ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.

BACKGROUND: Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver. METHODS: In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments. RESULTS: The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals. CONCLUSIONS: The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

New isolate of sweet potato virus 2 from Ipomoea nil: molecular characterization, codon usage bias, and phylogenetic analysis based on complete genome.

BACKGROUND: Viral diseases of sweet potatoes are causing severe crop losses worldwide. More than 30 viruses have been identified to infect sweet potatoes among which the sweet potato latent virus (SPLV), sweet potato mild speckling virus (SPMSV), sweet potato virus G (SPVG) and sweet potato virus 2 (SPV2) have been recognized as distinct species of the genus Potyvirus in the family Potyviridae. The sweet potato virus 2 (SPV2) is a primary pathogen affecting sweet potato crops. METHODS: In this study, we detected an SPV2 isolate (named SPV2-LN) in Ipomoea nil in China. The complete genomic sequence of SPV2-LN was obtained using sequencing of small RNAs, RT-PCR, and RACE amplification. The codon usage, phylogeny, recombination analysis and selective pressure analysis were assessed on the SPV2-LN genome. RESULTS: The complete genome of SPV2-LN consisted of 10,606 nt (GenBank No. OR842902), encoding 3425 amino acids. There were 28 codons in the SPV2-LN genome with a relative synonymous codon usage (RSCU) value greater than 1, of which 21 end in A/U. Among the 12 proteins of SPV2, P3 and P3N-PIPO exhibited the highest variability in their amino acid sequences, while P1 was the most conserved, with an amino acid sequence identity of 87-95.3%. The phylogenetic analysis showed that 21 SPV2 isolates were clustered into four groups, and SPV2-LN was clustered together with isolate yu-17-47 (MK778808) in group IV. Recombination analysis indicated no major recombination sites in SPV2-LN. Selective pressure analysis showed dN/dS of the 12 proteins of SPV2 were less than 1, indicating that all were undergoing negative selection, except for P1N-PISPO. CONCLUSION: This study identified a sweet potato virus, SPV2-LN, in Ipomoea nil. Sequence identities and genome analysis showed high similarity between our isolate and a Chinese isolate, yu-17-47, isolated from sweet potato. These results will provide a theoretical basis for understanding the genetic evolution and viral spread of SPV2.

Revealing spatiotemporal heterogeneity of water conservation and its drivers: Enlightenment to water ecology protection and restoration.

Water conservation (WC) has emerged as one of the most vital services provided by basin ecosystems. Climate change, the conversion of farmland to forests, and the implementation of check dam projects significantly impact the WC function in the Malian River Basin (MRB) of the gully region, Loess Plateau. This study systematically and comprehensively reveals the variation rules of WC and the mechanisms of action of influence factors in the MRB and selects factors representing natural environmental changes and human activities, such as climate, geomorphology, vegetation, and soil, influencing the WC. The InVEST model and a modified formula were used to evaluate the WC and its spatial-temporal changes in the MRB. The response of influence factors to the WC was explored using a "geographical detection - spatial drive/inhibition - influence degree" framework. The results indicate that under the comprehensive influence of multiple factors, the spatial distribution of WC in the MRB remained relatively consistent over different periods, characterized by higher values in the southeast and lower in the northwest. The WC values in 1990, 2000, 2010, and 2020 were 2.57 × 104, 1.48 × 104, 2.19 × 104, and 1.93 × 104 m3, respectively. The interaction of two factors on WC had a more significant effect than single-factor interactions, particularly the interaction between Soil Saturated Water Conductivity (Ksat) and Annual Precipitation (Pre), Annual Evapotranspiration (AET), and Net Primary Productivity (NPP). Pre, Plant Available Water Content (PAWC), and Ksat are key positive drivers, while AET, Temperature (Temp), and Elevation (DEM) are crucial negative drivers. Climate factors had the largest explanatory power for the WC spatial pattern (34.03-36.54%), geomorphic factors had the least (16.60-17.50%), and vegetation factors more than soil factors. This study provides valuable insights for optimal water resource allocation and sustainable development of the gully region, Loess Plateau.

Lycium barbarum pulp addition improves the dough properties and gluten protein structure.

This study investigated the effects of Lycium barbarum pulp (LBP) on the properties of mixed dough and gluten protein. The results showed that appropriate addition of LBP (5 %) significantly improved the performance of the dough, promoted the aggregation of gluten protein, enhanced the water binding ability, and delayed the gelatinization of starch during cooking. Compared with the control group, the peak temperature (Tp) of the LBP sample gradually increased from 63.23 °C to 65.56 °C, the expansion force reduced by about 21.56 %, the absolute Zeta potential lowered by about 18.4 %, and the α -helix content and ß -folding increased by 32.36 % and 10.23 %, respectively, indicating the more orderly and stable overall structure. However, LBP did not change the crystal configuration of starch and still showed typical type A line diffraction. Moreover, the addition of LBP increased the polyphenol content, which further improved the antioxidant properties and provided the possibility to improve the health potential of the flour.

A new strategy for the treatment of intracerebral hemorrhage: Ferroptosis.

Intracerebral hemorrhage, is a cerebrovascular disease with high morbidity, mortality, and disability. Due to the lack of effective clinical treatments, the development of new drugs to treat intracerebral hemorrhage is necessary. In recent years, ferroptosis has been found to play an important role in the pathophysiological process of intracerebral hemorrhage, which can be treated by inhibiting ferroptosis and thus intracerebral hemorrhage. This article aims to explain the mechanism of ferroptosis and its relationship to intracerebral hemorrhage. In the meantime, it briefly discusses the molecules identified to alleviate intracerebral hemorrhage by inhibiting ferroptosis, along with other clinical agents that are expected to treat intracerebral hemorrhage through this mechanism. In addition, a brief overview of the morphological alterations of different forms of cell death and their role in ICH is provided. Finally, the challenges that may arise in translating ferroptosis inhibitors from basic research to clinical use are presented. This article serves as a reference and provides insights to aid in the treatment of intracerebral hemorrhage in the clinic.

Inhibiting S-palmitoylation arrests metastasis by relocating Rap2b from plasma membrane in colorectal cancer.

Rap2b, a proto-oncogene upregulated in colorectal cancer (CRC), undergoes protein S-palmitoylation at specific C-terminus sites (C176/C177). These palmitoylation sites are crucial for Rap2b localization on the plasma membrane (PM), as mutation of C176 or C177 results in cytosolic relocation of Rap2b. Our study demonstrates that Rap2b influences cell migration and invasion in CRC cells, independent of proliferation, and this activity relies on its palmitoylation. We identify ABHD17a as the depalmitoylating enzyme for Rap2b, altering PM localization and inhibiting cell migration and invasion. EGFR/PI3K signaling regulates Rap2b palmitoylation, with PI3K phosphorylating ABHD17a to modulate its activity. These findings highlight the potential of targeting Rap2b palmitoylation as an intervention strategy. Blocking the C176/C177 sites using an interacting peptide attenuates Rap2b palmitoylation, disrupting PM localization, and suppressing CRC metastasis. This study offers insights into therapeutic approaches targeting Rap2b palmitoylation for the treatment of metastatic CRC, presenting opportunities to improve patient outcomes.

Protective Effect of Modified Ginseng Baidu Powder Prophylactic Administration on LPS-Induced Acute Respiratory Distress Syndrome in Mice.

Severe Corona Virus Disease 2019 (COVID-19) patients may develop acute respiratory distress syndrome (ARDS). Modified Ginseng Baidu Powder (referred to as Baidu Powder) was used for respiratory system diseases caused by colds. To study the effect of Baidu Powder on protecting ARDS mice model and its underlying active ingredients and targets intervening in COVID-19. The optimal LPS concentration was selected for the induction of mouse ARDS model, and the protective effect of Baidu Powder prophylactic administration on LPS-induced ARDS mouse models was explored by mouse survival time analysis, lung wet/dry weight (W/D) ratio, pathological staining, and inflammatory factor detection. On the basis of pharmacodynamics, the network pharmacological analysis was used for target prediction for future mechanism study. 5 mg/kg LPS was selected for the construction of a mouse ARDS model, based on a mortality rate of 87% and the lung W/D ratio of 5.29 ± 0.23. Prophylactic administration of Baidu Powder at 125 g/L significantly reduced death, lung damage, inflammatory cell infiltration, and cytokine production (TNF-α, IL-6, and IL-10) caused by LPS-induced ARDS. The results of network pharmacological analysis showed that 42 target genes of Baidu Powder intervening in COVID-19 were involved in 30 biological processes related to COVID-19 and inflammation, and 11 signaling pathways related to lung diseases or inflammation. 5 mg/kg LPS can successfully establish a mice ARDS disease model; 125 g/L Baidu Powder prophylactic administration does not have toxicity and has a certain effect on protecting ARDS mouse models induced by LPS. Baidu Powder may intervene COVID-19-induced ARDS through multiple targets.

A Highly Robust, Multifunctional, and Breathable Bicomponent Fibers Thermoelectric Fabric for Dual-Mode Sensing.

Wearable thermoelectric (TE) materials are seen as excellent candidates for flexible electronics because of their unique self-powered properties, multistimulus sensing and human waste heat conversion. However, currently reported flexible TE materials still face challenges such as poor durability, uncomfortable wearing and sensing signals crosstalking each other. Herein, this study describes a hot-air cross-linking method for the preparation of multifunctional TE fabrics with enhanced durability. Poly(ethylene terephthalate) (PET) fibers with core and sheath structures having different melting points were selected as flexible substrates. Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) and single-walled carbon nanotubes (SWCNTs) were embedded stably on the surface of the sheath layer in the presence of heat treatment. The fiber-welded structure created by thermal cross-linking improves the durability of TE fabrics, including consistent mechanical and electrical properties after a 6 h wash test and 6000 compression cycles. The unique fiber structure of TE fabrics ensures excellent breathability (313.7 mm s-1 at 200 Pa), which meets the breathability requirements for human wear. In addition, the fiber-prepared sensors have excellent compressive strain response (20 ms response time and 30 ms recovery time) and precise temperature discrimination (0.17 K minimum discrimination temperature) for accurate real-time monitoring of the sensed signals. Thus, the TE fabrics can be used for human motion recognition, including pulse monitoring, sign language expression, and motions in joint areas. Moreover, the fabricated wearable TE device is connected to a Bluetooth module for wireless transmission, which can be used for mechanical and temperature sensing of the robot arm without signals crosstalking. This new durable TE fabric paves the way for the next generation of smart wearable technology.

Discussion on clinical application and regularity of the theory of "mind-regulating" in clinical acupuncture and moxibustion treatment. / "调神"思想在针灸临床中的运用概况及规律探讨.

The active role of "Shen" (mind) in the process of disease treatment has always been valued by scholars of traditional Chinese medicine (TCM). "Tiaoshen" (mind-regulating) is regarded as the fundamental component of TCM therapy. "Mind-regulating" acupuncture and moxibustion therapy, as a treatment method for both body and mind, is consistent with the present bio-psycho-social medical model. In recent years, a large number of clinical studies have confirmed the exact efficacy of "mind-regulating" acupuncture and moxibustion therapy. This article reviewed the clinical applications of that in psychosomatic diseases, neurological diseases, and digestive diseases over the last decade. This article also summarized the research progress of various "mind-regulating" acupuncture and moxibustion methods, investigated the theoretical connotations of "Tongdu Tiaoshen" (dredging Governor Vessel and regulating mind) acupuncture, "Shugan Tiaoshen" (soothing liver and regulating mind) acupuncture, and the "Tiaoshen needling technique" (mind-regulating needling technique), and generalized the main acupoint selection rules. Lastly, future development directions were provided for the theoretical basis of clinical application of "mind-regulating" acupuncture and moxibustion therapy for further improvement.

Divergent Reactions of α-Diazo 1,3-Dicarbonyl Compounds with Allylic Carbonates Involving Ketene versus Carbene Intermediates Enabled by Cooperative Rh(II)/Pd(0) Dual Catalysis.

A cooperative Rh(II)/Pd(0) dual-catalysis strategy that enabled divergent reactions of α-diazo 1,3-dicarbonyl compounds with allylic carbonates involving ketene versus carbene intermediates is described. The efficient synthesis of α-quaternary allylated ß-keto-esters was accomplished by the Rh(II)/Pd(0) dual-catalysis allylic alkylation of α-diazo 1,3-dicarbonyl compounds. Alternatively, an unprecedented (1+4) annulation of α-diazo 1,3-dicarbonyl compounds with 2-(hydroxymethyl)allyl carbonates via Rh(II)/Pd(0) dual catalysis was also successfully developed, affording a wide variety of α-quaternary tetrahydrofurans in good to high yields.

OS-PSO: A Modified Ratio of Exponentially Weighted Averages-Based Optical and SAR Image Registration.

Optical and synthetic aperture radar (SAR) images exhibit non-negligible intensity differences due to their unique imaging mechanisms, which makes it difficult for classical SIFT-based algorithms to obtain sufficiently correct correspondences when processing the registration of these two types of images. To tackle this problem, an accurate optical and SAR image registration algorithm based on the SIFT algorithm (OS-PSO) is proposed. First, a modified ratio of exponentially weighted averages (MROEWA) operator is introduced to resolve the sudden dark patches in SAR images, thus generating more consistent gradients between optical and SAR images. Next, we innovatively construct the Harris scale space to replace the traditional difference in the Gaussian (DoG) scale space, identify repeatable key-points by searching for local maxima, and perform localization refinement on the identified key-points to improve their accuracy. Immediately after that, the gradient location orientation histogram (GLOH) method is adopted to construct the feature descriptors. Finally, we propose an enhanced matching method. The transformed relation is obtained in the initial matching stage using the nearest neighbor distance ratio (NNDR) and fast sample consensus (FSC) methods. And the re-matching takes into account the location, scale, and main direction of key-points to increase the number of correctly corresponding points. The proposed OS-PSO algorithm has been implemented on the Gaofen and Sentinel series with excellent results. The superior performance of the designed registration system can also be applied in complex scenarios, including urban, suburban, river, farmland, and lake areas, with more efficiency and accuracy than the state-of-the-art methods based on the WHU-OPT-SAR dataset and the BISTU-OPT-SAR dataset.

'Risk-benefit' assessment for comprehensive safety evaluation of Chinese patent medicines containing four common toxic ingredients: an analysis of clinical risk factors.

Background: Chinese patent medicines are specialty preparations in China that are produced using traditional prescriptions processed by modern pharmaceutical technology. They contain complex ingredients and much attention is paid to their clinical safety. Demonstrating the clinical safety of Chinese patent medicines containing toxic ingredients in modern pharmacological studies has become one of the urgent issues to be solved for the safe use of clinical medicines. Objectives: The aim of this research is to evaluate the safety of Chinese patent medicines containing toxic ingredients by applying the risk-benefit assessment method. Additionally, a database of 'toxic ingredients-toxic Chinese herbal medicines-adverse reactions' will be established to explore the relationship between toxic ingredients and adverse reactions. This will lay the foundation for the rational clinical use of Chinese patent medicines containing toxic ingredients. Methods: 1) Establish a database of 'toxic Chinese herbal medicines-toxic ingredients-toxic Chinese patent medicines' to count the Chinese patent medicines containing toxic ingredients in the 2020 edition of Chinese Pharmacopoeia. 2) Filtered the clinical studies, extracted the drug-related ADEs, and analyzed the characteristics and correlations of these ADEs. 3) Finally, this section summarizes the causes of ADEs related to Chinese patent medicines containing toxic ingredients and extracts the main risk factors to provide a reference for further study. Outcomes: 1) There are four main types of Chinese patent medicines containing toxic ingredients. These include medicines with diester aconitine metabolites, mineral composition, Araceae metabolites, and hydrogen cyanide. 2) Digestive system, skin and its appendages, and allergic reactions were the main types of ADEs related to four types of Chinese patent medicines containing toxic ingredients. 3) There are four primary risk factors associated with the clinical use of Chinese patent medicines containing toxic ingredients: medicine, medication, individual and regulatory factors.

Development of Neural Cells and Spontaneous Neural Activities in Engineered Brain-Like Constructs for Transplantation.

Stem cell transplantation has demonstrated efficacy in treating neurological disorders by generating functional cells and secreting beneficial factors. However, challenges remain for current cell suspension injection therapy, including uncontrollable cell distribution, the potential for tumor formation, and limited ability to treat spatial defects. Therefore, implants with programmable cell development, tailored 3D structure, and functionalized biomaterials have the potential to both control cell distribution and reduce or heal spatial defects. Here, a biomimetic material system comprising gelatin, alginate, and fibrinogen has been developed for neural progenitor cell constructs using 3D printing. The resulting constructs exhibit excellent formability, stability, and developmental functions in vitro, as well as biocompatibility and integration into the hippocampus in vivo. The controllability, reproducibility, and material composition of the constructs show potential for use in personalized stem cell-based therapies for defective neurological disorders, neural development research, disease modeling, and organoid-derived intelligent systems.

A study on the determination of the metabolites of 2,4,6-Trinitrotoluene using a dual-drift tube ion mobility spectrometer.

2,4,6-Trinitrotoluene (TNT) and its four metabolites, namely 2-ADNT, 4-ADNT, 2,4-DANT, and 2,6-DANT, are highly toxic substances. These metabolites also serve as biomarkers for assessing the health of individuals exposed to TNT. In this study, a homemade DDT-IMS apparatus was utilized to detect these metabolites. Under negative detection mode, the drift times of 2-ADNT and 4-ADNT showed subtle shifts within a drift tube temperature range of 100 °C-120 °C, aiding in their differentiation. In positive detection mode for 2,4-DANT and 2,6-DANT, significant variations were observed in both the number and drift time of their positive product ions across a drift tube temperature range of 80 °C-120 °C. Consequently, optimal analytical performance for these metabolites was achieved at approximately 100 °C. Evaluation of the instrumental response during the measurement of the four metabolites in both positive and negative modes revealed that negative detection mode offered greater advantages of detecting these compounds. The working ranges for measuring the four metabolites spanned two orders of magnitude, with detection limits for each metabolite nearly below 1 ng. Notably, clear identification of the signals for these metabolites was achieved even when samples were mixed in urine, highlighting the ability of the DDT-IMS in detecting TNT metabolites. The developed DDT-IMS detection method has significant potential for enhancing environmental risk assessment and biological hazard evaluation, particularly in relation to human exposure to TNT.

Significant chlorine emissions from biomass burning affect the long-term atmospheric chemistry in Asia.

Biomass burning (BB) is a major source of trace gases and particles in the atmosphere, influencing air quality, radiative balance, and climate. Previous studies have mainly focused on the BB emissions of carbon and nitrogen species with less attention on chlorine. Reactive chlorine chemistry has significant effects on atmospheric chemistry and air quality. However, quantitative information on chlorine emissions from BB, particularly the long-term trend and associated atmospheric impacts, is limited both on regional and global scales. Here, we report a long-term (2001-2018) high-resolution BB emission inventory for the major chlorine-containing compounds (HCl, chloride, and CH3Cl) in Asia based on satellite observations. We estimate an average of 730 Gg yr-1 chlorine emitted from BB activity in Asia, with China contributing the largest share at 24.2% (177 Gg yr-1), followed by Myanmar at 18.7% and India at 18.3%. Distinct seasonal patterns and significant spatial and interannual variability are observed, mainly driven by human-mediated changes in agricultural activity. By incorporating the newly developed chlorine emission inventory into a global chemistry-climate model (CAM-Chem), we find that the BB-chlorine emissions lead to elevated levels of HCl and CH3Cl (monthly average up to 2062 and 1421 parts per trillion by volume (pptv), respectively), subsequently resulting in noticeable changes in oxidants (up to 3.1% in O3 and 17% in OH radicals). The results demonstrate that BB is not only a significant source of air pollutants but also of oxidants, suggesting a larger role of BB emissions in the atmospheric chemistry and oxidation process than previously appreciated. In light of the projected increase in BB activity toward the end of the century and the extensive control of anthropogenic emissions worldwide, the contribution of BB emissions may become fundamental to air quality composition in the future.

Hopping backward to move forward: Single-leg backward hopping can better detect decreased quadriceps strength induced by a fatigue protocol compared to forward and vertical hopping.

BACKGROUND: Deficits in quadriceps strength of the injured leg have been observed in patients following anterior cruciate ligament (ACL) reconstructions and may contribute to ACL re-injury risk. Single-leg forward hopping is a widely used task for assessing knee function in patients following ACL reconstructions as it has been shown not to be particularly challenging to the knee. This study aimed to quantify the effect of decreased quadriceps strength induced by a fatigue protocol on hopping performance and lower limb mechanics in single-leg forward, vertical, and backward hopping. METHODS: Thirty-four injury-free participants performed single-leg forward, vertical, and backward hopping on both legs pre- and post-fatigue, with 1 leg experiencing a fatigue protocol. Peak moments, power, and work of hip, knee, and ankle joints were quantified during the jumping phase. Hopping performance and bilateral asymmetries in performance were assessed. RESULTS: Single-leg backward hopping demonstrated the greatest knee moments, power, and work compared to forward and vertical hopping, regardless of leg and fatigue. Fatigue protocol resulted in significantly less knee moments, power, and work, and decreased performance of the fatigued leg among all tasks. Bilateral symmetries in hopping performance decreased in post-fatigue, with the greatest decrease in backward hopping. CONCLUSION: The greater sensitivity of the backward hopping to detect quadriceps fatigue suggests it may act as a better or at least an additional metric to evaluate quadriceps strength deficits. The findings may contribute to the development of a clinically applicable and valid strength assessment to monitor the rehabilitation progress in patients following ACL reconstructions.

LncRNA-Mediated TPI1 and PKM2 Promote Self-Renewal and Chemoresistance in GBM.

Temozolomide (TMZ) resistance is one of the major reasons for poor prognosis in patients with glioblastoma (GBM). Long noncoding RNAs (lncRNAs) are involved in multiple biological processes, including TMZ resistance. Linc00942 is a potential regulator of TMZ sensitivity in GBM cells is shown previously. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. In this study, the sequence of Linc00942 by rapid amplification of cDNA ends assay in TMZ-resistant GBM cells is identified and confirmed that Linc00942 contributes to self-renewal and TMZ resistance in GBM cells. Chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) and followed by Western blotting (ChIRP-WB) assays shows that Linc00492 interacted with TPI1 and PKM2, subsequently promoting their phosphorylation, dimerization, and nuclear translocation. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, the knockdown of SOX9 reversed TMZ resistance induced by Linc00492 both in vitro and in vivo. In summary, Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self-renewal and TMZ resistance in GBM cells. These findings suggest potential combined therapeutic strategies to overcome TMZ resistance in patients with GBM.

Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a predominant type of heart failure. Exploring new pathogenesis and identifying potential novel therapeutic targets for HFpEF is of paramount importance. Methods: HFpEF mouse model was established by the "Multiple-hit" strategy, in that 18- to 22-month-old female C57B6/J mice fed with a high-fat diet were further challenged with chronic infusion of Angiotensin II. RNA sequencing analysis showed that USP7 was significantly increased in the heart of HFpEF mice. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, in conjunction with co-immunoprecipitation (Co-IP) techniques, identified expression of SMAD3, the key molecule of endothelial-to-mesenchymal transition (EndMT), was also significantly elevated. USP7 endothelium-specific knockout mice was generated to investigate the involvement of USP7 in HFpEF. The biological significance of the interaction between USP7 and SMAD3 was further explored. Results: USP7 promotes EndMT and cardiac fibrosis by binding to SMAD3 directly via its UBL (Ubiquitin-like) domain and cysteine at position 223 of USP7, leading SMAD3 deubiquitination to maintain the stability of SMAD3 by removing the K63 ubiquitin chain and preventing the degradation of SMAD3 by proteasomal process. USP7 also promotes SMAD3 phosphorylation and nuclear translocation, thereby aggravating EndMT and cardiac fibrosis. Endothelium-specific USP7 knockout led to improvement of HFpEF phenotypes and reduction of cardiac fibrosis. Overexpression of SMAD3 in endothelium-specific knockout HFpEF mice reversed the protective effects of USP7 knockout in this HFpEF mouse model. Conclusion: Our results indicated that USP7 is one of the key pathogenic molecules of HFpEF, and knocking out USP7 could attenuate HFpEF injury by promoting the degradation of SMAD3. USP7 and SMAD3 inhibition might be potential therapeutic options for HFpEF.

A new input-output-based framework for measuring the active and passive water use.

•Construct a dual-perspective framework for measuring water use.•Define the water use fluctuating due to macroeconomic condition changes.•Introduce a new indicator to measure the rate of passive water use.•Estimate the key water use channels from a passive perspective through SPA.•Discuss the supply chain's intermediate sector's role for the water use.

Identification and mechanistic analysis of neurovascular coupling related biomarkers for diabetic macular edema.

Introduction: Diabetic macular edema (DME) is a major cause of vision loss in the sick with diabetic retinopathy. The occurrence of DME is closely related to the breakdown of neurovascular coupling; however, its underlying mechanism has not been fully elucidated. The aim of this study was to investigate the diagnostic biomarkers and potential molecular mechanisms associated with neurovascular coupling in DME. Methods: The differential expression analysis, STEM, and WGCNA were performed from GSE160306 to identify hub genes. The gene expression was validated by RT-qPCR. The relevant mechanisms of action were investigated through GO, KEGG, and GSEA analyses, as well as co-expression networks. Additionally, the LASSO regression analysis and a nomogram were used to demonstrate the diagnostic effectiveness of the model. Finally, the GenDoma platform was utilized to identify drugs with potential therapeutic effects on DME. Results: Neurotrophic factor receptor (NGFR) was identified as a hub gene related to neurovascular coupling and DME. The expression of NGFR was verified by RT-qPCR in vitro cells. GSEA analysis indicated that high expression of NGFR may affect immunity and inflammatory pathway, thereby regulating neurovascular coupling and mediating the development of DME. The NGFR co-expression network was constructed, which exhibited the correlation with the neurotrophin signaling pathway. Moreover, a diagnostic model for DME based on NGFR and PREX1 demonstrated relatively good diagnostic performance using LASSO regression analysis and the nomogram. And then the GenDoma platform identified drugs with potential therapeutic effects on DME. Conclusion: The high expression of NGFR may lead to abnormal neurovascular coupling and participate in the occurrence of DME by regulating the immunity, inflammatory and neurotrophin signaling pathway. Detection of NGFR and related expression genes may be beneficial for monitoring the occurrence and development of DME.