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Polymer network is a crucial component of hydrogels, and network imperfection is a prominent feature of polymer networks, significantly influencing the performance of hydrogels. Two essential features of network imperfection are unequal chain lengths and dangling chains, both of which have a significant impact on the mechanical properties of single-network (SN) hydrogels. However, a theoretical framework considering network imperfection in SN hydrogels is still lacking. Here, we propose a theoretical model for SN hydrogels with network imperfection to study the damage behavior during deformation, in which we adopt different chain length distributions to accurately depict the real physical characteristics of the polymer network and incorporate the normalized critical chain force for a more precise measurement of network damage. To verify our theory, we discuss the effects of model parameters on the stress-stretch responses of SN hydrogels and predict the results of uniaxial loading-unloading tests of SN hydrogels, which agree well with experimentally measured stress-stretch behaviors. Finally, we implement the constitutive model into ABAQUS as a user subroutine to study the inhomogeneous deformation of hydrogels.

Summary: Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/β/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma’s chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kβ being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kβ, defined as MGMT-deficient/PI3Kβ-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kβ-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kβ, but not other kinases, sensitized MGMT-deficient/PI3Kβ-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kβ-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kβ in chemoresistance, making PI3Kβ-selective blockade an effective chemosensitizer for glioblastoma.

Abstract Introduction ‘Let’s Talk About Children’ is a brief family focused intervention developed to improve mental health outcomes of children of parents with mental illness (COPMI). This study aims to assess the efficacy of LTC in improving mental health of children of parents with schizophrenia or bipolar disorder in China. Methods The planned study is a multicentre parallel group randomized wait-list controlled trial. A total of 400 eligible families with children aged 8 to 18 years will be recruited, 200 each for families with parental schizophrenia or bipolar disorder. The intervention group will receive Let’s Talk About Children delivered by a trained therapist, while the control group will receive treatment as usual. The primary outcomes are child mental health measured by the strengths and difficulties questionnaire and parent–child communication measured using the parent-adolescent communication scale. Parental mental health and family functioning are secondary outcomes. This study also plans to explore mediating factors for the effect of Let’s Talk About Children on child mental health, as well as conduct a cost-effectiveness analysis on using Let’s Talk About Children in China. Conclusion The present study will provide evidence for the efficacy of Let’s Talk About Children in families with parental schizophrenia and bipolar disorder in China. In addition, it will evaluate potential mechanisms of action and cost-effectiveness of Let’s Talk About Children, providing a basis for future implementation. Trial registration ChiCTR2300073904.

Abstract Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims.

Abstract Circumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1–a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide–inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit β (PIK3CB, also called PI3Kβ or p110β), suggesting that Cx43 activates PIK3CB/p110β independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110β, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110β-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110β together is an effective therapeutic approach for overcoming chemoresistance.

Abstract Objective Ovarian cancer is the most deadly deadliest gynecological tumor in the female reproductive system. Therefore, the present study sought to determine the diagnostic performance of International Ovarian Tumor Analysis Simple Rules (IOTA SR), the Ovarian-Adnexal Reporting and Data System (O-RADS), and Cancer Antigen 125 (CA125) in discriminating benign and malignant ovarian tumors. The study also assessed whether a combination of the two ultrasound categories systems and CA125 can improve the diagnostic performance. Methods A total of 453 patients diagnosed with ovarian tumors were retrospectively enrolled from Fujian Cancer Hospital between January 2017 and September 2020. The data collected from patients included age, maximum lesion diameter, location, histopathology, levels of CA125, and detailed ultrasound reports. Additionally, all ultrasound images were independently assessed by two ultrasound physicians with more than 5 years of experience in the field, according to the IOTA simple rules and O-RADS guidelines. Furthermore, the area under the curve (AUC), sensitivity, and specificity of the above mentioned predictors were calculated using the receiver operating characteristic curve. Results Out of the 453 patients, 184 had benign lesions, while 269 had malignant ovarian tumors. In addition, the AUCs of IOTA SR, O-RADS, and CA125 in the overall population were 0.831, 0.804, and 0.812, respectively, and the sensitivities of IOTA SR, O-RADS, and CA125 were 94.42, 94.42, and 80.30%, respectively. On the other hand, the AUCs of IOTA SR combined with CA125, O-RADS combined with CA125, and IOTA SR plus O-RADS combined with CA125 were 0.900, 0.891, and 0.909, respectively. The findings also showed that the AUCs of a combination of the three approaches were significantly higher than those of individual strategies (p0.05). Conclusion The findings showed that a combination of IOTA SR or O-RADS in combination with CA125 may improve the ability to distinguish benign from malignant ovarian tumors.

The Gleeble-3500 thermal simulation tester was used to perform hot deformation behavior on the extruded AZ40 Mg alloy to analyze the trend of the true stress-strain curve after compression and to obtain the influence of the flow stress on the deformation temperature and strain rate. Subsequently, the constitutive equation was constructed for extruded AZ40 alloy based on the hyperbolic-sine relationship, and the thermal processing map of extruded AZ40 alloy was established based on the dynamic material model (DMM), thereby estimating the processing range of extruded AZ40 alloy. The results show that the rheological curve of extruded AZ40 alloy is characterized by obvious dynamic recrystallization. Furthermore, during the compression process, the peak stress of extruded AZ40 alloy decreases with the increase of deformation temperature, while increases with the increase of strain rate. Moreover, the proportion of dynamic recrystallized grains (DRGs) decreases with the increase of the strain rate under the same deformation temperature condition; while the DRGs size increases with the increase of the deformation temperature under the same strain rate condition. The coarse uncrystallized grains show obvious crystallographic orientations of 〈1010〉‖ND and 〈2110〉‖ND, while crystallographic orientation of DRGs is random distributed. Finally, through thermal processing map and tissue analysis, the optimal processing window was identified as T=573 K, $\dot \varepsilon $=0.1 s-1.

Summary: The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms – elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.

The manufacture of detergent products such as laundry detergents, household cleaners and fabric softeners are of increasing interest to the consumer oriented chemical industry. Surfactants are the most important ingredient in detergent formulations, as they are responsible for the bulk of the cleaning power. In this research, a methodology has been developed to design a detergent product using computational tools. Different surfactant systems, such as single anionic, single nonionic, and binary mixtures of anionic-nonionic surfactants are covered in this work. Important surfactant properties such as critical micelle concentration (CMC), cloud point (CP), hydrophilic-lipophilic balance (HLB) and molecular weight (MW) have been identified. A group contribution (GC) method with the aid of computer modelling was used to determine the CMC, CP, and MW of surfactant molecules. The design of a surfactant molecule can be formulated as a multi-objective optimization problem that tradeoffs between CMC, CP, HLB and MW. Consequently, a list of plausible nonionic surfactant structures has been developed with the selected surfactant being incorporated into a binary surfactant mixture. Additives such as antimicrobial agents, anti-redeposition agents, builders, enzymes, and fillers were also considered and incorporated into a hypothetical detergent formulation together with the binary surfactant mixture. The typical ingredients and their compositions in detergent formulations are presented in the final stage of the detergent product design.

The high mortality associated with invasive fungal infections, narrow spectrum of available antifungals, and increasing evolution of antifungal resistance necessitate the development of alternative therapies. Host defense peptides are regarded as the first line of defense against microbial invasion in both vertebrates and invertebrates. In this work, we investigated the effectiveness of four naturally occurring pore-forming antimicrobial peptides (melittin, magainin 2, cecropin A, and mastoparan B) against a panel of clinically relevant pathogens, including Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida glabrata. We present data on the antifungal activities of the four pore-forming peptides, assessed with descriptive statistics, and their cytocompatibility with cultured human cells. Among the four peptides, mastoparan B (MB) displayed potent antifungal activity, whereas cecropin A was the least potent. We show that MB susceptibility of phylogenetically distant non-candida albicans can vary and be described by different intrinsic physicochemical parameters of pore-forming α-helical peptides. These findings have potential therapeutic implications for the design and development of safe antifungal peptide-based drugs.

Hyperbaric oxygen (HBO) therapy is a treatment modality useful for diseases. Hypoxia could stimulate the induction of insulin resistance. Therefore, we sought to determine whether hyperbaric oxygen would ameliorate insulin sensitivity by promoting glucose transporter type 4 (GLUT4) expression in muscle and by stimulating UCP1 in brown adipose tissue (BAT) in a streptozocin (STZ)-induced type 2 diabetes mellitus (T2DM) mouse model. Male C57BL/6J mice were treated three times with low-dose of streptozocin (60 mg/kg, i.p.) and were fed with high-fat diets (HFD) to establish the T2DM model. HBO was administered daily as 100% oxygen at 2.0 atmosphere absolute (ATA) for 1 h for a week. We found that HBO significantly reduced blood glucose levels and attenuated insulin resistance in T2DM mice. HBO modulated food intake by influencing the activity of neuropeptide Y (NPY)-positive neurons in the arcuate nucleus (Arc). HBO treatment increased GLUT4 amount and level of phosphorylated Akt (p-Akt) in muscles of T2DM mice whereas this treatment stimulated the phosphorylation of AMPK in muscles of both T2DM and HFD mice. The morphological staining of BAT and the increased expression of uncoupling of protein 1 (UCP1) demonstrated the promotion of metabolism after HBO treatment. These findings suggest that HBO ameliorates insulin sensitivity of T2DM mice by stimulating the Akt signaling pathway and by promoting GLUT4 expression in muscle, and by increasing UCP1 expression in BAT.

Background: Pre-diabetes is a risk factor for full-blown diabetes; it presents opportunities to prevent the actual diseases. It is therefore essential to identify effective preventive strategies, and to clarify the direction of future research.Methods: PubMed, Embase and Cochrane Central Register of Controlled Trials were searched using key terms (Supplementary Table 1). We applied network meta-analysis to multiple comparisons among various diabetic preventive strategies, including lifestyle and pharmacological interventions; traditional meta-analysis for the synthesis of basal metabolic changes after interventions; and trial sequential analysis for determinations as to whether analysis conclusions meet expectations.Results: We included 32 randomized controlled trials comprising 43,669 patients and 14 interventions in the meta-analysis. Both lifestyle modifications and anti-diabetic medications improved physical conditions, including weight loss, blood glucose, and blood pressure. Network meta-analysis suggested that the progression of diabetes could be delayed to varying degrees by lifestyle and pharmacological interventions, except for angiotensin-converting enzyme inhibitors, statins, sulfonylureas and vitamin D. The risk ratios (RR) [95% credible interval (CrI)] compared with control were: GLP-1RAs 0.28 (0.15, 0.50), Orlistat 0.33 (0.18, 0.55), TZM 0.33 (0.16, 0.63), TZD 0.39 (0.27, 0.53), LST 0.54 (0.32, 0.88), lifestyle 0.58 (0.49, 0.67), LSM 0.62 (0.45, 0.80), GI 0.66 (0.46, 0.88), SU 0.67 (0.40, 1.00), Vitamin D 0.91 (0.59, 1.40), ACEI 0.93 (0.62, 1.40), statins 1.20 (0.84, 1.60).Conclusions: In adults with pre-diabetes, firm evidence supports the notion that lifestyle modifications and metformin reduces the incidence of diabetes with an average of 20% relative risk reduction, while statins increase the relative risk 20%. We found that lifestyle modifications, promising long-term strategies involving three factors (nutrition, exercise, and weight loss) contribute to health by reducing BMI, body weight, waist and hip circumference, systolic and diastolic pressure, fasting, and 2-h postprandial blood glucose, total cholesterol and by increasing HDL. We made this determination using TSA, avoiding further waste of experimental resources.

Glioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes were identified as survival genes in 15 glioblastoma cell lines. RAN, member RAS oncogene family (RAN) was expressed in glioblastoma at the highest level among all candidates based upon cDNA microarray data. However, Kaplan-Meier survival analysis did not show any correlation between RAN mRNA levels and patient survival. Because RAN is a small GTPase that regulates nuclear transport controlled by karyopherin subunit beta 1 (KPNB1), RAN was further analyzed together with KPNB1. Indeed, GBM patients with high levels of RAN also had more KPNB1 and levels of KPNB1 alone did not relate to patient prognosis. Through a Cox multivariate analysis, GBM patients with high levels of RAN and KPNB1 showed significantly shorter life expectancy when temozolomide and promoter methylation of O6-methylguanine DNA methyltransferase were used as covariates. These results indicate that RAN and KPNB1 together are associated with drug resistance and GBM poor prognosis. Furthermore, the functional blockade of RAN and KPNB1 by importazole remarkably suppressed cell viability and activated apoptosis in GBM cells expressing high levels of RAN, while having a limited effect on astrocytes and GBM cells with undetectable RAN. Together, our results demonstrate that RAN activity is important for GBM survival and the functional blockade of RAN/KPNB1 is an appealing therapeutic approach.

Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including glioblastoma, the most common and aggressive form of brain cancer. Targeting the PI3K pathway to treat glioblastoma has been tested in the clinic with modest effect. In light of the recent finding that PI3K catalytic subunits (PIK3CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, and PIK3CG/p110γ) are not functionally redundant, it is imperative to determine whether these subunits play divergent roles in glioblastoma and whether selectively targeting PI3K catalytic subunits represents a novel and effective strategy to tackle PI3K signaling. This article summarizes recent advances in understanding the role of PI3K catalytic subunits in glioblastoma and discusses the possibility of selective blockade of one PI3K catalytic subunit as a treatment option for glioblastoma.

Purpose. To report a new approach for removal of silicone oil. Methods. All surgeries were performed using 23-gauge vitrectomy system with two transconjunctival sutureless cannulas. At the beginning, most of the silicone oil was removed by traditional microinvasive vitrectomy system through inferior-temporal cannula. Then, the blood transfusion tube is removed from the inferior-temporal cannula, and the fluid-air exchange is performed. A passive fluid-air exchange was performed to aspirate the residual silicone oil after gradually turning the patient’s head temporally by approximately 90° gradually. Results. After the surgery, all patients had a clear anterior chamber and vitreous cavity on slit lamp and B scan examination, respectively. The mean time taken for silicone oil removal and total surgery was 8.0±1.4 minutes and 12.4±2.5 minutes, respectively. The mean intraocular pressure 1 day, 3 days, 1 week, 1 month, and 3 months after surgery was 9.0±5.8 mmHg, 11.3±7.6 mmHg, 16.1±6.9 mmHg, 17.7±4.8 mmHg, and 17.1±3.5 mmHg, respectively. Conclusion. This new approach may provide a safe and fast method to remove the silicone oil.

This study was conducted to determine the effects of different levels of crude protein (CP) supplements to the diet of early-weaned yaks on their growth performance, intestinal development, and immune response. Forty 3-month-old weaned yaks were selected and assigned to four dietary groups (Control, 17, 19 and 21% CP). Dietary CP supplements had a significant effect on average daily gain (ADG), crypt depth (CD) (duodenum, jejunum and ileum), villous height (VH) (duodenum, jejunum and ileum) and CD/VH (jejunum and ileum). Average daily gain, CD (duodenum, jejunum and ileum) and VH (ileum) showed quadratic increases as the dietary CP increased, whereas CD/VH (jejunum and ileum) ratios showed quadratic decreases. Blood urea nitrogen (BUN), glucose (GLU), immunoglobulin G (IgG), IgM, interleukin-1 (IL-1), IL-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ concentrations increased significantly, whereas albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased significantly with dietary CP supplements. Dietary CP supplements significantly increased the concentrations of IL-6, TNF-α, IFN-γ and the nuclear factor of activated T cell transcription factor (NFAT) for gene expression. As the dietary CP supplements increased, IL-6, IFN-γ and NF-AT gene expression showed quadratic increases. These results showed that the appropriate dietary CP supplementation improved the growth performance and intestinal development of earlyweaned yaks and thus that the CP supplements were beneficial and enhanced the humoral immunity response of yaks.