The amino acid sensor methionyl-tRNA synthetase is required for methionine-induced milk protein synthesis in a domestic pigeon model.

This study was conducted to investigate whether methionyl-tRNA synthetase (MetRS) is a mediator of methionine (Met)-induced crop milk protein synthesis via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling pathway in breeding pigeons. In Experiment 1, a total of 216 pairs of breeding pigeons were divided into three groups (control, Met-deficient, and Met-rescue groups). In Experiments 2 and 3, forty pairs of breeding pigeons from each experiment were allocated into four groups. The second experiment included a control group and three MetRS inhibitor (REP8839) groups. The third experiment included a Met-deficient group, Met-sufficient group, REP8839 + Met-deficient group and REP8839 + Met-sufficient group. Experiment 1 showed that Met supplementation increased crop development, crop milk protein synthesis, the protein expression of MetRS and JAK2/STAT5 signalling pathway, and improved squab growth. Experiment 2 showed that crop development, crop milk protein synthesis and the protein expression of MetRS and the JAK2/STAT5 signalling pathway were decreased, and squab growth was inhibited by the injection of 1·0 mg/kg body weight REP8839, which was the selected dose for the third experiment. Experiment 3 showed that Met supplementation increased crop development, crop milk protein synthesis and the expression of MetRS and JAK2/STAT5 signalling pathway and rescued squab growth after the injection of REP8839. Moreover, the co-immunoprecipitation results showed that there was an interaction between MetRS and JAK2. Taken together, these findings indicate that MetRS mediates Met-induced crop milk protein synthesis via the JAK2/STAT5 signalling pathway, resulting in improved squab growth in breeding pigeons.

The difference in extracellular matrix metabolism in women with and without pelvic organ prolapse: A systematic review and meta-analysis.

BACKGROUND: Studies on the changes of extracellular matrix (ECM) in pelvic organ prolapse (POP) are still controversial. OBJECTIVE: To identify the changes in the ECM in POP patients. SEARCH STRATEGY: Comprehensive searching in Embase, PubMed, Web of Science and the Cochrane Library was carried out until 23 February 2023. SELECTION CRITERIA: Studies comparing the protein levels of ECM-related components between women with and without POP. DATA COLLECTION AND ANALYSIS: Quality and risk of bias were assessed using the Agency for Healthcare Research and Quality assessment. Indicators were pooled with random or fixed effect meta-analysis based on heterogeneity and sub-grouped analysed by the biopsy site. MAIN RESULTS: Thirty cross-sectional studies were included, comprising 840 POP cases and 755 controls. Overall results showed that the expression of type III collagen (COLIII) and several matrix metalloproteinases (MMP-1, -2 and -9) were increased, whereas those of type I collagen (COLI), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were decreased in patients with POP. Subgroup analysis showed that the expression of COLIII in the anterior vaginal wall (AVW) and COLIII, MMP-2 and -9 in the uterosacral ligament (USL) were consistent with the overall results. However, the expression of COLI and MMP-1 in the AVW showed no difference and the expression of COLI and MMP-1 in the USL is still controversial based on current studies. CONCLUSIONS: Patients with POP have lower expression of COLI and TIMP-1 and higher expression of COLIII and MMPs compared with non-POP cases, but further studies are required to investigate in specified anatomical sites.

N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants.

Activating mutations within FLT3 make up 30 % of all newly diagnosed acute myeloid leukemia (AML) cases, with the most common mutation being an internal tandem duplication (FLT3-ITD) in the juxtamembrane region (25 %). Currently, two generations of FLT3 kinase inhibitors have been developed, with three inhibitors clinically approved. However, treatment of FLT3-ITD mutated AML is limited due to the emergence of secondary clinical resistance, caused by multiple mechanism including on-target FLT3 secondary mutations - FLT3-ITD/D835Y and FLT3-ITD/F691L being the most common, as well as the off-target activation of alternative pathways including the BCR-ABL pathway. Through the screening of imidazo[1,2-a]pyridine derivatives, N-(3-methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine (compound 1) was identified as an inhibitor of both the FLT3-ITD and BCR-ABL pathways. Compound 1 potently inhibits clinically related leukemia cell lines driven by FLT3-ITD, FLT3-ITD/D835Y, FLT3-ITD/F691L, or BCR-ABL. Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.

Eosinophils and risk of ulcerative colitis in European population: Evidence from Mendelian randomization study.

BACKGROUND: Observational studies have indicated that peripheral blood eosinophil count is elevated in individuals diagnosed with ulcerative colitis (UC) and correlates with the disease activity of UC. However, this conclusion contradicts with findings from other studies. Therefore, we employed Mendelian randomization (MR) method to assess the genetic link between eosinophil count and UC. METHOD: This MR study utilized summary data from genome-wide association studies (GWAS) on eosinophil count and UC. The main approach used for conducting MR analysis was the inverse variance weighted (IVW) method. Meta-analysis of the IVW results was performed alongside multiple sensitivity analyses to confirm the robustness of the MR analysis results. RESULTS: The IVW method unveiled a causal relationship between eosinophil count and UC (OR = 1.18, 95% CI: 1.04-1.33, p = .01) in the discovery cohort. This finding was further corroborated by the replication cohorts (OR = 1.16, 95% CI: 1.04-1.29, p = .01; OR = 1.12, 95% CI: 1.01-1.24, p = .03). The meta-analysis indicated that the overall odds ratio (OR) for all studies was 1.15 (common effect model, 95% CI: 1.08-1.23, p < .01). Sensitivity analysis suggested the absence of heterogeneity and horizontal pleiotropy in all MR analyses. CONCLUSION: Based on bidirectional two-sample MR analysis, there is an indication that elevated eosinophil count may increase the risk of UC. However, potential confounding factors cannot be ruled out, and further research is necessary to explore how eosinophils contribute to the onset and progression of UC.

Impact of female stress urinary incontinence and related treatments on the sexual function of male partners: a systematic review and meta-analysis.

BACKGROUND: No conclusions have been reached on whether female stress urinary incontinence (SUI) and related treatments affect male partners' sexual function. AIM: To assess the effects of female SUI and related treatments on male partners' sexual function. METHODS: A comprehensive search of the PubMed, Embase, Web of Science, Cochrane, and Scopus databases was performed up to September 6, 2022. Studies were included that investigated the effect of female SUI and related treatments on male partners' sexual function. OUTCOME: Male partners' sexual function. RESULTS: Of the 2294 citations identified, 18 studies with 1350 participants were included. Two studies assessed the effect of female SUI without treatment on male partners' sexual function, finding that partners had more erectile dysfunction, more sexual dissatisfaction, and less sexual frequency than partners of women without urinary incontinence. Seven studies directly assessed the effect of female SUI treatments on male partners' sexual function by surveying the male partners. Among these, 4 assessed transobturator suburethral tape (TOT) surgery; 1 assessed TOT and tension-free vaginal tape obturator surgery; and the remaining 2 assessed pulsed magnetic stimulation and laser treatment. Among the 4 TOT studies, 3 used the International Index of Erectile Function (IIEF). TOT surgery significantly improved the total IIEF score (mean difference [MD] = 9.74, P < .00001), along with erectile function (MD = 1.49, P < .00001), orgasmic function (MD = 0.35, P = .001), sexual desire (MD = 2.08, P < .00001), intercourse satisfaction (MD = 2.36, P < .00001), and overall satisfaction (MD = 3.46, P < .00001). However, the improvements in IIEF items may be of unclear clinical significance, as 4 points in the erectile function domain of the IIEF are typically defined as the minimal clinically important difference. In addition, 9 studies indirectly assessed the effect of female SUI surgery on male partners' sexual function by surveying patients with the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire. The results demonstrated no significant differences in erectile function (MD = 0.08, P = .40) or premature ejaculation (MD = 0.07, P = .54). CLINICAL IMPLICATIONS: The effects of female SUI and related treatments on male partners' sexual function were summarized for the first time, providing a reference for future clinical practice and scientific research. STRENGTHS AND LIMITATIONS: A limited number of studies that used various scales met the standardized eligibility criteria. CONCLUSION: Female SUI may affect male partners' sexual function, and female patients' anti-incontinence surgery does not appear to have a clinically significant improvement on the sexual function of their partners.

Ovariectomy with simulated vaginal delivery to establish a rat model for pelvic organ prolapse.

The widespread prevalence of Pelvic Organ Prolapse (POP) and the paucity of ongoing treatments prompted us to develop a unique rat model combining ovariectomy and simulated vaginal delivery. We hypothesized that the tissue changes caused by low hormone levels and mechanical stretch could complement each other. Thus, the combined model can potentially mimic the collagen metabolism of vaginal wall tissue as well as mechanical stretch properties to complement disease progression in POP. Ovariectomy with sequential simulated vaginal delivery was performed on rats in the modeling group. Sham surgeries were performed as control. At 2, 4, and 12 weeks after modeling, the vaginal tissues of rats were evaluated by Masson's trichrome staining, Picro-Sirius red staining, immunohistochemistry, western blotting, and uniaxial tensile tests. Compared to the control group, the vaginal tissues of the model rats showed an atrophic epithelial layer and loose collagen fibers. The smooth muscle fibers were ruptured, smaller in diameter, and disorganized. The ratio of collagen type I/III significantly increased, but the contents of both Collagen I and III decreased. The expression of metalloproteinases 2 and 9 in the tissues increased, and the expression of tissue inhibitors of metalloproteinases 1 and 2 decreased. The tangent modulus of the tissues was significantly increased in the model rats. We verified a novel method to establish a pelvic organ prolapse model in rats. This approach combined the advantages of low hormone levels and mechanical stretch effects.

Rhodium-Catalyzed Asymmetric Annulation of Unactivated Alkynes with 3-(ortho-Boronated Aryl) Conjugated Enones: Enantioselective Synthesis of 2,3-Disubstituted Indenes.

A rhodium-catalyzed tandem arylation/cyclization reaction of 3-(ortho-boronated aryl) conjugated enones with unactivated alkynes is reported. By using a rhodium(I)/chiral-diene complex as the catalyst, the protocol was processed smoothly to provide various 2,3-disubstituted indene compounds in high yields with excellent regioselectivities and enantioselectivities. The approach outlined herein is appealing, as simple diarylalkynes, diakylalkynes, and alkyl(aryl)alkynes are the starting materials.

L-glutamate requires ß-catenin signalling through Frizzled7 to stimulate porcine intestinal stem cell expansion.

Intestinal stem cells (ISCs) decode and coordinate various types of nutritional information from the diet to support the crypt-villus axis architecture, but how specific dietary molecules affect intestinal epithelial homeostasis remains unclear. In the current study, L-glutamate (Glu) supplementation in either a nitrogen-free diet (NFD) or a corn-soybean meal diet (CSMD) stimulated gut growth and ISC expansion in weaned piglets. Quantitative proteomics screening identified the canonical Wnt signalling pathway as a central regulator of intestinal epithelial development and ISC activity in vivo. Importantly, the Wnt transmembrane receptor Frizzled7 (FZD7) was upregulated in response to dietary Glu patterns, and its perturbations in intestinal organoids (IOs) treated with a specific inhibitor and in FZD7-KO IPEC-J2 cells disrupted the link between Glu inputs and ß-catenin signalling and a subsequent reduction in cell viability. Furthermore, co-localization, coimmunoprecipitation (Co-IP), isothermal titration calorimetry (ITC), and microscale thermophoresis (MST) revealed that Glu served as a signalling molecule directly bound to FZD7. We propose that FZD7-mediated integration of the extracellular Glu signal controls ISC proliferation and differentiation, which provides new insights into the crosstalk of nutrients and ISCs.

Novel recombinant R-spondin1 promotes hair regeneration by targeting the Wnt/ß-catenin signaling pathway.

Roof plate-specific spondin 1 (R-spondin1, RSPO1) is a Wnt/ß-catenin signaling pathway activator that binds with Wnt ligands to stimulate the Wnt/ß-catenin signaling pathway, which is key to hair regeneration. However, it is not clear whether recombinant RSPO1 (rRSPO1) affects hair regeneration. Here, we treat C57BL/6 male mice with rRSPO1 and investigate the expression of the Wnt/ß-catenin signaling pathway and the activation of hair follicle stem cells in the dorsal skin. The mouse skin color score and hair-covered area are determined to describe hair growth, and the skin samples are subjected to H&E staining, western blot analysis and immunofluorescence staining to evaluate hair follicle development and the expressions of Wnt/ß-catenin signaling pathway-related proteins. We find that rRSPO1 activates mouse hair follicle stem cells (mHFSCs) and accelerates hair regeneration. rRSPO1 increases the hair-covered area, the number of hair follicles, and the hair follicle diameter and length. Moreover, rRSPO1 enhances the activity of Wnt/ß-catenin signaling pathway-related proteins and the expressions of HFSC markers, as well as mHFSC viability. These results indicate that subcutaneous injection of rRSPO1 can improve hair follicle development by activating the Wnt/ß-catenin signaling pathway, thereby promoting hair regeneration. This study demonstrates that rRSPO1 has the potential to treat hair loss by activating the Wnt/ß-catenin signaling pathway.

Dietary supplementation with probiotics increases growth performance, improves the intestinal mucosal barrier and activates the Wnt/ß-catenin pathway activity in chicks.

BACKGROUND: Probiotics comprise effective feed additives that can replace antibiotics in animal livestock production. However, mono-strain probiotics appear less effective because of their instability. Therefore, the present study aimed to investigate dietary supplementation with compound probiotics (CPP) on growth performance, diarrhea rate and intestinal mucosal barrier, as well as the possible molecular mechanism, in chicks. In total, 360 1-day-old chicks of the Hy-Line Brown Chicks were randomly divided into the control group (CON, basal diet), chlortetracycline group (500 mg kg-1 CTC) and compound probiotics group (1000 mg kg-1 CPP, consisting of Bacillus subtilis, Bacillus licheniformis, Enterococcus faecium and yeast). The experiment period was 56 days. RESULTS: The results showed that, in comparison with the CON group, CPP significantly increased the average daily feed intake and average daily gain of chicks and reduced diarrhea (P < 0.05). The probiotic group exhibited increased immune organ (i.e. spleen and thymus) mass and increased levels of serum immunoglobulin (Ig)A, IgM and IgG (P < 0.05) compared to the CTC group. In addition, the jejunal mass and morphology were improved in the probiotic group (P < 0.05). Moreover, CPP reinforced jejunal barrier function, as indicated by increased transepithelial electrical resistance, protein expression of occludin and claudin-1, and diamine oxidase levels in the jejunum (P < 0.05). Likewise, enhanced fluorescence signals of proliferating cell nuclear antigen-labeled mitotic cells and villin-labeled absorptive cells in the jejunum (P < 0.05) suggested that CPP promoted intestinal stem cells activity. Mechanistically, the Wnt/ß-catenin signaling pathway, including ß-catenin, TCF4, c-Myc, cyclin D1 and Lgr5, was amplified in the jejunum by CPP addition (P < 0.05). CONCLUSION: The present study demonstrated that dietary supplementation with CPP reinforced the jejunal epithelial integrity by activating Wnt/ß-catenin signaling and enhanced immune function in chicks. © 2023 Society of Chemical Industry.

Heat-stable enterotoxin inhibits intestinal stem cell expansion to disrupt the intestinal integrity by downregulating the Wnt/ß-catenin pathway.

Enterotoxigenic Escherichia coli causes severe infectious diarrhea with high morbidity and mortality in newborn and weanling pigs mainly through the production of heat-stable enterotoxins (STs). However, the precise regulatory mechanisms involved in ST-induced intestinal epithelium injury remain unclear. Consequently, we conducted the experiments in vivo (mice), ex vivo (mouse and porcine enteroids), and in vitro (MODE-K and IPEC-J2 cells) to explore the effect of STp (one type of STa) on the integrity of the intestinal epithelium. The results showed that acute STp exposure led to small intestinal edema, disrupted intestinal integrity, induced crypt cell expansion into spheroids, and downregulated Wnt/ß-catenin activity in the mice. Following a similar trend, the enteroid-budding efficiency and the expression of Active ß-catenin, ß-catenin, Lgr5, PCNA, and KRT20 were significantly decreased after STp treatment, as determined ex vivo. In addition, STp inhibited cell proliferation, induced cell apoptosis, destroyed cell barriers, and reduced Wnt/ß-catenin activity by downregulating its membrane receptor Frizzled7 (FZD7). In contrast, Wnt/ß-catenin reactivation protected the IPEC-J2 cells from STp-induced injury. Taking these findings together, we conclude that STp inhibits intestinal stem cell expansion to disrupt the integrity of the intestinal mucosa through the downregulation of the Wnt/ß-catenin signaling pathway.

Impaired intestinal stem cell activity in ETEC infection: enterotoxins, cyclic nucleotides, and Wnt signaling.

Enterotoxigenic Escherichia coli (ETEC) in humans and animals colonizes the intestine and thereafter secrets heat-stable enterotoxin (ST) with or without heat-labile enterotoxin (LT), which triggers massive fluid and electrolyte secretion into the gut lumen. The crosstalk between the cyclic nucleotide-dependent protein kinase/cystic fibrosis transmembrane conductance regulator (cAMP or cGMP/CFTR) pathway involved in ETEC-induced diarrhea channels, and the canonical Wnt/ß-catenin signaling pathway leads to changes in intestinal stem cell (ISC) fates, which are strongly associated with developmental disorders caused by diarrhea. We review how alterations in enterotoxin-activated ion channel pathways and the canonical Wnt/ß-catenin signaling pathway can explain inhibited intestinal epithelial activity, characterize alterations in the crosstalk of cyclic nucleotides, and predict harmful effects on ISCs in targeted therapy. Besides, we discuss current deficits in the understanding of enterotoxin-intestinal epithelial cell activity relationships that should be considered when interpreting sequelae of diarrhea.

Microstructure evolution, IMC growth, and microhardness of Cu, Ni, Ag-microalloyed Sn-5Sb/Cu solder joints under isothermal aging.

In this work, various Cu, Ni, Ag-microalloyed Sn-5Sb/Cu joints, ordinary Sn-5Sb/Cu joints, and low-melting-point Sn-3Ag-0.5Cu (SAC305)/Cu (used for comparison) were prepared, focusing on the influence of Cu, Ni, and Ag on the microstructure evolution, interfacial IMC growth, and microhardness of Sn-5Sb/Cu joint under long-time isothermal aging process. Results showed that the microstructure of microalloyed joints consisted of ß-Sn matrix, SbSn, and (Cu, Ni)6Sn5 and Ag3Sn compounds. (Cu, Ni)6Sn5 compounds generated a coarsening effect in the aging microalloyed joints, yet its coarsening speed is significantly lower than the ordinary Sn-5Sb/Cu. Meanwhile, the total IMC layer thickness increased with the rising aging time. A single fine dendritic (Cu, Ni)6Sn5 IMC at the interface of microalloyed joint was observed and evolved into a larger scallop or layer-like duplex IMCs ((Cu, Ni)6Sn5 + Cu3Sn) after the aging. Considering the combined effect of Cu, Ni, and Ag, the microalloyed joints exhibited the improved microstructure relative to ordinary counterparts and low-melting-point SAC305 materials, significantly inhibiting the interfacial IMC growth, especially Cu3Sn. The Cu3Sn IMC thickness and diffusion coefficient in the Sn-5Sb-0.5Cu-0.1Ni-0.5Ag/Cu joint were 0.71-2.81 µm and 0.96 × 10-6 µm·s-2, respectively. Besides, the precipitation strengthening mechanism triggered by the microalloyed elements was extremely obvious and the soldering and aging joints revealed superior microhardness values of 20-35 HV. This could effectively improve the application range of Sn-5Sb-based materials in higher-temperature package conditions such as third-generation semiconductors.

Current situation of complications related to reconstructive surgery for pelvic organ prolapse: a multicenter study.

INTRODUCTION AND HYPOTHESIS: This study aimed to investigate the evaluation and management of complications after pelvic floor reconstructive surgery for pelvic organ prolapse in China. METHODS: Complications of pelvic floor reconstructive surgery for pelvic organ prolapses from 27 institutions were reported from November 2017 to October 2019. All complications were coded according to the category-time-site system proposed by the International Urogynecological Association (IUGA) and the International Continence Society (ICS). The severity of the complications was graded by the Clavien-Dindo grading system. Four scales were used to evaluate patient satisfaction and quality of life after management of the complications: the Patient Global Impression of Improvement (PGI-I), the Pelvic Floor Impact Questionnaire Short Form (PFIQ-7), the Pelvic Organ Prolapse Symptom Score (POP-SS), and a 5-point Likert-type scale that evaluated the patient's choice of surgery. RESULTS: Totally, 256 cases were reported. The occurrence of complications related to transvaginal mesh (TVM) and laparoscopic sacrocolpopexy (LSC) had a significantly longer post-surgery delay than those of native tissue repair surgery (p < 0.001 and p = 0.010, respectively). Both PFIQ-7 and POP-SS score were lower after management of complications (p < 0.001). Most respondents (81.67%) selected very much better, much better, or a little better on the PGI-I scale. Only 13.3% respondents selected unlikely or highly unlikely on the 5-point Likert-type scale. CONCLUSIONS: The occurrence of complications related to TVM surgery and LSC had a longer post-surgery delay than native tissue repair surgery. Long-term regular follow-up was vital in complication management. Patient satisfaction with the management of TVM complications was acceptable.

Wnt/ß-catenin-mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress.

Heat stress induced by continuous high ambient temperatures or strenuous exercise in humans and animals leads to intestinal epithelial damage through the induction of intracellular stress response. However, the precise mechanisms involved in the regulation of intestinal epithelial cell injury, especially intestinal stem cells (ISCs), remain unclear. Thereby, in vitro a confluent monolayer of IPEC-J2 cells was exposed to the high temperatures (39, 40, and 41°C), the IPEC-J2 cell proliferation, apoptosis, differentiation, and barrier were determined, as well as the expression of GRP78, which is a marker protein of endoplasmic reticulum stress (ERS). The Wnt/ß-catenin pathway-mediated regenerative response was validated using R-spondin 1 (Rspo1). And ex-vivo, three-dimensional cultured enteroids were developed from piglet jejunal crypt and employed to assess the ISC activity under heat exposure. The results showed that exposure to 41°C for 72 hr, rather than 39°C and 40°C, decreased IPEC-J2 cell viability, inhibited cell proliferation and differentiation, induced ERS and cell apoptosis, damaged barrier function and restricted the Wnt/ß-catenin pathway. Nevertheless, Wnt/ß-catenin reactivation via Rspo1 protects the intestinal epithelium from heat exposure-induced injury. Furthermore, exposure to 41°C for 24 hr reduced ISC activity, stimulated crypt-cell apoptosis, upregulated the expression of GRP78 and caspase-3, and downregulated the expression of ß-catenin, Lgr5, Bmi1, Ki67, KRT20, ZO-1, occludin, and claudin-1. Taken together, we conclude that heat exposure induces ERS and downregulates the Wnt/ß-catenin signaling pathway to disrupt epithelial integrity by inhibiting the intestinal epithelial cell proliferation and stem cell expansion.

Regulation of mTORC1 by Small GTPases in Response to Nutrients.

Mechanistic target of rapamycin complex 1 (mTORC1) is a highly evolutionarily conserved serine/threonine kinase that regulates cell growth and metabolism in response to multiple environmental cues, such as nutrients, hormones, energy, and stress. Deregulation of mTORC1 can lead to diseases such as diabetes, obesity, and cancer. A series of small GTPases, including Rag, Ras homolog enriched in brain (Rheb), adenosine diphosphate ribosylation factor 1 (Arf1), Ras-related protein Ral-A, Ras homolog (Rho), and Rab, are involved in regulating mTORC1 in response to nutrients, and mTORC1 is differentially regulated via these small GTPases according to specific conditions. Leucine and arginine sensing are considered to be well-confirmed amino acid-sensing signals, activating mTORC1 via a Rag GTPase-dependent mechanism as well as the Ragulator complex and vacuolar H+-adenosine triphosphatase (v-ATPase). Glutamine promotes mTORC1 activation via Arf1 independently of the Rag GTPase. In this review, we summarize current knowledge regarding the regulation of mTORC1 activity by small GTPases in response to nutrients, focusing on the function of small GTPases in mTORC1 activation and how small GTPases are regulated by nutrients.

Dietary supplementation with pioglitazone hydrochloride and chromium methionine manipulates lipid metabolism with related genes to improve the intramuscular fat and fatty acid profile of yellow-feathered chickens.

BACKGROUND: Intramuscular fat (IMF) and polyunsaturated fatty acids (PUFAs) have been thought to play a crucial role in improving meat quality. Considering the ability of pioglitazone hydrochloride (PGZ) to deposit fat, and the anti-stress capability of chromium methionine (CrMet), we combined these compounds to produce higher quality meat in poultry. A total of 3000 female chickens were divided into four groups (five replicates, each with 150 chickens): control, control plus15 mg·kg-1 PGZ, control plus 200 µg·kg-1 CrMet, and control plus15 mg·kg-1 PGZ plus 200 µg·kg-1 CrMet. The experiment lasted for 28 days. RESULTS: Compared to the control group and the PGZ group, the average daily gain (ADG) was significantly increased in the PGZ plus CrMet group, whereas the feed-to-gain ratio (F/G) was decreased from 0 to 14 days. Meanwhile, the redness value of breast muscle and IMF of thigh muscle increased in the PGZ plus CrMet group compared with the control group and these detections in the PGZ plus CrMet group exhibited highest value among the four groups. The cooking loss decreased in the breast muscle and thigh muscle after PGZ combined with CrMet in diets. The percentages of C16:1, C18:2n-6 and PUFAs increased in the PGZ plus CrMet group. The mRNA abundance of peroxisome proliferator activated receptor (PPAR) γ, PPAR coactivator 1 α, and fatty acid binding protein 3 was significantly enhanced with PGZ plus CrMet supplementation. CONCLUSION: Collectively, dietary supplementation with PGZ plus CrMet improved growth performance and meat quality by decreasing the cooking loss and increasing the IMF and PUFA levels. © 2019 Society of Chemical Industry.

Dietary supplementation with pioglitazone hydrochloride improves intramuscular fat, fatty acid profile, and antioxidant ability of thigh muscle in yellow-feathered chickens.

BACKGROUND: Muscle fat content and fatty acid composition play an important role in poultry flavor and taste. To investigate the effects of pioglitazone hydrochloride (PGZ) on growth performance and thigh muscle quality in yellow-feathered chickens, 360 female chickens were randomly divided into three groups and treated with three doses of PGZ (0, 7.5, and 15 mg kg-1 ) for 28 days. Each group had six replicates of 20 chickens. RESULTS: The results showed that dietary supplementation with 15 mg kg-1 PGZ increased average daily feed intake (ADFI) and the average daily gain (ADG) from 0 to 14 days. Furthermore, the triglyceride (TG) level was decreased by 15 mg kg-1 PGZ, whereas the eviscerated yield was increased. The relative weight of the heart and kidneys showed a linear increase with dietary PGZ supplementation, and the drip loss of the thigh muscle was significantly decreased by 15 mg kg-1 PGZ supplementation. Moreover, a* value, intramuscular fat (IMF), and polyunsaturated fatty acids (PUFAs) showed a linear increase, and pH24 h and drip loss showed a quadratic influence with the levels of PGZ supplementation. In particular, the PUFA proportion was increased by 7.63% and 9.14% in the 7.5 mg kg-1 PGZ and 15 mg kg-1 PGZ groups, respectively. Additionally, 15 mg kg-1 of PGZ increased the total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-PX ) activity. CONCLUSION: In summary, 15 mg kg-1 PGZ has substantial effects on growth performance and meat quality, particularly by decreasing drip loss and increasing IMF content, PUFA proportions, and antioxidant ability. © 2019 Society of Chemical Industry.

mTORC1 signaling activation increases intestinal stem cell activity and promotes epithelial cell proliferation.

The crypt-villus axis of the intestine undergoes a continuous renewal process that is driven by intestinal stem cells (ISCs). However, the homeostasis is disturbed under constant exposure to high ambient temperatures, and the precise mechanism is unclear. We found that both EdU+ and Ki67+ cell ratios were significantly reduced after exposure to 41°C, as well as the protein synthesis rate of IPEC-J2 cells, and the expression of ubiquitin and heat shock protein 60, 70, and 90 were significantly increased. Additionally, heat exposure decreased enteroid expansion and budding efficiency, as well as induced apoptosis after 48 hr; however, no significant difference was observed in the apoptosis ratio after 24 hr. In the process of heat exposure, the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway was significantly inhibited in both IPEC-J2 cells and enteroids. Correspondingly, treatment of IPEC-J2 and enteroids with the mTORC1 agonist MHY1485 at 41°C significantly attenuated the inhibition of proliferation and protein synthesis, increased the ISC activity, and promoted expansion and budding of enteroid. In summary, we conclude that the mTORC1 signaling pathway regulates intestinal epithelial cell and stem cell activity during heat exposure-induced injury.

Comparison of outcomes between single-incision sling and transobturator sling for treating stress urinary incontinence: A 10-year prospective study.

AIMS: To evaluate and compare the clinical outcomes of the transobturator sling with the single-incision sling, for the treatment of stress urinary incontinence at a long-term follow-up. METHODS: From October 2008 to October 2010, 94 patients who were enrolled and underwent either TVT-O, one of standard mid-urethral sling or TVT-S, one of single-incision mini-sling (SIMS) procedure. The study population was followed until February 2019. Surgical outcomes were analyzed by subjective and objective evaluations and Chinese version questionnaires. Data were analyzed by IBM 23.0 SPSS Statistics. The level of statistical significance was set at P < 0.05. RESULTS: At the 10-year follow-up, 31(64.6%) TVT-O patients and 33(71.7%) TVT-S patients were still available. Objective cure and subjective satisfaction rate were not significantly different for TVT-O compared with TVT-S (P > 0.05). However, TVT-S showed a greater drop in success from the second to the tenth year compared with TVT-O (15.1% vs 0% and 9.2% vs 3.2%, respectively). Both groups experienced significantly improved quality of life in the TVT-O group and in the TVT-S group (P < 0.05). The total PISQ-12 scores at 10 years postoperatively of the TVT-O and TVT-S groups were 33.4(4.7) compared with 33.6(3.9) before surgery (P = 0.67 > 0.05) and 35.5(5.9) compared with 31.5(6.3) before surgery (P = 0.045 < 0.05). CONCLUSIONS: It is difficult to state that there is superiority of one sling over another sling without a significant difference. But TVT-O showed superior objective cure and subjective satisfaction rates and a less decline in success during 10 years compared with TVT-S.