Prenatal inflammation exposure-programmed cardiovascular diseases and potential prevention

In recent years, the rapid development of medical and pharmacological interventions has led to a steady decline in certain noncommunicable chronic diseases (NCDs), such as cancer. However, the overall incidence of cardiovascular diseases (CVDs) has not seemed to decline. CVDs have become even more prevalent in many countries and represent a global health threat and financial burden. An increasing number of epidemiological and experimental studies have demonstrated that maternal insults not only can result in birth defects but also can cause developmental functional defects that contribute to adult NCDs. In the current review, we provide an overview of evidence from both epidemiological investigations and experimental animal studies supporting the concept of developmental reprogramming of adult CVDs in offspring that have experienced prenatal inflammation exposure (PIE) during fetal development (PIE-programmed CVDs), a disease-causing event that has not been effectively controlled. This review describes the epidemiological observations, data from animal models, and related mechanisms for the pathogenesis of PIE-programmed CVDs. In addition, the potential therapeutic interventions of PIE-programmed CVDs are discussed. Finally, we also deliberate the need for future mechanistic studies and biomarker screenings in this important field, which creates a great opportunity to combat the global increase in CVDs by managing the adverse effects of inflammation for prepregnant and pregnant individuals who are at risk for PIE-programmed CVDs

FLT3L and Plerixafor Combination Increases Hematopoietic Stem Cell Mobilization and Leads to Improved Transplantation Outcome

AbstractHematopoietic stem cell (HSC) transplantation has curative potential for patients with hematological malignancies. Clinically, HSCs derived from mobilized peripheral blood are used more frequently than bone marrow. However, current standard mobilizing agents yield grafts that may not contain sufficient HSCs. Here, using murine models, we discovered that FLT3L synergized with plerixafor to mobilize phenotypically defined HSCs and their combination (FP) was superior to granulocyte colony-stimulating factor (G-CSF) alone or in combination with plerixafor (GP). Additionally, FP mobilized more regulatory T cells, natural killer cells, and plasmacytoid dendritic cells compared with G-CSF alone or GP. Both syngeneic and allogeneic grafts mobilized by FP led to long-term survival in transplanted mice. Collectively, FP represents a promising novel and potent mobilization regimen with potential clinical application in both the autologous and allogeneic transplantation settings

Profiling analysis of long non-coding RNAs in early postnatal mouse hearts

Mammalian cardiomyocytes undergo a critical hyperplastic-to-hypertrophic growth transition at early postnatal age, which is important in establishing normal physiological function of postnatal hearts. In the current study, we intended to explore the role of long non-coding (lnc) RNAs in this transitional stage. We analyzed lncRNA expression profiles in mouse hearts at postnatal day (P) 1, P7 and P28 via microarray. We identified 1,146 differentially expressed lncRNAs with more than 2.0-fold change when compared the expression profiles of P1 to P7, P1 to P28, and P7 to P28. The neighboring genes of these differentially expressed lncRNAs were mainly involved in DNA replication-associated biological processes. We were particularly interested in one novel cardiac-enriched lncRNA, ENSMUST00000117266, whose expression was dramatically down-regulated from P1 to P28 and was also sensitive to hypoxia, paraquat, and myocardial infarction. Knockdown ENSMUST00000117266 led to a significant increase of neonatal mouse cardiomyocytes in G0/G1 phase and reduction in G2/M phase, suggesting that ENSMUST00000117266 is involved in regulating cardiomyocyte proliferative activity and is likely associated with hyperplastic-to-hypertrophic growth transition. In conclusion, our data have identified a large group of lncRNAs presented in the early postnatal mouse heart. Some of these lncRNAs may have important functions in cardiac hyperplastic-to-hypertrophic growth transition

Precision measurements of A1N in the deep inelastic regime

We have performed precision measurements of the double-spin virtual-photon asymmetry A1A1 on the neutron in the deep inelastic scattering regime, using an open-geometry, large-acceptance spectrometer and a longitudinally and transversely polarized 3He target. Our data cover a wide kinematic range 0.277≤x≤0.5480.277≤x≤0.548 at an average Q2Q2 value of 3.078 (GeV/c)2, doubling the available high-precision neutron data in this x range. We have combined our results with world data on proton targets to make a leading-order extraction of the ratio of polarized-to-unpolarized parton distribution functions for up quarks and for down quarks in the same kinematic range. Our data are consistent with a previous observation of anA1n zero crossing near x=0.5x=0.5. We find no evidence of a transition to a positive slope in(Δd+Δd¯)/(d+d¯) up to x=0.548x=0.548

Impact of the Dam Construction on the Downstream Thermal Conditions of the Yangtze River

Water temperature is an important factor in aquatic environments. Dam construction, especially the construction of multiple dams in rivers, can greatly affect the downstream water temperature. Several dams, including Wudongde, Baihetan, Xiluodu, Xiangjiaba, Three Gorges, and Gezhouba, have been constructed between Panzhihua and Yichang along the Yangtze River. The aim of this paper was to quantify the impact of these dams on the water temperature downstream. One-dimensional and two-dimensional models were used to simulate the water temperatures, and the results showed that the dams had different cumulative effects on it. For example, in January, after the construction of the Xiangjiaba and Xiluodu dams, the discharge water temperature of Xiangjiaba was 3 °C higher than the natural conditions, and after the construction of the Baihetan and Wudongde dams was completed, it increased by a further 2 °C. The natural river ran over 416 km with no dams from the Xiangjiaba dam to the Cuntan Station. With the influence of climate and tributary inflow, the impact of upstream dams on the water temperature was mitigated by more than 48% at Cuntan Station, displaying a recovery. It seemed that the cumulative effects of dams on the discharge water temperature of the Three Gorges decreased with the increase in the upstream storage capacity from March to May, and the construction of dams even had a negative effect. From September to February of the next year, the cumulative effects increased with the increase of the upstream storage capacity, but only the total storage capacity until a certain level, where no further impact was observed

Study of the thermal regime of a reservoir on the Qinghai-Tibetan Plateau, China.

The Qinghai-Tibetan Plateau region has unique meteorological characteristics, with low air temperature, low air pressure, low humidity, little precipitation, and strong diurnal variation. A two-dimensional hydrodynamic CE-QUAL-W2 model was configured for the Pangduo Reservoir to better understand the thermal structure and diurnal variation inside the reservoir under the local climate and hydrological conditions on the Qinghai-Tibetan Plateau. Observation data were used to verify the model, and the results showed that the average error of the 6 profile measured monthly from August to December 2016 was 0.1°C, and the root-mean-square error (RMSE) was 0.173°C. The water temperature from August 2016 to September 2017 was simulated by inputting measured data as model inputs. The results revealed that the reservoir of the Qinghai-Tibetan Plateau was a typical dimictic reservoir and the water mixed vertically at the end of March and the end of October. During the heating period, thermal stratification occurred, with strong diurnal variation in the epilimnion. The mean variance of the diurnal water temperature was 0.10 within a 5 m water depth but 0.04 in the whole water column. The mixing mode of inflow changed from undercurrent, horizontal-invaded flow and surface layer flow in one day. In winter, the diurnal variation was weak due to the thermal protection of the ice cover, while the mean variance of diurnal water temperature was 0.00 within both 5 m and the whole water column. Compared to reservoirs in areas with low altitude but the same latitude, significant differences occurred between the temperature structure of the low-altitude reservoir and the Pangduo Reservoir (P<0.01). The Pangduo Reservoir presented a shorter stratification period and weaker stratification stability, and the annual average SI value was 26.4 kg/m2, which was only 7.5% that of the low-altitude reservoir. The seasonal changes in the net heat flux received by the surface layers determined the seasonal cycle of stratification and mixing in reservoirs. This study provided a scientific understanding of the thermal changes in stratified reservoirs under the special geographical and meteorological conditions on the Qinghai-Tibetan Plateau. Moreover, this model can serve as a reference for adaptive management of similar dimictic reservoirs in cold and high-altitude areas

Exploring MicroRNAs in Diabetic Chronic Cutaneous Ulcers: Regulatory Mechanisms and Therapeutic Potentials

Diabetic chronic cutaneous ulcers (DCU) is one of the serious complications of diabetes mellitus, which mainly occurs in diabetic patients with peripheral neuropathy. Recent studies have indicated that microRNAs (miRNAs/miRs) and their target genes are essential regulators of cell physiology and pathology including biological processes that are involved in the regulation of diabetes and diabetes-related microvascular complications. In vivo and in vitro models have revealed that the expression of some miRNAs can be regulated in the inflammatory response, cell proliferation, and wound remodeling of DCU. Nevertheless, the application potential of miRNAs in the clinic is still limited. Thus, we provide a contemporary overview of the miRNAs as well as their associated target genes and pathways (such as Wnt/β-catenin, NF-κB, TGF-β/Smad, PI3K/AKT/mTOR) related to DCU healing. Besides, we summarize the current development of drugs for DCU treatment and discuss the therapeutic challenges of DCU treatment and its potential future research directions

Pregnancy induced hypertension and umbilical cord blood DNA methylation in newborns: an epigenome-wide DNA methylation study

Abstract Objectivies Pregnancy induced hypertension (PIH) syndrome is a disease that unique to pregnant women and is associated with elevated risk of offspring cardiovascular diseases (CVDs) and neurodevelopmental disorders in their kids. Previous research on cord blood utilizing the Human Methylation BeadChip or EPIC array revealed that PIH is associated with specific DNA methylation site. Here, we investigate the whole genome DNA methylation landscape of cord blood from newborns of PIH mother. Methods Whole-genome bisulfite sequencing (WGBS) was used to examine the changes in whole genome DNA methylation in the umbilical cord blood of three healthy (NC) and four PIH individuals. Using methylKit, we discovered Hypo- and hyper- differentially methylated probes (DMPs) or methylated regions (DMRs) in the PIH patients’ cord blood DNA. Pathway enrichments were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment assays. DMPs or DMRs relevant to the immunological, neurological, and circulatory systems were also employed for enrichment assay, Metascape analysis and PPI network analysis. Results 520 hyper- and 224 hypo-DMPs, and 374 hyper- and 186 hypo-DMRs between NC and PIH group, respectively. Both DMPs and DMRs have enhanced pathways for cardiovascular, neurological system, and immune system development. Further investigation of DMPs or DMRs related to immunological, neurological, and circulatory system development revealed that TBK1 served as a hub gene for all three developmental pathways. Conclusion PIH-associated DMPs or DMRs in umbilical cord blood DNA may play a role in immunological, neurological, and circulatory system development. Abnormal DNA methylation in the immune system may also contribute to the development of CVDs and neurodevelopment disorders

Optimization of selective withdrawal strategy in a warm monomictic reservoir based on thermal stratification

Selective withdrawal from reservoirs is an effective strategy for balancing economic goals and environmental demands. Multilevel intake operation (MIO) is one of the main options for improving the thermal regime of deep reservoirs. In this study, a combination of measured data and a two-dimensional hydrodynamic model (CE-QUAL-W2) was utilized to analyze the impact of MIO processes on the thermal stability of a reservoir and the improvement effect of the withdrawal water temperature (WWT). The purpose of this study was to identify an optimal selective withdrawal strategy to meet the water temperature needs of fish downstream during their spawning and breeding activities. The results showed that the MIOs raised the withdrawal water intake position (8.3–11.2 m) for the WWT. Meanwhile, MIOs resulted in statistically significant changes in the water temperature structure of the reservoir (p < 0.01). The stratification stability of the water column weakened (6.8 %-34.5 %), and there were interannual differences. The WWT increased by 0.0 °C∼1.9 °C every ten days, and the time to reach the optimum temperature (18 °C) for fish spawning was 7 to 17 days earlier. There was a statistically significant positive correlation between the WWT improvement and the stability index (SI) (R = 0.7817, p < 0.01). The threshold values of the SI (above the water intake) for average WWT improvements of 0.5 and 1.0 °C were 90.3 and 221.9 kg/m2, respectively, and the recommended operating period was from early-April to May. Under MIOs, the weakening stratification and the increasing WWT during the warming period reduced risks to the water quality and ecological health in the reservoir and downstream rivers. This study provides a helpful reference for the implementation of selective withdrawal operations and the optimization of water quality management strategies in similar large, deep reservoirs