MiR-214 promotes renal fibrosis in diabetic nephropathy via targeting SOCS1

Purpose: To elucidate how miR-214 regulates the pathogenesis of diabetic nephropathy (DN). Methods: The extent of fibrosis in DN mice kidneys was examined using Masson’s staining. Quantitative polymerase chain reaction (qPCR) was used to determine the levels of miR-214. Dual luciferase reporter assay was used to identify the target of miR-214. The expression of fibrosis marker proteins of high glucose-stimulated NRK-52E cells transfected with miR-214 was determined using western blotting. Results: Fibrosis in renal tissue of DN mice was significantly increased and miR-214 was upregulated (p < 0.001). Suppressor of cytokine signaling 1 protein (SOCS1) was the target gene of miR-214, and overexpression of miR-214 promoted fibrosis (p < 0.05, p < 0.001). On the other hand, overexpression of SOCS1 inhibited this process, indicating that miR-214 promoted fibrosis via targeting SOCS1 (p < 0.001). Finally, inhibition of miR-214 c ameliorated renal fibrosis in DN mice (p < 0.01, p < 0.001). Conclusions: MiR-214 is upregulated in db/db DN mice kidney tissue; miR-214 regulates renal fibrosis in DN mice by targeting SOCS1

Revealing and Resolving the Restrained Enzymatic Cleavage of DNA Self-Assembled Monolayers on Gold: Electrochemical Quantitation and ESI-MS Confirmation

Herein we report a combined electrochemical and ESI-MS study of the enzymatic hydrolysis efficiency of DNA self-assembled monolayers (SAMs) on gold, platform systems for understanding nucleic acid surface chemistry and for constructing DNA-based biosensors. Our electrochemical approach is based on the comparison of the amounts of surface-tethered DNA nucleotides before and after Exonuclease I (Exo I) incubation using electrostatically bound [Ru(NH3)6]3+ as redox indicators. It is surprising to reveal that the hydrolysis efficiency of ssDNA SAMs does not depend on the packing density and base sequence, and that the cleavage ends with surface-bound shorter strands (9-13 mers). The ex-situ ESI-MS observations confirmed that the hydrolysis products for ssDNA SAMs (from 24 to 56 mers) are dominated with 10-15 mer fragments, in contrast to the complete digestion in solution. Such surface-restrained hydrolysis behavior is due to the steric hindrance of the underneath electrode to the Exo I/DNA binding, which is essential for the occurrence of Exo I-catalyzed processive cleavage. More importantly, we have shown that the hydrolysis efficiency of ssDNA SAMs can be remarkably improved by adopting long alkyl linkers (locating DNA strands further away from the substrates)

TRPA1 Activation-Induced Myelin Degradation Plays a Key Role in Motor Dysfunction After Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) is a devastating disease that is characterized by high morbidity and high mortality. ICH has an annual incidence of 10–30/100,000 people and accounts for approximately 10%–30% of all types of stroke. ICH mostly occurs at the basal ganglia, which is rich in nerve fibers; thus, hemiplegia is quite common in ICH patients with partial sensory disturbance and ectopic blindness. In the clinic, those symptoms are considered to originate from the white matter injury in the area, but the exact mechanisms are unknown, and currently, no effective drug treatments are available to improve the prognosis. Clarifying the mechanisms will contribute to the development of new treatment methods for patients. The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that plays a role in inflammatory pain sensation and nociception and may be a potential regulator in emotion, cognition and social behavior. Here, we report that TRPA1 is involved in myelin damage and oxidative stress injury in a mouse ICH model. Intervention with the TRPA1 channel may be a new method to improve the motor function of patients in the early stage of ICH

Twenty-first-century glacio-hydrological changes in the Himalayan headwater Beas River basin

The Himalayan Mountains are the source region of one of the world's largest supplies of freshwater. The changes in glacier melt may lead to droughts as well as floods in the Himalayan basins, which are vulnerable to hydrological changes. This study used an integrated glacio-hydrological model, the Glacier and Snow Melt – WASMOD model (GSM-WASMOD), for hydrological projections under 21st century climate change by two ensembles of four global climate models (GCMs) under two Representative Concentration Pathways (RCP4.5 and RCP8.5) and two bias-correction methods (i.e., the daily bias correction (DBC) and the local intensity scaling (LOCI)) in order to assess the future hydrological changes in the Himalayan Beas basin up to Pandoh Dam (upper Beas basin). Besides, the glacier extent loss during the 21st century was also investigated as part of the glacio-hydrological modeling as an ensemble simulation. In addition, a high-resolution WRF precipitation dataset suggested much heavier winter precipitation over the high-altitude ungauged area, which was used for precipitation correction in the study. The glacio-hydrological modeling shows that the glacier ablation accounted for about 5&thinsp;% of the annual total runoff during 1986–2004 in this area. Under climate change, the temperature will increase by 1.8–2.8&thinsp;∘C at the middle of the century (2046–2065), and by 2.3–5.4&thinsp;∘C until the end of the century (2080–2099). It is very likely that the upper Beas basin will get warmer and wetter compared to the historical period. In this study, the glacier extent in the upper Beas basin is projected to decrease over the range of 63&thinsp;%–87&thinsp;% by the middle of the century and 89&thinsp;%–100&thinsp;% at the end of the century compared to the glacier extent in 2005. This loss in glacier area will in general result in a reduction in glacier discharge in the future, while the future streamflow is most likely to have a slight increase because of the increase in both precipitation and temperature under all the scenarios. However, there is widespread uncertainty regarding the changes in total discharge in the future, including the seasonality and magnitude. In general, the largest increase in river total discharge also has the largest spread. The uncertainty in future hydrological change is not only from GCMs, but also from the bias-correction methods and hydrological modeling. A decrease in discharge is found in July from DBC, while it is opposite for LOCI. Besides, there is a decrease in evaporation in September from DBC, which cannot be seen from LOCI. The study helps to understand the hydrological impacts of climate change in northern India and contributes to stakeholder and policymaker engagement in the management of future water resources in northern India.</p

Timing of human-induced climate change emergence from internal climate variability for hydrological impact studies

This study proposes a method to estimate the timing of human-induced climate change (HICC) emergence from internal climate variability (ICV) for hydrological impact studies based on climate model ensembles. Specifically, ICV is defined as the inter-member difference in a multi-member ensemble of a climate model in which human-induced climate trends have been removed through a detrending method. HICC is defined as the mean of multiple climate models. The intersection between HICC and ICV curves is defined as the time of emergence (ToE) of HICC from ICV. A case study of the Hanjiang River watershed in China shows that the temperature change has already emerged from ICV during the last century. However, the precipitation change will be masked by ICV up to the middle of this century. With the joint contributions of temperature and precipitation, the ToE of streamflow occurs about one decade later than that of precipitation. This implies that consideration for water resource vulnerability to climate should be more concerned with adaptation to ICV in the near-term climate (present through mid-century), and with HICC in the long-term future, thus allowing for more robust adaptation strategies to water transfer projects in China

Clonal Dissemination of Multidrug-Resistant and Hypervirulent Klebsiella pneumoniae Clonal Complex in a Chinese Hospital

The emergence of high antimicrobial-resistant and hypervirulent Klebsiella pneumoniae (hvKp) clones in clinics has become a cause of concern in recent years. Despite the global spread of the clonal complex (CC) 258, hvKp of other non-CC258 subgroups also emerged. Here, by performing a retrospective study from July 2019 to August 2020 in a Chinese hospital, we obtained 25 K. pneumoniae isolates belonging to CC15. By antimicrobial susceptibility testing and whole genome sequencing and analysis, we obtained the resistant phenotypes and genotypes of these isolates. Twenty-one isolates (84%) were carbapenem-resistant, and eighteen were blaKPC-2 positive. In addition, ten isolates were identified as putative hvKp and seven were carbapenem-resistant hvKp. Nine isolates carried the pLVPK-like virulence plasmid, which contains the fragment including rmpA2, peg-589, iutA, and iucABCD. Another isolate carried iucA. Phylogenetic analysis revealed that the isolates belonged to four lineages, and the putative hvKp isolates were identified in three of these. Two independent sublineages of putative hvKp were caused by the acquisition of pLVPK-like virulence plasmid. Based on comparative genomic analysis, the number of pairwise single nucleotide polymorphisms amongst the four sublineages, Lineage 1a, 1b, 2a, and 2b, were 1–43, 2–13, 129–279, and 3–4, respectively, indicating clonal transmission of Lineage 1a, 1b, and 2b. These results indicate that multiple lineages of CC15 carbapenem-resistant hvKp have emerged in the hospital and caused nosocomial transmission, and that the spreading of virulence plasmids among classic K. pneumoniae subtypes might become more common and happen more easily. These findings highlight the importance of surveillance of local epidemics of non-CC258 subgroups in hospitals

PDK1/mTOR Signaling in Myeloid Cells Differentially Regulates the Early and Late Stages of Sepsis

The cecal ligation and perforation (CLP) model is the gold standard for the polymicrobial sepsis. In the CLP mice, the myeloid cells play an important role in septic shock. The phenotypes and the activation state of the macrophage and neutrophil correlate with their metabolism. In the present study, we generated the specific myeloid deletion of PDK1 and mTOR mice, which was the important regulator of metabolic signaling. We found that the deletion of PDK1 in the myeloid cells could aggravate the early septic shock in the CLP mice, as well as the deletion of mTORC1 and mTORC2. Moreover, PDK1 deletion attenuated the inflammation induced by LPS in the late stage on CLP mice, which was exacerbated in mTORC1 and mTORC2 knockout mice. Both PDK1 and mTORC1/2 could not only regulate the cellular metabolism but also play important roles on the myeloid cells in the secondary stimulation of sepsis. The present study will provide a theoretical prospect for the therapy of the septic shock in different stages

Impacts of climate change and LULC change on runoff in the Jinsha River Basin

The climate change and Land Use/Land Cover (LULC) change both have an important impact on the rainfall-runoff processes. How to quantitatively distinguish and predict the impacts of the above two factors has been a hot spot and frontier issue in the field of hydrology and water resources. In this research, the SWAT (Soil and Water Assessment Tool) model was established for the Jinsha River Basin, and the method of scenarios simulation was used to study the runoff response to climate change and LULC change. Furthermore, the climate variables exported from 7 typical General Circulation Models (GCMs) under RCP4.5 and RCP8.5 emission scenarios were bias corrected and input into the SWAT model to predict runoff in 2017–2050. Results showed that: (1) During the past 57 years, the annual average precipitation and temperature in the Jinsha River Basin both increased significantly while the rising trend of runoff was far from obvious. (2) Compared with the significant increase of temperature in the Jinsha River Basin, the LULC change was very small. (3) During the historical period, the LULC change had little effect on the hydrological processes in the basin, and climate change was one of the main factors affecting runoff. (4) In the context of global climate change, the precipitation, temperature and runoff in the Jinsha River Basin will rise in 2017–2050 compared with the historical period. This study provides significant references to the planning and management of large-scale hydroelectric bases at the source of the Yangtze River

Twenty-first-century glacio-hydrological changes in the Himalayan headwater Beas River basin

The Himalayan Mountains are the source region of one of the world's largest supplies of freshwater. The changes in glacier melt may lead to droughts as well as floods in the Himalayan basins, which are vulnerable to hydrological changes. This study used an integrated glacio-hydrological model, the Glacier and Snow Melt-WASMOD model (GSM-WASMOD), for hydrological projections under 21st century climate change by two ensembles of four global climate models (GCMs) under two Representative Concentration Pathways (RCP4.5 and RCP8.5) and two bias-correction methods (i.e., the daily bias correction (DBC) and the local intensity scaling (LOCI)) in order to assess the future hydrological changes in the Himalayan Beas basin up to Pandoh Dam (upper Beas basin). Besides, the glacier extent loss during the 21st century was also investigated as part of the glacio-hydrological modeling as an ensemble simulation. In addition, a high-resolution WRF precipitation dataset suggested much heavier winter precipitation over the high-altitude ungauged area, which was used for precipitation correction in the study. The glacio-hydrological modeling shows that the glacier ablation accounted for about 5% of the annual total runoff during 1986-2004 in this area. Under climate change, the temperature will increase by 1.8-2.8°C at the middle of the century (2046-2065), and by 2.3-5.4°C until the end of the century (2080-2099). It is very likely that the upper Beas basin will get warmer and wetter compared to the historical period. In this study, the glacier extent in the upper Beas basin is projected to decrease over the range of 63%-87% by the middle of the century and 89%-100% at the end of the century compared to the glacier extent in 2005. This loss in glacier area will in general result in a reduction in glacier discharge in the future, while the future streamflow is most likely to have a slight increase because of the increase in both precipitation and temperature under all the scenarios. However, there is widespread uncertainty regarding the changes in total discharge in the future, including the seasonality and magnitude. In general, the largest increase in river total discharge also has the largest spread. The uncertainty in future hydrological change is not only from GCMs, but also from the bias-correction methods and hydrological modeling. A decrease in discharge is found in July from DBC, while it is opposite for LOCI. Besides, there is a decrease in evaporation in September from DBC, which cannot be seen from LOCI. The study helps to understand the hydrological impacts of climate change in northern India and contributes to stakeholder and policymaker engagement in the management of future water resources in northern India

Inhibition of Mitochondrial ROS by MitoQ Alleviates White Matter Injury and Improves Outcomes after Intracerebral Haemorrhage in Mice

White matter injury (WMI) is an important cause of high disability after intracerebral haemorrhage (ICH). It is widely accepted that reactive oxygen species (ROS) contributes to WMI, but there is still no evidence-based treatment. Here, mitoquinone (MitoQ), a newly developed selective mitochondrial ROS scavenger, was used to test its neuroprotective potential. The data showed that MitoQ attenuated motor function deficits and motor-evoked potential (MEP) latency prolongation. Further research found that MitoQ blunted the loss of oligodendrocytes and oligodendrocyte precursor cells, therefore reduced demyelination and axon swelling after ICH. In the in vitro experiments, MitoQ, but not the nonselective antioxidant, almost completely attenuated the iron-induced membrane potential decrease and cell death. Mechanistically, MitoQ blocked the ATP deletion and mitochondrial ROS overproduction. The present study demonstrates that the selective mitochondrial ROS scavenger MitoQ may improve the efficacy of antioxidant treatment of ICH by white matter injury alleviation