative and reported no history of anogenital cancer were recruited into the HPV Infection in Men (HIM) cohort study. A subset of the cohort who provided two or more oral rinse-and-gargle samples with valid HPV results and who completed a minimum of 2 weeks of follow-up were included in this analysis. Oral rinse-and-gargle samples and questionnaire data were obtained every 6 months for up to 4 years. Samples were analysed for the presence of oncogenic and non-oncogenic HPV infections by the linear array method. Findings 1626 men aged 18–73 years and with a median follow-up of 12·7 months (IQR 12·1–14·7) were included in the analysis. During the first 12 months of follow-up, 4·4% (95% CI 3·5–5·6; n=115 incident infections) of men acquired an incident oral HPV infection, 1·7% (1·2–2·5; n=53 incident infections) an oral oncogenic HPV infection, and 0·6% (0·3–1·1; n=18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6·9 months (95 % CI 6·2–9·3; n=45 cleared infections) for any HPV, 6·3 months (6·0–9·9; n=18 cleared infections) for oncogenic HPV, and 7·3 months (6·0–not estimable; n=5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits. Interpretation Newly acquired oral oncogenic HPV infections in healthy men were rare and most were cleared within 1 year. Additional studies into the natural history of HPV are needed to inform development of infection-related prevention efforts. Funding US National Cancer Institute, Merck Sharp & Dohme.
The discovery of a two-dimensional electron gas (2DEG) at the LaAlO
/SrTiO
interface
has resulted in the observation of many properties
not present in conventional semiconductor heterostructures, and ...so become a focal point for device applications
. Its counterpart, the two-dimensional hole gas (2DHG), is expected to complement the 2DEG. However, although the 2DEG has been widely observed
, the 2DHG has proved elusive. Herein we demonstrate a highly mobile 2DHG in epitaxially grown SrTiO
/LaAlO
/SrTiO
heterostructures. Using electrical transport measurements and in-line electron holography, we provide direct evidence of a 2DHG that coexists with a 2DEG at complementary heterointerfaces in the same structure. First-principles calculations, coherent Bragg rod analysis and depth-resolved cathodoluminescence spectroscopy consistently support our finding that to eliminate ionic point defects is key to realizing a 2DHG. The coexistence of a 2DEG and a 2DHG in a single oxide heterostructure provides a platform for the exciting physics of confined electron-hole systems and for developing applications.
The corallivorous crown-of-thorns starfish (COTS),
Acanthaster planci
, is recognised as a major cause of coral reef degradation throughout much of the Pacific Ocean. However, the effects of COTS on ...the high diversity reefs in Indonesia have been largely overlooked. In 2007, high densities of COTS were observed in two regions of Indonesia: Aceh and Halmahera. Densities of COTS ranged from 0 to 52 starfish 2,000 m
2
across 24 sites in Aceh and from 0 to 18 starfish 2,000 m
2
at 10 sites in Halmahera. Mortality rates of
Acropora
spp. were very high at affected sites: over 50 % of colonies had been killed at seven of the 16 affected sites. A review of historical sources going back to 1969 suggests that COTS have damaged many reefs throughout Indonesia, including much activity within the Indonesian section of the Coral Triangle. Furthermore, the data suggest that COTS activity has increased rapidly since 2000. Very little of this activity has been reported in the primary literature, and there is a general lack of awareness in Indonesia of COTS as a potential cause of reef degradation. This lack of awareness, combined with limited monitoring efforts, means that damage caused by COTS is often attributed to other causes, such as destructive fishing, bleaching or tsunami. COTS are clearly a major source of coral mortality in Indonesia of which scientists and government need to be more cognizant.
Summary Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in children. We aimed to assess the safety and efficacy of an anti-RSV monoclonal ...antibody (motavizumab) in healthy term (≥36 weeks' gestational age) infants for the prevention of medically attended RSV acute lower respiratory tract infections. Methods This phase 3, double-blind, placebo-controlled, randomised trial enrolled healthy Native American infants aged 6 months or younger who were born at 36 weeks' gestational age in southwestern USA, on the Navajo Nation, the White Mountain Apache reservation, and the San Carlos Apache Indian reservation. Participants were randomly assigned (2:1) to receive either five monthly intramuscular doses of motavizumab (15 mg/kg) or placebo. They were followed up for 150 days after the first dose, and the primary endpoints were respiratory admission to hospital with a positive result for RSV by RT-PCR and death caused by RSV. Participants were followed up for medically attended wheezing until they reached age 3 years. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov , number NCT00121108. Findings During the autumn seasons (October to December) between 2004 and 2007, 2127 infants of the 2596 infants enrolled were randomly assigned to receive either motavizumab (1417) or placebo (710). After ITT analysis, motavizumab resulted in an 87% relative reduction (relative risk RR 0·13, 95% CI 0·08–0·21) in the proportion of infants admitted to hospital with RSV (21 2% of 1417 participants who received motavizumab; 80 11% of 710 participants who received placebo, p<0·0001). Serious adverse events were less common in particpants taking motavizumab (212 15%) than particpants on placebo (148 21%). Six deaths occurred in study participants (motavizumab, n=4 0·3%; placebo, n=2 0·3%); none were deemed to be related to the study product. Hypersensitivity events were more common in patients given motavizumab (208 14·7%) than in placebo recipients (87 12·3%; p=0·14). There was no effect on rates of medically attended wheezing in children aged 1–3 years (190 14·9% of participants randomly assigned to receive motavizumab vs 90 14·0% participants randomly assigned to receive placebo). Interpretation To our knowledge, this is the only trial of an anti-RSV antibody to prevent serious RSV disease in healthy term infants. Motavizumab significantly reduced the RSV-associated inpatient and outpatient burden and set a benchmark for the efficacy of RSV prevention strategies. The findings do not support a direct, generalisable, causal association between RSV lower respiratory tract infection and subsequent long-term wheezing in term infants. Funding MedImmune.
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