Clinical study: the impact of goal-directed fluid therapy on volume management during enhanced recovery after surgery in gastrointestinal procedures.

Background: Goal-directed fluid therapy, as a crucial component of accelerated rehabilitation after surgery, plays a significant role in expediting postoperative recovery and enhancing the prognosis of major surgical procedures. Methods: In line with this, the present study aimed to investigate the impact of target-oriented fluid therapy on volume management during ERAS protocols specifically for gastrointestinal surgery. Patients undergoing gastrointestinal surgery at our hospital between October 2019 and May 2021 were selected as the sample population for this research. Results: 41 cases of gastrointestinal surgery patients were collected from our hospital over 3 recent years. Compared with T1, MAP levels were significantly increased from T2 to T5; cardiac output (CO) was significantly decreased from T2 to T3, and significantly increased from T4 to T5; and SV level was significantly increased from T3 to T5. Compared with T2, HR and cardiac index (CI) were significantly elevated at T1 and at T3-T5. Compared with T3, SVV was significantly decreased at T1, T2, T4, and T5; CO and stroke volume (SV) levels were increased significantly at T4 and T5. In this study, pressor drugs were taken for 23 days, PACU residence time was 40.22 ± 12.79 min, time to get out of bed was 12.41 ± 3.97 h, exhaust and defecation time was 18.11 ± 7.52 h, and length of postoperative hospital stay was 4.47 ± 1.98 days. The average HAMA score was 9.11 ± 2.37, CRP levels were 10.54 ± 3.38 mg/L, adrenaline levels were 132.87 ± 8.97 ng/L, and cortisol levels were 119.72 ± 4.08 ng/L. Prealbumin levels were 141.98 ± 10.99 mg/L at 3 d after surgery, and 164.17 ± 15.84 mg/L on the day of discharge. Lymphocyte count was 1.22 ± 0.18 (109/L) at 3 d after surgery, and 1.47 ± 0.17 (109/L) on the day of discharge. Serum albumin levels were 30.51 ± 2.28 (g/L) at 3 d after surgery, and 33.52 ± 2.07 (g/L) on the day of discharge. Conclusion: Goal-directed fluid therapy (GDFT) under the concept of Enhanced Recovery After Surgery (ERAS) is helpful in volume management during radical resection of colorectal tumors, with good postoperative recovery. Attention should be paid to the influence of pneumoperitoneum and intraoperative posture on GDFT parameters.

CT-Based Radiomics Models for Differentiation of Benign and Malignant Thyroid Nodules: A Multicenter Development-and-Validation.

Background: CT is increasingly detecting thyroid nodules. Prior studies indicated a potential role of CT-based radiomics models in characterizing thyroid nodules, although lacked external validation. Objectives: To develop and validate a CT-based radiomics model for the differentiation of benign and malignant thyroid nodules. Methods: This retrospective study included 378 patients (mean age, 46.3±13.9 years; 86 men, 292 women) with 408 resected thyroid nodules (145 benign, 263 malignant) from two centers (center 1: 293 nodules, January 2018-December 2022; center 2: 115 nodules, January 2020-December 2022), who underwent preoperative multiphase neck CT (noncontrast, arterial, and venous phases). Nodules from center 1 were divided into training (n=206) and internal validation (n=87) sets; all nodules from center 2 formed an external validation set. Radiologists assessed nodules for morphologic CT features. Nodules were manually segmented on all phases, and radiomic features were extracted. Conventional (clinical and morphologic CT), noncontrast radiomics, arterial-phase radiomics, venous-phase radiomics, multiphase radiomics, and combined (clinical, morphologic, and multiphase radiomics) models were established using feature selection methods and evaluated by ROC curve analysis, calibration curves, and decision-curve analysis. Results: The combined model included patient age, three morphologic features (cystic change, edge interruption sign, abnormal cervical lymph nodes), and 28 radiomic features (from all three phases). In the external validation set, the combined model had AUC of 0.923 and, at an optimal threshold derived in the training set, sensitivity of 84.0%, specificity of 94.1%, and accuracy of 87.0%. In the external validation set, AUC was significantly higher for the combined model than for the conventional model (0.827), noncontrast radiomics model (0.847), arterial-phase radimoics model (0.826), venous-phase radiomics model (0.773), and multiphase radiomics model (0.824) (all p<.05). In the external validation set, the calibration curves indicated lowest (i.e., best) Brier score for the combined model; in decision-curve analysis, the combined model had the highest net benefit for most of the range of threshold probabilities. Conclusion: A combined model incorporating clinical, morphologic CT, and multiphasic radiomics CT features, exhibited robust performing in differentiating benign and malignant thyroid nodules. Clinical Impact: The combined radiomics model may help guide further management for thyroid nodules detected on CT.

Plasma leucine-rich α-2 glycoprotein 1 in ST-elevation myocardial infarction: vertical variation, correlation with T helper 17/regulatory T ratio, and predictive value on major adverse cardiovascular events.

Objective: Leucine-rich α-2 glycoprotein 1 (LRG1) promotes inflammation and myocardial injury, but its clinical role in ST-elevation myocardial infarction (STEMI) is rarely disclosed. Herein, this prospective study aimed to explore the value of plasma LRG1 at different time points to predict major adverse cardiovascular event (MACE) risk in patients with STEMI. Methods: In total, 209 patients with STEMI were enrolled for determining plasma LRG1 at admission and on day (D)1/D7/D30 after admission via enzyme-linked immunosorbent assay, as well as for determination of peripheral blood T helper 17 (Th17) cells and regulatory T (Treg) cells by flow cytometry. In addition, plasma LRG1 was obtained from 30 healthy controls at enrollment. Results: LRG1 was increased in patients with STEMI at admission compared with healthy controls (P < 0.001). In patients with STEMI, LRG1 varied at different time points (P < 0.001), which elevated from admission to D1, and gradually declined thereafter. LRG1 at admission was positively associated with Th17 cells (P = 0.001) and Th17/Treg ratio (P = 0.014). LRG1 at admission (P = 0.013), D1 (P = 0.034), D7 (P = 0.001), and D30 (P = 0.010) were increased in patients with MACE compared with those without. LRG1 at D7 exhibited good ability to estimate MACE risk (area under curve = 0.750, 95% confidence interval = 0.641-0.858). LRG1 at admission > 60 µg/ml (P = 0.031) and D7 > 60 µg/ml (P = 0.018) were linked with increased accumulating MACE. Importantly, LRG1 at D7 > 60 µg/ml was independently correlated with increased MACE risk (hazard ratio = 5.216, P = 0.033). Conclusion: Plasma LRG1 increases from admission to D1 and gradually declines until D30, which positively links with Th17 cells and MACE risk in patients with STEMI.

Snowflake Cu2S@ZIF-67: A novel heterostructure substrate for enhanced adsorption and sensitive detection in BPA.

Developing semiconductor substrates with superior stability and sensitivity is challenging in surface-enhanced Raman scattering (SERS) research. Here, a snowflake Cu2S@ZIF-67 heterostructure was fabricated using a straightforward method, exhibiting a notable enhancement factor of 9.0 × 109 and a limit of detection (LOD) of 10-14 M for methylene blue (MB). In addition, the Cu2S@ZIF-67 heterostructure substrate demonstrates outstanding homogeneity (relative standard deviation (RSD) = 9.2%) and stability (120 days). Employing Cu2S generates highly sensitive hotspots via an electromagnetic (EM) mechanism, and the growth of ZIF-67 on its surface augments the adsorption capacity and charge transfer capability (chemical mechanism, CM), thereby enhancing the SERS detection sensitivity. Furthermore, the Cu2S@ZIF-67 heterostructure, which was used as a SERS substrate, facilitated the detection of bisphenol A (BPA) with an LOD of 10-11 M. The Cu2S@ZIF-67 heterostructure substrate has excellent selectivity and anti-interference, which is very suitable for BPA detection in complex environment applications. The accuracy of the Cu2S@ZIF-67 heterostructure as a SERS substrate for detecting BPA in real water samples (water bottles, tap water, and pure milk) was confirmed by comparison with high-performance liquid chromatography (HPLC). These results demonstrate that through the rational design of heterostructures can achieve the quantitative and accurate detection of hazardous substances in food and the environment can be achieved.

Time Kinetics and prognosis roles of calcitonin after surgery for medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated. METHODS: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated. RESULTS: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13-0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42-0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15-12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29-4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17-27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45-6.65; P = 0.004) were independent predictor of DFS. CONCLUSION: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly.

Dietary Selenium Insufficiency Induces Cardiac Inflammatory Injury in Chicks.

BACKGROUND: Laying hens undergo intensive metabolism and are vulnerable to cardiac insults. Previous research demonstrated overt heart disorders of broiler chickens induced by dietary Se deficiency. OBJECTIVES: This study aimed to reveal effects and mechanism of dietary Se insufficiency on cardiac injuries of egg-type chicks in their early life. METHODS: White Leghorn chicks (0-d-old, female) were fed a corn-soy, Se-insufficient basal diet (BD, 0.05 mg Se/kg; n = 11) or the BD supplemented with 0.3 mg Se/kg (as sodium selenite; n = 8) for 35 d. Cardiac tissues were collected at the end of study for histology and to determine its relationship with heart Se contents, selenoprotein expression profiles, antioxidant and inflammatory status, and the Toll-like receptor 4/extracellular signal-regulated kinases/p38 map kinase/c-Jun N-terminal kinase (TLR4/ERK/P38/JNK) pathway. RESULTS: Compared with those fed 0.35 mg Se/kg, chicks fed BD had significantly lower body weights and average daily gain, and 28% lower heart Se, and developed cardiac mononuclear inflammatory cell infiltration, along with elevated (P < 0.05) serum concentrations of creatine kinase, aldolase, and interleukin-1 (IL-1). The BD decreased (P < 0.05) body weight and heart glutathione contents and expression of selenoproteins but increased (P < 0.05) heart concentrations of malondialdehyde and reactive oxygen species. These changes were associated with increased (P < 0.05) mRNA and/or protein concentrations of cyclooxygenases, lipoxygenase-12, cytokines (IL-1ß), nuclear factor (NF) κB subunit, chemokines, and receptors (CCL20, CXCR1, and CXCLI2) and increased (P < 0.1) TLR4/ERK /P38/JNK in the heart of Se-insufficient chicks. CONCLUSIONS: Dietary Se insufficiency induces infiltration of mononuclear inflammatory cells in the heart of egg-type chicks. This cardiac injury was mediated by decreased functional expressions of selenoproteins, which resulted in apparent elevated oxidative stress and subsequent activations of the TLR4 pathway and NF κB.

CRISPR/Cas9 edited SlGT30 improved both drought resistance and fruit yield through endoreduplication.

There is often a trade-off effect between different agronomic traits due to gene pleiotropy, leading to a negative correlation between yield and resistance. Consequently, using gene-editing techniques to develop superior traits becomes challenging. Genetic resources that defy this constraint are scarce but hold great potential as targets for improvement through the utilisation of CRISPR. Transcription factors are critical in modulating numerous gene expressions across diverse biological processes. Here, we found that the trihelix transcription factor SlGT30 plays a role in drought resistance and tomato fruit development. We edited the SlGT30 gene with CRISPR/Cas9 technology and found that the knockout lines showed decreased stomata density in the leaves and large fruits. Subsequent examination revealed that cell ploidy was impacted in the leaves and fruits of SlGT30 knockout lines. SlGT30 knockout affected cell size through the endoreduplication pathway, manifested in decreased stomata density and reduced water loss. Consequently, this resulted in an enhancement of drought resistance. For the fruit, both cell size and cell number increased in the fruit pericarp of knockout lines, improving the fruit size and weight accordingly. Therefore, SlGT30 represents a promising candidate gene for gene editing in breeding practice.

Long-term risk of overweight in offspring of Chinese women with gestational diabetes defined by IADPSG's but not by WHO's criteria.

AIMS: To examine long-term risk of overweight in offspring of women with gestational diabetes mellitus (GDM) defined by the International Association of Diabetes and Pregnancy Study Group (IADPSG)'s criteria but not by the 1999 World Health Organization (WHO)'s criteria. METHODS: We followed up 1681 mother-child pairs for 8 years in Tianjin, China. Overweight in children aged 1-5 and 6-8 were respectively defined as body mass index-for-age and -sex above the 2 z-score and 1 z-score curves of the WHO's child growth standards. Logistic regression was performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of hyperglycemia indices at oral glucose tolerance test and GDMs defined by different criteria for offspring overweight at different ages. RESULTS: Offspring of women with fasting plasma glucose ≥5.1 mmol/L were at increased risk of overweight at 6-8 years old (OR:1.45, 95% CI: 1.09-1.93). GDM defined by the IADPSG's criteria only was associated with increased risk of childhood overweight at 6-8 years old (1.65, 1.13-2.40), as compared with non-GDM by either of the two sets of criteria. CONCLUSIONS: Newly defined GDM by the IADPSG's criteria increased the risk of offspring overweight aged 6-8 years.

Exploring the maximum nitrite production rate through the granular sludge-type reactor to match the needs of anammox process realizing efficient nitrogen removal.

The reliable and efficient nitrite production rate (NPR) through nitritation process is the prerequisite for the efficient running of subsequent processes, like the anammox process and the nitrite shunt. However, there has been scant research on stable and productive nitritation process in recent years. In this study, at a stable hydraulic retention time of 12.0 h and with precise and strict DO control, the upper limit of the NPR was initially investigated using a continuous-flow granular sludge reactor. The NPR of 1.69 kg/m3/d with a nitrite production efficiency of 81.97% was finally achieved, which set a record until now in similar research. The median sludge particle size of 270.0 µm confirmed the development of clearly defined granular sludge. The genus Nitrosomonas was the major ammonium oxidizing bacteria. In conclusion, this study provides valuable insights for the practical application of the effective nitritation process driving subsequent nitrogen removal processes.

Superhydrophobic MOF/polymer composite with hierarchical porosity for boosting catalytic performance in an humid environment.

The poor hydrostability of most reported metal-organic frameworks (MOFs) has become a daunting challenge in their practical applications. Recently, MOFs combined with multifunctional polymers can act as a functional platform and exhibit unique catalytic performance; they can not only inherit the outstanding properties of the two components but also offer unique synergistic effects. Herein, an original porous polymer-confined strategy has been developed to prepare a superhydrophobic MOF composite to significantly enhance its moisture or water resistance. The selective nucleation and growth of MOF nanocrystals confined in the pore of PDVB-vim are closely related to the structure-directing and coordination-modulating properties of PDVB-vim. The resultant MOF/PDVB-vim composite not only produces superior superhydrophobicity without significantly disturbing the original features but also exhibits a novel catalytic activity in the Friedel-Crafts alkylation reaction of indoles with trans-ß-nitrostyrene because of the accessible sites and synergistic effects.

Correction: A compact and high-performance setup of capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D).

Correction for 'A compact and high-performance setup of capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D)' by Lin Li et al., Analyst, 2024, https://doi.org/10.1039/d4an00354c.

Effect of Lycium barbarum polysaccharide on osteoblast proliferation and differentiation in postmenopausal osteoporosis.

OBJECTIVE: We aimed to investigate the effect of Lycium barbarum polysaccharide (LBP) on the proliferation and differentiation of osteoblasts in postmenopausal individuals with osteoporosis using in vitro cell experiments. METHODS: We assessed the effect of long-term LBP consumption on the intestinal metabolites of individuals using a simulation of the human intestinal microbiota ecosystem. We also tested the capacity of LBP in proliferating MC3T3-E1 cells using the cell counting kit-8 (CCK-8) method and analyzed the effect of intestinal metabolites on the osteogenic differentiation of MC3T3-E1 cells by testing bone metabolism viability with relevant indicators. RESULTS: The level of short-chain fatty acids (SCFAs) significantly increased (p < 0.05), and the concentrations of acetic acid, propionic acid, and butyric acid all showed an upward trend after the treatment using LBP. At appropriate concentrations, the fermentation supernatant can enhance osteoblast proliferation by significantly increasing the active expression of bone-alkaline phosphatase (B-ALP) and osteocalcin (OCN) in osteoblasts (p < 0.05). CONCLUSION: By modulating the metabolites of intestinal microbiota, production of SCFAs, the prebiotic properties of LBP can enhance osteoblast differentiation through in vitro simulation experiment and cell-based assay.

Me31B: a key repressor in germline regulation and beyond.

Maternally Expressed at 31B (Me31B), an evolutionarily conserved ATP-dependent RNA helicase, plays an important role in the development of the germline across diverse animal species. Its cellular functionality has been posited as a translational repressor, participating in various RNA metabolism pathways to intricately regulate the spatiotemporal expression of RNAs. Despite its evident significance, the precise role and mechanistic underpinnings of Me31B remain insufficiently understood. This article endeavors to comprehensively review historic and recent research on Me31B, distill the major findings, discern generalizable patterns in Me31B's functions across different research contexts, and provide insights into its fundamental role and mechanism of action. The primary focus of this article centers on elucidating the role of Drosophila Me31B within the germline, while concurrently delving into pertinent research on its orthologs within other species and cellular systems.

Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.

Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.

Protective effect of soluble dietary fiber from Rosa roxburghii Tratt residue on dextran sulfate sodium-induced ulcerative colitis by regulating serum metabolism and NF-κB pathway in mice.

BACKGROUND: Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS: The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1ß, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION: This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.

Effects and mechanisms of N6-methyladenosine RNA methylation in environmental pollutant-induced carcinogenesis.

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.

Multidimensional data analysis revealed thyroiditis-associated TCF19 SNP rs2073724 as a highly ranked protective variant in thyroid cancer.

BACKGROUND: Thyroid cancer represents the most prevalent malignant endocrine tumour, with rising incidence worldwide and high mortality rates among patients exhibiting dedifferentiation and metastasis. Effective biomarkers and therapeutic interventions are warranted in aggressive thyroid malignancies. The transcription factor 19 (TCF19) gene has been implicated in conferring a malignant phenotype in cancers. However, its contribution to thyroid neoplasms remains unclear. RESULTS: In this study, we performed genome-wide and phenome-wide association studies to identify a potential causal relationship between TCF19 and thyroid cancer. Our analyses revealed significant associations between TCF19 and various autoimmune diseases and human cancers, including cervical cancer and autoimmune thyroiditis, with a particularly robust signal for the deleterious missense variation rs2073724 that is associated with thyroid function, hypothyroidism, and autoimmunity. Furthermore, functional assays and transcriptional profiling in thyroid cancer cells demonstrated that TCF19 regulates important biological processes, especially inflammatory and immune responses. We demonstrated that TCF19 could promote the progression of thyroid cancer in vitro and in vivo and the C>T variant of rs2073724 disrupted TCF19 protein binding to target gene promoters and their expression, thus reversing the effect of TCF19 protein. CONCLUSIONS: Taken together, these findings implicate TCF19 as a promising therapeutic target in aggressive thyroid malignancies and designate rs2073724 as a causal biomarker warranting further investigation in thyroid cancer.

Protective Effect of Hop Ethyl Acetate Extract on Corticosterone-Induced PC12 and Improvement of Depression-like Behavior in Mice.

Depression is a common mental disorder. In recent years, more and more attention has been paid to depression and its etiology and pathogenesis. This review aims to explore the neuroprotective and antidepressant effects of hop components. By establishing an in vitro cell damage model using PC12 cells induced by corticosterone (CORT) and an in vivo depression model through the intracranial injection of lipopolysaccharide (LPS) in mice, hop ethyl acetate extract (HEA) was used to study the protective effect and mechanism of HEA on neuronal cells in vitro and the antidepression effect and mechanism in vivo. The results showed that HEA increased the survival and decreased the rate of lactate dehydrogenase (LDH) release, apoptosis, and the ROS and NO content of CORT-induced PC12 cells. HEA alleviated depressive-like behavior, neuroinflammation, reduction of norepinephrine, and dendritic spines induced by intracerebroventricular injection of LPS in mice and increases the expression levels of BDNF, SNAP 25, and TrkB proteins without any significant side effects or toxicity. Hops demonstrated significant comprehensive utilization value, and this work provided an experimental basis for the role of hops in the treatment of depression and provided a basis for the development of HEA for antidepressant drugs or dietary therapy products.

Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels.

Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.