Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever.

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays.

Utilizing a dual endogenous reporter system to identify functional regulators of aberrant stem cell and differentiation activity in colorectal cancer.

Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators that regulate these key cellular programs in CRC, we developed an endogenous reporter system by genome-editing human CRC cell lines with knock-in fluorescent reporters at the SOX9 and KRT20 locus to report aberrant stem cell-like activity and differentiation, respectively, and then performed pooled genetic perturbation screens. Constructing a dual reporter system that simultaneously monitored aberrant stem cell-like and differentiation activity in the same CRC cell line improved our signal to noise discrimination.

Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas disease.

Introduction: Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation.

Proteasome Inhibitors in Multiple Myeloma: Biological Insights on Mechanisms of Action or Resistance Informed by Functional Genomics.

During the last 20 years, proteasome inhibitors have been a cornerstone for the therapeutic management of multiple myeloma (MM). This review highlights how MM research has evolved over time in terms of our understanding of the mechanistic basis for the pronounced clinical activity of proteasome inhibitors in MM, compared with the limited clinical applications of this drug class outside the setting of plasma cell dyscrasias.

Light exposure during sleep is bidirectionally associated with irregular sleep timing: The multi-ethnic study of atherosclerosis (MESA).

Exposure to light at night (LAN) may influence sleep timing and regularity. Here, we test whether greater light exposure during sleep (LEDS) is bidirectionally associated with greater irregularity in sleep onset timing in a large cohort of older adults in cross-sectional and short-term longitudinal (days) analyses. Light exposure and activity patterns, measured via wrist-worn actigraphy (ActiWatch Spectrum), were analyzed in 1933 participants with 6+ valid days of data in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study.

Corrigendum: Defining discriminatory antibody fingerprints in active and latent tuberculosis.

[This corrects the article DOI: 10.3389/fimmu.2022.

Identification of drug candidates targeting monocyte reprogramming in people living with HIV.

Introduction: People living with HIV (PLHIV) are characterized by functional reprogramming of innate immune cells even after long-term antiretroviral therapy (ART). In order to assess technical feasibility of omics technologies for application to larger cohorts, we compared multiple omics data layers.

Methods: Bulk and single-cell transcriptomics, flow cytometry, proteomics, chromatin landscape analysis by ATAC-seq as well as drug stimulation were performed in a small number of blood samples derived from PLHIV and healthy controls from the 200-HIV cohort study.

Replicative stress in gastroesophageal cancer is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.

Gastroesophageal adenocarcinoma (GEA) is an aggressive malignancy with chromosomal instability (CIN). To understand adaptive responses enabling DNA damage response (DDR) and CIN, we analyzed matched normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DDR, and p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, such as number of high-level focal amplifications and whole-genome duplication (WGD).

Light exposure during sleep is associated with irregular sleep timing: the Multi-Ethnic Study of Atherosclerosis (MESA).

Objective: Exposure to light at night (LAN) may influence sleep timing and regularity. Here, we test whether greater light exposure during sleep (LEDS) associates with greater irregularity in sleep onset timing in a large cohort of older adults.

Methods: Light exposure and activity patterns, measured via wrist-worn actigraphy (ActiWatch Spectrum), were analyzed in 1,933 participants with 6+ valid days of data in the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 5 Sleep Study.

Long-term effects of COVID-19 on the endocrine system - a pilot case-control study.

Background: Coronavirus disease 2019 (COVID-19) has permanently changed the world. Despite having been a pandemic for nearly 3 years, the mid- and long-term complications of this disease, including endocrine disorders, remain unclear. Our study aimed to evaluate the lasting effects of COVID-19 on the endocrine system 6 months after initial infection.

Delayed and Attenuated Antibody Responses to Coronavirus Disease 2019 Vaccination With Poor Cross-Variant Neutralization in Solid-Organ Transplant Recipients-A Prospective Longitudinal Study.

Background: Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. To elucidate the kinetics and variant cross-protection of vaccine-induced antibodies in this population, we conducted a prospective longitudinal study in heart and lung transplant recipients receiving the SARS-CoV-2 messenger RNA (mRNA) 3-dose vaccination series.

Methods: We measured longitudinal serum antibody and neutralization responses against the ancestral and major variants of SARS-CoV-2 in SARS-CoV-2-uninfected lung (n = 18) and heart (n = 17) transplant recipients, non-lung-transplanted patients with cystic fibrosis (n = 7), and healthy controls (n = 12) before, during, and after the primary mRNA vaccination series.

'With this study, we have hope that something is coming': community members' perceptions of HIV cure-related research in Durban, South Africa - a qualitative focus group study.

Background: Developing a cure for HIV remains a global scientific priority. In 2022, the Females Rising through Education, Support and Health (FRESH) cohort launched an HIV cure-related trial involving an analytical treatment interruption (ATI) in Durban, South Africa.

Objectives: To explore community perspectives about HIV cure-related research.

Habitual nappers and non-nappers differ in circadian rhythms of expression in abdominal adipose tissue explants.

Background And Purpose: Napping is a widespread practice worldwide and has in recent years been linked to increased abdominal adiposity. Lipase E or encodes the protein hormone-sensitive lipase (HSL), an enzyme that plays an important role in lipid mobilization and exhibits a circadian expression rhythm in human adipose tissue. We hypothesized that habitual napping may impact the circadian expression pattern of , which in turn may attenuate lipid mobilization and induce abdominal fat accumulation.

Genome-scale functional genomics identify genes preferentially essential for multiple myeloma cells compared to other neoplasias.

Clinical progress in multiple myeloma (MM), an incurable plasma cell (PC) neoplasia, has been driven by therapies that have limited applications beyond MM/PC neoplasias and do not target specific oncogenic mutations in MM. Instead, these agents target pathways critical for PC biology yet largely dispensable for malignant or normal cells of most other lineages. Here we systematically characterized the lineage-preferential molecular dependencies of MM through genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) studies in 19 MM versus hundreds of non-MM lines and identified 116 genes whose disruption more significantly affects MM cell fitness compared with other malignancies.

Regulatory T cells in peripheral tissue tolerance and diseases.

Maintenance of peripheral tolerance by CD4Foxp3 regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome.

Uncovering a novel role of focal adhesion and interferon-gamma in cellular rejection of kidney allografts at single cell resolution.

Background: Kidney transplant recipients are currently treated with nonspecific immunosuppressants that cause severe systemic side effects. Current immunosuppressants were developed based on their effect on T-cell activation rather than the underlying mechanisms driving alloimmune responses. Thus, understanding the role of the intragraft microenvironment will help us identify more directed therapies with lower side effects.

Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies.

Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers.

Replicative stress in gastroesophageal adenocarcinoma is associated with chromosomal instability and sensitivity to DNA damage response inhibitors.

Gastroesophageal adenocarcinoma (GEA) is an aggressive, often lethal, malignancy that displays marked chromosomal instability (CIN). To understand adaptive responses that enable CIN, we analyzed paired normal, premalignant, and malignant gastric lesions from human specimens and a carcinogen-induced mouse model, observing activation of replication stress, DNA damage response (DDR), and cell cycle regulator p21 in neoplastic progression. In GEA cell lines, expression of DDR markers correlated with ploidy abnormalities, including high-level focal amplifications and whole-genome duplication (WGD).

Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer.

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade.

Fetal Hemoglobin Regulation in Beta-Thalassemia.

β-thalassemia is caused by mutations that reduce β-globin production, causing globin chain imbalance, ineffective erythropoiesis, and consequent anemia. Increased fetal hemoglobin (HbF) levels can ameliorate the severity of β-thalassemia by compensating for the globin chain imbalance. Careful clinical observations paired with population studies and advances in human genetics have enabled the discovery of major regulators of HbF switching (i.

TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state.

TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP.