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The intestinal microbiota plays a crucial role in the occurrence and development of colorectal cancer, and its anti - colorectal cancer mechanism has become a research hotspot. This article comprehensively expounds on the molecular mechanisms of the intestinal microbiota in anti - colorectal cancer, including aspects such as immune regulation, activation of carcinogenic signaling pathways (it should be noted that it is more reasonable to be “inhibition of carcinogenic signaling pathways”), metabolite - mediated effects, and maintenance of intestinal barrier function. At the same time, it explores the roles and potential mechanisms of intervention methods such as probiotic supplementation therapy, immunotherapy, and fecal microbiota transplantation. In addition, it analyzes the impact of the intestinal flora on the therapeutic efficacy of colorectal cancer. The existing research results are summarized, and the future research directions are prospected, with the aim of providing new theoretical bases and treatment ideas for the prevention and treatment of colorectal cancer.

Introduction Therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on motor recovery of Parkinson's disease (PD) have been reported; however, the protocols of these studies varied greatly. The aim of this meta‐analysis was to evaluate the optimal rTMS parameters for motor recovery of PD. Methods Electronic databases were searched for studies investigating the therapeutic effects of rTMS on motor function in patients with PD. The section III of the Unified Parkinson's Disease Rating Scale (UPDRS) was extracted as the primary outcome, and the standardized mean difference (SMD) with 95% confidence interval (CI) was calculated. Results Twenty‐three studies with a total of 646 participants were included. The pooled estimates of rTMS revealed significant short‐term (SMD, 0.37; p < 0.00001) and long‐term (SMD, 0.39; p = 0.005) effects on motor function improvement of PD. Subgroup analysis observed that high‐frequency rTMS (HF‐rTMS) was significant in improving motor function (SMD, 0.48; p < 0.00001), but low‐frequency rTMS (LF‐rTMS) was not. In particular, when HF‐rTMS targeted over the primary motor cortex (M1), in which the bilateral M1 revealed a larger effect size than unilateral M1. Compared to single‐session, multi‐session of HF‐rTMS over the M1 showed significant effect size. In addition, HF‐rTMS over the M1 with a total of 18,000–20,000 stimulation pulses yielded more significant effects (SMD, 0.97; p = 0.01) than other dosages. Conclusions In conclusion, multi‐session of HF‐rTMS over the M1 (especially bilateral M1) with a total of 18,000–20,000 pulses appears to be the optimal parameters for motor improvement of PD. (a) rTMS improves motor recovery measured by UPDRS‐III scores in both the short‐ and long‐terms in people with PD. (b) HF‐rTMS was significantly more effective than LF‐rTMS in improving motor recovery measured by UPDRS‐III scores. (c) Multi‐session of HF‐rTMS stimulation over M1 (especially bilateral M1) with a total of 18,000–20,000 pulses appears to be the optimal parameters for achieving motor improvement in the short‐terms in people with PD.

Refracturing treatment is widely used to enhance the well productivity in shale gas reservoirs, particularly for initially fractured wells with low productivity. The principal of this work is based on the transient behavior of pressure and rate for a vertically refractured well in a shale gas reservoir, considering the fracture reorientation and adsorption and desorption property. Based on the point-source theory and Laplace transform, a semi-analytical solution for a refractured well is obtained by coupling the point-source solution of a shale gas reservoir and the solution of artificial fractures. The validation of this new solution is carried out smoothly by comparison with the results from the commercial software COMSOL. Five typical flow regimes are identified on the transient pressure curve, namely bi-linear flow regime, formation linear flow regime, mid-radial flow regime, inter-porosity flow regime, and pseudo-radial flow regime. A groove segment occurs on the transient-pressure derivative curve, and its width and depth largely depend on the adsorption and desorption constant and storativity ratio. Due to fracture reorientation, bi-linear flow regime, formation linear flow regime, and mid-radial flow regime may be significantly impacted. In addition, the transient rate of the refractured well in a shale gas reservoir is positively proportional to the storativity ratio, inter-porosity coefficient, and adsorption and desorption constant, while it is inversely proportional to fracture reorientation. These results provide important references for parameter design, property inversion, and productivity prediction of refracturing treatment in shale gas reservoirs.

Polymer flooding has been proved by many scholars for use in heavy oil reservoirs. However, due to mobility control effects and injectivity, selecting the appropriate solution viscosity is essential. It is difficult to form a deep understanding of the effect and mechanism of polymer flooding using conventional experimental methods with oil recovery as the reference standard, so it is necessary to conduct further study with the aid of simulation methods. In this study, a one-dimensional displacement mathematical model based on the Buckley–Leverett theory was established, and in the range of water–oil viscosity ratio from 0.1 to 0.6, the variation of water saturation along the flow caused by polymer solution was studied. The research results showed that under the action of a polymer solution, compared with water flooding, there was a decreasing region of water saturation along the flow due to oil phase accumulation. The larger the water–oil viscosity ratio, the larger the area of water saturation decline and the greater the degree of water saturation decline, resulting in a better the displacement effect. However, under the condition of oil–phase viscosity of 70 mPa·s, when the water–oil viscosity ratio reached 0.4, the range and degree of water saturation decline along the way no longer changed, all the crude oil that could be swept had been displaced, and the outlet end was close to producing only water, not oil; therefore, further increasing the water–oil viscosity ratio could not increase the oil recovery. At the same time, the increase in pressure had not changed, that is, the increase in pressure had not resulted in the same increase in oil recovery. When the viscosity of oil phase increased to 140 mPa·s, the same rule was displayed, the appropriate water–oil viscosity ratio was also 0.4. The paper analyzed the action mechanism of polymer solution through process description, and the results provided a clear selection method for selecting reasonable polymer solution concentration, as well as a reference for polymer solution range under different crude oil viscosity conditions.

The Ten-Eleven Translocation (TET) family genes are implicated in a wide array of biological functions across various human cancers. Nonetheless, there is a scarcity of studies that comprehensively analyze the correlation between TET family members and the molecular phenotypes and clinical characteristics of different cancers. Leveraging updated public databases and employing several bioinformatics analysis methods, we assessed the expression levels, somatic variations, methylation levels, and prognostic values of TET family genes. Additionally, we explored the association between the expression of TET family genes and pathway activity, tumor microenvironment (TME), stemness score, immune subtype, clinical staging, and drug sensitivity in pan-cancer. Molecular biology and cytology experiments were conducted to validate the potential role of TET3 in tumor progression. Each TET family gene displayed distinct expression patterns across at least ten detected tumors. The frequency of Single Nucleotide Variant (SNV) in TET genes was found to be 91.24%, primarily comprising missense mutation types, with the main types of copy number variant (CNV) being heterozygous amplifications and deletions. TET1 gene exhibited high methylation levels, whereas TET2 and TET3 genes displayed hypomethylation in most cancers, which correlated closely with patient prognosis. Pathway activity analysis revealed the involvement of TET family genes in multiple signaling pathways, including cell cycle, apoptosis, DNA damage response, hormone AR, PI3K/AKT, and RTK. Furthermore, the expression levels of TET family genes were shown to impact the clinical staging of tumor patients, modulate the sensitivity of chemotherapy drugs, and thereby influence patient prognosis by participating in the regulation of the tumor microenvironment, cellular stemness potential, and immune subtype. Notably, TET3 was identified to promote cancer progression across various tumors, and its silencing was found to inhibit tumor malignancy and enhance chemotherapy sensitivity. These findings shed light on the role of TET family genes in cancer progression and offer insights for further research on TET3 as a potential therapeutic target for pan-cancer.

The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or α -methyl-5-HT, a 5-HT 2 receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT 2A receptor antagonists while a selective 5-HT 2B receptor agonist and a selective 5-HT 2C receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT 2A receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT 2A receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT 2A receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT 2A receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT 2A receptors because stress had no significant impact on other serotonin receptors, as well as histamine H 3 receptor and α 2 adrenoceptor signaling in the BLA. This severe impairment of 5-HT 2A receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.

Background and Purpose. This meta-analysis aimed to evaluate the therapeutic potential of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the contralesional hemisphere on upper limb motor recovery and cortex plasticity after stroke. Methods. Databases of PubMed, Medline, ScienceDirect, Cochrane, and Embase were searched for randomized controlled trials published before Jun 31, 2017. The effect size was evaluated by using the standardized mean difference (SMD) and a 95% confidence interval (CI). Resting motor threshold (rMT) and motor-evoked potential (MEP) were also examined. Results. Twenty-two studies of 1 Hz LF-rTMS over the contralesional hemisphere were included. Significant efficacy was found on finger flexibility (SMD = 0.75), hand strength (SMD = 0.49), and activity dexterity (SMD = 0.32), but not on body function (SMD = 0.29). The positive changes of rMT (SMD = 0.38 for the affected hemisphere and SMD = −0.83 for the unaffected hemisphere) and MEP (SMD = −1.00 for the affected hemisphere and SMD = 0.57 for the unaffected hemisphere) were also significant. Conclusions. LF-rTMS as an add-on therapy significantly improved upper limb functional recovery especially the hand after stroke, probably through rebalanced cortical excitability of both hemispheres. Future studies should determine if LF-rTMS alone or in conjunction with practice/training would be more effective. Clinical Trial Registration Information. This trial is registered with unique identifier CRD42016042181.

Cholangiocarcinoma (CCA), an aggressive malignancy with limited therapeutic options and poor survival rates, poses an urgent clinical challenge necessitating innovative therapeutic strategies. Saikosaponin D (SSd), a bioactive compound derived from , has demonstrated anticancer potential in various malignancies. However, its role in CCA remains unexplored. This study investigated the antitumor effects and potential mechanisms of SSd, both alone and in combination with gemcitabine, utilizing patient-derived cholangiocarcinoma organoids (PDCOs). Four PDCO models were established from surgical tumor tissues and metastatic ascites of CCA patients. Histological, immunohistochemical (Cytokeratin 7, Cytokeratin 19 and Ki-67), and immunofluorescence analyses validated the fidelity of organoids to the primary tumors. Drug sensitivity testing evaluated SSd (0.001-50µM) and gemcitabine alone or in combination (ratios 1:1, 1:2, 1:4) using dose-response curves and combination index (CI) analysis. Apoptosis mechanisms were assessed via TUNEL staining, caspase-3 activity assays, and the JC-1 assay for the mitochondrial membrane potential. SSd exhibited dose-dependent growth inhibition across PDCOs, with half-maximal inhibitory concentration (IC50) values ranging from 0.9µM to 13µM. Gemcitabine showed IC50 values spanning 0.03µM to 11.1µM. Notably, the SSd-gemcitabine combination at 1:4 ratio demonstrated synergistic effects (CI=0.0005), significantly reducing organoid viability. Ascites-derived PDCOs (eg, CCA182) displayed lower sensitivity to SSd, correlating with prior chemotherapy exposure. Apoptosis induction by SSd was confirmed through increased TUNEL-positive cells, elevated caspase-3 activity, and mitochondrial depolarization. Histological and molecular profiles of PDCOs closely mirrored those of the primary tumors, preserving spatial heterogeneity (eg, glandular structures in tissue-derived PDCOs vs compact morphology in ascites-derived models). The combination of SSd and gemcitabine exerts a synergistic antitumor effect in patient-derived cholangiocarcinoma organoids through activating caspase-3 and triggering mitochondrial dysfunction-mediated apoptosis.

Backgrounds Recent experiments suggest that Citrus bergamia extracts could benefit people with dyslipidemia and obesity but this needs to be further validated. Methods A total of 98 people age-matched older adults (65 years) with elevated blood lipids were enrolled to receive 12-week supplementation of a Citrus bergamia extracts-based formulation (CitriCholess)( n  = 48) and placebo ( n  = 50). Results No group differences were found in baseline bodyweight, body mass index (BMI), blood cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and glucose levels. CitriCholess supplementation resulted in lower levels than placebo in TG (1.83 ± 0.92 vs. 1.95 ± 1.34 mmol/L, P  = 0.612), TC (5.14 ± 0.98 vs. 5.44 ± 0.77 mmol/L, P  = 0.097), and LDL-C (3.13 ± 0.74 vs. 3.43 ± 0.62 mmol/L, P  = 0.032). Compared to placebo, CitriCholess also resulted in greater reductions in body weight (−0.604 ± 0.939 vs. 0.06 ± 0.74 kg, P  < 0.01), waist circumferences (−0.60 ± 1.349 cm vs. -0.16 ± 1.503 cm, P < 0.01) and BMI (−0.207 ± 0.357 vs. 0.025 ± 0.274, P < 0.01). Additionally, females had a significantly higher level of HDL-C than males. TC was significantly correlated with LDL-C, and to a less degree, with TG. TG was inversely correlated with HDL-C. Body weight and waist circumference were negatively correlated with HDL-C and positively correlated with glucose. Conclusion 12-week supplementation of CitriCholess could benefit lipid metabolism and weight management in old adults with dyslipidemia.

Backgrounds To study the effects of supplementation of a marine omega-3 poly-unsaturated fatty acids (n3-PUFA) formulation (Omega3Q10) in older adults with hypertension and/or hypercholesterolemia. Methods A total of 97 people were enrolled to receive 12-week supplementation of either Omega3Q10 ( n  = 48) or soybean oil ( n  = 49). Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and hypertension-related symptoms were determined before and after the supplementation. Results There were no baseline differences between the two groups. Omega3Q10 supplementation significantly reduced diastolic blood pressure (DBP) (from 81.6 ± 5.3 mmHg to 79.3 ± 5.2 mmHg, P  < 0.05). Blood concentrations of TC and LDL-C decreased significantly and blood HDL-C level increased significantly after 12 weeks of Omega3Q10 (5.5 ± 0.7 vs. 5.3 ± 0.5, P  < 0.05; 3.7 ± 0.8 vs. 3.3 ± 0.6, P  < 0.05; 1.2 ± 0.6 vs. 1.3 ± 0.5, P  < 0.05, respectively) and soybean oil supplementation (5.7 ± 0.8 vs. 5.6 ± 0.7, P  < 0.05; 3.6 ± 0.7 vs. 3.4 ± 0.8, P < 0.05; 1.0 ± 0.8 vs. 1.2 ± 0.7, P  < 0.05, respectively) but no group differences were found. A significantly greater proportion of the people in the Omega3Q10 group became free from headache and palpitations & chest tightness symptoms after the 12-week supplementation compared to that of the soybean oil group (95.5% vs. 71.4%, P  < 0.01; 95.8 vs. 75.5%, P  < 0.01, respectively). Conclusion 12-week supplementation of Fish oil-based PUFA appear to be more effective in improving DBP and hypertension-related symptoms than soybean oil in old adults with hypertension and hypercholesterolemia although both supplementation improved TC, LDL-C and HDL-C concentrations.