Downeyschmidt8641

s supported by the South African Medical Research Council, the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Johns Hopkins Center for Global Health.

This research was supported by the South African Medical Research Council, the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Johns Hopkins Center for Global Health.

Recent studies have suggested that gestational diabetes (GDM) is a heterogeneous condition with distinct subtypes determined by whether the predominant metabolic abnormality is impaired insulin sensitivity or deficient insulin secretion. Saracatinib purchase However, it is not known if the elevated future risk of pre-diabetes/diabetes associated with GDM varies according to these subtypes. Thus, we sought to evaluate maternal metabolic function in the 1st year postpartum in relation to GDM subtypes.

In this prospective cohort study conducted in Toronto, Canada, 613 women underwent GDM screening by oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at both 3-months and 12-months postpartum between 09/2003 and 03/2016. The antepartum OGTT identified 3 groups of women GDM with predominant sensitivity defect (GDM-sensitivity), GDM with predominant secretion defect (GDM-secretion), and non-GDM.

Antepartum findings persisted after pregnancy, with lower insulin sensitivity in GDM-sensitivity (Matsuda index; Hanada.Pathogenic viruses induce metabolic changes in host cells to secure the availability of biomolecules and energy to propagate. Influenza A virus (IAV) and severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) both infect the human airway epithelium and are important human pathogens. The metabolic changes induced by these viruses in a physiologically relevant human model and how this affects innate immune responses to limit viral propagation are not well known. Using an ex vivo model of pseudostratified primary human airway epithelium, we here demonstrate that infection with both IAV and SARS-CoV-2 resulted in distinct metabolic changes including increases in lactate dehydrogenase A (LDHA) expression and LDHA-mediated lactate formation. Interestingly, LDHA regulated both basal and induced mitochondrial anti-viral signaling protein (MAVS)-dependent type I interferon (IFN) responses to promote IAV, but not SARS-CoV-2, replication. Our data demonstrate that LDHA and lactate promote IAV but not SARS-CoV-2 replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium.Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.Low reproducibility in gene expression profiles has been observed in transcriptome studies, and this often limits applying findings to clinical practice. Here, we show time-of-day effects on gene expression and analytical schemes to increase the reproducibility in expression patterns. We recruited patients with relapsing-remitting multiple sclerosis (RRMS) and healthy subjects and collected blood from individuals twice a day, day (2 pm) and night (9 pm). RNA sequencing analyses found that gene expression in RRMS in relapse (Relapse) is significantly changed at night compared with either Relapse at day or RRMS in remission (Remission). Gene set overrepresentation analysis demonstrated that gene sets significantly changed in Relapse at night are enriched to immune responses related to MS pathology. In those gene sets, 68 genes are significantly changed expression in Relapse at night compared with Relapse at day and Remission. This supports that times of sample collections should be standardized to obtain reproducible gene expression patterns.Acetylation coordinates many biological processes to ensure cells respond appropriately to nutrients. However, how acetylation regulates lipid surplus-induced inflammation remains poorly understood. Here, we found that a high-fat diet (HFD) enhanced mitochondrial fatty acid β-oxidation, which enhanced acetyl-CoA levels in the liver of the large yellow croaker. The HFD activated ACLY to govern the "citrate transport" to transfer acetyl-CoA from the mitochondria to the nucleus. Elevated acetyl-CoA activated CBP to increase p65 acetylation and then aggravated inflammation. SIRT1 was deactivated with a decline in NAD+/NADH, which further aggravated inflammation. Therefore, acetylation-dependent regulation of transcription factor activity is an adaptation to proinflammatory stimuli under nutrient stress, which was also confirmed in AML12 hepatocytes. In vitro octanoate stimulation further verified that acetyl-CoA derived from fatty acid β-oxidation mediated acetylation homeostasis in the nucleus. The broad therapeutic prospects of intermediate metabolites and acetyltransferases/deacetylases might provide critical insights for the treatment of metabolic diseases in vertebrates.Prostaglandin E2 (PGE2) has recently been recognized to play a role in immune regulation and tissue regeneration. However, the short half-life of PGE2 limits its clinical application. Improving the delivery of PGE2 specifically to the target organ with a prolonged release method is highly desirable. Taking advantage of the adequate space and proximity of the renal parenchyma, renal subcapsular delivery allows minimally invasive and effective delivery to the entire kidney. Here, we report that by covalently cross-linking it to a collagen matrix, PGE2 exhibits an adequate long-term presence in the kidney with extensive intraparenchymal penetration through renal subcapsular delivery and significantly improves kidney function. Sox9 cell lineage tracing with intravital microscopy revealed that PGE2 could activate the endogenous renal progenitor Sox9+ cells through the Yap signaling pathway. Our results highlight the prospects of utilizing renal subcapsular-based drug delivery and facilitate new applications of PGE2-releasing matrices for regenerative therapy.Chemotaxis is ubiquitous in many biological processes, but it still remains elusive how cells sense and decipher multiple chemical cues. In this study, we postulate a hypothesis that the chemotactic performance of cells under complex cues is regulated by the signal processing capacity of the cellular sensory machinery. The underlying rationale is that cells in vivo should be able to sense and process multiple chemical cues, whose magnitude and compositions are entangled, to determine their migration direction. We experimentally show that the combination of transforming growth factor-β and epidermal growth factor suppresses the chemotactic performance of cancer cells using independent receptors to sense the two cues. Based on this observation, we develop a biophysical framework suggesting that the antagonism is caused by the saturation of the signal processing capacity but not by the mutual repression. Our framework suggests the significance of the signal processing capacity in the cellular sensory machinery.Intracellular signaling dynamics play fundamental roles in cell biology. Precise modulation of the amplitude, duration, and frequency of signaling activation will be a powerful approach to investigate molecular mechanisms as well as to engineer signaling to control cell behaviors. Here, we showed a practical approach to achieve precise amplitude modulation (AM), frequency modulation (FM), and duration modulation (DM) of MAP kinase activation. Alternating current (AC) electrical stimulation induced synchronized ERK activation. Amplitude and duration of ERK activation were controlled by varying stimulation strength and duration. ERK activation frequencies were arbitrarily modulated with trains of short AC applications with accurately defined intervals. Significantly, ERK dynamics coded by well-designed AC can rewire PC12 cell fate independent of growth factors. This technique can be used to synchronize and modulate ERK activation dynamics, thus would offer a practical way to control cell behaviors in vivo without the use of biochemical agents or genetic manipulation.Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). APOE4 is known to affect the function of microglia, but to what extent this gene drives microglial gene expression has thus far not been examined. Using a transgenic mouse model of AD that expresses human APOE, we identify a unique transcriptional profile associated with APOE4 expression. We also show a sex and APOE interaction, such that both female sex and APOE4 drive expression of this gene profile. We confirm these findings in human cells, using microglia derived from induced pluripotent stem cells (iMGL). Moreover, we find that these interactions are driven in part by genes related to metal processing, and we show that zinc treatment has APOE genotype-dependent effects on iMGL. These data identify a sex- and APOE4-associated microglial transcription profile and highlight the importance of considering interactive risk factors such as sex and environmental exposures.We have developed a fabrication methodology for label-free optical trapping of individual nanobeads and proteins in inverted-bowtie-shaped plasmonic gold nanopores. Arrays of these nanoapertures can be reliably produced using focused ion beam (FIB) milling with gap sizes of 10-20 nm, single-nanometer variation, and with a remarkable stability that allows for repeated use. We employ an optical readout where the presence of the protein entering the trap is marked by an increase in the transmission of light through the nanoaperture from the shift of the plasmonic resonance. In addition, the optical trapping force of the plasmonic nanopores allows 20-nm polystyrene beads and proteins, such as beta-amylase and Heat Shock Protein (HSP90), to be trapped for very long times (approximately minutes). On demand, we can release the trapped molecule for another protein to be interrogated. Our work opens up new routes to acquire information on the conformation and dynamics of individual proteins.Inflorescence architecture is diverse in flowering plants, and two determinants of inflorescence architecture are the inflorescence meristem and pedicel length. Although the ERECTA (ER) signaling pathway, in coordination with the SWR1 chromatin remodeling complex, regulates inflorescence architecture with subsequent effects on pedicel elongation, the mechanism underlying SWR1-ER signaling pathway regulation of inflorescence architecture remains unclear. This study determined that SDG2 genetically interacts with the SWR1-ER signaling pathways in regulating inflorescence architecture. Transcriptome results showed that auxin might potentially influence inflorescence growth mediated by SDG2 and SWR1-ER pathways. SWR1 and ER signaling are required to enrich H2A.Z histone variant and SDG2 regulated SDG2-mediated H3K4me3 histone modification at auxin-related genes and H2A.Z histone variant enrichment. Our study shows how the regulation of inflorescence architecture is mediated by SDG2 and SWR1-ER, which affects auxin hormone signaling pathways.