Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model.

Physical exercise represents a primary defense against age-related cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD). To impartially investigate the underlying mechanisms, we conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and ATAC-seq) on the hippocampus of mice carrying AD-linked NL-G-F mutations in the amyloid precursor protein gene (APPNL-G-F) following prolonged voluntary wheel-running exercise. Our study reveals that exercise mitigates amyloid-induced changes in both transcriptomic expression and chromatin accessibility through cell type-specific transcriptional regulatory networks. These networks converge on the activation of growth factor signaling pathways, particularly the epidermal growth factor receptor (EGFR) and insulin signaling, correlating with an increased proportion of immature dentate granule cells and oligodendrocytes. Notably, the beneficial effects of exercise on neurocognitive functions can be blocked by pharmacological inhibition of EGFR and the downstream phosphoinositide 3-kinases (PI3K). Furthermore, exercise leads to elevated levels of heparin-binding EGF (HB-EGF) in the blood, and intranasal administration of HB-EGF enhances memory function in sedentary APPNL-G-F mice. These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGF-related growth factor signaling as a druggable contributor to exercise-induced memory enhancement, thereby suggesting therapeutic avenues for combatting AD-related cognitive decline.

MALDI imaging mass spectrometry visualizes the distribution of antidepressant duloxetine and its major metabolites in mouse brain, liver, kidney, and spleen tissues.

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We utilized high-resolution IMS with matrix-assisted laser desorption/ionization (MALDI-IMS) to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none of these tissues is DLX or its metabolites homogeneously distributed, which has implications for both efficacy and toxicity. We found duloxetine to be similarly distributed in spleen red pulp and white pulp but differentially distributed in different anatomic regions of the liver, kidney, and brain, with dose-dependent patterns. Comparison with hematoxylin and eosin staining of tissue sections reveals that the ion images of endogenous lipids help delineate anatomic regions in the brain and kidney, while heme ion images assist in differentiating regions within the spleen. These endogenous metabolites may serve as a valuable resource for examining the spatial distribution of other drugs in tissues when staining images are not available. These findings may facilitate future mechanistic studies of the therapeutic and adverse effects of duloxetine. In the current work, we did not perform absolute quantification of duloxetine, which will be reported in due course Significance Statement The study utilized imaging mass spectrometry to examine the spatial distribution of duloxetine and its primary metabolites in mouse brain, liver, kidney and spleen. These results may pave the way for future investigations into the mechanisms behind duloxetine's therapeutic and adverse effects. Furthermore, the mass spectrometry images of specific endogenous metabolites such as heme could be valuable in analyzing the spatial distribution of other drugs within tissues in scenarios where histological staining images are unavailable.

The seasonal variability of future evapotranspiration over China during the 21st century.

The evapotranspiration (ET) plays a crucial role in shaping regional climate patterns and serves as a vital indicator of ecosystem function. However, there remains a limited understanding of the seasonal variability of future ET over China and its correlation with environmental drivers. This study evaluated the skills of 27 models from the Six Phase of Coupled Model Intercomparison Project in modeling ET and the Bayesian Model Averaging (BMA) method was employed to merge monthly simulated ET based on the top five best-performing models. The seasonal changes in ET under three climate scenarios from 2030 to 2099 were analyzed based on the BMA-merged ET, which was well validated with observed ET collected from fourteen flux sites across China. Significant increasing ET over China are projected under all seasons during 2030-2099, with 0.05-0.13 mm yr-1, 0.11-0.23 mm yr-1, and 0.20-0.41 mm yr-1 under SSP1-2.6, SSP2-4.5 and SSP5-8.5 scenarios, respectively. Relative to the historical period (1980-2014), the relative increase in ET over China is highest in winter and lowest in summer. Seasonal ET increases significantly in all seven climate sub-regions under high forcing scenario. Higher ET increase is generally found in southeastern humid regions, while lowest ET increase occurs in northwest China. At the country level, the primary factor driving ET increase during spring, summer, and autumn seasons is the increasing net radiation and warming. In contrast, ET increase during winter is influenced not only by energy factors but also by vegetation-related factors. Future seasonal ET increase is predominantly driven by increasing energy factors in the southeastern humid region and Tibetan Plateau, while seasonal ET changes in the northwest region prevailingly depend on soil moisture. Results indicate that China will experience a "wet season will get wetter, and dry season will become drier" in the 21st century with high radiation forcing scenario.

Critical Role of histone deacetylase 3 in the regulation of kidney inflammation and fibrosis.

Chronic kidney disease (CKD) is characterized by kidney inflammation and fibrosis. However, the precise mechanisms leading to kidney inflammation and fibrosis are poorly understood. Since histone deacetylase is involved in inflammation and fibrosis in other tissues, we examined the role of histone deacetylase 3 (HDAC3) in the regulation of inflammation and kidney fibrosis. HDAC3 is induced in the kidneys of animal models of CKD but mice with conditional HDAC3 deletion exhibit significantly reduced fibrosis in the kidneys compared with control mice. The expression of proinflammatory and profibrotic genes was significantly increased in the fibrotic kidneys of control mice, which was impaired in mice with HDAC3 deletion. Genetic deletion or pharmacological inhibition of HDAC3 reduced the expression of proinflammatory genes in cultured monocytes/macrophages. Mechanistically, HDAC3 deacetylates Lys122 of NF-κB p65 subunit turning on transcription. RGFP966, a selective HDAC3 inhibitor, reduced fibrosis in cells and in animal models by blocking NF-κB p65 binding to κB-containing DNA sequences. Thus, our study identified HDAC3 as a critical regulator of inflammation and fibrosis of the kidney through deacetylation of NF-κB unlocking its transcriptional activity. Hence, targeting HDAC3 could serve as a novel therapeutic strategy for CKD.

The YAP1/TAZ-TEAD transcriptional network regulates gene expression at neuromuscular junctions in skeletal muscle fibers.

We examined YAP1/TAZ-TEAD signaling pathway activity at neuromuscular junctions (NMJs) of skeletal muscle fibers in adult mice. Our investigations revealed that muscle-specific knockouts of Yap1 or Taz, or both, demonstrate that these transcriptional coactivators regulate synaptic gene expression, the number and morphology of NMJs, and synaptic nuclei. Yap1 or Taz single knockout mice display reduced grip strength, fragmentation of NMJs, and accumulation of synaptic nuclei. Yap1/Taz muscle-specific double knockout mice do not survive beyond birth and possess almost no NMJs, the few detectable show severely impaired morphology and are organized in widened endplate bands; and with motor nerve endings being mostly absent. Myogenic gene expression is significantly impaired in the denervated muscles of knockout mice. We found that Tead1 and Tead4 transcription rates were increased upon incubation of control primary myotubes with AGRN-conditioned medium. Reduced AGRN-dependent acetylcholine receptor clustering and synaptic gene transcription were observed in differentiated primary Tead1 and Tead4 knockout myotubes. In silico analysis of previously reported genomic occupancy sites of TEAD1/4 revealed evolutionary conserved regions of potential TEAD binding motifs in key synaptic genes, the relevance of which was functionally confirmed by reporter assays. Collectively, our data suggest a role for YAP1/TAZ-TEAD1/TEAD4 signaling, particularly through TAZ-TEAD4, in regulating synaptic gene expression and acetylcholine receptor clustering at NMJs.

Effects of litter and root inputs on soil CH4 uptake rates and associated microbial abundances in natural temperature subalpine forests.

Climate change altered the quantities of aboveground plant litter and root inputs, but the effects on soil CH4 uptake rates and underlying mechanisms remain unclear. To investigate these factors, a three-year detritus input and removal treatment (DIRT) study including six treatments (namely, CK, control; NL, litter removal; DL, double litter; NR, root exclusion; NRNL, root exclusion plus litter removal; and NRDL, root exclusion plus double litter) was conducted in broadleaf and coniferous forest subalpine forest ecosystems. The results showed that both the subalpine forest soils acted as sink for atmospheric CH4 across all treatments, while the broadleaf forest had consistently higher CH4 uptake rates than the coniferous forest. Based on the annual mean values, root exclusion (NR, NRNL and NRDL) significantly decreased soil CH4 uptake rates by 35.9 %, 31.0 % and 43.4 % in the broadleaf forest and 36.7 %, 31.9 % and 40.6 % in the coniferous forest compared with CK treatments, respectively. Meanwhile, the mean soil CH4 uptake rates were significantly reduced by 23.6 % and 17.3 % in the broadleaf forest and the coniferous forest under the DL treatments, respectively; nevertheless, the NL treatment significantly increased soil CH4 uptake rates by 19.68 % and 14.4 %, respectively. The results clearly demonstrated that root exclusion exerted a greater influence on soil CH4 uptake rates than plant litter manipulations. Correlation and redundancy analysis (RDA) revealed that the separation of root exclusion treatments from aboveground plant litter manipulations was based on higher soil water content, NH4+-N and NO3--N concentrations, and lower DOC (dissolved organic carbon) concentrations and methanotroph pmoA gene abundance. The results suggest that future alterations in aboveground plant litter and root input, particularly a reduction in root input, can exert a stronger influence on regulating soil CH4 uptake than aboveground litter manipulations in subalpine forests with cold and humid climatic conditions in response to future climate scenarios.

Genome-Wide Identification and Expression Analysis of bZIP Family Genes in Stevia rebaudiana.

The basic (region) leucine zippers (bZIPs) are evolutionarily conserved transcription factors widely distributed in eukaryotic organisms. In plants, they are not only involved in growth and development, defense and stress responses and regulation of physiological processes but also play a pivotal role in regulating secondary metabolism. To explore the function related to the bZIP gene family in Stevia rebaudiana Bertoni, we identified 105 SrbZIP genes at the genome-wide level and classified them into 12 subfamilies using bioinformation methods. Three main classes of cis-acting elements were found in the SrbZIP promoter regions, including development-related elements, defense and stress-responsive elements and phytohormone-responsive elements. Through protein-protein interaction network of 105 SrbZIP proteins, SrbZIP proteins were mainly classified into four major categories: ABF2/ABF4/ABI5 (SrbZIP51/SrbZIP38/SrbZIP7), involved in phytohormone signaling, GBF1/GBF3/GBF4 (SrbZIP29/SrbZIP63/SrbZIP60) involved in environmental signaling, AREB3 (SrbZIP88), PAN (SrbZIP12), TGA1 (SrbZIP69), TGA4 (SrbZIP82), TGA7 (SrbZIP31), TGA9 (SrbZIP95), TGA10 (SrbZIP79) and HY5 (SrbZIP96) involved in cryptochrome signaling, and FD (SrbZIP72) promoted flowering. The transcriptomic data showed that SrbZIP genes were differentially expressed in six S. rebaudiana cultivars ('023', '110', 'B1188', '11-14', 'GP' and 'GX'). Moreover, the expression levels of selected 15 SrbZIP genes in response to light, abiotic stress (low temperature, salt and drought), phytohormones (methyl jasmonate, gibberellic acid and salicylic acid) treatment and in different tissues were analyzed utilizing qRT-PCR. Some SrbZIP genes were further identified to be highly induced by factors affecting glycoside synthesis. Among them, three SrbZIP genes (SrbZIP54, SrbZIP63 and SrbZIP32) were predicted to be related to stress-responsive terpenoid synthesis in S. rebaudiana. The protein-protein interaction network expanded the potential functions of SrbZIP genes. This study firstly provided the comprehensive genome-wide report of the SrbZIP gene family, laying a foundation for further research on the evolution, function and regulatory role of the bZIP gene family in terpenoid synthesis in S. rebaudiana.

ROCK1 activates mitochondrial fission leading to oxidative stress and muscle atrophy.

Chronic kidney disease (CKD) is often associated with protein-energy wasting (PEW), which is characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress have been implicated to play a role in the pathogenesis of muscle wasting, the underlying mechanisms remain unclear. In this study, we used transcriptomics, metabolomics analyses and mouse gene manipulating approaches to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting in mouse CKD models. Our results showed that the expression of oxidative stress response genes was increased, and that of oxidative phosphorylation genes was decreased in the muscles of mice with CKD. This was accompanied by reduced oxygen consumption rates, decreased levels of mitochondrial electron transport chain proteins, and increased cellular oxidative damage. Excessive mitochondrial fission was also observed, and we found that the activation of ROCK1 was responsible for this process. Inducible expression of muscle-specific constitutively active ROCK1(mROCK1ca)exacerbated mitochondrial fragmentation and muscle wasting in CKD mice. Conversely, ROCK1 depletion (ROCK1-/-) alleviated these phenomena. Mechanistically, ROCK1 activation promoted the recruitment of Drp1 to mitochondria, thereby facilitating fragmentation. Notably, the pharmacological inhibition of ROCK1 mitigated muscle wasting by suppressing mitochondrial fission and oxidative stress. Our findings demonstrate that ROCK1 participates in CKD-induced muscle wasting by promoting mitochondrial fission and oxidative stress, and pharmacological suppression of ROCK1 could be a therapeutic strategy for combating muscle wasting in CKD conditions.

Reprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice.

A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a hierarchical structure of transcription factors that delineate a regulatory network in atrophic muscle, identifying ELK4 as a key atrophy-related transcription factor that instigates muscle atrophy through TGF-ß1 regulation. This study furnishes a rich genomic resource, essential for decoding the regulatory dynamics of skeletal muscle in both physiological and pathological states.

Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes.

Many studies have highlighted the importance of moderate exercise. While it can attenuate diabetic kidney disease, its mechanism has remained unclear. The level of myokine irisin in plasma increases during exercise. We found that irisin was decreased in diabetic patients and was closely related to renal function, proteinuria, and podocyte autophagy injury. Muscle-specific overexpression of PGC-1α (mPGC-1α) in a mouse model is known to increase plasma irisin levels. The mPGC-1α mice were crossed with db/m mice to obtain db/db mPGC-1α+ mice in the present study. Compared to db/db mice without mPGC-1α, plasma irisin was increased, and albuminuria and glomerular pathological damage were both alleviated in db/db mPGC-1α+ mice. Impaired autophagy in podocytes was restored as well. Irisin inhibited the activation of the PI3K/AKT/mTOR signaling pathway in cultured human podocytes and improved damaged autophagy induced by high glucose levels. Then, db/db mice were treated with recombinant irisin, which had similar beneficial effects on the kidney as those in db/db mPGC-1α+ mice, with alleviated glomerular injury and albuminuria. Moreover, the autophagy in podocytes was also significantly restored. These results suggest that irisin secreted by skeletal muscles protects the kidney from diabetes mellitus damage. It also restores autophagy in podocytes by inhibiting the abnormal activation of the PI3K/AKT/mTOR signaling pathway. Thus, irisin may become a new drug for the prevention and treatment of diabetic nephropathy.

Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation.

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1ß, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1ß levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1ß signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1ß levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3-/- mice or neutralizing anti-IL-1ß antibodies effectively reduced IL-1ß levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1ß antibodies may be beneficial in preventing CKD-induced AF.

Extracellular vesicle-packaged ILK from mesothelial cells promotes fibroblast activation in peritoneal fibrosis.

Progressive peritoneal fibrosis and the loss of peritoneal function often emerged in patients undergoing long-term peritoneal dialysis (PD), resulting in PD therapy failure. Varieties of cell-cell communications among peritoneal cells play a significant role in peritoneal fibrogenesis. Extracellular vesicles (EVs) have been confirmed to involve in intercellular communication by transmitting proteins, nucleic acids or lipids. However, their roles and functional mechanisms in peritoneal fibrosis remain to be determined. Using integrative analysis of EV proteomics and single-cell RNA sequencing, we characterized the EVs isolated from PD patient's effluent and revealed that mesothelial cells are the main source of EVs in PD effluent. We demonstrated that transforming growth factor-ß1 (TGF-ß1) can substitute for PD fluid to stimulate mesothelial cells releasing EVs, which in turn promoted fibroblast activation and peritoneal fibrogenesis. Blockade of EVs secretion by GW4869 or Rab27a knockdown markedly suppressed PD-induced fibroblast activation and peritoneal fibrosis. Mechanistically, injured mesothelial cells produced EVs containing high level of integrin-linked kinase (ILK), which was delivered to fibroblast and activated them via p38 MAPK signalling pathway. Clinically, the expression of ILK was up-regulated in fibrotic peritoneum of patients undergoing long-term PD. The percentage of ILK positive EVs in PD effluent correlated with peritoneal dysfunction and the degree of peritoneal damage. Our study highlights that peritoneal EVs mediate communications between mesothelial cells and fibroblasts to initiate peritoneal fibrogenesis. Targeting EVs or ILK could provide a novel therapeutic strategy to combat peritoneal fibrosis.

Cr(VI) anion-imprinted polymer synthesized on mesoporous silicon via synergistic action of bifunctional monomers for precise identification and separation of Cr(VI) from aqueous solution by fixed-bed adsorption.

The novel Cr(VI) anion-imprinted polymer (Cr(VI)-IIP) was prepared by a surface imprinting technique with bifunctional monomers pre-assembly system based on mesoporous silicon (SBA-15). The synthesized Cr(VI)-IIP was characterized by Fourier transmission infrared spectra (FT-IR), energy dispersive spectrometer (EDS), scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray powder diffractometer, N2 adsorption-desorption and thermogravimetric analysis (TGA), proving to be with a highly ordered mesoporous structure, as well as favorable thermal stability. The saturated adsorption amount was 96.32 mg/g, which was 2.7 times higher than that of non-imprinted polymer (NIP). Kinetic experiments showed that the adsorption equilibrium state was obtained within 70 min. In addition, in the selectivity experiments, Cr(VI)-IIP exhibited strong specific recognition ability for Cr(VI) and could realize the separation of Cr(VI) and Cr(III) from an aqueous solution. The dynamic adsorption experiments exhibited that the dynamic adsorption efficiency of Cr(VI)-IIP was as high as 71.57%. Meanwhile, the dynamic regeneration experiments showed that the adsorption amount of Cr(VI)-IIP did not decrease significantly after repeating for five times. All of the findings suggested that Cr(VI)-IIP could achieve precise identification as well as efficient separation of Cr(VI) from aqueous solution.

Proteomic Characterization of Peritoneal Extracellular Vesicles in a Mouse Model of Peritoneal Fibrosis.

Peritoneal fibrosis progression is regarded as a significant cause of the loss of peritoneal function, markedly limiting the application of peritoneal dialysis (PD). However, the pathogenesis of peritoneal fibrosis remains to be elucidated. Tissue-derived extracellular vesicles (EVs) change their molecular cargos to adapt the environment alteration, mediating intercellular communications and play a significant role in organ fibrosis. Hence, we performed, for the first time, four-dimensional label-free quantitative liquid chromatography-tandem mass spectrometry proteomic analyses on EVs from normal peritoneal tissues and PD-induced fibrotic peritoneum in mice. We demonstrated the alterations of EV concentration and protein composition between normal control and PD groups. A total of 2339 proteins containing 967 differentially expressed proteins were identified. Notably, upregulated proteins in PD EVs were enriched in processes including response to wounding and leukocyte migration, which participated in the development of fibrosis. In addition, EV proteins of the PD group exhibited unique metabolic signature compared with those of the control group. The glycolysis-related proteins increased in PD EVs, while oxidative phosphorylation and fatty acid metabolism-related proteins decreased. We also evaluated the effect of cell-type specificity on EV proteins, suggesting that mesothelial cells mainly cause the alterations in the molecular composition of EVs. Our study provided a useful resource for further validation of the key regulator or therapeutic target of peritoneal fibrosis.

Riverine CO2 variations in permafrost catchments of the Yangtze River source region: Hot spots and hot moments.

Rivers and streams are pivotal modulators in regional and global carbon cycles, but riverine CO2 flux is still uncertain for permafrost watersheds. Here we present the seasonal CO2 partial pressure (pCO2) and CO2 emission flux (FCO2) of 8 rivers and streams in the Yangtze River source region (YRSR), which have high permafrost coverage and seasonally thawed active layer. The YRSR rivers and streams are generally supersaturated with CO2, although there are a few sites with CO2 undersaturation during spring. The small headwater streams are CO2 hot spots that show significantly higher pCO2 (52 % higher) and FCO2 (792 % higher) than larger rivers. Both pCO2 and FCO2 show distinct seasonality across the study sites. pCO2 and FCO2 peak in summer and exhibit much lower levels in autumn and spring, indicating that hot moments of riverine CO2 occur in summer. Seasonal pCO2 and FCO2 variations are jointly controlled by hydrology, active layer dynamics and associated processes. The warm summer causes active layer thaw and highly active soil respiration, which release a large quantity of soil carbon and increase the CO2 sources via strengthened hydrologic connectivity. The high rainfall and more thaw-released water in summer bring high discharge, which can increase the water velocity and gas exchange rate and thus CO2 emission flux. Most of the variances of seasonal FCO2 (95 %) can be explained by hydrology and active layer thaw depth. Nevertheless, the hydrological process and seasonally thawed active layer over Qinghai-Tibet Plateau (QTP) play crucial roles in riverine carbon export due to the summer monsoon-dominated climate in QTP. Our results suggest that full seasonal coverage of CO2 dynamics is essential to quantify the annual CO2 flux accurately. Changing climate and warming permafrost may alter the annual CO2 emission due to deeper flow paths, hydrology changes, and longer emission windows throughout the year.

Buyang Huanwu decoction improves neural recovery after spinal cord injury in rats through the mTOR signaling pathway and autophagy.

BACKGROUND: Spinal cord injury (SCI) refers to the interruption of the tracts inside the spinal cord caused by various factors. The repair of damaged axons has always been a difficult point in clinical treatment and neuroscience research. The treatment of SCI with Buyang huanwu decoction (BYHWD), a well-known recipe for invigorating Qi (a vital force forming part of any living entity in traditional Chinese culture) and promoting blood circulation, shows a good effect. METHODS: The rubrospinal tract (RST) transection model in rats was established in this study and rats were administrated with low (BL), medium (BM), or high (BH) doses of BYHWD. RESULTS: Compared with the SCI group, BL, BM moderately, and BH significantly improved the motor function of forelimbs and increased the number of red nucleus neurons in SCI rats. As for the possible molecular mechanism, BL, BM moderately, and BH significantly increased mTOR whereas decreased Beclin-1 and LC3 in the red nucleus. CONCLUSION: In conclusion, low, medium, and high doses of BYHWD could promote neural recovery in SCI rats through improving motor function and neuron survival in the red nucleus. The neuroprotective effects of BYHWD might be associated with affecting the mTOR signaling pathway and autophagy.

Integrative transcriptome analysis reveals TEKT2 and PIAS2 involvement in diabetic nephropathy.

Cell heterogeneity has impeded the accurate interpretation of the bulk transcriptome data from patients with diabetic nephropathy (DN). We performed an analysis by integrating bulk and single-cell transcriptome datasets to uncover novel mechanisms leading to DN, especially in the podocytes. Microdissected glomeruli and tubules transcriptome datasets were selected from Gene Expression Omnibus (GEO). Then the consistency between datasets was evaluated. The analysis of the bulk dataset and single-nucleus RNA dataset was integrated to reveal the cell type-specific responses to DN. The candidate genes were validated in kidney tissues from DN patients and diabetic mice. We compared 4 glomerular and 4 tubular datasets and found considerable discrepancies among datasets regarding the deferentially expressed genes (DEGs), involved signaling pathways, and the hallmark enrichment profiles. Deconvolution of the bulk data revealed that the variations in cell-type proportion contributed greatly to this discrepancy. The integrative analysis uncovered that the dysregulation of spermatogenesis-related genes, including TEKT2 and PIAS2, was involved in the development of DN. Importantly, the mRNA level of TEKT2 was negatively correlated with the mRNA levels of NPHS1 (r = -.66, p < .0001) and NPHS2 (r = -.85, p < .0001) in human diabetic glomeruli. Immunostaining confirmed that the expression of TEKT2 and PIAS2 were up-regulated in podocytes of DN patients and diabetic mice. Knocking down TEKT2 resisted high glucose-induced cytoskeletal remodeling and down-regulation of NPHS1 protein in the cultured podocyte. In conclusion, the integrative strategy can help us efficiently use the publicly available transcriptomics resources. Using this approach and combining it with classical research methods, we identified TEKT2 and PIAS2, two spermatogenesis-related genes involved in the pathogenesis of DN. Furthermore, TEKT2 is involved in this pathogenesis by regulating the podocyte cytoskeleton.

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Current studies on water conservation capacity of litter in the mountainous area of Southwest China (MASC) mainly focus on local scale. Such results are difficult to evaluate the storage and water-holding capacity of litter in the whole MASC. In this study, the results of site-scale research in the MASC from 2004 to 2021 were collated (a total of 16 research sites and 70 data), as well as the storage and water-holding characteristics of litters of three typical forests in the MASC were compared and analyzed. The results showed that the water-holding processes of litter in coniferous forest, broadleaved forest and mixed forest were similar, which could be divided into three stages: rapid water absorption, gradual slowing, and stable. The absorption rate and duration of different forests were different in each stage. The broadleaved forest had the fastest water absorption rate, while coniferous forest had the slowest with the longest duration to reach stability. There was no significant difference in litter storage among diffe-rent forest types. The total litter storage of coniferous forest, broadleaved forest and mixed forest ranged from 8.26 to 8.82 t·hm-2. The significant spatial variations of litter storage in semi-decomposed layer resulted in that of total litter storage. The total maximum water-holding capacity of litters of the three forests ranged from 17.85 t·hm-2 to 19.87 t·hm-2, and the maximum water-holding rate of litter ranged from 200.6% to 228.0%. There was a positive correlation between the maximum water-holding capacity and litter storage in different forests. The total effective retention capacity of three forest litters ranged from 11.66 to 12.29 t·hm-2, while the total effective retention rate of three forests ranged from 128.1% to 145.2%. There were no significant differences in litter storage and water holding capacity among three forest types with two decomposition degrees in MASC.

SIRPα Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. RESULTS: We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. CONCLUSIONS: Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.