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Background: Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives: Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods: We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controlsrone case. Results: In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR = 2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR = 2.5; 95% CI, 1.4-4.7). Conclusions: PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology.

Given the ongoing SARS-CoV-2 pandemic, identification of immunogenic targets against the coronavirus spike glycoprotein will provide crucial advances towards the development of sensitive diagnostic tools and potential vaccine candidate targets. In this study, using pools of overlapping linear B-cell peptides, we report two IgG immunodominant regions on SARS-CoV-2 spike glycoprotein that are recognised by sera from COVID-19 convalescent patients. Notably, one is specific to SARS-CoV-2, which is located in close proximity to the receptor binding domain. The other region, which is localised at the fusion peptide, could potentially function as a pan-SARS target. Functionally, antibody depletion assays demonstrate that antibodies targeting these immunodominant regions significantly alter virus neutralisation capacities. Taken together, identification and validation of these neutralising B-cell epitopes will provide insights towards the design of diagnostics and vaccine candidates against this high priority coronavirus. Characterisation of the human antibody response to SARS-CoV-2 can help the design of serological tests and vaccines. Here, the authors identify two linear epitopes in SARS-CoV-2 spike protein that elicit neutralising antibodies in several patients and could thus be useful for serology and vaccine development.

Through a proteomic analysis of ER–PM junctions, Zhou and colleagues and Wang and colleagues discover that the transmembrane protein STIMATE is a positive regulator of STIM localization and function, thereby stimulating Ca 2+ influx. Specialized junctional sites that connect the plasma membrane (PM) and endoplasmic reticulum (ER) play critical roles in controlling lipid metabolism and Ca 2+ signalling 1 , 2 , 3 , 4 . Store-operated Ca 2+ entry mediated by dynamic STIM1–ORAI1 coupling represents a classical molecular event occurring at ER–PM junctions, but the protein composition and how previously unrecognized protein regulators facilitate this process remain ill-defined. Using a combination of spatially restricted biotin labelling in situ coupled with mass spectrometry 5 , 6 and a secondary screen based on bimolecular fluorescence complementation 7 , we mapped the proteome of intact ER–PM junctions in living cells without disrupting their architectural integrity. Our approaches led to the discovery of an ER-resident multi-transmembrane protein that we call STIMATE ( STIM -activating enhancer, encoded by TMEM110 ) as a positive regulator of Ca 2+ influx in vertebrates. STIMATE physically interacts with STIM1 to promote STIM1 conformational switch. Genetic depletion of STIMATE substantially reduces STIM1 puncta formation at ER–PM junctions and suppresses the Ca 2+ –NFAT signalling. Our findings enable further genetic studies to elucidate the function of STIMATE in normal physiology and disease, and set the stage to uncover more uncharted functions of hitherto underexplored ER–PM junctions.

Epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, has been implicated to contribute to the molecular heterogeneity of epithelial ovarian cancer (EOC). Here we report that a transcription factor—Grainyhead-like 2 (GRHL2) maintains the epithelial phenotype. EOC tumours with lower GRHL2 levels are associated with the Mes/Mesenchymal molecular subtype and a poorer overall survival. shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype results in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, microRNA-200b/a is identified as the direct transcriptional target of GRHL2 and regulates the epithelial status of EOC through ZEB1 and E-cadherin. Our study demonstrates that loss of GRHL2 increases the levels of histone mark H3K27me3 on promoters and GRHL2-binding sites at miR-200b/a and E-cadherin genes. These findings support GRHL2 as a pivotal gatekeeper of EMT in EOC via miR-200-ZEB1.

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS‐CoV‐2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS‐CoV‐2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169 + expressing monocytes in the peripheral blood. Systemic levels of pro‐inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro‐inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus‐specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS‐CoV‐2 was observed in asymptomatic patients. In addition, asymptomatic COVID‐19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro‐inflammatory and more protective immune responses against SARS‐CoV‐2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID‐19. Synopsis Whole blood transcriptomic analyses highlight distinct immune responses during acute phase of disease. Asymptomatic patients elicit a more robust TH17 response compared to symptomatic patients. Asymptomatic patients present a less inflammatory profile, with lower counts of CD169 + monocytes, activated neutrophils, and a muted inflammatory response. Higher levels of cellular repair biomarkers are also observed in asymptomatic patients. Graphical Abstract We show that asymptomatic patients elicit a different repertoire of immune responses from symptomatic patients. Our data suggest that asymptomatic patients could limit symptom development with a well‐balanced inflammatory response and more protective immune responses against SARS‐CoV‐2.

The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting 1 . Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with cancer that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed 2 – 4 . Although the role of tumour neoantigen-specific CD8 + T cells in tumour rejection is well established 5 – 9 , the roles of other subsets of T cells have received less attention. Here we show that spontaneous and immunotherapy-induced anti-tumour responses require the activity of both tumour-antigen-specific CD8 + and CD4 + T cells, even in tumours that do not express major histocompatibility complex (MHC) class II molecules. In addition, the expression of MHC class II-restricted antigens by tumour cells is required at the site of successful rejection, indicating that activation of CD4 + T cells must also occur in the tumour microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumour response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore needs to be considered when identifying patients who will most benefit from immunotherapy. In a mouse tumour model, immunotherapy-induced rejection of tumour cells requires presentation of both MHC class I and MHC class II antigens, which activate CD4 + and CD8 + T cells, respectively.

Short- and medium-chain acyl-CoA synthetases catalyze similar two-step reactions in which acyl substrate and ATP bind to form an enzyme-bound acyl-adenylate, then CoA binds for formation of the acyl-CoA product. We investigated the roles of active site residues in CoA binding in acetyl-CoA synthetase (Acs) and a medium-chain acyl-CoA synthetase (Macs) that uses 2-methylbutyryl-CoA. Three highly conserved residues, Arg193, Arg528, and Arg586 of Methanothermobacter thermautotrophicus Acs (AcsMt), are predicted to form important interactions with the 5′- and 3′-phosphate groups of CoA. Kinetic characterization of AcsMt variants altered at each of these positions indicates these Arg residues play a critical role in CoA binding and catalysis. The predicted CoA binding site of Methanosarcina acetivorans Macs (MacsMa) is structurally more closely related to that of 4-chlorobenzoate:coenzyme A ligase (CBAL) than Acs. Alteration of MacsMa residues Tyr460, Arg490, Tyr525, and Tyr527, which correspond to CoA binding pocket residues in CBAL, strongly affected CoA binding and catalysis without substantially affecting acyl-adenylate formation. Both enzymes discriminate between 3′-dephospho-CoA and CoA, indicating interaction between the enzyme and the 3′-phosphate group is important. Alteration of MacsMa residues Lys461 and Lys519, located at positions equivalent to AcsMt Arg528 and Arg586, respectively, had only a moderate effect on CoA binding and catalysis. Overall, our results indicate the active site architecture in AcsMt and MacsMa differs even though these enzymes catalyze mechanistically similar reactions. The significance of this study is that we have delineated the active site architecture with respect to CoA binding and catalysis in this important enzyme superfamily.

Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These \"Super-Lo-MYC\" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a \"paradoxical\" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

Cerebrospinal fluid (CSF) should be sent for basic studies, IgG index, and oligoclonal bands, in addition to testing for atypical infections and repeat high-volume cytology with adjunct flow cytometry. [...]a computed tomography (CT) of the chest, abdomen, and pelvis should be performed to look for an underlying malignancy or evidence of systemic involvement from an inflammatory, granulomatous, or infectious process. The only nerve with possible demyelinating findings was in the left ulnar motor nerve conduction study, which had slowed conduction velocities across three segments and temporal dispersion in the forearm segment. Results of nerve conduction studies and electromyography Motor conduction studies Sensory conduction studies Distal latency Conduction velocity (m/s) Amplitude (mV) Temporal dispersion Conduction velocity (m/s) Amplitude (mV) R Median N N N — R Radial R Ulnar N N N N R Ulnar N Elbow (41) N — L Median N Forearm (42) ↓ (5.4) — L Radial L Ulnar L Median N N N N ↓ ↓ L Ulnar N ↓ Forearm (36) ↓ Elbow (31) ↓ Arm (24) ↓ (3.4) Forearm R Tibial N N N — R Sural N N R Peroneal N N ↓ (1.7) — L Sural N ½ of R Sural L Tibial N N ↓ (5.7) — L Peroneal N N ↓ (3.6) — Electromyography Fibs PSW Motor Units Recruitment L Deltoid + + + + Large ↓ L Biceps brachiae + + + + Large ↓ L Triceps + + + + Large ↓ L Extensor digitorum communis (EDC) + + + + N/A No units recruited L Flexor carpi radialis (FCR) + + + + N/A No units recruited L Pronator teres + + + + N/A No units recruited L Mid-thoracic paraspinals - - N N L Vastus medialis - - N N L Tibialis anterior

Introduction The associated mortality and morbidity in hip fracture patients pose a major healthcare burden for ageing populations worldwide. We aim to analyse how an individual’s comorbidity profile based on age-adjusted Charlson Comorbidity Index (CCI) may impact on functional outcomes and 90-day readmission rates after hip fracture surgery. Materials and Methods Surgically treated hip fracture patients between 2013 and 2016 were followed up for 1-year and assessed using Parker Mobility Score (PMS), EuroQol-5D (EQ-5D) and Physical and Mental Component Scores (PCS and MCS, respectively) of Short Form-36 (SF-36). Statistical analysis was done by categorising 444 patients into three groups based on their CCI: (1) CCI 0–3, (2) CCI 4–5 and (3) CCI ≥ 6. Results PMS, EQ-5D and SF-36 PCS were significantly different amongst the CCI groups pre-operatively and post-operatively at 3, 6 and 12 months (all P < 0.05), with CCI ≥ 6 predicting for poorer outcomes. In terms of 90-day readmission rates, patients who have been readmitted have poorer outcome scores. Multivariate analysis showed that high CCI scores and 90-day readmission rate both remained independent predictors of worse outcomes for SF-36 PCS, PMS and EQ-5D. Discussion CCI scores ≥6 predict for higher 90-day readmission rates, poorer quality of life and show poor potential for functional recovery 1-year post-operation in hip fracture patients. 90-day readmission rates are also independently associated with poorer functional outcomes. Peri-operatively, surgical teams should liaise with medical specialists to optimise patients’ comorbidities and ensure their comorbidities remain well managed beyond hospital discharge to reduce readmission rates. With earlier identification of patient groups at risk of poorer functional outcomes, more planning can be directed towards appropriate management and subsequent rehabilitation. Conclusion Further research should focus on development of a stratified, peri-operative multidisciplinary, hip-fracture care pathway treatment regime based on CCI scores to determine its effectiveness in improving functional outcomes.