Chromatinized Protein Kinase C-θ: Can It Escape the Clutches of NF-κB?

We recently provided the first description of a nuclear mechanism used by Protein Kinase C-theta (PKC-θ) to mediate T cell gene expression. In this mode, PKC-θ tethers to chromatin to form an active nuclear complex by interacting with proteins including RNA polymerase II, the histone kinase MSK-1, the demethylase LSD1, and the adaptor molecule 14-3-3ζ at regulatory regions of inducible immune response genes. Moreover, our genome-wide analysis identified many novel PKC-θ target genes and microRNAs implicated in T cell development, differentiation, apoptosis, and proliferation. We have expanded our ChIP-on-chip analysis and have now identified a transcription factor motif containing NF-κB binding sites that may facilitate recruitment of PKC-θ to chromatin at coding genes. Furthermore, NF-κB association with chromatin appears to be a prerequisite for the assembly of the PKC-θ active complex. In contrast, a distinct NF-κB-containing module appears to operate at PKC-θ targeted microRNA genes, and here NF-κB negatively regulates microRNA gene transcription. Our efforts are also focusing on distinguishing between the nuclear and cytoplasmic functions of PKCs to ascertain how these kinases may synergize their roles as both cytoplasmic signaling proteins and their functions on the chromatin template, together enabling rapid induction of eukaryotic genes. We have identified an alternative sequence within PKC-θ that appears to be important for nuclear translocation of this kinase. Understanding the molecular mechanisms used by signal transduction kinases to elicit specific and distinct transcriptional programs in T cells will enable scientists to refine current therapeutic strategies for autoimmune diseases and cancer

Differences in the diagnosis and management of systemic lupus erythematosus by primary care and specialist providers in the American Indian/Alaska Native population

Objectives The objective of this study is to investigate differences in the diagnosis and management of systemic lupus erythematosus (SLE) by primary care and specialist physicians in a population-based registry. Methods This study includes individuals from the 2009 Indian Health Service lupus registry population with a diagnosis of SLE documented by either a primary care provider or specialist. SLE classification criteria, laboratory testing, and medication use at any time during the course of disease were determined by medical record abstraction. Results Of the 320 individuals with a diagnosis of SLE, 249 had the diagnosis documented by a specialist, with 71 documented by primary care. Individuals with a specialist diagnosis of SLE were more likely to have medical record documentation of meeting criteria for SLE by all criteria sets (American College of Rheumatology, 79% vs 22%; Boston Weighted, 82% vs 32%; and Systemic Lupus International Collaborating Clinics, 83% vs 35%; p &lt; 0.001 for all comparisons). In addition, specialist diagnosis was associated with documentation of ever having been tested for anti-double-stranded DNA antibody and complement 3 and complement 4 ( p &lt; 0.001). Documentation of ever receiving hydroxychloroquine was also more common with specialist diagnosis (86% vs 64%, p &lt; 0.001). Conclusions Within the population studied, specialist diagnosis of SLE was associated with a higher likelihood of having SLE classification criteria documented, being tested for biomarkers of disease, and ever receiving treatment with hydroxychloroquine. These data support efforts both to increase specialist access for patients with suspected SLE and to provide lupus education to primary care providers. </jats:sec

Cancer disparities in Southeast Asia: intersectionality and a call to action.

Southeast Asia has a population of over 680 million people—approximately half the population of India and twice the population of the United States—and is a region marked by rich and complex histories and cultures, dynamic growth, and unique and evolving health challenges.1 Despite the momentum of economic development, health inequalities persist. These inequities have been aggravated since the COVID-19 pandemic, which pushed millions further into poverty, possibly exacerbating health disparities, especially among populations who suffer vulnerabilities.2 Particularly salient are the challenges associated with providing adequate care for people with cancer, a leading cause of morbidity and mortality in the region.1,2 Cancer incidence and mortality in the region are projected to rise in the coming decades, given population growth and rapidly changing socioeconomic and geopolitical factors, as well as a host of interrelated and dynamic environmental, behavioral, and occupational risk factors.1, 2, 3 Large epidemiologic studies have demonstrated differences among Southeast Asian countries in terms of cancer incidence and mortality.3 Epidemiologic patterns can be attributed to variations in complex risk factors, access to screening and cancer care, and likely genetic predisposition.1, 2, 3 However, these differences also underscore that within each country exist richly diverse populations that experience disparities in cancer risk, screening, care access, outcomes, and survivorship in ways that require further examination. We draw attention to disparities in cancer in Southeast Asian countries. We highlight the need to study cancer disparities affecting minoritised groups in Southeast Asia—not only along lines of race/ethnicity, but also people minoritised along lines of sex/gender, socioeconomic status, religion, geography, and others. We highlight the intersectionality of elements of an individual's identity. Intersectionality, developed by critical race theorist Professor Kimberlé Crenshaw in 1989, is an analytic framework borne out of Black American feminist scholarship, that examines how a person's sociopolitical identities lead to disparate balances of privilege and discrimination.4 An intersectional approach would demonstrate that an individual or a community does not only experience economic poverty as the sole barrier to improved health; such an approach would examine how other identities such as religion or immigration status affect access to care. These different social determinants of health are not mutually exclusive; their interrelationships are complex, with consequences for health.5 We leverage the intersectional approach, which parallels the inherently syncretic cultures and histories of Southeast Asian nations, and explore how these identities impact access to cancer care. Meaningful cancer research focusing on peoples of Southeast Asia could present many opportunities for intervention and improvement

Effects of choral singing versus health education on cognitive decline and aging: a randomized controlled trial.

We conducted a randomized controlled trial to examine choral singing's effect on cognitive decline in aging. Older Singaporeans who were at high risk of future dementia were recruited: 47 were assigned to choral singing intervention (CSI) and 46 were assigned to health education program (HEP). Participants attended weekly one-hour choral singing or weekly one-hour health education for two years. Change in cognitive function was measured by a composite cognitive test score (CCTS) derived from raw scores of neuropsychological tests; biomarkers included brain magnetic resonance imaging, oxidative damage and immunosenescence. The average age of the participants were 70 years and 73/93 (78.5%) were female. The change of CCTS from baseline to 24 months was 0.05 among participants in the CSI group and -0.1 among participants in the HEP group. The between-group difference (0.15, p=0.042) became smaller (0.12, p=0.09) after adjusting for baseline CCTS. No between-group differences on biomarkers were observed. Our data support the role of choral singing in improving cognitive health in aging. The beneficial effect is at least comparable than that of health education in preventing cognitive decline in a community of elderly people. Biological mechanisms underlying the observed efficacy should be further studied

Vapochromic Behaviour of M[Au(CN)2]2-Based Coordination Polymers (M = Co, Ni)

A series of M[Au(CN)2]2(analyte)x coordination polymers (M = Co, Ni; analyte = dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), pyridine; x = 2 or 4) was prepared and characterized. Addition of analyte vapours to solid M(μ-OH2)[Au(CN)2]2 yielded visible vapochromic responses for M = Co but not M = Ni; the IR νCN spectral region changed in every case. A single crystal structure of Zn[Au(CN)2]2(DMSO)2 revealed a corrugated 2-D layer structure with cis-DMSO units. Reacting a Ni(II) salt and K[Au(CN)2] in DMSO yielded the isostructural Ni[Au(CN)2]2(DMSO)2 product. Co[Au(CN)2]2(DMSO)2 and M[Au(CN)2]2(DMF)2 (M = Co, Ni) complexes have flat 2-D square-grid layer structures with trans-bound DMSO or DMF units; they are formed via vapour absorption by solid M(μ-OH2)[Au(CN)2]2 and from DMSO or DMF solution synthesis. Co[Au(CN)2]2(pyridine)4 is generated via vapour absorption by Co(μ-OH2)[Au(CN)2]2; the analogous Ni complex is synthesized by immersion of Ni(μ-OH2)[Au(CN)2]2 in 4% aqueous pyridine. Similar immersion of Co(μ-OH2)[Au(CN)2]2 yielded Co[Au(CN)2]2(pyridine)2, which has a flat 2-D square-grid structure with trans-pyridine units. Absorption of pyridine vapour by solid Ni(μ-OH2)[Au(CN)2]2 was incomplete, generating a mixture of pyridine-bound complexes. Analyte-free Co[Au(CN)2]2 was prepared by dehydration of Co(μ-OH2)[Au(CN)2]2 at 145 °C; it has a 3-D diamondoid-type structure and absorbs DMSO, DMF and pyridine to give the same materials as by vapour absorption from the hydrate

A consensus guide to using functional near-infrared spectroscopy in posture and gait research

BACKGROUND: Functional near-infrared spectroscopy (fNIRS) is increasingly used in the field of posture and gait to investigate patterns of cortical brain activation while people move freely. fNIRS methods, analysis and reporting of data vary greatly across studies which in turn can limit the replication of research, interpretation of findings and comparison across works. RESEARCH QUESTION AND METHODS: Considering these issues, we propose a set of practical recommendations for the conduct and reporting of fNIRS studies in posture and gait, acknowledging specific challenges related to clinical groups with posture and gait disorders. RESULTS: Our paper is organized around three main sections: 1) hardware set up and study protocols, 2) artefact removal and data processing and, 3) outcome measures, validity and reliability; it is supplemented with a detailed checklist. SIGNIFICANCE: This paper was written by a core group of members of the International Society for Posture and Gait Research and posture and gait researchers, all experienced in fNIRS research, with the intent of assisting the research community to lead innovative and impactful fNIRS studies in the field of posture and gait, whilst ensuring standardization of research

The Cost of Virulence: Retarded Growth of Salmonella Typhimurium Cells Expressing Type III Secretion System 1

Virulence factors generally enhance a pathogen's fitness and thereby foster transmission. However, most studies of pathogen fitness have been performed by averaging the phenotypes over large populations. Here, we have analyzed the fitness costs of virulence factor expression by Salmonella enterica subspecies I serovar Typhimurium in simple culture experiments. The type III secretion system ttss-1, a cardinal virulence factor for eliciting Salmonella diarrhea, is expressed by just a fraction of the S. Typhimurium population, yielding a mixture of cells that either express ttss-1 (TTSS-1+ phenotype) or not (TTSS-1− phenotype). Here, we studied in vitro the TTSS-1+ phenotype at the single cell level using fluorescent protein reporters. The regulator hilA controlled the fraction of TTSS-1+ individuals and their ttss-1 expression level. Strikingly, cells of the TTSS-1+ phenotype grew slower than cells of the TTSS-1− phenotype. The growth retardation was at least partially attributable to the expression of TTSS-1 effector and/or translocon proteins. In spite of this growth penalty, the TTSS-1+ subpopulation increased from <10% to approx. 60% during the late logarithmic growth phase of an LB batch culture. This was attributable to an increasing initiation rate of ttss-1 expression, in response to environmental cues accumulating during this growth phase, as shown by experimental data and mathematical modeling. Finally, hilA and hilD mutants, which form only fast-growing TTSS-1− cells, outcompeted wild type S. Typhimurium in mixed cultures. Our data demonstrated that virulence factor expression imposes a growth penalty in a non-host environment. This raises important questions about compensating mechanisms during host infection which ensure successful propagation of the genotype

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction