Timmgarcia4398

s, and a RatHat places components in the brain using atlas coordinates. The RatHat is an easily shared resource facilitating open science goals for replications and the archiving of specific experimental applications. Copyright © 2020 Allen et al.City-size distributions are known to be well approximated by power laws across a wide range of countries. But such distributions are also meaningful at other spatial scales, such as within certain regions of a country. Using data from China, France, Germany, India, Japan, and the United States, we first document that large cities are significantly more spaced out than would be expected by chance alone. We next construct spatial hierarchies for countries by first partitioning geographic space using a given number of their largest cities as cell centers and then continuing this partitioning procedure within each cell recursively. We find that city-size distributions in different parts of these spatial hierarchies exhibit power laws that are, again, far more similar than would be expected by chance alone-suggesting the existence of a spatial fractal structure. Copyright © 2020 the Author(s). Published by PNAS.Chronic inflammation during Alzheimer's disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric Aβ, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. find more Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to Aβ-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron-specific inflammatory response may precede insoluble Aβ plaque and tau tangle formation. Thus, we reveal the Aβ-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aβ as a significant immunological component in the AD pathogenesis. Copyright © 2020 the Author(s). Published by PNAS.A type of chromosome-free cell called SimCells (simple cells) has been generated from Escherichia coli, Pseudomonas putida, and Ralstonia eutropha. The removal of the native chromosomes of these bacteria was achieved by double-stranded breaks made by heterologous I-CeuI endonuclease and the degradation activity of endogenous nucleases. We have shown that the cellular machinery remained functional in these chromosome-free SimCells and was able to process various genetic circuits. This includes the glycolysis pathway (composed of 10 genes) and inducible genetic circuits. It was found that the glycolysis pathway significantly extended longevity of SimCells due to its ability to regenerate ATP and NADH/NADPH. The SimCells were able to continuously express synthetic genetic circuits for 10 d after chromosome removal. As a proof of principle, we demonstrated that SimCells can be used as a safe agent (as they cannot replicate) for bacterial therapy. SimCells were used to synthesize catechol (a potent anticancer drug) from salicylic acid to inhibit lung, brain, and soft-tissue cancer cells. SimCells represent a simplified synthetic biology chassis that can be programmed to manufacture and deliver products safely without interference from the host genome. Copyright © 2020 the Author(s). Published by PNAS.Visuomotor impairments characterize numerous neurological disorders and neurogenetic syndromes, such as autism spectrum disorder (ASD) and Dravet, Fragile X, Prader-Willi, Turner, and Williams syndromes. Despite recent advances in systems neuroscience, the biological basis underlying visuomotor functional impairments associated with these clinical conditions is poorly understood. In this study, we used neuroimaging connectomic approaches to map the visuomotor integration (VMI) system in the human brain and investigated the topology approximation of the VMI network to the Allen Human Brain Atlas, a whole-brain transcriptome-wide atlas of cortical genetic expression. We found the genetic expression of four genes-TBR1, SCN1A, MAGEL2, and CACNB4-to be prominently associated with visuomotor integrators in the human cortex. TBR1 gene transcripts, an ASD gene whose expression is related to neural development of the cortex and the hippocampus, showed a central spatial allocation within the VMI system. Our findings delineate gene expression traits underlying the VMI system in the human cortex, where specific genes, such as TBR1, are likely to play a central role in its neuronal organization, as well as on specific phenotypes of neurogenetic syndromes.High-risk patients with antiphospholipid syndrome (APS) experience increased risk of thrombosis when treated with direct oral anticoagulant (DOAC) therapy compared with warfarin. It is essential to establish the APS diagnosis to choose therapy and determine treatment duration. It requires testing for antiphospholipid antibodies, including lupus anticoagulant (LAC). In this viewpoint, we discuss the options for timing of LAC testing, which includes testing before starting anticoagulant treatment (DOAC or warfarin), after switching to heparin or after withdrawal of anticoagulant treatment. DOACs interfere with LAC testing and recommendations emerge stating not to conduct on-therapy LAC testing. All approaches are to some extent currently practised, but have limitations and the area is therefore seemingly a catch 22. We put forward that the anticoagulant effect of DOAC can be eliminated in the laboratory and therefore patients can be tested on-therapy. While it may not eliminate all cases of interference, it could aid the interpretation in these situations and this approach is attractive from the patient and clinician's perspective. Nevertheless, to prevent misdiagnosis the diagnostic workup for APS requires collaboration between the clinician and the laboratory. We advocate for standardisation in laboratory and clinical practice when diagnosing APS. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.OBJECTIVES To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. RESULTS Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI less then 4 was much larger than the opposite (ie, ASDAS less then 2.1, if BASDAI≥4) 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months 61% vs 25% and at 6 months 42% vs 25%). CONCLUSION The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.OBJECTIVE To perform a systematic literature review (SLR) about the effect of non-pharmacological interventions delivered by non-physician health professionals to prevent and manage osteoporotic fractures. METHODS Eight clinical questions based on two criteria guided the SLR (1) adults≥50 years at high risk of osteoporotic fracture and (2) interventions delivered by non-physician health professionals to prevent and manage osteoporotic fractures. Interventions focused on diagnostic procedures to identify risk of falling, therapeutic approaches and implementation strategies. Outcomes included fractures, falls, risk of falling and change in bone mineral density. Systematic reviews and randomised controlled trials were preferentially selected. Data were synthesised using a qualitative descriptive approach. RESULTS Of 15 917 records, 43 articles were included. Studies were clinically and methodologically diverse. We identified sufficient evidence that structured exercise, incorporating progressive resistance training delivered to people who had undergone hip fracture surgery, and multicomponent exercise, delivered to people at risk of primary fracture, reduced risk of falling. The effectiveness of multidisciplinary fracture liaison services in reducing refracture rate was confirmed. There was insufficient evidence found to support the effectiveness of nutrients and falls prevention programmes in this patient population. CONCLUSION Despite study heterogeneity, our SLR showed beneficial effects of some interventions delivered by non-physician health professionals and the positive impact of multidisciplinary team working and patient educational approaches to prevent and manage osteoporotic fractures. These results informed a EULAR taskforce that developed points to consider for non-physician health professionals to prevent and manage osteoporotic fractures. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.PURPOSE Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. RESULTS Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers.