Deterministic Restriction on Pluripotent State Dissolution by Cell-Cycle Pathways.

During differentiation, human embryonic stem cells (hESCs) shut down the regulatory network conferring pluripotency in a process we designated pluripotent state dissolution (PSD). In a high-throughput RNAi screen using an inclusive set of differentiation conditions, we identify centrally important and context-dependent processes regulating PSD in hESCs, including histone acetylation, chromatin remodeling, RNA splicing, and signaling pathways. Strikingly, we detected a strong and specific enrichment of cell-cycle genes involved in DNA replication and G2 phase progression. Genetic and chemical perturbation studies demonstrate that the S and G2 phases attenuate PSD because they possess an intrinsic propensity toward the pluripotent state that is independent of G1 phase. Our data therefore functionally establish that pluripotency control is hardwired to the cell-cycle machinery, where S and G2 phase-specific pathways deterministically restrict PSD, whereas the absence of such pathways in G1 phase potentially permits the initiation of differentiation.

HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling.

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.

Vitamin D May Play a Vital Role in Alleviating Type 2 Diabetes Mellitus by Modulating the Ferroptosis Signaling Pathway.

Ferroptosis is an iron-dependent death mode mediated by the aggregation of lipid peroxides and lipid-reactive oxygen species. It is characterized by iron-dependent lipid peroxide accumulation accompanied by oxidoreductase deficiency. Pancreatic beta cell dysfunction and insulin resistance are two major causes of type 2 diabetes mellitus (T2DM). Iron accumulation and metabolism may play a role in the development of T2DM. The molecular mechanism of ß cell apoptosis and iron death in T2DM were reviewed. In addition, we discuss recent insights on the relationship between the trace element iron and apoptosis of ß cells in T2DM.

Ac2-26 activated the AKT1/GSK3ß pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. METHODS: Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups were injected with shRNA, inhibitor and agonist of GSK3ß respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein ß(S100ß) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. RESULTS: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3ß. The agonist of GSK3ß recovered the protection of Ac2-26 in presence of shRNA. CONCLUSIONS: Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3ß pathway.

CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.

Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.

Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.

A new cassane diterpenoid from the seed of Caesalpinia sappan.

In this study, a previously undescribed cassane diterpenoid, named caesalpinin JF (1), along with two known cassane diterpenoids caesanine C (2) and tomocinol B (3), was isolated from 95% EtOH extract of the seeds of Caesalpinia sappan Linn. Additionally, three known compounds including pulcherrin R (4), syringaresinol-4'-O-ß-D-glucopyranoside (5) and kaempferol (6) were also identified. The structures of the isolated compounds were elucidated by comprehensive 1D and 2D NMR spectroscopic analyses. Additionally, electronic circular dichroism (ECD) calculation was used to identify the absolute structure of compound 1. Among the isolated compounds, compound 1 displayed a potent anti-neuroinflammation with an IC50 value of 9.87 ± 1.71 µM.

[Noise exposure-induced stress response and its measurement methods].

Noise, as an unavoidable stress (pressure) source in the modern life, affects animals in many ways, both behaviorally and physiologically. Behavioral changes may be driven by changes in hormone secretion in animals. When animals face with noise stress, the neuroendocrine systems, mainly the hypothalamic-pituitary-adrenal (HPA) axis, are activated, which promotes the secretion and release of stress hormones, and then leads to a series of behavioral changes. The behavioral changes can be easily observed, but the changes in physiological indicators such as hormone levels need to be accurately measured. Currently, many studies have measured the variations of stress hormone levels in animals under different noise conditions. Taking glucocorticoid as an example, this paper summarizes the different measurement methods of stress hormones, especially the non-invasive measurement methods, and compares the advantages and shortcomings of them. It provides a variety of measurement choices for the study of related issues, and also helps us to further understand the sources of animal stress, in order to provide a better habitat for animals.

Near-Full-Spectrum Emission Realized in a Single Lead Halide Perovskite across the Visible-Light Region.

The engineering of tunable photoluminescence (PL) in single materials with a full-spectrum emission represents a highly coveted objective but poses a formidable challenge. In this context, the realization of near-full-spectrum PL emission, spanning the visible light range from 424 to 620 nm, in a single-component two-dimensional (2D) hybrid lead halide perovskite, (ETA)2PbBr4 (ETA+ = (HO)(CH2)2NH3+), is reported, achieved through high-pressure treatment. A pressure-induced phase transition occurs upon compression, transforming the crystal structure from an orthorhombic phase under ambient conditions to a monoclinic structure at high pressure. This phase transition driven by the adaptive and dynamic configuration changes of organic amine cations enables an effective and continuous narrowing of the bandgap in this halide crystal. The hydrogen bonding interactions between inorganic layers and organic amine cations (N-H…Br and O-H…Br hydrogen bonds) efficiently modulate the organic amine cations penetration and the octahedral distortion. Consequently, this phenomenon induces a phase transition and results in red-shifted PL emissions, leading to the near-full-spectrum emission. This work opens a possibility for achieving wide PL emissions with coverage across the visible light spectrum by employing high pressure in single halide perovskites.

Highly Efficient Stable Luminescent Radical-Based X-ray Scintillator.

Stable luminescent radicals are open-shell emitters with unique doublet emission characteristics. This feature makes stable luminescent radicals exhibit widespread application prospects in constructing optical, electrical, and magnetic materials. In this work, a stable luminescent radical-based X-ray scintillator of AuPP-1.0 was prepared, which exhibited a high X-ray excited luminescence (XEL) efficiency as well as excellent stability. A mechanism study showed that the heavy atom of Au in AuPP-1.0 endowed it with effective absorption of X-rays, and the doublet emission characteristics of AuPP-1.0 significantly increased its exciton utilization rate in the radioluminescence process. Moreover, AuPP-1.0 has good processability to fabricate a flexible screen for high-quality X-ray imaging, whose resolution can reach 20 LP mm-1. This work demonstrates that the doublet emission is beneficial for improving the exciton utilization rate of radioluminescence, providing a brand-new strategy for the construction of high-performance X-ray scintillators.

No-touch endoscopic full-thickness resection technique for gastric gastrointestinal stromal tumors.

BACKGROUND : There remain concerns regarding the technical feasibility of endoscopic resection for large gastrointestinal stromal tumors (GISTs), mainly relating to the risk of tumor rupture and the adequacy of the resection margins. This study aimed to evaluate the feasibility and therapeutic outcomes of the newly developed no-touch endoscopic full-thickness resection (NT-EFTR) technique for GISTs. METHODS : In this retrospective study, 92 patients with gastric GISTs undergoing NT-EFTR were included. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS : The median tumor size was 2.5 cm and en bloc resection was achieved in all patients with negative surgical margins. The median time of the NT-EFTR procedure was 59.5 minutes. Large tumors (> 3.0 cm), extraluminal tumor growth pattern, and large gastric defects were significant contributors to long operative times. Patients were discharged within 4 days postoperatively. During follow-up, all patients were free from local recurrence and distant metastasis. CONCLUSIONS : NT-EFTR was a feasible method for the resection of gastric GISTs and can be expected to achieve complete radical resection. Large tumors with extraluminal growth and large gastric defects impact procedural difficulty.

Recent advances in radical-mediated intermolecular (4 + 2) cycloaddition.

(4 + 2) Cycloaddition plays an important role in the synthesis of versatile carbocyclic/heterocyclic compounds with its high atom- and step-economy. Additionally, with mild conditions and indispensable functional group compatibility, the radical reaction has been recognized as a useful tool in organic chemistry. Given the enormous impact of radical-mediated (4 + 2) cycloaddition processes and their promising applications, we summarize and highlight the recent works in this attractive area. On the basis of the types of radicals that initiate different (4 + 2) cycloaddition processes, we classify them into processes involving alkenyl cations or alkenyl radicals, aryl radicals, acyl radicals, alkyl radicals, and heteroatom radicals, and this review places special emphasis on the reaction design and mechanisms, which will stimulate future developments in radical-mediated intermolecular (4 + 2) cycloaddition.

Comparing vitamin B2 versus 5% dextrose in water for optimal ureteric jet visualisation at the time of pelvic reconstructive surgery: A randomised controlled trial.

OBJECTIVE: To compare preoperative vitamin B2 versus intraoperative cystoscopy distension using 5% dextrose in water (D5W) for ureteric jet visualisation during pelvic reconstructive surgery. DESIGN: Double-blinded, randomised controlled trial. SETTING: Three tertiary hospitals in Toronto, Canada. POPULATION: Adult women undergoing pelvic reconstructive surgery. METHODS: Patients were randomised to receive 100 mg of vitamin B2 preoperatively versus bladder distension with D5W intraoperatively. MAIN OUTCOMES: The primary outcome was the rate of accurate detection of bilateral ureteric jets during cystoscopy. Secondary outcomes included the time elapsed until visualisation, use of intravenous furosemide or fluorescein to assist with visualisation, surgeon satisfaction, and positive urine culture 1 week after surgery. RESULTS: The intervention was completed by 236 patients (vitamin B2 n = 117, D5W n = 119). Preoperative characteristics were similar across groups. Accurate detection of both ureteric jets was high in both groups (vitamin B2 97.4% vs. D5W 90.8%, p = 0.051). The vitamin B2 group had significantly lower use of fluorescein rescue compared with the D5W group (3.4% vs. 11.8%, respectively, p = 0.025). Surgeon satisfaction while using vitamin B2 was significantly higher (p < 0.001). There were no significant differences in the time elapsed until visualisation, the use of furosemide, or the incidence of positive urine culture at 1 week after surgery. CONCLUSIONS: Both preoperative vitamin B2 and intraoperative cystoscopy distension with D5W are highly available and inexpensive methods to detect ureteric jets with high accuracy at the time of pelvic reconstructive surgery. Vitamin B2 was shown to have lower rates of fluorescein rescue for visualisation and higher rates of surgeon satisfaction.

The CSN5/HSF/SPI1/PU.1 Axis Regulates Cell Proliferation in Hypocellular Myelodysplastic Syndrome Patients.

OBJECTIVE: This study explored the relationship between the activation of the jak/stat3 signaling pathway and the CSN5 gene transcript and protein expression levels in the hematopoietic stem cells of patients with myelodysplastic syndromes (MDSs). This study also aimed to investigate the correlation between the expression level of CSN5 and the deubiquitination of HSF1, as well as the transcript level of the spi1/pu.1 genes to explore the pathogenesis of MDS. MATERIALS AND METHODS: We isolated cells from normal individuals and MDS patients, and the mRNA and protein expression levels of spi1/pu.1 in cd34+ cells (hematopoietic stem cells) were measured by PCR and western blotting, respectively. A ChIP assay was used to detect the binding of HSF1 to the spi1/pu.1 promoter in cd34+ cells. The ubiquitination of HSF1 in cd34+ cells was detected by CO-IP. The binding of HSF1 and Fbxw7α was detected in in cd34+ cells by CO-IP. The binding of HSF1 and CSN5 was evaluated. A luciferase reporter assay was used to detect the effect of STAT3 on CSN5 promoter activation in cd34+ cells. Western blotting was used to detect the phosphorylation of STAT3 in cd34+ cells of MDS patients. The binding of STAT3 and C/EBP beta in cd34+ cells was detected by CO-IP. RESULTS: Inhibition of SPI1/PU.1 expression was observed in MDS samples with low proliferation ability. Further experiments proved that phosphorylation of STAT3 affected CSN5 function and mediated the ubiquitination of HSF, the upstream regulator of SPI1/PU.1 transcription, which led to the inhibition of SPI1/PU.1 expression. Restoration of CSN5 rescued the inhibition of HSF1 ubiquitination, causing SPI1/PU.1 transcription to resume and increasing SPI1/PU.1 expression, promoting the recovery of cell proliferation in hypocellular MDS. CONCLUSIONS: Our research revealed the regulatory role of the CSN5/HSF/SPI1/PU.1 axis in hypocellular MDS, providing a probable target for clinical intervention.

Inhibition of USP10 induces myeloma cell apoptosis by promoting cyclin D3 degradation.

The cell cycle regulator cyclin D3 (CCND3) is highly expressed in multiple myeloma (MM) and it promotes MM cell proliferation. After a certain phase of cell cycle, CCND3 is rapidly degraded, which is essential for the strict control of MM cell cycle progress and proliferation. In the present study, we investigated the molecular mechanisms regulating CCND3 degradation in MM cells. By utilizing affinity purification-coupled tandem mass spectrometry, we identified the deubiquitinase USP10 interacting with CCND3 in human MM OPM2 and KMS11 cell lines. Furthermore, USP10 specifically prevented CCND3 from K48-linked polyubiquitination and proteasomal degradation, therefore enhancing its activity. We demonstrated that the N-terminal domain (aa. 1-205) of USP10 was dispensable for binding to and deubiquitinating CCND3. Although Thr283 was important for CCND3 activity, it was dispensable for CCND3 ubiquitination and stability modulated by USP10. By stabilizing CCND3, USP10 activated the CCND3/CDK4/6 signaling pathway, phosphorylated Rb, and upregulated CDK4, CDK6 and E2F-1 in OPM2 and KMS11 cells. Consistent with these findings, inhibition of USP10 by Spautin-1 resulted in accumulation of CCND3 with K48-linked polyubiquitination and degradation that synergized with Palbociclib, a CDK4/6 inhibitor, to induce MM cell apoptosis. In nude mice bearing myeloma xenografts with OPM2 and KMS11 cells, combined administration of Spautin-l and Palbociclib almost suppressed tumor growth within 30 days. This study thus identifies USP10 as the first deubiquitinase of CCND3 and also finds that targeting the USP10/CCND3/CDK4/6 axis may be a novel modality for the treatment of myeloma.

ß-arrestin2 deficiency ameliorates S-100-induced autoimmune hepatitis in mice by inhibiting infiltration of monocyte-derived macrophage and attenuating hepatocyte apoptosis.

Autoimmune hepatitis (AIH) is a progressive hepatitis syndrome characterized by high transaminase levels, interface hepatitis, hypergammaglobulinemia, and the presence of autoantibodies. Misdiagnosis or delayed treatment of AIH can lead to cirrhosis or liver failure, which poses a major risk to human health. ß-Arrestin2, a key scaffold protein for intracellular signaling pathways, has been found to be involved in many autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. However, whether ß-arrestin2 plays a role in AIH remains unknown. In the present study, S-100-induced AIH was established in both wild-type mice and ß-arrestin2 knockout (Arrb2 KO) mice, and the experiments identified that liver ß-arrestin2 expression was gradually increased, and positively correlated to serum ANA, ALT and AST levels during AIH progression. Furthermore, ß-arrestin2 deficiency ameliorated hepatic pathological damage, decreased serum autoantibody and inflammatory cytokine levels. ß-arrestin2 deficiency also inhibited hepatocyte apoptosis and prevented the infiltration of monocyte-derived macrophages into the damaged liver. In vitro experiments revealed that ß-arrestin2 knockdown suppressed the migration and differentiation of THP-1 cells, whereas ß-arrestin2 overexpression promoted the migration of THP-1 cells, which was regulated by the activation of the ERK and p38 MAPK pathways. In addition, ß-arrestin2 deficiency attenuated TNF-α-induced primary hepatocyte apoptosis by activating the Akt/GSK-3ß pathway. These results suggest that ß-arrestin2 deficiency ameliorates AIH by inhibiting the migration and differentiation of monocytes, decreasing the infiltration of monocyte-derived macrophages into the liver, thereby reducing inflammatory cytokines-induced hepatocytes apoptosis. Therefore, ß-arrestin2 may act as an effective therapeutic target for AIH.

GPR97 deficiency ameliorates renal interstitial fibrosis in mouse hypertensive nephropathy.

Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.

Pain resolution and functional outcomes of total mesh excision: a case series.

INTRODUCTION AND HYPOTHESIS: The objective was to assess the impact of total excision of polypropylene midurethral slings (MUS) on patient pain levels and to report on functional outcomes including recurrent/de novo stress urinary incontinence (SUI), sexual function, and quality of life measures. METHODS: This is a retrospective analysis of patients who underwent total MUS excision from March 2017 to December 2019. The primary outcome was the impact on pain assessed by a Numeric Rating Scale (NRS). Questionnaires analyzed were: Pain Catastrophizing Scale, Pelvic Floor Distress Inventory Short Form-20, Female Sexual Function Index, and McGill Pain Index questionnaires. RESULTS: Thirty-two women underwent total mesh excision within the inclusion period; with follow-up data available for 31 out of 32; 14 (43.8%) had previously undergone one or more partial vaginal mesh excision procedures. Types of MUS removed were: 14 (43.8%) transobturator midurethral slings, 12 (37.5%) retropubic midurethral slings, 4 (12.5%) mini-slings, and 2 (6.3%) mesh slings placed by laparotomy. Pain was the main reason for referral in 31 patients (96.9%). Mean pain NRS reduced from 6.1 pre-operatively to 3.3 post-operatively, with paired comparison showing a significant difference (p<0.01). Qualitatively, complete symptoms resolution was observed in 10 out of 31 (32.3%), another 9 out of 31 (29.0%) patients experienced clinically significant improvement, 2 out of 31 (6.5%) did not experience improvement in pain, and 10 out of 31 (32.3%) reported new/worsening pain. Post-operative complications occurred in 9 (29.0%) patients; all were Clavien-Dindo grade II. Nineteen (61.3%) reported de novo/recurrent SUI post-operatively. CONCLUSION: Total MUS mesh excision yields high complication and SUI recurrence rates, counter-balanced by a 61.3% pain resolution/improvement rate. These data are pertinent for patient counseling.

Immobilization effect of heavy metals in biochar via the copyrolysis of sewage sludge and apple branches.

The excess sludge produced by sewage treatment plants can be recycled into energy through pyrolysis, and the byproduct biochar can be used for soil remediation. However, the heavy metals in sludge are retained in biochar after pyrolysis and may cause secondary pollution during its soil application. Herein, a fast copyrolysis method of activated sludge (AS) and apple branches (AT) was proposed to immobilize heavy metals while improving bio-oil yield. The results showed that the heavy metal release from the copyrolyzed biochar was markedly reduced compared with that from the biochar produced through the pyrolysis of AS alone (78% for Cr and 28% for Pb). The kinetic behavior of ion release from different biochars could be described by a first-order kinetic model. The excellent fixation of heavy metals was attributed to complexation by abundant oxygen-containing surface functional groups (-O-, =O, and -CHO) that were mainly donated by AT. Furthermore, high-temperature pyrolysis was conducive to the fixation of metals, and the release of Pb2+ and Cr3+ from the biochar pyrolyzed at 600 °C was approximately 2/3 and 1/10 of that from the biochar pyrolyzed at 400 °C, respectively. A growth experiment on Staphylococcus aureus and Escherichia coli revealed that the toxicity of the copyrolyzed biochar was greatly reduced. This work can provide a method for heavy metal fixation and simultaneous resource recovery from organic wastes.