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Complex diseases are characterized by spatiotemporal cellular and molecular changes that may be difficult to comprehensively capture. However, understanding the spatiotemporal dynamics underlying pathology can shed light on disease mechanisms and progression. Here we introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection in the same tissue section. As proof of principle, we analyze brain tissues of a mouse model of Alzheimer’s disease at 8 and 13 months of age. Our approach provides a comprehensive cellular map of disease progression. It reveals a core–shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like (DAA-like) cells and oligodendrocyte precursor cells (OPCs) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerges mainly in excitatory neurons in the CA1 region and correlates with the local enrichment of oligodendrocyte subtypes. The STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing a tool to pinpoint the molecular and cellular changes underlying pathology. Understanding the spatiotemporal dynamics underlying pathology can shed light on its mechanisms. Here the authors introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection.

This paper examines the demand- and supply-side factors associated with audit partner selection and assignment in the United States. First, we examine whether audit partner gender and experience are associated with board and management gender and experience. Second, we investigate whether engagement audit quality varies with audit partner gender and experience, controlling for selection effects. The results indicate that companies with more gender-diverse boards of directors and top management teams are more likely to have a female lead audit partner. In addition, the experience of the client's board is positively associated with the experience of the lead audit partner. In terms of audit quality, we find that higher audit fees are positively associated with female and more experienced audit partners. Our results shed light on the important role that partner characteristics play in the demand and supply sides of audit quality.

Abstract Rationale In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood. Objectives To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype. Methods This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV1 and weight and height z-scores). Measurements and Main Results A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV1 and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV1 and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], −1.11 [0.48] percent predicted/yr; P = 0.02). Conclusions Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.

The possible effects of dairy product intake against obesity have been suggested in animal studies; however, the association is still not well established in epidemiological studies. Few studies in Asian countries with relatively low intake of dairy products exist. We investigated the association between dairy products and calcium intake and obesity in Korean population with relatively low intake of dairy products. Our study population consisted of adults (n = 7173) aged 19-64 among participants of the 2007, 2008 and 2009 Korean National Health and Nutrition Examination Survey who had not made any attempt of intentional weight loss. Dietary intake data from food frequency questionnaire (FFQ) and 24-hour recall were used. Dairy products included milk and yogurt in the FFQ. Obesity was defined as BMI≥25 kg/m². Higher frequency of dairy product intake was associated with a reduced prevalence of obesity (OR = 0.63; 95% CI = 0.45-0.89 for ≥2 times/day vs. ≤1 time/month; p for trend = 0.003) using the intake data from FFQ. Similarly, high frequency of milk or yogurt intake had an inverse association with obesity. The association between milk and yogurt intake and obesity was similar when the intake from 24-hour recall was examined. Higher calcium intake from dairy products as well as total dietary calcium intake was associated with a decreased prevalence of obesity (OR = 0.83; 95% CI = 0.71-0.98 for highest vs. lowest quintile of dairy calcium intake; p for trend = 0.02, OR = 0.78; 95% CI = 0.64-0.94 for highest vs. lowest quintile of total calcium intake; p for trend = 0.04). The associations appeared to be stronger in women than in men. These results suggest that high consumption of dairy products is associated with a lower prevalence of obesity and that calcium in dairy products may be one of the components contributing to the association. Further longitudinal studies are warranted to replicate our findings.

Background There are few data on the clinical implications of immunosuppressive protein expression in tumors and immune cell infiltration within the tumor microenvironment in patients with gastric cancer (GC). Methods In this study, 243 patients with curatively resected GC were included. The levels of immunosuppressive protein expression [programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO)] in tumors and the densities of immune cells [CD3(+), CD4(+), CD8(+), or PD-1(+) cells] within the tumor microenvironment were measured using immunohistochemical analysis. Results Positive PD-L1, CTLA-4, and IDO expression was observed in 43.6, 65.8, and 47.7 % of the patients, respectively. Expression of PD-L1, CTLA-4, and IDO was related to less advanced stage, intestinal type, and well/moderately differentiated adenocarcinoma ( P  < 0.05). PD-L1 expression was related to better disease-free survival (DFS) and overall survival (OS) in GC [PD-L1(+) vs. PD-L1(−) tumors: 5-year DFS rate, 82.6 vs. 66.9 %; 5-year OS rate, 83.0 vs. 69.1 % ( P values <0.05)]. Survival outcomes were also better in patients with a higher density of CD3(+) cells within the tumor microenvironment than in those with a lower density of CD3(+) cells [5-year DFS rate, 80.9 vs. 67.0 %; 5-year OS rate, 82.5 vs. 68.0 % ( P values <0.05)]. In multivariate analysis, these two immune markers had a prognostic impact on survival, independent of other clinical variables. Conclusions GC patients with immunosuppressive protein expression (PD-L1, CTLA-4, or IDO) had distinct clinicopathological characteristics. PD-L1(+) expression and a high-CD3 tumor microenvironment are favorable prognostic markers in GC.

Abstract Rationale Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations. Objectives To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents. Methods Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0–18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as “definite PCD” (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), “probable/possible PCD” (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and “other diagnosis or undefined.” Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD. Measurements and Main Results: From 534 participants 18 years of age and younger, 205 were identified as having “definite PCD” (including 164 with two mutations in a PCD-associated gene), 187 were categorized as “other diagnosis or undefined,” and 142 were defined as having “probable/possible PCD.” Participants with “definite PCD” were compared with the “other diagnosis or undefined” group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively. Conclusions Systematically defined early clinical features could help identify children, including infants, likely to have PCD. Clinical trial registered with ClinicalTrials.gov (NCT00323167).

This study finds a positive, economically meaningful impact of generalist chief executive officers (CEOs) on shareholder value using 164 sudden deaths and 345 non-sudden exogenous turnovers. The higher a departing CEO's general ability index (GAI), independently and relative to her successor, the lower is the abnormal stock return to turnover announcements. Returns reflect post-turnover changes in operating performance. Further, CEOs' and successors' GAIs are significantly positively related, but only for non-sudden turnovers. Consistently, for sudden deaths, we find positive stock returns to appointments of generalist successors. The results provide a market-based explanation for the generalist pay premium.

Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized. To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites. At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min), asthma (267.8 ± 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD. Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.

Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator. Zinc Regulator MT3: Implications for Osteoporosis Treatment Bone diseases such as osteoporosis often result from imbalances in bone remodeling, a process involving bone breakdown by cells called osteoclasts and formation by cells called osteoblasts. This study examines the role of Metallothionein 3, a protein that binds to zinc, in osteoclasts. Using a mix of single-cell RNA sequencing database and knockout mouse models, the study investigates how MT3 affects osteoclast development and activity. The researchers used various methods, including gene knockdown and overexpression techniques, to alter MT3 levels in cells and observed the effects on osteoclast formation and bone breakdown. The results indicate that MT3 inhibits osteoclast development and decreases bone loss, suggesting its potential as a treatment target for bone diseases. The study concludes that MT3 plays a crucial role in bone remodeling by controlling osteoclast activity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.