Explore the vast range of titles available.

Background Amongst risk alleles associated with late-onset Alzheimer’s disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. Methods We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aβ and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. Results We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aβ and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aβ and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec - 10 , the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. Conclusions Using scRNA-Seq in mouse models bearing amyloid-β and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aβ and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aβ and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets.

Practical quantum computing will require error rates well below those achievable with physical qubits. Quantum error correction 1 , 2 offers a path to algorithmically relevant error rates by encoding logical qubits within many physical qubits, for which increasing the number of physical qubits enhances protection against physical errors. However, introducing more qubits also increases the number of error sources, so the density of errors must be sufficiently low for logical performance to improve with increasing code size. Here we report the measurement of logical qubit performance scaling across several code sizes, and demonstrate that our system of superconducting qubits has sufficient performance to overcome the additional errors from increasing qubit number. We find that our distance-5 surface code logical qubit modestly outperforms an ensemble of distance-3 logical qubits on average, in terms of both logical error probability over 25 cycles and logical error per cycle ((2.914 ± 0.016)% compared to (3.028 ± 0.023)%). To investigate damaging, low-probability error sources, we run a distance-25 repetition code and observe a 1.7 × 10 −6 logical error per cycle floor set by a single high-energy event (1.6 × 10 −7 excluding this event). We accurately model our experiment, extracting error budgets that highlight the biggest challenges for future systems. These results mark an experimental demonstration in which quantum error correction begins to improve performance with increasing qubit number, illuminating the path to reaching the logical error rates required for computation. A study demonstrating increasing error suppression with larger surface code logical qubits, implemented on a superconducting quantum processor.

Palomar Gattini-IR is a new wide-field, near-infrared (NIR) robotic time domain survey operating at Palomar Observatory. Using a 30 cm telescope mounted with a H2RG detector, Gattini-IR achieves a field of view (FOV) of 25 sq. deg. with a pixel scale of 8 7 in J-band. Here, we describe the system design, survey operations, data processing system and on-sky performance of Palomar Gattini-IR. As a part of the nominal survey, Gattini-IR scans 7500 square degrees of the sky every night to a median 5 depth of 15.7 AB mag outside the Galactic plane. The survey covers 15,000 square degrees of the sky visible from Palomar with a median cadence of 2 days. A real-time data processing system produces stacked science images from dithered raw images taken on sky, together with point-spread function (PSF)-fit source catalogs and transient candidates identified from subtractions within a median delay of 4 hr from the time of observation. The calibrated data products achieve an astrometric accuracy (rms) of 0 7 with respect to Gaia DR2 for sources with signal-to-noise ratio > 10, and better than 0 35 for sources brighter than 12 Vega mag. The photometric accuracy (rms) achieved in the PSF-fit source catalogs is better than 3% for sources brighter than 12 Vega mag and fainter than the saturation magnitude of 8.5 Vega mag, as calibrated against the Two Micron All Sky Survey catalog. The detection efficiency of transient candidates injected into the images is better than 90% for sources brighter than the 5 limiting magnitude. The photometric recovery precision of injected sources is 3% for sources brighter than 13 mag, and the astrometric recovery rms is 0 9. Reference images generated by stacking several field visits achieve depths of 16.5 AB mag over 60% of the sky, while it is limited by confusion in the Galactic plane. With a FOV 40× larger than any other existing NIR imaging instrument, Gattini-IR is probing the reddest and dustiest transients in the local universe such as dust obscured supernovae in nearby galaxies, novae behind large columns of extinction within the galaxy, reddened microlensing events in the Galactic plane and variability from cool and dust obscured stars. We present results from transients and variables identified since the start of the commissioning period.

The increasing prevalence of overweight and obesity needs effective approaches for weight loss in primary care and community settings. We compared weight loss with standard treatment in primary care with that achieved after referral by the primary care team to a commercial provider in the community. In this parallel group, non-blinded, randomised controlled trial, 772 overweight and obese adults were recruited by primary care practices in Australia, Germany, and the UK. Participants were randomly assigned with a computer-generated simple randomisation sequence to receive either 12 months of standard care as defined by national treatment guidelines, or 12 months of free membership to a commercial programme (Weight Watchers), and followed up for 12 months. The primary outcome was weight change over 12 months. Analysis was by intention to treat (last observation carried forward [LOCF] and baseline observation carried forward [BOCF]) and in the population who completed the 12-month assessment. This trial is registered, number ISRCTN85485463. 377 participants were assigned to the commercial programme, of whom 230 (61%) completed the 12-month assessment; and 395 were assigned to standard care, of whom 214 (54%) completed the 12-month assessment. In all analyses, participants in the commercial programme group lost twice as much weight as did those in the standard care group. Mean weight change at 12 months was −5·06 kg (SE 0·31) for those in the commercial programme versus −2·25 kg (0·21) for those receiving standard care (adjusted difference −2·77 kg, 95% CI −3·50 to −2·03) with LOCF; −4·06 kg (0·31) versus −1·77 kg (0·19; adjusted difference −2·29 kg, −2·99 to −1·58) with BOCF; and −6·65 kg (0·43) versus −3·26 kg (0·33; adjusted difference −3·16 kg, −4·23 to −2·11) for those who completed the 12-month assessment. Participants reported no adverse events related to trial participation. Referral by a primary health-care professional to a commercial weight loss programme that provides regular weighing, advice about diet and physical activity, motivation, and group support can offer a clinically useful early intervention for weight management in overweight and obese people that can be delivered at large scale. Weight Watchers International, through a grant to the UK Medical Research Council.

Objectives There was initially insufficient understanding regarding suitable pharmacological treatment for pediatric Coronavirus Disease 2019 (COVID-19) patients. Lopinavir-ritonavir (LPV/r) was originally used for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection. It was also used in patients with severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) with positive results. Nonetheless, results from recent randomized controlled trials and observational studies on COVID-19 patients were unfavorable. We sought to evaluate the clinical outcomes associated with early treatment with LPV/r for pediatric COVID-19 patients. Study Design A total of 933 COVID-19 patients aged ≤ 18 years were admitted between 21 January 2020 and 31 January 2021 in Hong Kong. Exposure was receiving LPV/r within the first two days of admission. Time to clinical improvement, hospital discharge, seroconversion and hyperinflammatory syndrome, cumulative costs, and hospital length of stay were assessed. Multivariable Cox proportional hazard and linear models were performed to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of time-to-event and continuous outcomes, respectively. Results LPV/r users were associated with longer time to clinical improvement (HR 0.51, 95% CI 0.38–0.70; p  < 0.001), hospital discharge (HR 0.51, 95% CI 0.38–0.70; p  < 0.001) and seroconversion (HR 0.59, 95% CI 0.43–0.80; p  < 0.001) when compared with controls. LPV/r users were also associated with prolonged hospital length of stay (6.99 days, 95% CI 6.23–7.76; p  < 0.001) and higher costs at 30 days (US$11,709 vs US$8270; p  < 0.001) as opposed to controls. Conclusion Early treatment with LPV/r for pediatric COVID-19 patients was associated with longer time to clinical improvement. Our study advocates the recommendation against LPV/r use for pediatric patients across age groups.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells 1 , 2 . Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections 3 , 4 . Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes . Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes -specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase 5 to deacetylate terminal sialic acid residues on IgG variable-region N -linked glycans. Deacetylated L. monocytogenes- specific IgG protected neonates through the sialic acid receptor CD22 6 , 7 , which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal–fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life. Pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes .

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53 . We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies. Understanding the molecular basis of leukaemia predisposition is essential for intervention. The authors here investigate germline genetic leukaemia predisposition by studying Shwachman-Diamond syndrome and report compensatory inactivating mutations in EIF6 and transforming biallelic TP53 alterations.

During the COVID-19 pandemic, meatpacking workers were disproportionately affected by disease. Large outbreaks at meatpacking facilities resulted in loss of life and threatened the well-being of workers across the globe. Much work was done throughout the pandemic to understand and prevent these outbreaks. This study combined ventilation system evaluation and measurement of human-generated respiratory aerosol to investigate and identify areas of highest risk for disease transmission. These findings confirm that improved ventilation reduces exposure to human-generated aerosols in meatpacking facilities, including those that may contain infectious agents, such as SARS-CoV-2. This study suggests areas of greatest risk are likely areas where workers break from work, such as cafeterias and locker rooms, where ventilation is poorer, use of face masks is reduced, and people congregate. Furthermore, these findings also suggest that ventilation of production areas of the plant, which have been designed for food safety, is sufficient to reduce exposures and likely contributes to reduced transmission in those spaces. Based on these findings, two controls should be prioritized to minimize the likelihood of exposure to potentially infectious aerosols: (1) improving mechanical ventilation and/or adding mitigation strategies such as media filters, germicidal ultraviolet, and other air cleaning technology and (2) applying administrative practices that minimize large congregations of people in poorly ventilated spaces. Importantly, this work demonstrates a method for in situ measurements of human-generated particles that can be used more broadly to understand exposure and risk in various occupied spaces.

In C. elegans, the cell surface protein Sid-1 imports extracellular dsRNA into the cytosol of most non-neuronal cells, enabling systemic spread of RNA interference (RNAi) throughout the worm. Sid-1 homologs are found in many other animals, although for most a function for the protein has not yet been established. Sid-1 proteins are composed of an N-terminal extracellular domain (ECD) followed by 9-12 predicted transmembrane regions. We developed a baculovirus system to express and purify the ECD of the human Sid-1 protein SidT1. Recombinant SidT1 ECD is glycosylated and spontaneously assembles into a stable and discrete tetrameric structure. Electron microscopy (EM) and small angle x-ray scattering (SAXS) studies reveal that the SidT1 ECD tetramer is a compact, puck-shaped globular particle, which we hypothesize may control access of dsRNA to the transmembrane pore. These characterizations provide inroads towards understanding the mechanism of this unique RNA transport system from structural prospective.

Background Osteoarthritis (OA) subsequent to acute joint injury accounts for a significant proportion of all arthropathies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells classically known for potent immune-suppressive activity; however, MDSCs can also differentiate into osteoclasts. In addition, this population is known to be expanded during metabolic disease. The objective of this study was to determine the role of MDSCs in the context of OA pathophysiology. Methods In this study, we examined the differentiation and functional capacity of MDSCs to become osteoclasts in vitro and in vivo using mouse models of OA and in MDSC quantitation in humans with OA pathology relative to obesity status. Results We observed that MDSCs are expanded in mice and humans during obesity. MDSCs were expanded in peripheral blood of OA subjects relative to body mass index and in mice fed a high-fat diet (HFD) compared to mice fed a low-fat diet (LFD). In mice, monocytic MDSC (M-MDSC) was expanded in diet-induced obesity (DIO) with a further expansion after destabilization of the medial meniscus (DMM) surgery to induce post-traumatic OA (PTOA) (compared to sham-operated controls). M-MDSCs from DIO mice had a greater capacity to form osteoclasts in culture with increased subchondral bone osteoclast number. In humans, we observed an expansion of M-MDSCs in peripheral blood and synovial fluid of obese subjects compared to lean subjects with OA. Conclusion These data suggest that MDSCs are reprogrammed in metabolic disease, with the potential to contribute towards OA progression and severity.