Notes

Girl or boy variants book inside crisis medicine journals.
Chronic kidney disease (CKD) is a global health problem with increasing prevalence. Several sex-specific differences have been reported for disease progression and mortality. Selection and survival bias might have influenced the results of previous cohort studies. The objective of this study was to investigate sex-specific differences of CKD progression and mortality among patients with CKD not receiving maintenance dialysis.

Observational cohort study.

Adult patients with incident CKD glomerular filtration rate categories 3b to 5 (G3b-G5) identified between 2010 and 2018 within the nationwide Swedish Renal Registry-CKD (SRR-CKD).

Sex.

Time to CKD progression (defined as a change of at least 1 CKD stage or initiation of kidney replacement therapy [KRT]) or death. Repeated assessments of estimated glomerular filtration rate (eGFR).

CKD progression and mortality before KRT were assessed by the cumulative incidence function methods and Fine and Gray models, with death handled as a competing event. Se an increased risk of CKD progression, and a steeper decline in eGFR.Neutrophils play an essential role in the innate immune defense system in vertebrates. During hematopoiesis, the full function of neutrophils involves maturation of granules and related enzymes. Yet, transcription regulators that promote neutrophil maturation remain largely undefined. Here, two hematopoiesis-defective zebrafish mutants, runx1w84x and c-mybhkz3, were used to investigate the in vivo roles of Runx1 in cooperation with c-Myb in regulating neutrophil maturation. Loss of runx1 impairs primitive neutrophil development. Additional regulation of c-myb+/- and c-myb-/- induces a more severe phenotypes suggesting a synergistic genetic interaction between c-myb and runx1 in neutrophil maturation. Further studies revealed that the two transcription factors act cooperatively to control neutrophil maturation processes via transactivating a series of neutrophil maturation-related genes. These data reveal the in vivo roles of Runx1 in regulating primitive neutrophil maturation while also indicating a novel genetic and molecular orchestration of Runx1 and c-Myb in myeloid cell development. The study will provide new evidence on the regulation of neutrophil maturation during hematopoiesis.Cancer stem-like cells (CSCs) contribute to the high rate of tumor heterogeneity, metastasis, therapeutic resistance, and recurrence. Histone lysine demethylase 4D (KDM4D or JMJD2D) is highly expressed in colon and liver tumors, where it promotes cancer progression; however, the role of JMJD2D in CSCs remains unclear. Here, we show that JMJD2D expression was increased in liver cancer stem-like cells (LCSCs); downregulation of JMJD2D inhibited the self-renewal of LCSCs in vitro and in vivo and inhibited the lung metastasis of LCSCs by reducing the survival and the early lung seeding of circulating LCSCs. Mechanistically, JMJD2D promoted LCSC self-renewal by enhancing the expression of CSC markers EpCAM and Sox9; JMJD2D reduced H3K9me3 levels on the promoters of EpCAM and Sox9 to enhance their transcription via interaction with β-catenin/TCF4 and Notch1 intracellular domain, respectively. Restoration of EpCAM and Sox9 expression in JMJD2D-knockdown liver cancer cells rescued the self-renewal of LCSCs. Pharmacological inhibition of JMJD2D using 5-c-8HQ reduced the self-renewal of LCSCs and liver cancer progression. Collectively, our findings suggest that JMJD2D promotes LCSC self-renewal by enhancing EpCAM and Sox9 expression via Wnt/β-catenin and Notch signaling pathways and is a potential therapeutic target for liver cancer.Proper repair of damaged DNA is critical for the maintenance of genome stability. A complex composed of Integrator subunit 3 (Ints3), single-stranded DNA-binding protein 1 (SSB1), and SSB-interacting protein 1 (SSBIP1) is required for efficient homologous recombination-dependent repair of double-strand breaks (DSBs) and ataxia-telangiectasia mutated (ATM)-dependent signaling pathways. It is known that in this complex the Ints3 N-terminal domain scaffolds SSB1 and SSBIP1. However, the molecular basis for the function of the Ints3 C-terminal domain remains unclear. Here, we present the crystal structure of the Ints3 C-terminal domain, uncovering a HEAT-repeat superhelical fold. Using structure and mutation analysis, we show that the C-terminal domain exists as a stable dimer. A basic groove and a cluster of conserved residues on two opposite sides of the dimer bind single-stranded RNA/DNA (ssRNA/ssDNA) and Integrator complex subunit 6 (Ints6), respectively. Dimerization is required for nucleic acid binding, but not for Ints6 binding. Additionally, in vitro experiments using HEK 293T cells demonstrate that Ints6 interaction is critical for maintaining SSB1 protein level. Taken together, our findings establish the structural basis of a multifunctional Ints3 C-terminal module, allowing us to propose a novel mode of nucleic acid recognition by helical repeat protein and paving the way for future mechanistic studies.Noisy galvanic vestibular stimulation (nGVS) is an emerging non-invasive brain stimulation technique. It involves applying alternating currents of different frequencies and amplitudes presented in a random, or noisy, manner through electrodes on the mastoid bones behind the ears. Because it directly activates vestibular hair cells and afferents and has an indirect effect on a variety of brain regions, it has the potential to impact many different functions. The objective of this review is twofold (1) to review how nGVS affects motor, sensory, and cognitive performance in healthy adults; and (2) to discuss potential clinical applications of nGVS. First, we introduce the technique. We then describe the regions receiving and processing vestibular information. Next, we discuss the effects of nGVS on motor, sensory, and cognitive function in healthy adults. Subsequently, we outline its potential clinical applications. Finally, we highlight other electrical stimulation technologies and discuss why nGVS offers an alternative or complementary approach. Overall, nGVS appears promising for optimizing human performance and as an assistive technology, though further research is required.This study was conducted to establish the toxicological profile of combination treatment with therapeutic HPV DNA vaccines (GX-188E) and the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (IL-7hyFc). GX-188E was administered intramuscularly by electroporation with or without IL-7hyFc intravaginally once per 2 weeks for 8 weeks (five times) in female Sprague-Dawley rats. Because up-regulation of immune responses and migration of antigen-specific T cells in cervicoviginal tissue were predicted as therapeutic effects, we distinguished adverse effects from therapeutic effects based on the severity of the systemic immune response, reversibility of lymphoid tissue changes, target tissue damage, and off-target immune responses. We observed that the number of neutrophils was increased, and the number of lymphocytes was decreased in the blood. Further, myofiber degeneration, necrosis, fibroplasia, and cell infiltration were observed at the GX-188E administration site. These changes were fully or partially recovered over a 4-week period. Analysis of lymphocytes in spleen revealed that CD4+ T cells and total T cells decreased in rats treated with GX-188E in combination with a high dose of IL-7hyFc (1.25 mg/animal). However, these changes were not considered adverse because they were transient and may have been related to electroporation-mediated DNA delivery or the local migration of lymphocytes induced by IL-7. Therefore, the potential toxicity of the combination of GX-188E and IL-7hyFc treatment was comparable to that of GX-188E treatment alone, and the no observed adverse effect level for GX-188E with IL-7hyFc was considered as 320 μg/animal for GX-188E and 1.25 mg/animal for IL-7hyFc.Endocrine disrupting compounds (EDCs) are ubiquitous environmental pollutants that alter endocrine system function, induce birth defects, and a myriad of other negative health outcomes. Although the mechanism of toxicity of many EDCs have been studied in detail, little work has focused on understanding the mechanisms through which pregnant dams and fetuses protect themselves from EDCs, or if those protective mechanisms are sexually dimorphic in fetuses. In this study, we examined proteomic alterations in the livers of mouse dams and their male and female fetuses induced by vinclozolin, a model antiandrogenic EDC. Dam livers upregulated nine phase I and phase II detoxification pathways and pathway analysis revealed that more pathways are significantly enriched in dam livers than in fetal livers. Phase I and II detoxification proteins are also involved in steroid and steroid hormone biosynthesis and vinclozolin likely alters steroid levels in both the dam and the fetus. The response of the fetal liver proteome to vinclozolin exposure is sexually dimorphic. Female fetal livers upregulated proteins in xenobiotic metabolism pathways, whereas male fetal livers upregulated proteins in oxidative phosphorylation pathways. These results suggest that female fetuses increase protective mechanisms, whereas male fetuses increase ATP production and several disease pathways that are indicative of oxidative damage. Females fetuses upregulate proteins and protective pathways that were similar to the dams whereas males did not. If this sexually dimorphic pattern is typical, then males might generally be more sensitive to EDCs.Arsenic is a ubiquitous metalloid element present in both inorganic and organic forms in the environment. The liver is considered to be a primary organ of arsenic biotransformation and methylation, as well as the main target of arsenic toxicity. Studies have confirmed that Chang human hepatocytes have an efficient arsenic methylating capacity. Our previous studies have proven that arsenite activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in hepatocytes. This study aimed to explore the activation of the Nrf2 pathway upon treatment of arsenic in various forms, including inorganic and organic arsenic. Our results showed that inorganic arsenic-both As2O3 and Na2HAsO4 significantly induced the expression of Nrf2 protein and mRNA, enhanced the transcription activity of Nrf2, and induced the expression of downstream target genes. Selleck CC-92480 These results confirmed the inorganic arsenic-induced Nrf2 pathway activation in hepatocytes. Although all arsenic chemicals used in the study induced Nrf2 protein accumulation, the organic arsenic C2H7AsO2 did not affect the expression of Nrf2 downstream genes which were elevated by inorganic arsenic exposures. Through qRT-PCR and Nrf2 luciferase reporter assays, we further confirmed that C2H7AsO2 neither increased Nrf2 mRNA level nor activated the Nrf2 transcription activity. Mechanistically, our results confirmed inorganic arsenic-induced both the nuclear import of Nrf2 and export of Bach1 (BTB and CNC homology 1), which is an Nrf2 transcriptional repressor, while organic arsenic only induced Nrf2 translocation. The unique pattern of Nrf2 regulation by organic arsenic underlines the critical role of Nrf2 and Bach1 in the arsenic toxicology.
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