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Abstract Integration of solar cell and secondary battery cannot only promote solar energy application but also improve the electrochemical performance of battery. Lithium–sulfur battery (LSB) is an ideal candidate for photoassisted batteries owing to its high theoretical capacity. Unfortunately, the researches related the combination of solar energy and LSB are relatively lacking. Herein, a freestanding photoelectrode is developed for photoassisted lithium–sulfur battery (PALSB) by constructing a heterogeneous structured Au@N‐TiO2 on carbon cloths (Au@N‐TiO2/CC), which combines multiple advantages. The Au@N‐TiO2/CC photoelectrode can produce the photoelectrons to facilitate sulfur reduction during discharge process, while generating holes to accelerate sulfur evolution during charge process, improving the kinetics of electrochemical reactions. Meanwhile, Au@N–TiO2/CC can work as an electrocatalyst to promote the conversion of intermediate polysulfides during charge/discharge process, mitigating induced side reactions. Benefiting from the synergistic effect of electrocatalysis and photocatalysis, PALSB assembled with an Au@N‐TiO2/CC photoelectrode obtains ultrahigh specific capacity, excellent rate performance, and outstanding cycling performance. What is more, the Au@N‐TiO2/CC assembled PALSB can be directly charged under light illumination. This work not only expands the application of solar energy but also provides a new insight to develop advanced LSBs.

Minks, cats, and some other species of carnivores are susceptible of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have a high risk of transmitting SARS-CoV-2 to humans. The development of animal vaccines can be an effective measure to protect animals against SARS-CoV-2 and reduce the potential risk of human infection. We previously developed a messenger ribonucleic acid (mRNA) vaccine SYS6006 that has been proven to be an efficient coronavirus disease 2019 (COVID-19) vaccine widely used in humans. Here, we further evaluated the safety and immunogenicity of SYS6006 as an animal COVID-19 vaccine candidate for SARS-CoV-2 susceptible animals or wild animals. SYS6006 was safe and immunogenic in mice and completely protected mice against mouse-adapted SARS-CoV-2 infection in the upper and lower respiratory tracts. SYS6006 was able to induce neutralizing antibodies against the SARS-CoV-2 wild-type, Delta, and Omicron BA.2 strain on day 7 after prime immunization, and two doses of immunization could enhance the neutralizing antibody responses and produce long-lasting potent antibodies for more than 8 months in minks and cats, blue foxes, and raccoon dogs, while all immunized animals had no abnormal clinical signs during immunization. These results provided here warrant further development of this safe and efficacious mRNA vaccine platform against animal COVID-19.

The endoplasmic reticulum (ER) is one of the largest organelles, and Endoplasmic Reticulum Stress Response Pathway is a series of responses triggered by the homeostatic imbalance of the ER and the state in which unfolded or misfolded proteins accumulate in the ER, which can trigger cell death. Cell death plays a crucial role in the development of diseases such as gynecological oncology. Herein, we review the current research on the response and ovarian cancer, discussing the key sensors (IRE1, PERK, ATF6), and the conditions under which it occurs (Ca2+ homeostasis disruption, hypoxia, others). Using the response as a starting point, provide a comprehensive overview of the relationship with the four types of cell death (apoptosis, autophagy, immunogenic cell death, paraptosis) in an attempt to provide new targeted therapeutic strategies for the organelle-Endoplasmic Reticulum Stress Response Pathway-cell death in ovarian cancer therapy.

BackgroundSevere burns can lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) due to inflammation-immunity dysregulation. This study aimed to identify key immune-related molecules and potential drugs for immune regulation in severe burn treatment.MethodMicroarray datasets GSE77791 and GSE37069 were analyzed to identify immune-related differentially expressed genes (DEGs), enriched pathways and prognosis-related genes. The DGIdb database was used to identify potentially clinically relevant small molecular drugs for hub DEGs. Hub DEGs were validated by total RNA from clinical blood samples through qPCR. The efficacy of drug candidates was tested in a severe burn mouse model. Pathologic staining was used to observe organ damage. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the serum IL-1b, IL-6, TNF-a and MCP-1 contents. Activation of the NF-κB inflammatory pathway was detected by western blotting. Transcriptome sequencing was used to observe inflammatory-immune responses in the lung.ResultsA total of 113 immune-related DEGs were identified, and the presence of immune overactivation was confirmed in severe burns. S100A8 was not only significantly upregulated and identified to be prognosis-related among the hub DEGs but also exhibited an increasing trend in clinical blood samples. Methotrexate, which targets S100A8, as predicted by the DGIdb, significantly reduces transcription level of S100A8 and inflammatory cytokine content in blood, organ damage (lungs, liver, spleen, and kidneys) and mortality in severely burned mice when combined with fluid resuscitation. The inflammatory-immune response was suppressed in the lungs.ConclusionS100A8 with high transcription level in blood is a potential biomarker for poor severe burn prognosis. It suggested that methotrexate has a potential application in severe burn immunotherapy. Besides, it should be emphasized that fluid resuscitation is necessary for the function of methotrexate.

Abstract Clinical studies have shown that there may be a certain relationship between pathological changes of the myodural bridge complex (MDBC) and chronic headaches of unknown cause. But there is still a lack of experimental evidence to explain the possible mechanism. This study aims to further confirm this relationship between MDBC and chronic headaches and explore its potential occurrence mechanism in rats. Bleomycin (BLM) or phosphate-buffered saline (PBS) was injected into the myodural bridge fibers of rats to establish the hyperplastic model of MDBC. After 4 weeks, the occurrence of headaches in rats was evaluated through behavioral scores. The immunohistochemistry staining method was applied to observe the expression levels of headache-related neurotransmitters in the brain. Masson trichrome staining results showed that the number of collagen fibers of MDBC was increased in the BLM group compared to those of the other two groups. It revealed hyperplastic changes of MDBC. The behavioral scores of the BLM group were significantly higher than those of the PBS group and the blank control group. Meanwhile, expression levels of CGRP and 5-HT in the headache-related nuclei of the brain were increased in the BLM group. The current study further confirms the view that there is a relationship between pathological changes of MDBC and chronic headaches of unknown cause. This study may provide anatomical and physiological explanations for the pathogenesis of some chronic headaches of unknown cause.

Organoids are in vitro 3D models that maintain their own tissue structure and function. They largely overcome the limitations of traditional tumor models and have become a powerful research tool in the field of oncology in recent years. Gynecological malignancies are major diseases that seriously threaten the life and health of women and urgently require the establishment of models with a high degree of similarity to human tumors for clinical studies to formulate individualized treatments. Currently, organoids are widely studied in exploring the mechanisms of gynecological tumor development as a means of drug screening and individualized medicine. Ovarian, endometrial, and cervical cancers as common gynecological malignancies have high morbidity and mortality rates among other gynecological tumors. Therefore, this study reviews the application of modelling, drug efficacy assessment, and drug response prediction for ovarian, endometrial, and cervical cancers, thereby clarifying the mechanisms of tumorigenesis and development, and providing precise treatment options for gynecological oncology patients.

While the regulatory roles of circular RNAs (circRNAs) and zinc finger CCCH-type containing 13 (ZC3H13) were previously reported in various human cancers, the mechanisms underlying their interaction in papillary thyroid cancer (PTC) remain unclear. We aimed to determine the role of hsa_circ_0101050 and its regulatory relationship with ZC3H13 in PTC. The expression levels of hsa_circ_0101050 and ZC3H13 were determined in tumor samples and adjacent normal tissues from 46 patients with PTC and in two PTC cell lines (IHH-4 and PTC-1) using quantitative reverse transcription–polymerase chain reaction. The roles of hsa_circ_0101050 and ZC3H13 in cell viability, wound healing, and migration were determined using knockdown and overexpression approaches in PTC cell lines, and a xenograft model in nude mice was used to determine their role in vivo. Methylated RNA immunoprecipitation assay was used to analyze N6-methyladenosine (m6A) modification of hsa_circ_0101050 by ZC3H13. We found hsa_circ_0101050 overexpression and ZC3H13 downregulation in PTC samples and PTC cell lines. In PTC cell lines, silencing hsa_circ_0101050 reduced cell viability and migration whereas its overexpression promoted an aggressive PTC phenotype. ZC3H13 increased the m6A modification of hsa_circ_0101050 and repressed its expression. ZC3H13 overexpression inhibited PTC cell viability, migration, and invasion, which were reversed in cells overexpressing hsa_circ_0101050. Taken together, these results suggested that the downregulation of hsa_circ_0101050 mediated by ZC3H13 through m6A modification contributed to its oncogenic effect in PTC development, revealing the ZC3H13–m6A–hsa_circ_0101050 as a potential therapeutic target in PTC.

ObjectiveThis study aimed to assess the clinical importance of various biomarkers, including NLR, CEA, CA199, CA125, CA153, and HE4, through dynamic testing to evaluate the effectiveness of neoadjuvant chemotherapy (NACT) for individuals facing advanced ovarian cancer. This provides valuable information for tailoring treatment plans to individual patients, thereby leading to a more personalized and effective management of individuals facing ovarian cancer.MethodsThe levels of NLR, CA125, CA199, CEA, CA153, and HE4 were detected before chemotherapy and after 3 courses of chemotherapy. Patients were categorized into ineffective and effective groups according to the effectiveness of NACT. To evaluate the factors influencing NACT’s effectiveness in individuals facing advanced ovarian cancer, receiver operating characteristic (ROC) curves, predictive modeling, and multifactorial regression analysis were employed.ResultsIn the effective group, the patients’ age, maximum tumor diameter, and CEA and HE4 levels of the patients were significantly higher compared to those in the ineffective group (P

To reveal the role of gut microbiota (GM) in the occurrence and development of idiopathic central precocious puberty (ICPP) using 16S rDNA sequencing and bioinformatics analysis. The Danazol-induced ICPP model was successfully constructed in this study. ZBDH and GnRHa treatments could effectively inhibit ICPP in rats, as manifested by the delayed vaginal opening time, reduced weight, decreased uterine organ coefficient, and decreased uterine wall thickness and corpus luteum number, as well as remarkably reduced serum hormone (LH, FSH, and E2) levels. According to 16S rDNA sequencing analysis results, there was no significant difference in the GM community diversity across different groups; however, the composition of the microbial community and the abundance of the dominant microbial community were dramatically different among groups. ZBDH and GnRHa treatments could effectively reduce the abundance of Muribaculateae and Lactobacillus and promote Prevotella abundance. ZBDH and GnRHa were effective in treating Danazol-induced ICPP model rats. The therapeutic effects of ZBDH and GnRHa could be related to the changes in GM in rats.

Abstract The Myodural Bridge (MDB) is a physiological structure that is highly conserved in mammals and many of other tetrapods. It connects the suboccipital muscles to the cervical spinal dura mater (SDM) and transmits the tensile forces generated by the suboccipital muscles to the SDM. Consequently, the MDB has broader physiological potentials than just fixing the SDM. It has been proposed that MDB significantly contributes to the dynamics of cerebrospinal fluid (CSF) movements. Animal models of suboccipital muscle atrophy and hyperplasia were established utilizing local injection of BTX-A and ACE-031. In contrast, animal models with surgical severance of suboccipital muscles, and without any surgical operation were set as two types of negative control groups. CSF secretion and reabsorption rates were then measured for subsequent analysis. Our findings demonstrated a significant increase in CSF secretion rate in rats with the hyperplasia model, while there was a significant decrease in rats with the atrophy and severance groups. We observed an increase in CSF reabsorption rate in both the atrophy and hyperplasia groups, but no significant change was observed in the severance group. Additionally, our immunohistochemistry results revealed no significant change in the protein level of six selected choroid plexus-CSF-related proteins among all these groups. Therefore, it was indicated that alteration of MDB-transmitted tensile force resulted in changes of CSF secretion and reabsorption rates, suggesting the potential role that MDB may play during CSF circulation. This provides a unique research insight into CSF dynamics.

Abstract Seawater electrolysis is a viable method for producing hydrogen on a large scale and low-cost. However, the catalyst activity during the seawater splitting process will dramatically degrade as salt concentrations increasing. Herein, CoP is discovered that could reject chloride ions far from catalyst in electrolyte based on molecular dynamic simulation. Thus, a binder-free electrode is designed and constructed by in-situ growth of homogeneous CoP on rGO nanosheets wrapped around the surface of Ti fiber felt for seawater splitting. As expected, the as-obtained CoP/rGO@Ti electrode exhibits good catalytic activity and stability in alkaline electrolyte. Especially, benefitting from the highly effective repulsive Cl− intrinsic characteristic of CoP, the catalyst maintains good catalytic performance with saturated salt concentration, and the overpotential increasing is less than 28 mV at 10 mA cm−2 from 0 M to saturated NaCl in electrolyte. Furthermore, the catalyst for seawater splitting performs superior corrosion-resistance with a low solubility of 0.04%. This work sheds fresh light into the development of efficient HER catalysts for salinity tolerance hydrogen evolution.

The test material in this experiment was the wine grape variety 'Petit Verdot' (Vitis vinifera L.cv. Petit Verdot). Sucrose, glucose, fructose, and rhamnose were selected for sugars, with mass fractions of 2%, 5% and 8%, respectively. The grape was sprayed with exogenous sugars and cultured in vitro for 12 days in a plant growth incubator. The rate of fruit color change was monitored and analyzed, and the primary quality indicators such as titratable acids, reducing sugars, anthocyanins and non-anthocyanin phenolics were examined extensively using principal component analysis. According to the results, under in vitro culture conditions, fructose, sucrose and rhamnose improved grape fruit quality significantly, while glucose had no obvious effect on grape fruit quality. In terms of improving the comprehensive quality of fruit, the best treatment effect was fructose, with 8% Fru ranking the first, 5%Fru ranking the second and 2% Fru ranking the ninth. The optimum concentration of 2% Suc ranked third overall, 8% Suc ranked fifth overall, and 5% Suc ranked eighth. Rhamnose optimal concentration of 5%, ranked in the fourth, 2% Rha ranked sixth, 8% Rha ranking behind in the control group, as the 12th. Glucose function was not obvious to improve the quality of the grapes, 2% Glu ranking in the seventh, higher than that of control group two, while both 5% and 8% Glu ranked lower than the control, at 13 and 11, respectively. According to the scores of principal component 1 and principal component 2, fructose significantly promoted the accumulation of anthocyanins and phenols (principal component 1), in which 5% Fru scored the highest, 8% Fru the second and 2% Fru the third. Sucrose significantly increased the content of soluble solids, reducing sugars and titratable acids (principal component 2), with 2% Suc scoring highest, 5% Suc second, and 8% Suc sixth. To sum up, different kinds of sugar into the skin cells may have different metabolic pathways and metabolites, the mechanisms of metabolism of different types of sugars in grape skin cells need to be further explored.

Insect pathogenic fungi have shown great potential in agricultural pest control. Conidiation is crucial for the survival of filamentous fungi, and dispersal occurs through two methods: normal conidiation, where conidia differentiate from mycelium, and microcycle conidiation, which involves conidial budding. The conidiation process is related to cell separation. The forkhead box gene Sep1 in Schizosaccharomyces pombe plays a crucial role in cell separation. Nevertheless, the function of Sep1 has not been clarified in filamentous fungi. Here, MaSep1, the homolog of Sep1 in Metarhizium acridum, was identified and subjected to functional analysis. The findings revealed that conidial germination of the MaSep1-deletion strain (ΔMaSep1) was accelerated and the time for 50% germination rate of conidial was shortened by 1 h, while the conidial production of ΔMaSep1 was considerably reduced. The resistances to heat shock and UV-B irradiation of ΔMaSep1 were enhanced, and the expression of some genes involved in DNA damage repair and heat shock response was significantly increased in ΔMaSep1. The disruption of MaSep1 had no effect on the virulence of M. acridum. Interestingly, ΔMaSep1 conducted the normal conidiation on the microcycle conidiation medium, SYA. Furthermore, 127 DEGs were identified by RNA-Seq between the wild-type and ΔMaSep1 strains during microcycle conidiation, proving that MaSep1 mediated the conidiation pattern shift by governing some genes associated with conidiation, cell division, and cell wall formation.

AIM: To evaluate the clinical efficacy and systemic safety profile of conbercept in clinical practice on vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PLGF) levels after intravitreal injections for the neovascular age-related macular degeneration (AMD). METHODS: Thirty-five patients (35 eyes) with neovascular AMD received intravitreal injections of conbercept treatment with pro re nata protocol. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were detected before the intravitreal injection and at 1, 3, and 12mo after conbercept treatment. The levels of serum VEGF-A, VEGF-B, and PLGF were measured by enzyme-linked immunosorbent assay before the injection and 1 and 12mo after conbercept treatments. RESULTS: At baseline, the mean BCVA score was 39.89±14.64 letters. The mean BCVA scores were 51.03±15.78, 56.71±14.38, and 52.49±10.16 letters at 1, 3, and 12mo after conbercept treatment, and the BCVA improvements were all significant, respectively (P0.05). CONCLUSION: Conbercept intravitreal injection leads to BCVA and CRT improvement, however, it does not significantly affect systemic serum VEGF-A, VEGF-B, and PLGF levels at 1 and 12mo after intravitreal injection treating neovascular AMD.

AIM: To explore the feasibility of swept source optical coherence tomography angiography(SS-OCTA)in evaluating early retinal and choroidal microcirculation changes in patients with hypertension.METHODS:Prospective clinical study. A total of 27 patients with grade 2 or 3 essential hypertension(hypertension group)diagnosed in the Department of Cardiology of Xi'an First Hospital from July to November 2022 were included in the study. There were 14 males and 13 females. The mean age was(57.11±3.36)years. During the same period, 27 age- and sex-matched normal people without a history of hypertension were selected as the control group, including 12 males and 15 females. The average age was(55.74±2.95)years old. All patients underwent BCVA(LogMAR), intraocular pressure, axial length, slit lamp examination, fundus color photography and SS-OCTA examination. SS-OCTA was used to scan the macular area of the right eye in the range of 6×6 mm. The retina and choroid were divided into three concentric circles with diameters of 0-1 mm, 1-3 mm and 3-6 mm around the fovea according to ETDRS. Macular vessel density(VD), perfusion area(PA), retinal thickness(CMT), choroidal thickness(CT), choroidal vessel volume(CVV)and choroidal vasculr index(CVI)of the superficial capillary plexus(SCP)and the deep capillary plexus(DCP)in the macular area of 0-1 mm, 1-3 mm and 3-6 mm were analyzed and recorded. The changes in VD, PA, CMT, CT, CVV and CVI were compared between the two groups. Independent sample t-test was used to compare VD, PA, CMT and CVI between the two groups; CT, CVV and LogMAR visual acuity were analyzed by Wilcoxon signed rank test of independent samples.RESULTS:Compared with the control group, the hypertensive group had significantly lower VD in the macular area 0-3 mm(0-1 mm, t=-3.144; 1-3 mm, t=-3.611, P0.05). The CMT in the 0-1mm area of the macular area in the hypertension group was lower than that in the control group(t=-2.624, P0.05).CONCLUSION:The VD of DCP in the 0-3 mm area and the CMT in the 0-1 mm area are decreased in hypertensive patients. There were no significant differences in CT, CVV and CVI between the two groups. VD and CMT in macular DCP may be used as indicators to evaluate the early changes of retinal and choroidal microcirculation in hypertensive patients.

Hibiscus mutabilis, the city flower of Chengdu, is culturally significant and has nutritional and medicinal benefits. However, frequent infestations of Bemisia tabaci have caused economic losses. This study aimed to identify insect-resistant H. mutabilis varieties. Over two years, varieties like Jinqiusong, Zuiyun, and Zuifurong showed moderate to high resistance based on reproductive indices. Assessments of antixenosis and developmental impacts revealed that adult B. tabaci exhibited low selectivity toward these resistant varieties, indicating a strong repellent effect. Gas chromatography-mass spectrometry analysis identified volatile organic compounds, such as alcohols, alkanes, and terpenes. Notably, 2-ethylhexanol and 6-methylheptanol exhibited repellent properties. Using nontargeted metabolomics, this study compared the metabolite profiles of the insect-resistant variety Jinqiusong (JQS), moderately resistant Bairihuacai (BRHC), and highly susceptible Chongbanbai (CBB) post B. tabaci infestation. Fifteen key metabolites were linked to resistance, emphasizing the phenylpropanoid biosynthesis pathway as crucial in defense. These findings offer a theoretical foundation for breeding insect-resistant H. mutabilis varieties and developing eco-friendly strategies against B. tabaci infestations.

ABSTRACTMorphine addiction is closely associated with dysbiosis of the gut microbiota. miRNAs play a crucial role in regulating intestinal bacterial growth and are involved in the development of disease. Ginsenoside Rg1 exhibits an anti-addiction effect and significantly improves intestinal microbiota disorders. In pseudo-germfree mice, supplementation with Bacteroides vulgatus (B. vulgatus) synergistically enhanced Rg1 to alleviate morphine addiction. However, it is currently unknown the relationship between fecal miRNAs in morphine-exposed mice and their potential modulation of gut microbiome, as well as their role in mediating the resistance of ginsenoside Rg1 to drug addiction. Here, we studied the fecal miRNA abundance in mice treated with morphine to explore the different miRNAs expressed, their association with B. vulgatus and their role in the amelioration of morphine reward by ginsenoside Rg1. Our results indicated ginsenoside Rg1 attenuated the significant increase in miR-129-5p expression observed in the feces of morphine-treated mice. The miR-129-5p, specifically, inhibited the growth of B. vulgatus by modulating the transcript of the site-tag BVU_RS11835 and increased the levels of 5-hydroxytryptophan and indole-3-carboxaldehyde in vitro. Subsequently, we noticed that oral administration of synthetic miR-129-5p increased 5-HT levels in the hippocampus and inhibited the reversal effect of ginsenoside Rg1 both on the relative abundance of B. vulgatus in the feces and CPP effect induced by morphine exposure. In short, Ginsenoside Rg1 might play an indirect role in remodeling the B. vulgatus against morphine reward by suppressing miR-129-5p expression. These results highlight the role of miR-129-5p and B. vulgatus in morphine reward and the anti-morphine addiction of ginsenoside Rg1.

Glycolysis is the preferred energy metabolism pathway in cancer cells even when the oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.

Abstract The optimal approach to locally advanced head and neck squamous cell carcinoma (LAHNSCC) treatment remains controversial. For non-resectable LAHNSCC, the clinical interest of induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) or radiotherapy has been questioned. With the approval of immunotherapy and targeted therapy for this disease, treatment options have become more complex. Although new trial data have appeared every year, the results are still inconclusive. In this review, we provide readers with information on new strategies for LAHNSCC induction therapy, which will facilitate evidence-based decision making in LAHNSCC treatment.

The monoamine transporters, including the serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), are the therapeutic targets for the treatment of many neuropsychiatric disorders. Despite significant progress in characterizing the structures and transport mechanisms of these transporters, the regulation of their transport functions through dimerization or oligomerization remains to be understood. In the present study, we identified a conserved intramolecular ion-pair at the third extracellular loop (EL3) connecting TM5 and TM6 that plays a critical but divergent role in the modulation of dimerization and transport functions among the monoamine transporters. The disruption of the ion-pair interactions by mutations induced a significant spontaneous cross-linking of a cysteine mutant of SERT and an increase in cell surface expression but with an impaired specific transport activity. On the other hand, similar mutations of the corresponding ion-pair residues in both DAT and NET resulted in an opposite effect on their oxidation-induced dimerization, cell surface expression, and transport function. Reversible biotinylation experiments indicated that the ion-pair mutations slowed down the internalization of SERT but stimulated the internalization of DAT. In addition, cysteine accessibility measurements for monitoring SERT conformational changes indicated that substitution of the ion-pair residues resulted in profound effects on the rate constants for cysteine modification in both the extracellular and cytoplasmatic substrate permeation pathways. Furthermore, molecular dynamics simulations showed that the ion-pair mutations increased the interfacial interactions in a SERT dimer but decreased it in a DAT dimer. Taken together, we propose that the transport function is modulated by the equilibrium between monomers and dimers on the cell surface, which is regulated by a potential compensatory mechanism but with different molecular solutions among the monoamine transporters. The present study provided new insights into the structural elements regulating the transport function of the monoamine transporters through their dimerization.

The overall oocyte quality declines with aging, and this effect is strongly associated with a higher reactive oxygen species (ROS) level and the resultant oxidative damage. C-type natriuretic peptide (CNP) is a well-characterized physiological meiotic inhibitor that has been successfully used to improve immature oocyte quality during in vitro maturation. However, the underlying roles of CNP in maternally aged oocytes have not been reported. Here, we found that the age-related reduction in the serum CNP concentration was highly correlated with decreased oocyte quality. Treatment with exogenous CNP promoted follicle growth and ovulation in aged mice and enhanced meiotic competency and fertilization ability. Interestingly, the cytoplasmic maturation of aged oocytes was thoroughly improved by CNP treatment, as assessed by spindle/chromosome morphology and redistribution of organelles (mitochondria, the endoplasmic reticulum, cortical granules, and the Golgi apparatus). CNP treatment also ameliorated DNA damage and apoptosis caused by ROS accumulation in aged oocytes. Importantly, oocyte RNA-seq revealed that the beneficial effect of CNP on aged oocytes was mediated by restoration of mitochondrial oxidative phosphorylation, eliminating excessive mitophagy. CNP reversed the defective phenotypes in aged oocytes by alleviating oxidative damage and suppressing excessive PINK1/Parkin-mediated mitophagy. Mechanistically, CNP functioned as a cAMP/PKA pathway modulator to decrease PINK1 stability and inhibit Parkin recruitment. In summary, our results demonstrated that CNP supplementation constitutes an alternative therapeutic approach for advanced maternal age-related oocyte deterioration and may improve the overall success rates of clinically assisted reproduction in older women.

Depression is a multifactorial syndrome with a variety of underlying pathological mechanisms. While ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits a rapid antidepressant action in the central never system (CNS), the potential addiction and psychotomimetic adverse effects of ketamine limit its chronic use in clinical practice. Therefore, it is necessary to discover an additional agent that shows a synergistic antidepressant activity with ketamine to sustain its therapeutic action so as to reduce its use frequency in depression treatment. The present study indicated that Dajianzhong decoction (DJZT), an empirical herbal formula used for the clinical treatment of several inflammation-related intestinal disorders, sustains behavioral and synaptic action of ketamine in depressive mouse models. Additionally, ketamine was also demonstrated to exert a synergistic action with DJZT to alleviate the chronic unpredictable mild stress (CUMS)-induced abnormalities in gut barrier proteins and colonic histology, and subsequently to normalize the diversity and composition of gut microbiota. Furthermore, DJZT was shown to possess an anti-inflammatory activity to prevent activation of NF-κB from releasing proinflammatory cytokines, specifically through inhibiting Th17 cells/IL-17A pathway. Our results uncovered the mechanism of action of DJZT in conjunction with ketamine in depression treatment by which these agents target different pathological factors across biological systems and exert a synergistic activity through a bidirectional communication in the gut-brain axis, and also provided new insights into the systematic treatment of depression.

ObjectiveIn this study, we evaluated the role of a multidisciplinary team (MDT) in clinical practice for cervical cancer by analyzing the development of a single-case multidisciplinary consultation for cervical cancer.MethodsPatients in MDT consultations for cervical cancer were retrospectively analyzed for clinical information, decision content of MDT discussion, implementation, and follow-up results.ResultsOf the 392 patients who met the inclusion criteria, 359 had a first episode, of which 284 were stage IA-IIA2 (79.11%) and 75 were stage IIB-IVB (20.89%). Of these 392, 33 had a recurrence (8.42%). A total of 416 cases were analyzed, and neoadjuvant chemotherapy with surgery was recommended in 43 cases, of which 40 cases were implemented, and 36 of the 40 achieved the expected outcome. Surgical treatment was recommended in 241 cases, of which 226 underwent surgery, and 215 of them achieved the expected outcome. Radiotherapy was recommended in 31 cases, of which 26 cases underwent it, and 22 of them achieved the expected efficacy. Concurrent chemoradiotherapy was recommended in 57 cases, of which 49 underwent it, and 39 of them achieved the expected efficacy. Other treatments were recommended in 44 cases, of which 23 cases were implemented, and 10 of them achieved the expected efficacy, with statistically significant differences compared with cases without implementation (P 0.05). Some decisions were not fully implemented due to economic status and fear of certain treatments of the patient.ConclusionThe MDT plays an important role in clinical practice such as clinical staging, treatment plan, and the complete treatment management of patients with cervical cancer, which can significantly improve the near-term treatment effect, whereas its effect on a long-term prognosis needs further clinical observation and active exploration.

Background: Serum ferritin levels are associated with a higher risk of incident heart failure (HF). Whether serum ferritin levels, either increased or decreased, predict the risk of mortality in individuals with chronic heart failure (CHF) remains unknown.Objectives: This study aimed to clarify the potential predictive significance of serum ferritin levels in assessing the short-term mortality in critically ill patients with chronic heart failure (CHF).Methods: Critically ill patients with CHF were identified from the Multiparameter Intelligent Monitoring in Intensive Care III and IV (MIMIC III and IV) databases. Linear and logistic regression models and Cox proportional hazards models were applied to assess the associations between serum ferritin and survival.Results: A total of 1,739 and 2,322 patients with CHF identified from the MIMIC III and IV databases, respectively, fulfilled the inclusion criteria. In the MIMIC III group, compared with the reference group (serum ferritin ≥70 and

Numerous chemical compounds used in cancer treatment have been isolated from natural herbs to address the ever-increasing cancer incidence worldwide. Therein is icariin, which has been extensively studied for its therapeutic potential due to its anti-inflammatory, antioxidant, antidepressant, and aphrodisiac properties. However, there is a lack of comprehensive and detailed review of studies on icariin in cancer treatment. Given this, this study reviews and examines the relevant literature on the chemopreventive and therapeutic potentials of icariin in cancer treatment and describes its mechanism of action. The review shows that icariin has the property of inhibiting cancer progression and reversing drug resistance. Therefore, icariin may be a valuable potential agent for the prevention and treatment of various cancers due to its natural origin, safety, and low cost compared to conventional anticancer drugs, while further research on this natural agent is needed.

Composite materials are frequently exposed to external factors during their operational service, resulting in internal structural damage which subsequently impacts their structural performance. This paper employs ferromagnetic materials for their sensitivity to magnetic field strength. By detecting variations in the magnetic field within the embedded ferromagnetic microwires of composite materials, the aim is to indirectly assess the health status of the composite materials. Firstly, a theoretical numerical model for magnetic field intensity at the crack site was established. Subsequently, a finite element model was employed to analyze the variations in the magnetic characteristics of ferromagnetic microwires at the crack site. Under different parameter conditions, the patterns of magnetic signals at the crack site were determined. The results indicate that with an increase in the angle between the external magnetic field and the crack, the fitted curve of the magnetic signal shows a linear increase. The distance between the peak and valley of the radial magnetic signal in the axial direction decreases, and the axial magnetic signal transitions from double-peak to single-peak. With the increase in crack depth, the fitted curve of the magnetic signal shows a linear increase, and the magnetic signal at the crack tip also exhibits a linear increase. An increase in crack width leads to a non-linear decrease in the fitted curve of the magnetic signal, and after reaching a certain width, the magnetic signal stabilizes. For two identical cracks at different distances, the magnetic signal exhibits a transition from a complete pattern to two complete patterns. With the increase in the external magnetic field, the magnetic signal shows a completely regular linear increase. By analyzing and calculating the variations in magnetic signals, the patterns of magnetic characteristics under the damaged state of ferromagnetic microwires were obtained. This serves as a basis for assessing whether they can continue in service and for evaluating the overall health status of composite materials.

Large-scale deep neural networks consume expensive training costs, but the training results in less-interpretable weight matrices constructing the networks. Here, we propose a mode decomposition learning that can interpret the weight matrices as a hierarchy of latent modes. These modes are akin to patterns in physics studies of memory networks, but the least number of modes increases only logarithmically with the network width and even becomes a constant when the width grows further. The mode decomposition learning not only saves a significant large amount of training costs but also explains the network performance with the leading modes, displaying a striking piecewise power-law behavior. The modes specify a progressively compact latent space across the network hierarchy, making a more disentangled subspace compared to standard training. Our mode decomposition learning is also studied in an analytic online learning setting, which reveals multiple stages of learning dynamics with a continuous specialization of hidden nodes. Therefore the proposed mode decomposition learning points to a cheap and interpretable route towards the magical deep learning.

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a “JmjC-only” protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.

The recollision of photoexcited electrons with ions is a fundamental process in light-matter interaction, but so far only the rescattering of a single electron has been considered. Here by considering the recollision of a second electron theoretically, experimentally-observed momentum distributions can be understood.

Drug delivery systems with high-targeted doses can minimize excipients, reduce side effects, and improve efficacy. Human blood circulation is a complex circulatory system, and the motion control of microrobots in the static flow field in vitro is completely different from in vivo. How to achieve precise counterflow motion for targeted drug delivery without vascular blockage and immune rejection is the biggest challenge for micro-nano robots. Here, we propose a control method that enables vortex-like paramagnetic nanoparticle swarm (VPNS) to move upstream against the flow. By mimicking the clustering motion of wild herring schools and the rolling of leukocytes, VPNS are incredibly stable even when subjected to high-intensity jet impacts in the blood environment, can travel upstream, anchor at the target location, and dissipate when the magnetic field is withdrawn, which greatly reduces the risk of thrombosis. VPNS can also upstream along the vessel wall without an additional energy source and has a marked targeted therapeutic effect on subcutaneous tumors.

BackgroundAs a cellular process, senescence functions to prevent the proliferation of damaged, old and tumor-like cells, as well as participate in embryonic development, tissue repair, etc. This study aimed to analyze the themes and topics of the scientific publications related to cellular senescence in the past three decades by machine learning.MethodsThe MeSH term “cellular senescence” was used for searching publications from 1990 to 2021 on the PubMed database, while the R platform was adopted to obtain associated data. A topic network was constructed by latent Dirichlet allocation (LDA) and the Louvain algorithm.ResultsA total of 21,910 publications were finally recruited in this article. Basic studies (15,382, 70.21%) accounted for the most proportion of publications over the past three decades. Physiology, drug effects, and genetics were the most concerned MeSH terms, while cell proliferation was the leading term since 2010. Three senolytics were indexed by MeSH terms, including quercetin, curcumin, and dasatinib, with the accumulated occurrence of 35, 26, and 22, separately. Three clusters were recognized by LDA and network analyses. Telomere length was the top studied topic in the cluster of physiological function, while cancer cell had been a hot topic in the cluster of pathological function, and protein kinase pathway was the most popular topic in the cluster of molecular mechanism. Notably, the cluster of physiological function showed a poor connection with other clusters.ConclusionCellular senescence has obtained increasing attention over the past three decades. While most of the studies focus on the pathological function and molecular mechanism, more researches should be conducted on the physiological function and the clinical translation of cellular senescence, especially the development and application of senotherapeutics.

Abstract Periodontitis is a progressive infectious inflammatory disease, which leads to alveolar bone resorption and loss of periodontal attachment. It is imperative for us to develop a therapeutic scaffold to repair the alveolar bone defect of periodontitis. In this study, we designed a new composite scaffold loading metformin (MET) by using the freeze-drying method, which was composed of β-tricalcium phosphate (β-TCP), chitosan (CTS) and the mesoporous silica (SBA-15). The scaffolds were expected to combine the excellent biocompatibility of CTS, the good bioactivity of β-TCP, and the anti-inflammatory properties of MET. The MET-loaded β-TCP/CTS/SBA-15 scaffolds showed improved cell adhesion, appropriate porosity and good biocompatibility in vitro. This MET composite scaffold was implanted in the alveolar bone defects area of rats with periodontitis. After 12 weeks, Micro-CT and histological analysis were performed to evaluate different degrees of healing and mineralization. Results showed that the MET-loaded β-TCP/CTS/SBA-15 scaffolds promoted alveolar bone regeneration in a rat model of periodontitis. To our knowledge, this is the first report that MET-loaded β-TCP/CTS/SBA-15 scaffolds have a positive effect on alveolar bone regeneration in periodontitis. Our findings might provide a new and promising strategy for repairing alveolar bone defects under the condition of periodontitis.

Abstract Background Whole chloroplast genome (cpDNA) sequence is becoming widely used in the phylogenetic studies of plant and species identification, but in most cases the cpDNA were acquired from silica gel dried fresh leaves. So far few reports have been available to describe cpDNA acquisition from crude drugs derived from plant materials, the DNA of which usually was seriously damaged during their processing. In this study, we retrieved cpDNA from the commonly used crude drug Eriobotryae Folium (Pipaye in Chinese, which is the dried leaves of Eriobotrya japonica, PPY) using genome skimming technique. Results We successfully recovered cpDNA sequences and rDNA sequences from the crude drug PPY, and bioinformatics analysis showed a high overall consistency between the cpDNA obtained from the crude drugs and fresh samples. In the ML tree, each species formed distinct monophyletic clades based on cpDNA sequence data, while the phylogenetic relationships between Eriobotrya species were poorly resolved based on ITS and ITS2. Conclusion Our results demonstrate that both cpDNA and ITS/ITS2 are effective for identifying PPY and its counterfeits derived from distantly related species (i.e. Dillenia turbinata and Magnolia grandiflora), but cpDNA is more effective for distinguishing the counterfeits derived from the close relatives of Eriobotrya japonica, suggesting the potential of genome skimming for retrieving cpDNA from crude drugs used in Traditional Chinese Medicine for their identification.

Albizia julibrissin Durazz is one of the most common herbs used for depression and anxiety treatment, but its mechanism of action as an antidepressant or anxiolytic drug have not been fully understood. We previously isolated and identified one lignan glycoside compound from Albizia Julibrissin Durazz, (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside (SAG), that inhibited all three monoamine transporters with a mechanism of action different from that of the conventional antidepressants. In this study, we generated homology models for human dopamine transporter and human norepinephrine transporter, based on the X-ray structure of Drosophila dopamine transporter, and conducted the molecular docking of SAG to all three human monoamine transporters. Our computational results indicated that SAG binds to an allosteric site (S2) that has been demonstrated to be formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule connected to the central site (S1) in these monoamine transporters. In addition, we demonstrated that SAG stabilizes a conformation of serotonin transporter with both the extracellular and cytoplasmic pathways closed. Furthermore, we performed mutagenesis of the residues in both the allosteric and orthosteric sites to biochemically validate SAG binding in all three monoamine transporters. Our results are consistent with the molecular docking calculation and support the association of SAG with the allosteric site. We expect that this herbal molecule could become a lead compound for the development of new therapeutic agents with a novel mechanism of action.

Background: Hepatocellular carcinoma (HCC) is a highly lethal cancer and is the second leading cause of cancer-related deaths worldwide. Unlike apoptosis, necroptosis (NCPS) triggers an immune response by releasing damage-related molecular factors. However, the clinical prognostic features of necroptosis-associated genes in HCC are still not fully explored.Methods: We analyzed the single-cell datasets GSE125449 and GSE151530 from the GEO database and performed weighted co-expression network analysis on the TCGA data to identify the necroptosis genes. A prognostic model was built using COX and Lasso regression. In addition, we performed an analysis of survival, immunity microenvironment, and mutation. Furthermore, the hub genes and pathways associated with HCC were localized within the single-cell atlas.Results: Patients with HCC in the TCGA and ICGC cohorts were classified using a necroptosis-related model with significant differences in survival times between high- and low-NCPS groups (p < 0.05). High-NCPS patients expressed more immune checkpoint-related genes, suggesting immunotherapy and some chemotherapies might prove beneficial to them. In addition, a single-cell sequencing approach was conducted to investigate the expression of hub genes and associated signaling pathways in different cell types.Conclusion: Through the analysis of single-cell and bulk multi-omics sequencing data, we constructed a prognostic model related to necroptosis and explored the relationship between high- and low-NCPS groups and immune cell infiltration in HCC. This provides a new reference for further understanding the role of necroptosis in HCC.

The performance requirements for power devices in airborne equipment are increasingly demanding, while environmental and working stresses are becoming more diverse. The degradation mechanisms of devices subjected to multiple stresses become more complex. Most proposed degradation mechanisms and models in current research only consider a single stress, making it difficult to describe the correlation between multiple stresses and the correlation of failures. Then, a multi-physical field coupling model based on COMSOL is proposed. The influence relationship between temperature, moisture, electrical load, and vibration during device operation is considered, and a three-dimensional finite element model is built to investigate the multi-stress degradation mechanism under multi-physical field coupling. The simulation results show that, compared with single-stress models, the proposed multi-stress coupled model can more accurately simulate the degradation process of SiC MOSFET. This provides references for improving the reliability design of power device packaging.

Abstract Background Osteoporosis is a major public health concern for the elderly population and is characterized by fatigue load resulting in bone microdamage. The ability of bone mesenchymal stem cells (BMSCs) to repair bone microdamage diminishes with age, and the accumulation of bone microdamage increases the risk of osteoporotic fracture. There is a lack of effective means to promote the repair of bone microdamage in aged patients with osteoporosis. Exosomes have been shown to be related to the osteogenic differentiation of BMSCs. Here, we aimed to evaluate the changes in the osteogenic differentiation capacity of BMSCs in aged osteoporotic rats after fatigue loading and the treatment potential of serum exosomes from young rats. Methods The tibias of six aged osteoporotic rats were subjected to fatigue loading in vivo for 2 weeks, and the bone microdamage, microstructures, and mechanical properties were assessed. Subsequently, BMSCs were extracted to evaluate their proliferation and osteogenic differentiation abilities. In addition, the BMSCs of aged osteoporotic rats after fatigue loading were treated with serum exosomes from young rats under osteogenic induction conditions, and the expression of osteogenic-related miRNAs was quantified. The osteogenetic effects of miRNA-19b-3p in exosomes and the possible target protein PTEN was detected. Results Obvious bone microdamage at the fatigue load stress point, the bone microstructure and biomechanical properties were not obviously changed. A decreased osteogenic differentiation ability of BMSCs was observed after fatigue loading, while serum exosomes from young rats highly expressing miRNA-19b-3p improved the decreased osteogenic differentiation ability of BMSCs. Transfection with miRNA-19b-3p mimic could promote osteoblastic differentiation of BMSCs and decreased the expression of PTEN. After transfection of miRNA-19b-3p inhibitor, the promotional effect of exosomes on bone differentiation was weakened. Treatment with transfected exosomes increased the expression of PTEN. Conclusion Serum exosomes derived from young rats can improve the decreased osteogenic differentiation ability of BMSCs in aged rats with osteoporosis after fatigue loading and can provide a new treatment strategy for the repair of bone microdamage and prevention of fractures.

Abstract A dense bridge-like tissue named the myodural bridge (MDB) connecting the suboccipital muscles to the spinal dura mater was originally discovered in humans. However, recent animal studies have revealed that the MDB appears to be an evolutionarily conserved anatomic structure which may have significant physiological functions. Our previous investigations have confirmed the existence of the MDB in finless porpoises. The present authors conducted research to expound on the specificity of the MDB in the porpoise Neophocana asiaeorientalis (N.asiaeorientalis). Five carcasses of N.asiaeorientalis, with formalin fixation, were used for the present study. Two of the carcasses were used for head and neck CT scanning, three-dimensional reconstructions, and gross dissection of the suboccipital region. Another carcass was used for a P45 plastination study. Also, a carcass was used for a histological analysis of the suboccipital region and also one was used for a Scanning Electron Microscopy study. The results revealed that the MDB of the N.asiaeorientalis is actually an independent muscle originating from the caudal border of the occiput, passing through the posterior atlanto-occipital interspace, and then attaches to the cervical spinal dura mater. Thus the so called MDB of the N.asiaeorientalis is actually an independent and uniquely specialized muscle. Based on the origin and insertion of this muscle, the present authors name it the ‘Occipital-Dural Muscle’. It appears that the direct pull of this muscle on the cervical spinal dura mater may affect the circulation of the cerebrospinal fluid by altering the volume of the subarachnoid space via a pumping action.

Abstract Background The fibula is only indirectly involved in the composition of the human knee joint and has therefore been neglected in the research on knee osteoarthritis. Nonuniform settlement of the proximal tibia plateau is clinically defined as when the height of the medial tibial plateau is lower than that of the lateral side in medial compartment knee osteoarthritis (KOA). The non-uniform settlement of the proximal tibia plateau may be caused by fibular support on the lateral side. Orthopedic surgeons practice partial fibulectomy based on the clinical manifestation of nonuniform settlement, and this technique has been shown to reduce pain and improve function in patients with medial compartment KOA. However, this hypothesis of the mechanism of nonuniform settlement lacks an anatomical basis. Methods The P45 polyester plastination technique was used to prepare sections of the proximal tibiofibular joint to investigate the distribution of the bone trabeculae in the region of the lateral tibial plateau. Results There was uneven distribution of trabeculae in the lateral condyle of the tibia and the head and neck of the fibula. The fibula and the posterolateral cortex of the shaft of the tibia united to form an arch beam via the tibiofibular joint. Many thick, dense trabeculae were present in a longitudinal direction above the tibiofibular arch. Conclusions The fibula supports the lateral tibial plateau, and the trabeculae were concentrated above the tibiofibular arch.

Tyrosine sulfation plays a vital role in various biochemical reactions. Although sulfated tyrosine (sTyr) has a similar structure to phosphotyrosine (pTyr), the number of available sTyr sites is significantly less than that of pTyr sites, mainly because of the lack of effective sTyr probes. A few sTyr binders were identified on the basis of structural similarity by engineering the pTyr-binding pocket of an Src Homology 2 (SH2) domain through phage selections against sTyr peptides. Nevertheless, they still interact with pTyr peptides with comparable affinity. This study aims to identify sTyr superbinders using the SH2 domain as a template. We created a distinctive phage selection scheme that separately covered selections against sTyr and pTyr peptides, followed by next-generation sequencing (NGS). After selections, phage pools showed strong enzyme-linked immunosorbent assay (ELISA) signal intensities for both modified peptides, indicating that the variants evolved with a high affinity for these peptides, which causes difficulty in identifying sTyr-specific binders. In contrast, NGS data from selected pools showed significant differences, suggesting the enrichment of sTyr-specific variants during selections. Accordingly, we obtained the sTyr features based on NGS data analysis and prioritized a few potential sTyr binders. The variant SH2-4 showed a stronger affinity for sTyr than pTyr and was superior to previous sTyr binders as measured by the Biolayer Interferometry assay. In summary, we described the strategy of integrating NGS data mining with a novel selection scheme to identify sTyr superbinders.

Background: Morphine dependence, a devastating neuropsychiatric condition, may be closely associated with gut microbiota dysbiosis. Ginsenoside Rg1 (Rg1), an active ingredient extracted from the roots of Panax ginseng C.A. Meyer, has potential health-promoting effects on the nervous system. However, its role in substance use disorders remains unclear. Here, we explored the potential modulatory roles of Rg1 in protection against morphine dependence. Methods: Conditioned place preference (CPP) was used for establishing a murine model of morphine dependence. 16S rRNA gene sequencing and metabolomics were performed for microbial and metabolite analysis. Molecular analysis was tested for evaluating the host serum and brain responses. Results: Rg1 prevented morphine-induced CPP in mice. The 16S rRNA gene-based microbiota analysis demonstrated that Rg1 ameliorated morphine-induced gut microbiota dysbiosis, specifically for Bacteroidetes. Moreover, Rg1 also inhibited gut microbiota-derived tryptophan metabolism and reduced the serotonin, 5-hydroxytryptamine receptor 1B (5-HTR1B), and 5-hydroxytryptamine receptor 2 A (5-HTR2A) levels. However, the Rg1-induced amelioration of CPP was not observed in mice when their gut microbiome was depleted by non-absorbable antibiotics. Subsequently, gavage with Bacteroides vulgatus increased the abundance of Bacteroidetes. B. vulgatus supplementation synergistically enhanced Rg1-alleviated morphine-induced CPP in mice with microbiome knockdown. Co-treatment with B. vulgatus and Rg1 produced suppressive effects against morphine dependency by inhibiting tryptophan metabolism and reducing the serotonin and 5-HTR1B/5-HTR2A levels. Conclusions: The gut microbiota-tryptophan metabolism-serotonin plays an important role in gut–brain signaling in morphine disorders, which may represent a novel approach for drug dependence treatment via manipulation of the gut microbial composition and tryptophan metabolite.

Abstract Autophagy, a well-observed intracellular lysosomal degradation process, is particularly important to the cell viability in diabetic cardiomyopathy (DCM). Peroxidasin (PXDN) is a heme-containing peroxidase that augments oxidative stress and plays an essential role in cardiovascular diseases, while whether PXDN contributes to the pathogenesis of DCM remains unknown. Here we reported the suppression of cell viability and autophagic flux, as shown by autophagosomes accumulation and increased expression level of LC3-II and p62 in cultured H9C2 and human AC16 cells that treated with 400 μM palmitate acid (PA) for 24 h. Simultaneously, PXDN protein level increased. Moreover, cell death, autophagosomes accumulation as well as increased p62 expression were suppressed by PXDN silence. In addition, knockdown of PXDN reversed PA-induced downregulated forkhead box-1 (FoxO1) and reduced FoxO1 phosphorylation, whereas did not affect AKT phosphorylation. Not consistent with the effects of si-PXDN, double-silence of PXDN and FoxO1 significantly increased cell death, suppressed autophagic flux and declined the level of FoxO1 and PXDN, while the expression of LC3-II was unchanged under PA stimulation. Furthermore, inhibition of FoxO1 in PA-untreated cells induced cell death, inhibited autophagic flux, and inhibited FoxO1 and PXDN expression. Thus, we come to conclusion that PXDN plays a key role in PA-induced cell death by impairing autophagic flux through inhibiting FoxO1, and FoxO1 may also affect the expression of PXDN. These findings may develop better understanding of potential mechanisms regarding autophagy in insulin-resistant cardiomyocytes.

Gene regulatory network can intuitively reflect the interaction between genes, and an in-depth study of these relationships plays a significant role in the treatment and prevention of clinical diseases. Therefore, correct reconstruction of gene regulatory network has become the first critical step in the study of disease treatment and prevention at the genetic level. Among the methods for gene regulatory network reconstruction, the Bayesian network model has been widely concerned because of its advantages of expressing both the regulatory relationship and the degree of strength between genes. Nevertheless, the complexity of the Bayesian network model in structure learning is extremely high, making the efficiency of the reconstruction network is low and the scale is limited. Therefore, this paper proposed a dynamic Bayesian network modeling based on structure prediction (DBN-SP). The method combines the correlation model with the dynamic Bayesian network model. On the premise of making full use of the search strategy of dynamic Bayesian network model structure learning, the candidate parent node set is selected based on the structure prediction firstly. Based on this, some redundant information can be removed and the search space can be reduced in the DBN structure learning to improves the efficiency of the network reconstruction. After the network is reconstructed, structure optimization by using the conditional mutual information method can further remove redundant edges and make the network more accurate. The experimental results show that DBN-SP greatly improves the efficiency and scale of the gene regulatory network reconstruction, and the accuracy and other indexes are also improved. DBN-SP is freely accessible at https://github.com/quluxuan/DBN-SP.git.

AIM: To determine the prevalence of diabetic retinopathy (DR) among diabetic patients at the primary health clinics in Selangor, Malaysia. METHODS: All diabetic patients were screened in Retinal Disease Awareness Programme (RDAP) and those who had significant DR changes were referred to the hospital for further management. Descriptive analyses were done to determine the prevalence of DR and sociodemographic characteristics among patients with diabetic. Univariate and multivariable analysis using Logistic regression were performed to find association and predictor factors in this screening. RESULTS: A total of 3305 patients aged 40y and above were screened for DR. Of the patients screened, 9% patients were found to have DR and other visual complication such as maculopathy (0.9%), cataract (4.8%) and glaucoma (0.4%). The mean age of patients without retinopathy was 57.82±8.470y and the mean age of patients with DR was 63.93±9.857y. About 61.5% of the patients screened were aged below 60y and 38.5% were aged 60y and above. Majority of the patients screened were women 58.5% and Malay in the age group of 50-59y, while 27% were aged 60-69y. Significant association were found between age, sex, race, visual loss and DR. CONCLUSION: Although the prevalence of DR among patients is not alarming, effective interventions need to be implemented soon to avert a large burden of visual loss from DR.

Background: Exosomes plays a crucial role in intercellular communication of gastric cancer (GC), while long non-coding RNAs (lncRNAs) contributes to the tumorigenesis and progression of GC. This study aims to explore the prognostic exosomes-related lncRNAs of GC patients.Methods: Data of 375 GC patients were obtained from the TCGA database. The entire cohort was randomly divided into a training cohort and a validation cohort in a 2:1 ratio. Exosomes-related lncRNAs were identified by the Pearson correlation analysis with reported exosomes-related genes. LASSO Cox regression was used to construct the signature.Results: A prognostic signature consisting of 11 exosomes-related lncRNAs was identified, and patients with lower risk scores had a better prognosis than those with higher risk scores. ROC curves and multivariate Cox regression analysis showed that the signature was an independent risk factor for prognosis in both the training (HR: 3.254, 95% CI: 2.310–4.583) and validation cohorts (HR: 1.974, 95% CI: 1.108–3.517). Gene set enrichment analysis (GSEA) suggested associations between the signature and several immune-related pathways. The identified signature was shown to be associated with GC tumor microenvironment. The expression of two immune checkpoints was also increased in the high-risk group, including B7-H3 and VSIR, indicating the potential role of the identified signature in GC immunotherapies.Conclusion: A novel exosomes-related lncRNA signature, which may be associated with tumor immune microenvironment and potentially serve as an indicator for immunotherapy, has been identified to precisely predict the prognosis of GC patients.

Promoting energy expenditure is known to curb obesity and can be exploited for its treatment. Our previous study has demonstrated that activation of HSF1/PGC-1α axis efficiently induced mitochondrial biogenesis and adaptive oxidation and thus ameliorating lipid accumulation, however, whether it can be a therapeutic approach for metabolic disorders treatment needs explored. Here, a high-efficient and specific HSF1/PGC-1α activator screening system was established and the natural clinical liver-protecting agent matrine was identified as a robust HSF1/PGC-1α activator. Matrine treatment efficiently induced mitogenesis and thermogenic program in primary mouse adipose stem cell derived adipocytes by enriching HSF1 to the promoter of Pgc-1α. Deficiency of PGC-1α in adipocytes diminished the browning induction ability of matrine. Oral administration of matrine to the obese mice induced by high fat and high cholesterol diet increased energy expenditure and corrected the degeneration of thermogenesis in brown adipose tissue (BAT). Also, matrine treatment markedly induced the transformation of brown-like adipocytes in subcutaneous white adipose tissue (sWAT) via a mechanism of HSF1/PGC-1α, thereby attenuating obesity and myriads of metabolic disorders. This led to an improvement in adaptive thermogenesis to cold stimuli. These findings are of great significance in understanding the regulation mechanisms of the HSF1/PGC-1α axis in thermogenesis and providing a novel therapeutic approach for obesity treatment. Matrine may have potential therapeutic implications for the treatment of obesity in clinics.

In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it mediates the transfer of metabolic support molecules. However, aging-mediated dysregulation in communication between the oocytes and granulosa cells affects the oocyte quality. In the present study, we examined the defected germline-soma communication and reduced mRNA levels encoding key structural components of transzonal projections (TZPs) in maternally aged oocytes. Oral administration of melatonin to aged mice substantially increased TZPs and maintained the cumulus cells-oocyte communication, which played a central role in the production of adequate oocyte ATP levels and reducing the accumulation of reactive oxygen species (ROS), apoptosis, DNA damage, endoplasmic reticulum (ER) stress and spindle/chromosomal defects. This beneficial effect of melatonin was inhibited by carbenoxolone (CBX), a gap junctional uncoupler, which disrupts bidirectional communications between oocyte and somatic cells. Simultaneously, melatonin significantly increased the mRNA and protein levels corresponding to genes associated with TZPs and prevented TZP retraction in in vitro-cultured cumulus-oocyte complex (COCs). Furthermore, we infused melatonin and CBX into the COCs in vitro culture system and monitored the levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in cumulus cells and oocytes. Notably, COCs treated with melatonin demonstrated improved NADPH and GSH levels. Of note, CBX was capable of reducing NADPH and GSH levels, aggravated the ROS accumulation and ER stress. Collectively, our data demonstrate the role of melatonin in preventing age-associated germline-soma communication defects, aiding the relay of antioxidant metabolic molecules for the maintenance of oocyte quality from cumulus cells, which have important potential for improving deficient phenotypes of maternally aged oocytes and the treatment of woman infertility.

AIM:To evaluate the short-term efficacy and safety of intravitreal dexamethasone implant(IDI)for patients with retinal vein occlusion-related macular edema(RVO-ME)by using optical coherence tomography(OCTA).METHODS: Seventeen eyes in 17 patients with RVO-ME were treated with intravitreal injection of sustained-release IDI. The best corrected visual acuity(BCVA), central macular thickness(CMT)and superficial retinal vascular network were observed at baseline, 1d, 1mo, 2mo, 3mo, 4mo and 6mo.RESULTS: CMT was significantly reduced from baseline by 24h after injection and improved further during the 3mo follow-up, and the improvement of visual acuity was consistent with that of CMT. OCTA showed improvement from baseline in terms of decreased number and size of cysts and restoration of the retinal vascular network. A slight increase in intraocular pressure was observed in 2 eyes after injection. There were no systemic side effects associated with injection or medication during follow-up.CONCLUSION: CMT reduced as early as 24h after the injection of IDI, with further reduction during follow-up, and OCTA could visually observe the changes of retinal vascular network in macular area.

Abstract Background Angelica dahurica (Apiaceae) is an important herb in traditional Chinese medicine. Because of its important medicinal and economic values, its wild resources were over-exploited and increasingly reduced. Meanwhile, the diversity of cultivars of A. dahurica has decreased as a result of long-term artificial cultivation. However, there are no population genetics studies of natural A. dahurica reported yet, especially for using microsatellite markers (SSRs) to investigate population genetics of the species. Results Sixteen polymorphic EST-SSR loci were isolated from A. dahurica with transcriptome sequencing technology (RNA-Seq). The number of alleles varied from 2 to 15 per polymorphic locus over populations with the observed and expected heterozygosities ranging from 0.000 to 1.000 and from 0.000 to 0.829, respectively. Significant deviations from Hardy–Weinberg equilibrium were observed at 8 loci. Tests of linkage disequilibrium showed 11 informative locus pairs were significant across all populations. Cross-species amplification showed that 14 out of 16 SSR loci have the transferability in cultivar-A. dahurica cv. ‘Hangbaizhi’ and A. decursiva. Conclusions The 16 newly developed loci microsatellite primers with RNA-Seq will be useful for further investigating population genetics of A. dahurica, cultivars and other members of this genus.