Domain-general subregions of the medial prefrontal cortex contribute to recovery of language after stroke

We hypothesized that the recovery of speech production after left hemisphere stroke not only depends on the integrity of language-specialized brain systems, but also on ‘domain-general’ brain systems that have much broader functional roles. The presupplementary motor area/dorsal anterior cingulate forms part of the cingular-opercular network, which has a broad role in cognition and learning. Consequently, we have previously suggested that variability in the recovery of speech production after aphasic stroke may relate in part to differences in patients’ abilities to engage this domain-general brain region. To test our hypothesis, 27 patients (aged 59 ± 11 years) with a left hemisphere stroke performed behavioural assessments and event-related functional magnetic resonance imaging tasks at two time points; first in the early phase (∼2 weeks) and then ∼4 months after the ictus. The functional magnetic resonance imaging tasks were designed to differentiate between activation related to language production (sentential overt speech production—Speech task) and activation related to cognitive processing (non-verbal decision making). Simple rest and counting conditions were also included in the design. Task-evoked regional brain activations during the early and late phases were compared with a longitudinal measure of recovery of language production. In accordance with a role in cognitive processing, substantial activity was observed within the presupplementary motor area/dorsal anterior cingulate during the decision-making task. Critically, the level of activation within this region during speech production correlated positively with the longitudinal recovery of speech production across the two time points (as measured by the in-scanner performance in the Speech task). This relationship was observed for activation in both the early phase (r = 0.363, P = 0.03 one-tailed) and the late phase (r = 0.538, P = 0.004). Furthermore, presupplementary motor area/dorsal anterior cingulate activity was a predictor of both language recovery over time and language outcome at ∼4 months, over and above that predicted by lesion volume, age and the initial language impairment (general linear model overall significant at P < 0.0001; ExpB 1.01, P = 0.02). The particularly prominent relationship of the presupplementary motor area/dorsal anterior cingulate region with recovery of language was confirmed in voxel-wise correlation analysis, conducted unconstrained for the whole brain volume. These results accord with the hypothesis that the functionality of the presupplementary motor area/dorsal anterior cingulate contributes to language recovery after stroke. Given that this brain region is often spared in aphasic stroke, we propose that it is a sensible target for future research into rehabilitative treatments. More broadly, baseline assessment of domain-general systems could help provide a better prediction of language recovery

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD

Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia.

BACKGROUND: Genetic mutations underlying familial Alzheimer\u27s disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression of mutated transgenes have yielded key insights in mechanisms of disease, those models are subject to artifacts, including random genetic integration of the transgene, ectopic expression and non-physiological protein levels. The genetic engineering of novel mouse models using knock-in approaches addresses some of those limitations. With mounting evidence of the role played by microglia in AD, high-dimensional approaches to phenotype microglia in those models are critical to refine our understanding of the immune response in the brain. METHODS: We engineered a novel App knock-in mouse model (App RESULTS: Leveraging multi-omics approaches, we discovered profound alteration of diverse lipids and metabolites as well as an exacerbated disease-associated transcriptomic response in microglia with high intracellular Aβ content. The App DISCUSSION: Our findings demonstrate that fibrillar Aβ in microglia is associated with lipid dyshomeostasis consistent with lysosomal dysfunction and foam cell phenotypes as well as profound immuno-metabolic perturbations, opening new avenues to further investigate metabolic pathways at play in microglia responding to AD-relevant pathogenesis. The in-depth characterization of pathological hallmarks of AD in this novel and open-access mouse model should serve as a resource for the scientific community to investigate disease-relevant biology

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

A Hong Kong model of sustainable development

Purpose: The purpose of this paper is to discuss a Coasian interpretation of a model of sustainable development for Hong Kong that incorporates three segments, namely economy, society, and environment. Design/Methodology/Approach: The approach is analytical, using concepts of property rights informed by Coasian neo‐institutional economics and Yu\u27s ideas on the Schumpeterian process in innovation. Findings: First, the sustainable development criteria must be non‐dictatorial, decentralized, and compatible with market economics. The emphasis is contractarian rather than legislative or administrative. Second, the essence of segment cooperation is to create a win‐win situation rather than an “integrated” rent seeking game, which will likely result in more values being created. Third, the requirement that it be progressive over time implies that programs and policies that are duplicative need to be avoided, and innovations are to be encouraged. Fourth, the requirement of satisfying only two aspects of the three segments of cooperation implies a less stringent standard of making stepwise improvements, and thus makes entrepreneurial efforts more likely. Last, the three segments of cooperation, if practiced simultaneously and improved over time, can achieve most, if not all, the principles in the Rio Declaration without aiming at a specific principle in the Declaration. Research Limitations/Implications: This paper should focus on a “win‐win” rather than a mutually exploitative approach to public participation in sustainable development promotion. Practical Implications: This paper should assist policymakers and politicians in understanding how sustainable development may be conceptually modelled. Originality/Value: The paper is the first paper that defines for Hong Kong a model of sustainable development on the basis of Coasian economics, and contrasts it with other proposed models