Natural compound Alternol actives multiple endoplasmic reticulum stress-responding pathways contributing to cell death.

Background: Alternol is a small molecular compound isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Our previous studies showed that Alternol treatment induced reactive oxygen species (ROS)-dependent immunogenic cell death. This study conducted a comprehensive investigation to explore the mechanisms involved in Alternol-induced immunogenic cell death. Methods: Prostate cancer PC-3, C4-2, and 22RV1 were used in this study. Alternol interaction with heat shock proteins (HSP) was determined using CETSA assay. Alternol-regulated ER stress proteins were assessed with Western blot assay. Extracellular adenosine triphosphate (ATP) was measured using ATPlite Luminescence Assay System. Results: Our results showed that Alternol interacted with multiple cellular chaperone proteins and increased their expression levels, including endoplasmic reticulum (ER) chaperone hypoxia up-regulated 1 (HYOU1) and heat shock protein 90 alpha family class B member 1 (HSP90AB1), as well as cytosolic chaperone heat shock protein family A member 8 (HSPA8). These data represented a potential cause of unfolded protein response (UPR) after Alternol treatment. Further investigation revealed that Alternol treatment triggered ROS-dependent (ER) stress responses via R-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α). The double-stranded RNA-dependent protein kinase (PKR) but not activating transcription factor 6 (ATF6) cascades, leading to ATF-3/ATF-4 activation, C/EBP-homologous protein (CHOP) overexpression, and X-box binding protein XBP1 splicing induction. In addition, inhibition of these ER stress responses cascades blunted Alternol-induced extracellular adenosine triphosphate (ATP) release, one of the classical hallmarks of immunogenic cell death. Conclusion: Taken together, our data demonstrate that Alternol treatment triggered multiple ER stress cascades, leading to immunogenic cell death.

Natural compound Alternol exerts a broad anti-cancer spectrum and a superior therapeutic safety index in vivo.

Introduction: Alternol is a natural compound isolated from the fermentation of a mutated fungus. We have demonstrated its potent anti-cancer effect via the accumulation of radical oxygen species (ROS) in prostate cancer cells in vitro and in vivo. In this study, we tested its anti-cancer spectrum in multiple platforms. Methods: We first tested its anti-cancer spectrum using the National Cancer Institute-60 (NCI-60) screening, a protein quantitation-based assay. CellTiter-Glo screening was utilized for ovarian cancer cell lines. Cell cycle distribution was analyzed using flow cytometry. Xenograft models in nude mice were used to assess anti-cancer effect. Healthy mice were tested for the acuate systemic toxicity. Results: Our results showed that Alternol exerted a potent anti-cancer effect on 50 (83%) cancer cell lines with a GI50 less than 5 µM and induced a lethal response in 12 (24%) of those 50 responding cell lines at 10 µM concentration. Consistently, Alternol displayed a similar anti-cancer effect on 14 ovarian cancer cell lines in an ATP quantitation-based assay. Most interestingly, Alternol showed an excellent safety profile with a maximum tolerance dose (MTD) at 665 mg/kg bodyweight in mice. Its therapeutic index was calculated as 13.3 based on the effective tumor-suppressing doses from HeLa and PC-3 cell-derived xenograft models. Conclusion: Taken together, Alternol has a broad anti-cancer spectrum with a safe therapeutic index in vivo.

Aberrant expression of multiple glycolytic enzyme genes is significantly associated with disease progression and survival outcomes in prostate cancers.

Prostate cancer is the leading cause of cancer death after lung cancer in men. Recent studies showed that aberrant metabolic pathways are involved in prostate cancer development and progression. In this study, we performed a systemic analysis of glycolytic enzyme gene expression using the TCGA-PRAD RNAseq dataset. Our analysis revealed that among 25 genes, only four genes (HK2/GPI/PFKL/PGAM5) were significantly upregulated while nine genes (HK1/GCK/PFKM/PFKP/ALDOC/PGK1/PGAM1/ENO2/PKM) were downregulated in primary prostate cancer tissues compared to benign compartments. Among these 13 altered genes, four genes (ENO2/ALDOC/GPI/GCK) exhibited strong diagnostic potential in distinguishing malignant and benign tissues. Meanwhile, GPI expression exerted as a prognostic factor of progression-free and disease-specific survival. PFKL and PGAM5 gene expressions were associated with AR signaling scores in castration-resistant patients, and AR-targeted therapy suppressed their expression. In LuCap35 xenograft tumors, PFKL and PGAM5 expression was significantly reduced after animal castration, confirming the AR dependency. Conversely, GCK/PKLR genes were significantly associated with neuroendocrinal progression, representing two novel neuroendocrinal biomarkers for prostate cancer. In conclusion, our results suggest that GPI expression is a strong prognostic factor for prostate cancer progression and survival while GCK/PKLR are two novel biomarkers of prostate cancer progression to neuroendocrinal status.

Cardiorespiratory dose comparison among six radiotherapy regimens for patients with left-sided breast cancer.

There is uncertainty regarding the benefits and drawbacks of various radiation protocols for the treatment of left-sided breast cancer. To address this issue, we conducted a Bayesian network analysis. First, we searched several electronic databases for eligible literature. Next, we pooled the data from twelve studies concerning three-dimensional conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), combined with either deep inspiratory breath-holding (DIBH) or free-breathing (FB) modalities. The integrated cardiac and pulmonary dosimetric indexes for all included treatments were compared using Bayesian networks. A direct meta-analysis indicated that for the two methods of 3D-CRT and IMRT, DIBH technology was more effective than FB in reducing the radiation dose to the heart and lungs. Additionally, according to the network results, DIBH was superior to FB in all six treatment options, regardless of whether the plan was 3D-CRT, IMRT, or VMAT. Besides, the combined data indicated that the FB-3D-CRT regimen had the weakest dosimetric advantage of all the treatments. Excluding FB-3D-CRT, each of the other five treatments had its own specific benefits. This is the first Bayesian study of several radiotherapy regimens for breast cancer patients on the left side, and the findings can be used to select appropriate radiotherapy programs for breast cancer patients.

Sustainable, Insoluble, and Photonic Cellulose Nanocrystal Patches for Calcium Ion Sensing in Sweat.

Self-assembly of cellulose nanocrystals (CNCs) is invaluable for the development of sustainable optics and photonics. However, the functional failure of CNC-derived materials in humid or liquid environments inevitably impairs their development in biomedicine, membrane separation, environmental monitoring, and wearable devices. Here, a facile and robust method to fabricate insoluble hydrogels in a self-assembled CNC-polyvinyl alcohol (PVA) system is reported. Due to the reconstruction of inter- or intra-molecular hydrogen bond interactions, thermal dehydration makes an optimized CNC/PVA photonic film form a stable hydrogel network in an aqueous solution rather than dissolve. Notably, the resulting hydrogel exhibits superb mechanical performance (stress up to 3.3 Mpa and tough up to 0.73 MJ m-3 ) and reversible conversion between dry and wet states, enabling it convenient for specific functionalization. Sodium alginate (SA) can be adsorbed into the CNC photonic structure by swelling dry CNC/PVA film in a SA solution. The prepared hydrogel showcases the comprehensive properties of freezing resistance (-20°C), strong adhesion, satisfactory biocompatibility, and highly sensitive and selective Ca2+ sensing. The material could act as a portable wearable patch on the skin for the continuous analysis of calcium trends during different physical exercises, facilitating their development in precision nutrition and health monitoring.

Recurrent renal secondary hyperparathyroidism caused by supernumerary mediastinal parathyroid gland and parathyromatosis: A case report.

Background: Surgical parathyroidectomy (PTX) is necessary for patients with severe and progressive secondary hyperparathyroidism (SHPT) refractory to medical treatment. Recurrence of SHPT after PTX is a serious clinical problem. Both supernumerary mediastinal parathyroid gland and parathyromatosis are the rare causes of recurrent renal SHPT. We report a rare case of recurrent renal SHPT due to supernumerary mediastinal parathyroid gland and parathyromatosis. Case presentation: A 53-year-old man underwent total parathyroidectomy with autotransplantation due to the drug-refractory SHPT 17 years ago. In the last 11 months, the patient experienced symptoms including bone pain and skin itch, and the serum intact parathyroid hormone (iPTH) level elevated to 1,587 pg/ml. Ultrasound detected two hypoechoic lesions located at the dorsal area of right lobe of the thyroid gland, and both lesions presented as characteristics of hyperparathyroidism in contrast-enhanced ultrasound. 99mTc-MIBI/SPECT detected a nodule in the mediastinum. A reoperation involved a cervicotomy for excising parathyromatosis lesions and the surrounding tissue and a thoracoscopic surgery for resecting a mediastinal parathyroid gland. According to a histological examination, two lesions behind the right thyroid lobe and one lesion in the central region had been defined as parathyromatosis. A nodule in the mediastinum was consistent with hyperplastic parathyroid. The patient remained well for 10 months with alleviated symptoms and stabilized iPTH levels in the range of 123-201 pg/ml. Conclusion: Although rare, recurrent SHPT may be caused by a coexistence of both supernumerary parathyroid glands and parathyromatosis, which should receive more attention. The combination of imaging modalities is important for reoperative locations of parathyroid lesions. To successfully treat parathyromatosis, all the lesions and the surrounding tissue must be excised. Thoracoscopic surgery is a reliable and safe approach for the resection of ectopic mediastinal parathyroid glands.

Exopolysaccharide-producing bacteria enhanced Pb immobilization and influenced the microbiome composition in rhizosphere soil of pakchoi (Brassica chinensis L.).

Lead (Pb) contamination of planting soils is increasingly serious, leading to harmful effects on soil microflora and food safety. Exopolysaccharides (EPSs) are carbohydrate polymers produced and secreted by microorganisms, which are efficient biosorbent materials and has been widely used in wastewater treatment to remove heavy metals. However, the effects and underlying mechanism of EPS-producing marine bacteria on soil metal immobilization, plant growth and health remain unclear. The potential of Pseudoalteromonas agarivorans Hao 2018, a high EPS-producing marine bacterium, to produce EPS in soil filtrate, immobilize Pb, and inhibit its uptake by pakchoi (Brassica chinensis L.) was studied in this work. The effects of strain Hao 2018 on the biomass, quality, and rhizospheric soil bacterial community of pakchoi in Pb-contaminated soil were further investigated. The results showed that Hao 2018 reduced the Pb concentration in soil filtrate (16%-75%), and its EPS production increased in the presence of Pb2+. When compared to the control, Hao 2018 remarkably enhanced pakchoi biomass (10.3%-14.3%), decreased Pb content in edible tissues (14.5%-39.2%) and roots (41.3%-41.9%), and reduced the available Pb content (34.8%-38.1%) in the Pb-contaminated soil. Inoculation with Hao 2018 raised the pH of the soil, the activity of several enzymes (alkaline phosphatase, urease, and dehydrogenase), the nitrogen content (NH4 +-N and NO3 --N), and the pakchoi quality (Vc and soluble protein content), while also raising the relative abundance of bacteria that promote plant growth and immobilize metals, such as Streptomyces and Sphingomonas. In conclusion, Hao 2018 reduced the available Pb in soil and pakchoi Pb absorption by increasing the pH and activity of multiple enzymes and regulating microbiome composition in rhizospheric soil.

The deacylase sirtuin 5 reduces malonylation in nonmitochondrial metabolic pathways in diabetic kidney disease.

Early diabetic kidney disease (DKD) is marked by dramatic metabolic reprogramming due to nutrient excess, mitochondrial dysfunction, and increased renal energy requirements from hyperfiltration. We hypothesized that changes in metabolism in DKD may be regulated by Sirtuin 5 (SIRT5), a deacylase that removes posttranslational modifications derived from acyl-coenzyme A and has been demonstrated to regulate numerous metabolic pathways. We found decreased malonylation in the kidney cortex (∼80% proximal tubules) of type 2 diabetic BKS db/db mice, associated with increased SIRT5 expression. We performed a proteomics analysis of malonylated peptides and found that proteins with significantly decreased malonylated lysines in the db/db cortex were enriched in nonmitochondrial metabolic pathways: glycolysis and peroxisomal fatty acid oxidation. To confirm relevance of these findings in human disease, we analyzed diabetic kidney transcriptomic data from a cohort of Southwestern American Indians, which revealed a tubulointerstitial-specific increase in Sirt5 expression. These data were further corroborated by immunofluorescence data of SIRT5 from nondiabetic and DKD cohorts. Furthermore, overexpression of SIRT5 in cultured human proximal tubules demonstrated increased aerobic glycolysis. Conversely, we observed reduced glycolysis with decreased SIRT5 expression. These findings suggest that SIRT5 may lead to differential nutrient partitioning and utilization in DKD. Taken together, our findings highlight a previously unrecognized role for SIRT5 in metabolic reprogramming in DKD.

Jumonji domain-containing protein RIOX2 is overexpressed and associated with worse survival outcomes in prostate cancers.

Background: Histone demethylase RIOX2 was cloned as a c-Myc downstream gene involved in cell proliferation and has been implicated as an oncogenic factor in multiple tumor types. Its expression profiles and correlation with disease progression in prostate cancers are unknown. Methods: Transcriptomic profiles of Jumanji domain-containing protein genes were assessed using multiple public expression datasets generated from RNA-seq and cDNA microarray assays. RIOX2 protein expression was assessed using an immunohistochemistry approach on a tissue section array from benign and malignant prostate tissues. Gene expression profiles were analyzed using the bioinformatics software R package. Western blot assay examined androgen stimulation on RIOX2 protein expression in LNCaP cells. Results: Among 35 Jumanji domain-containing protein genes, 12 genes were significantly upregulated in prostate cancers compared to benign compartments. COX regression analysis identified that the ribosomal oxygenase 2 (RIOX2) gene was the only one significantly associated with disease-specific survival outcomes in prostate cancer patients. RIOX2 upregulation was confirmed at the protein levels using immunohistochemical assays on prostate cancer tissue sections. Meanwhile, RIOX2 upregulation was associated with clinicopathological features, including late-stage diseases, adverse Gleason scores, TP53 gene mutation, and disease-free status. In castration-resistant prostate cancers (CRPC), RIOX2 expression was positively correlated with AR signaling index but negatively correlated with the neuroendocrinal progression index. However, androgen treatment had no significant stimulatory effect on RIOX2 expression, indicating a parallel but not a causative effect of androgen signaling on RIOX2 gene expression. Further analysis discovered that RIOX2 expression was tightly correlated with its promoter hypomethylation and MYC gene expression, consistent with the notion that RIOX2 was a c-Myc target gene. Conclusion: The Jumanji domain-containing protein RIOX2 was significantly overexpressed in prostate cancer, possibly due to c-Myc upregulation. RIOX2 upregulation was identified as an independent prognostic factor for disease-specific survival.

Risk factor analysis and prediction of postoperative clinically relevant pancreatic fistula after distal pancreatectomy.

OBJECTIVE: Postoperative pancreatic fistula (POPF) following distal pancreatectomy (DP) is a serious complication. In the present study, we aimed to identify the risk factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF) and establish a nomogram model for predicting CR-POPF after DP. METHODS: In total, 115 patients who underwent DP at the General Hospital of Northern Theater Command between January 2005 and December 2020 were retrospectively studied. Univariate and multivariable logistic regression analyses were used to identify the independent risk factors associated with CR-POPF. Then, a nomogram was formulated based on the results of multivariable logistic regression analysis. The predictive performance was evaluated with receiver operating characteristic (ROC) curves. Decision curve and clinical impact curve analyses were used to validate the clinical application value of the model. RESULTS: The incidence of CR-POPF was 33.0% (38/115) in the present study. Multivariate logistic regression analysis identified the following variables as independent risk factors for POPF: body mass index (BMI) (OR 4.658, P = 0.004), preoperative albumin level (OR 7.934, P = 0.001), pancreatic thickness (OR 1.256, P = 0.003) and pancreatic texture (OR 3.143, P = 0.021). We created a nomogram by incorporating the above mentioned risk factors. The nomogram model showed better predictive value, with a concordance index of 0.842, sensitivity of 0.710, and specificity of 0.870 when compared to each risk factor. Decision curve and clinical impact curve analyses also indicated that the nomogram conferred a high clinical net benefit. CONCLUSION: Our nomogram could accurately and objectively predict the risk of postoperative CR-POPF in individuals who underwent DP, which could help clinicians with early identification of patients who might develop CR-POPF and early development of a suitable fistula mitigation strategy and postoperative management.

Risk Factor Analysis and Prediction of Severe Hypocalcemia after Total Parathyroidectomy without Auto-Transplantation in Patients with Secondary Hyperparathyroidism.

Objective: Our study aimed to develop and validate a nomogram to predict severe hypocalcemia (SH) before total parathyroidectomy (TPTX) without auto-transplantation in patients with secondary hyperparathyroidism. Methods: A total of 299 consecutive patients who underwent TPTX without transplantation for secondary hyperparathyroidism were selected from the General Hospital of Northern Theater Command between January 2013 and December 2021. Of these, patients who underwent surgery between January 2013 and December 2020 formed the training cohort (n = 208) to develop a nomogram, and those who underwent surgery thereafter formed the validation cohort (n = 91) to validate the performance of this nomogram. Univariate and multivariate logistic regression analyses were used to identify the risk factors associated with SH, and then, a nomogram was constructed. Results: The incidence of postoperative SH was 27.9% and 35.2% in the training and validation cohorts, respectively. The preoperative factors associated with SH were younger age, lower serum calcium (Ca) level, higher intact parathyroid hormone (iPTH) level, and higher serum alkaline phosphatase (ALP) level. Incorporating these 4 factors, the nomogram achieved good concordance indexes of 0.866 (95%CI, 0.816-0.916) and 0.867 (95% CI, 0.793-0.941) in predicting SH in the training and validation cohorts, respectively, and had well-fitted calibration curves. The positive predictive values of the nomogram were 64.7% (54.1%-78.4%) and 75.0% (58.6%-88.5%), and negative predictive values of the nomogram were 90.0% (82.9%-93.6%) and 86.4% (73.5%-94.0%) for the training and validation cohorts, respectively. Conclusions: We developed and validated a nomogram for the prediction of SH in patients who underwent TPTX without auto-transplantation for secondary hyperparathyroidism. Our nomogram may facilitate the identification of high-risk SH in patients after TPTX and optimization of preoperative decision-making.

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein.

Although second-generation therapies like abiraterone (ABI) and enzalutamide (ENZ) benefit patients with castration-resistant prostate cancer (CRPC), drug resistance frequently occurs, eventually resulting in therapy failure. In this study, we used two libraries, FDA-approved drug library and CRISP/Cas9 knockout (GeCKO) library to screen for drugs that overcome treatment resistance and to identify the potential drug-resistant genes involved in treatment resistance. Our screening results showed that the DNA-damaging agent idarubicin (IDA) overcame abiraterone and enzalutamide resistance in prostate cancer cells. IDA treatment inhibited the DNA repair protein XPA expression in a transcription-independent manner. Consistently, XPA knockout sensitized prostate cancer cells to abiraterone and enzalutamide treatment. In conclusion, IDA combats abiraterone and enzalutamide resistance by reducing XPA protein level in prostate cancer.

Lipidomic approaches to dissect dysregulated lipid metabolism in kidney disease.

Dyslipidaemia is a hallmark of chronic kidney disease (CKD). The severity of dyslipidaemia not only correlates with CKD stage but is also associated with CKD-associated cardiovascular disease and mortality. Understanding how lipids are dysregulated in CKD is, however, challenging owing to the incredible diversity of lipid structures. CKD-associated dyslipidaemia occurs as a consequence of complex interactions between genetic, environmental and kidney-specific factors, which to understand, requires an appreciation of perturbations in the underlying network of genes, proteins and lipids. Modern lipidomic technologies attempt to systematically identify and quantify lipid species from biological systems. The rapid development of a variety of analytical platforms based on mass spectrometry has enabled the identification of complex lipids at great precision and depth. Insights from lipidomics studies to date suggest that the overall architecture of free fatty acid partitioning between fatty acid oxidation and complex lipid fatty acid composition is an important driver of CKD progression. Available evidence suggests that CKD progression is associated with metabolic inflexibility, reflecting a diminished capacity to utilize free fatty acids through ß-oxidation, and resulting in the diversion of accumulating fatty acids to complex lipids such as triglycerides. This effect is reversed with interventions that improve kidney health, suggesting that targeting of lipid abnormalities could be beneficial in preventing CKD progression.

A Tumor-Targeting Metal-Organic Nanoparticle Constructed by Dynamic Combinatorial Chemistry toward Accurately Redressing Carcinogenic Wnt Cascade.

Targeted and immunological therapy have revolutionized the malignancy treatment, but is suffering from the dose-limiting side effects and inadequate responsiveness. The emerging nanoscale infinite coordination polymers provide a feasible strategy for tumor targeting and immune sensitization. Herein, a "one-pot" self-assembled strategy based on dynamic combinatorial chemistry (DCC) principle is designed to construct a tumor-targeting metal-organic nanoparticle (MOICP) through a spontaneous co-assembling among three metal-organic coordination polymers tuned by a Wnt-inhibitor carnosic acid (CA). Responding to the tumor microenvironment, MOICP presents an optimized tumor-preferential accumulation and the satisfactory biosafety. MOICP is more active in vitro and in vivo than CA in suppressing of Wnt signaling pathway, and potently inhibits tumor growth in a patient-derived xenograft model of Wnt-activated pancreatic carcinoma. Moreover, MOICP reverses the lack of intratumoral infiltration of T lymphocytes, and hence augments the action of Anti-PD1 (programmed cell death protein 1) immunotherapy in B16F10 melanoma allograft mice model. This clinically viable MOICP can not only be applied to Wnt inhibition for cancer targeted therapy and immunotherapeutic sensitization, but also provides a de novo pattern for nanomedicine architecture with cargo-initiated co-self-assembly guided by DCC, thereby bringing new inspiration in general for disease intervention.

Preparation of Near-Infrared/Photoacoustic Dual-Mode Imaging and Photothermal/Chemo Synergistic Theranostic Nanoparticles and Their Imaging and Treating of Hepatic Carcinoma.

At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 ± 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

How does satisfaction of solar PV users enhance their trust in the power grid? - Evidence from PPAPs in rural China.

BACKGROUND: Photovoltaic Poverty Alleviation Projects (PPAPs) have been implemented in Chinese rural areas since 2014. As a new energy policy, PPAPs have played an important role in alleviating rural poverty. However, the adoption of solar PV faces multiple barriers from the perspective of beneficiaries. Therefore, this study aims to discuss and analyze factors affecting beneficiaries' satisfaction and their trust in State Grid, promoting the adoption of solar PV. METHODS: Based on the integrated American Customer Satisfaction Index (ACSI) and Unified Theory of Acception and Use of Technology (UTAUT) model, this study used the Structural Equation Model (SEM) to reveal how the beneficiaries' satisfaction enhance their trust in State Grid. The data were obtained from a survey of 928 PPAPs' beneficiaries by stratified and random sampling in Chinese rural areas. RESULTS: The results confirm that environmental perception in this study has positive impact on beneficiaries' satisfaction. In addition, perceived quality also has a positive effect on beneficiaries' satisfaction and trust in State Grid; however, social influence has a negative impact on beneficiaries' satisfaction; behavior expectation can directly promote beneficiaries' satisfaction while indirectly propel their trust in State Grid. CONCLUSIONS: This study constructs an integrated customer satisfaction model from the perspective of beneficiaries and proposes relevant measures to promote the adoption of solar PV that can be applied to poverty reduction in other developing countries worldwide.

SPOP promotes CDCA5 degradation to regulate prostate cancer progression via the AKT pathway.

The E3 ubiquitin ligase adaptor Speckle-type POZ protein (SPOP) plays an important tumour suppressor role in prostate cancers (PCa), with mutation rate up to 15%. However, how SPOP mutations regulate prostate tumorigenesis remains elusive. Here, we report the identification of cell division cycle associated 5 (CDCA5) as a SPOP substrate. We found that SPOP interacts with CDCA5 and promotes its polyubiquitin degradation in a degron-dependent manner. This effect was greatly impaired by introducing PCa associated SPOP mutations. Importantly, we found that CDCA5 was essential for PCa cells to survive and proliferate. CDCA5 depletion in PCa cells led to cessation of proliferation, G2M arrest, severe sister chromatid aggregation disturbance, and apoptosis. we also found that CDCA5 knockdown decreased the protein expression of p-GSK3ß, increased the activity of caspase-3, caspase-9, and the Bax/Bcl-2 ratio. Besides, we confirmed that CDCA5 interrupted cancer cell behavior via the AKT pathway. In contrast, silencing SPOP or overexpressing CDCA5 increased cell proliferation. Consistently, depleting SPOP along with CDCA5, or overexpressing CDCA5 along with SPOP also caused the growth of cells repressed. Consistent with the functional role of CDCA5, the mRNA and protein levels of CDCA5 were significantly increased in PCa, compared to normal tissues, and its high expression was associated with more severe lymph node metastasis, higher Gleason score, and poorer prognosis. Together, our data showed that SPOP plays a crucial role in inhibiting tumorigenesis and partly achieved this by promoting the degradation of oncoprotein CDCA5.

Circulating Free Fatty Acid and Phospholipid Signature Predicts Early Rapid Kidney Function Decline in Patients With Type 1 Diabetes.

OBJECTIVES: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D. RESEARCH DESIGN AND METHODS: In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform. RESULTS: At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m2. A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 (P = 0.039). Observations were confirmed in the validation subset. CONCLUSIONS: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D.

Quantitative analysis of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells using UHPLC-MS/MS.

γ-Glutamylpeptides have been identified as potential biomarkers for a number of diseases including cancer, diabetes, and liver disease. In this study, we developed and validated a novel quantitative analytical strategy for measuring γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline, all of which have been previously reported as potential biomarkers for prostate cancer in HeLa cells using ultra-high-performance liquid chromatography-tandem mass spectrometry. A BEH C18 column was used as the stationary phase. Mobile phase A was 99:1 water:formic acid and mobile phase B was acetonitrile. Chemical isotope labeling using benzoyl chloride was used as the internal standardization strategy. Sample preparation consisted of the addition of water to a frozen cell pellet, sonication, derivatization, centrifugation, and subsequent addition of an internal standard solution. The method was validated for selectivity, accuracy, precision, linearity, and stability. The determined concentrations of γ-glutamylisoleucine, γ-glutamylthreonine, and γ-glutamylvaline in HeLa cells were 1.92 ± 0.06, 10.8 ± 0.4, and 1.96 ± 0.04 pmol/mg protein, respectively. In addition, the qualitative analysis of these analytes in human serum was achieved using a modified sample preparation strategy. To the best of our knowledge, this is the first report of the use of benzoyl chloride for chemical isotope labeling for metabolite quantitation in cells.