The Anterior Cingulate Cortex Promotes Long-Term Auditory Cortical Responses through an Indirect Pathway via the Rhinal Cortex in Mice.

Sensory cortical areas are robustly modulated by higher-order cortices. Our previous study shows that the anterior cingulate cortex (ACC) can immediately and transiently enhance responses in the mouse auditory cortex (ACx). Here, we further examined whether strong activation of ACC neurons can induce long-term effects in mice of both sexes. To our surprise, only stimulation of cell bodies in the ACC, but not ACC-to-ACx terminal activation, induced long-term enhancement of auditory responses in the ACx. Anatomical examination showed that the ACC indirectly projects to the ACx via the rhinal cortex (RCx). High-frequency stimulation of ACC-projecting terminals to the RCx or RCx-projecting terminals to the ACx induced a similar effect as the cell body activation of ACC neurons, whereas silencing the RCx blocked this long-term enhancement. High-frequency stimulation of ACC projections to the RCx also induced long-term augmentation of sound-evoked flight behavior in male mice. These results show that the ACC promotes the long-term enhancement of auditory responses in the ACx through an indirect pathway via the RCx.SIGNIFICANCE STATEMENT In this study, we demonstrate that the anterior part of the anterior cingulate cortex (ACC) evokes long-term enhancement of auditory responses in the auditory cortex (ACx) when it is strongly activated. Importantly, instead of a direct projection, we show that the ACC implements this effect via an indirect pathway through the lateral rhinal cortex using a series of physiological, optogenetic, anatomic, and behavioral experiments. Along with a short-term effect, this long-term enhancement induced by an indirect ACC-to-ACx projection could increase the odds of survival when animals are faced with threats after a significant event.

A Novel CCK Receptor GPR173 Mediates Potentiation of GABAergic Inhibition.

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.

Heterogeneous Porous Synergistic Photocatalysts for Organic Transformations.

Recent interest has surged in using heterogeneous carriers to boost synergistic photocatalysis for organic transformations. Heterogeneous catalysts not only facilitate synergistic enhancement of distinct catalytic centers compared to their homogeneous counterparts, but also allow for the easy recovery and reuse of catalysts. This mini-review summarizes recent advancements in developing heterogeneous carriers, including metal-organic frameworks, covalent-organic frameworks, porous organic polymers, and others, for synergistic catalytic reactions. The advantages of porous materials in heterogeneous catalysis originate from their ability to provide a high surface area, facilitate enhanced mass transport, offer a tunable chemical structure, ensure the stability of active species, and enable easy recovery and reuse of catalysts. Both photosensitizers and catalysts can be intricately incorporated into suitable porous carriers to create heterogeneous dual photocatalysts for organic transformations. Notably, experimental evidence from reported cases has shown that the catalytic efficacy of heterogeneous catalysts often surpasses that of their homogeneous analogues. This enhanced performance is attributed to the proximity and confinement effects provided by the porous nature of the carriers. It is expected that porous carriers will provide a versatile platform for integrating diverse catalysts, thus exhibiting superior performance across a range of organic transformations and appealing prospect for industrial applications.

Fabrication of PHFPO Surface-Modified Conductive AgNWs/PNAGA Hydrogels with Enhanced Water Retention Capacity toward Highly Sensitive Strain Sensors.

Conductive hydrogels, characterized by their unique features of flexibility, biocompatibility, electrical conductivity, and responsiveness to environmental stimuli, have emerged as promising materials for sensitive strain sensors. In this study, a facile strategy to prepare highly conductive hydrogels is reported. Through rational structural and synthetic design, silver nanowires (AgNWs) are incorporated into poly(N-acryloyl glycinamide) (PNAGA) hydrogels, achieving high electrical conductivity (up to 0.88 S m-1), significantly enhanced mechanical properties, and elevated deformative sensitivity. Furthermore, surface modification with polyhexafluoropropylene oxide (PHFPO) has substantially improved the water retention capacity and dressing comfort of this hydrogel material. Based on the above merits, these hydrogels are employed to fabricate highly sensitive wearable strain sensors which can detect and interpret subtle hand and finger movements and enable precise control of machine interfaces. The AgNWs/PNAGA based strain sensors can effectively sense finger motion, enabling the control of robotic fingers to replicate the human hand's gestures. In addition, the high deformative sensitivity and elevated water retention performance of the hydrogels makes them suitable for flow sensing. These conceptual applications demonstrate the potential of this conductive hydrogel in high-performance strain sensors in the future.

Interaction effects between sleep-related disorders and depression on hypertension among adults: a cross-sectional study.

BACKGROUND: Hypertension, sleep disorders, and depression represent notable public health issues, and their interconnected nature has long been acknowledged. The objective of this study is to explore the interplay between sleep disorders and depression in the context of hypertension. METHODS: This cross-sectional study involved 42,143 participants aged 18 and above from the NHANES database across seven survey cycles between 2005 and 2018. After excluding those with missing data on depression, sleep disorders, and hypertension, as well as incomplete main variables, 33,383 participants remained. We used weighted logistic regression to examine the relationship between sleep disorders, depression, and hypertension. Additionally, we assessed the interaction between sleep disorders and depression on hypertension using both multiplicative and additive approaches to quantify their combined effect. RESULTS: Compared to individuals without sleep disorders, those with sleep disorders have an increased risk of hypertension (OR = 1.51, 95% CI: 1.37-1.67). Furthermore, individuals with depression experience a significantly higher risk of hypertension compared to those with sleep disorders alone (OR = 2.34, 95% CI: 1.95-2.80). Our study reveals a positive interaction between sleep disorders and depression in relation to hypertension risk (OR = 1.07, 95% CI: 1.02-1.13). In addition, we observed the quantitative additive interaction indicators (RERI = 0.73, 95% CI: 0.56 ~ 0.92; API = 0.31, 95% CI: 0.11 ~ 0.46; SI = 2.19, 95% CI: 1.08-3.46) influencing hypertension risk. Furthermore, our research also identified that individuals with less than 7 h of sleep, a sleep latency period between 5 and 30 min, or a latency period exceeding 30 min experience a significantly increased risk of hypertension. CONCLUSIONS: Our research uncovered separate links between sleep disorders, depression, and hypertension prevalence. Moreover, we identified an interaction between depression and sleep disorders in hypertension prevalence. Enhancing mental well-being and tackling sleep disorders could help prevent and manage hypertension. Yet, more investigation is required to establish causation and clarify mechanisms.

Predation risk-mediated indirect effects promote submerged plant growth: Implications for lake restoration.

Biological manipulation, involving fish stockings, is commonly used to counteract the deterioration of submerged vegetation in eutrophic lakes. Nevertheless, the non-consumptive effects (NCEs) of stocked carnivorous fish are often overlooked. Using a controlled experimental system, we investigated the NCEs of a native carnivorous fish, snakehead (Channa argus), on two key biological factors, herbivore-dominated grass carp (Ctenopharyngodon idella) and disturbance-dominated loach (Misgurnus anguillicaudatus), influencing submerged plants growth. Additionally, we conducted a meta-analysis on predation risk and primary productivity. The results reveal that predation risk induces oxidative stress damage and affects grass carp growth. Non-significant changes in cortisol and glucose may be linked to predation risk prediction. Simultaneously, predation risk reduces fish feeding and disturbance behavior, relieving pressure on submerged plants to be grazed and disturbed, thereby supporting plant development. The presence of submerged plants, in turn, enhances loach activity and influences water body characteristics through negative feedback. Furthermore, the meta-analysis results indicate the facilitative effect of predation risk on primary producers. Our findings contribute to the understanding of biological manipulation theory. We demonstrate that the predation risk associated with introducing carnivorous fish can promote the growth of submerged plants through behaviorally mediated indirect effects. This highlights the potential utility of predation risk in lake restoration efforts.

New Monoterpenoid Glycosides from the Fruits of Hypericum patulum Thunb.

The whole Hypericum patulum Thunb. plant is utilized in traditional medicine for its properties of clearing heat, detoxifying, soothing meridians, relaxing the liver, and stopping bleeding. In folk medicine, it is frequently used to treat hepatitis, colds, tonsillitis, and bruises. Phytochemical investigation of a 30% ethanol extract of the fresh ripe fruits of H. patulum has resulted in the isolation of two new pinane-type monoterpenoid glycosides 1-2, named patulumside E-F, and three new chain-shaped monoterpenoid glycosides 3-5, named patulumside G-H, J. Their structures were determined using extensive spectroscopic techniques, such as HR-ESI-MS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD) calculation. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. This research represents the inaugural comprehensive phytochemical study of H. patulum, paving the way for further exploration of monoterpenoid glycosides.

[Discrimination of anti-tumor and cardioprotective effect quality markers from Aidi Injection based on "spider web" mode].

Chinese medicinal preparations play an equally important role in reducing toxicity and treating tumors. Few studies discriminate the quality markers(Q-markers) conferring different therapeutic effects of traditional Chinese medicine preparations. Therefore, we take Aidi Injection(AD) as an example to comprehensively identify the Q-markers of anti-tumor and cardioprotective effects based on the "spider web" mode. Firstly, based on the principle of measurability, the chemical components in the prescription were qualitatively analyzed, and then the components with high content and capable to be measured were quantitatively analyzed as measurable evaluation indexes. Based on the principle of stability, the effects of light and temperature on the content of each component of AD were investigated as indicators of stability. Based on the principle of compatibility, the compounds were classified according to the law of compatibility of sovereign, minister, assistant, and guide medicinal materials in the prescription. Based on the principle of efficacy, the anti-tumor and antiangiogenic activities of the Q-markers were evaluated, and their synergistic effects with doxorubicin(DOX) in inhibiting tumorigenesis and angiogenesis and lowering cardiotoxicity were evaluated as the evaluation indexes of effectiveness. The seven-dimensional spider web of "compatibility-content-stability-antitumor activity-synergistic anti-tumor activity with DOX-antiangiogenic activity-synergistic anti-angiogenic activity with DOX" and the four-dimensional spider web of "compatibility-content-stability-protective effects against DOX-induced myocardial toxicity" were established, on the basis of which the Q-markers of anti-tumor and cardioprotective effects of AD were comprehensively analyzed. The results showed that 12 components were selected as the Q-markers of AD, among which cantharidin, ginsenoside Re, ginsenoside Rb_1, astragaloside Ⅱ, cryptochlorogenic acid, and ginsenoside Rg_2 were the anti-tumor Q-markers of AD. Ginsenoside Rd, isofraxidin, syringin, eleutheroside E, calycosin-7-O-ß-D-glucoside, and azelaic acid were the cardioprotective Q-markers of AD. Taking into account both the anti-tumor and cardioprotective effects, these Q-markers could cover the four herbs constituting the prescription. The findings provides a scientific basis for the quality control of AD and an effective method for identifying comprehensive and reasonable Q-markers for the two effects of Chinese medicinal preparations.

[Material basis and mechanism of Bletillae Rhizoma for melasma, gastrointestinal hemorrhage, lung cancer and bronchoplumonary inflammation as "homotherapy for heteropathy" based on UHPLC-Q-Exactive Orbitrap HRMS coupled with network pharmacology and molecular docking].

Based on UHPLC-Q-Exactive Orbitrap HRMS coupled with the network pharmacology and molecular docking, the common material basis and molecular mechanisms of Bletillae Rhizoma for melasma, gastrointestinal hemorrhage, lung cancer and bronchoplumonary inflammation as "homotherapy for heteropathy" were explored. The fingerprint of 17 batches of Bletillae Rhizoma from different areas was established using HPLC, and the similarity analysis was carried out. The common chemical components of the 17 batches of Bletillae Rhizoma were identified using UHPLC-Q-Exactive Orbitrap HRMS. Depending on the bioavailability and drug-like properties of the common components, the active chemical components were screened, and then their protein targets were collected using the Traditional Chinese Medicine Database and Analysis Platform(TCMSP) and SwissTargetPrediction database. The protein targets related to diseases were retrieved from the databases DrugBank, TTD and GeneCards to produce a Venn diagram. The shared targets were obtained between drugs and diseases as "homotherapy for heteropathy" targets. The protein-protein interaction(PPI) was analyzed with the STRING database, and KEGG and GO analyses of the "homotherapy for heteropathy" targets were performed using the Bioconductor database. Cytoscape 3.7.2 software was employed to construct the "chemical components of Bletillae Rhizoma-homotherapy for heteropathy targets" network and PPI network, and topological analysis was conducted to screen out the key active chemical components and core targets. Finally, the affinity between the active components and core targets was evaluated using the molecular docking by AutoDock Vina 4.2.6, which verified the interaction between them. Thirteen common peaks were identified by fingerprint chromatography, and the similarity between different batches was 0.941-0.998. Fifty-three chemical components were identified by mass spectrometry in Bletillae Rhizoma, and 18 common chemical constituents were obtained in the 17 batches of Bletillae Rhizoma. Network pharmacologic screening showed that the pharmacodynamic substances of Bletillae Rhizoma for melasma, gastrointestinal hemo-rrhage, lung cancer and bronchoplumonary inflammation with "homotherapy for heteropathy" were 11 compounds, such as polysaccharides, biphenanthrenes, dihydrophenanthrenes and bibenzyls. There were 42 common targets identified for the treatment of different diseases. These targets were involved in biological processes such as cell response to chemical stress, reactive oxygen species and positive regulation of protein kinase B signal transduction. They were also involved in 121 signaling pathways, encompassing vital pathways such as PI3K-Akt, ErbB, Rap1, FoxO, MAPK and estrogen. Molecular docking results showed a strong affinity between the key active components and the core targets. This study provides a preliminary explanation of how Bletillae Rhizoma exerts its therapeutic effect on chloasma, gastrointestinal hemorrhage, lung cancer, and bronchopneumonic lesions as "homotherapy for heteropathy" through a combined action involving multiple components, targets, and pathways. These findings offer a certain theoretical basis for the further deve-lopment and application of Bletillae Rhizoma.

Comprehensive analysis of cuproptosis-related lncRNAs in immune infiltration and prognosis in hepatocellular carcinoma.

BACKGROUND: Being among the most common malignancies worldwide, hepatocellular carcinoma (HCC) accounting for the third cause of cancer mortality. The regulation of cell death is the most crucial step in tumor progression and has become a crucial target for nearly all therapeutic options. Cuproptosis, a copper-induced cell death, was recently reported in Science. However, its primary function in carcinogenesis is still unclear. METHODS: Cuproptosis-related lncRNAs significantly associated with overall survival (OS) were screened by stepwise univariate Cox regression. The signature of cuproptosis-related lncRNAs for HCC prognosis was constructed by the LASSO algorithm and multivariate Cox regression. Further Kaplan-Meier analysis, proportional hazards model, and ROC analysis were performed. Functional annotation was performed using gene set enrichment analysis (GSEA). The relationship between prognostic cuproptosis-related lncRNAs and HCC prognosis was further explored by GEPIA( http://gepia.cancer-pku.cn/ ) online analysis tool. Finally, we used the ESTIMATE and XCELL algorithms to estimate stromal and immune cells in tumor tissue and cast each sample to infer the underlying mechanism of cuproptosis-related lncRNAs in the tumor immune microenvironment (TIME) of HCC patients. RESULTS: Four cuproptosis-related lncRNAs were used to construct a prognostic lncRNA signature, which was an independent factor in predicting OS in HCC patients. Kaplan-Meier curves showed significant differences in survival rates between risk subgroups (p = 0.002). At the same time, we found that the expression levels of most immune checkpoint genes increased with increasing risk scores. Tumorigenesis and immunological-related pathways were primarily enhanced in the high-risk group, as determined by GSEA. The results of drug sensitivity analysis showed that compared with patients in the high-risk group, the IC50 values of erlotinib and lapatinib were lower in patients in the low-risk group, while the opposite was true for sunitinib, paclitaxel, gemcitabine, and imatinib. We also found that elevated AL133243.2 expression was significantly associated with worse OS and disease-free survival (DFS), more advanced T stage and higher tumor grade, and reduced immune cell infiltration, suggesting that HCC patients with low AL133243.2 expression in tumor tissues may have a better response to immunotherapy. CONCLUSION: Collectively, the cuproptosis-associated lncRNA signature can serve as an independent predictor to guide individual treatment strategies. Furthermore, AL133243.2 is a promising marker for predicting immunotherapy response in HCC patients. This data may facilitate further exploration of more effective immunotherapy strategies for HCC.

Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling.

Despite the clinical benefits of androgen deprivation therapy, most patients with advanced androgen-dependent prostate cancer (ADPC) eventually relapse and progress to lethal androgen-independent prostate cancer (AIPC), also termed castration-resistant prostate cancer (CRPC). MiRNAs can be packaged into exosomes (Exos) and shuttled between cells. However, the roles and mechanisms of exosomal miRNAs involved in CRPC progression have not yet been fully elucidated. Here, we find that miR-222-3p is elevated in AIPC cells, which results in remarkable enhancement of cell proliferation, migration, and invasion ability. Furthermore, Exos released by AIPC cells can be uptaken by ADPC cells, thus acclimating ADPC cells to progressing to more aggressive cell types in vitro and in vivo through exosomal transfer of miR-222-3p. Mechanistically, Exos-miR-222-3p promoted ADPC cells transformed to AIPC-like cells, at least in part, by activating mTOR signaling through targeting MIDN. Our results show that AIPC cells secrete Exos containing miRNA cargo. These cargos can be transferred to ADPC cells through paracrine mechanisms that have a strong impact on cellular functional remodeling. The current work underscores the great therapeutic potential of targeting Exo miRNAs, either as a single agent or combined with androgen receptor pathway inhibitors for CRPC treatment.

Deep multilayer brain omics identifies the potential involvement of menopause molecular networks in Gliomas' disease progression.

The risk of high-grade gliomas is lower in young females, however, its incidence enhances after menopause, suggesting potential protective roles of female sex hormones. Hormone oscillations after menopause have received attention as a possible risk factor. Little is known about risk factors for adult gliomas. We examined the association of the aging brain after menopause, determining the risk of gliomas with proteomics and the MALDI-MSI experiment. Menopause caused low neurotransmitter levels such as GABA and ACH, high inflammatory factor levels like il-1ß, and increased lipid metabolism-related levels like triglycerides in the brain. Upregulated and downregulated proteins after menopause were correlated with differentially expressed glioma genes, such as ACTA2, CAMK2D, FNBPIL, ARL1, HEBP1, CAST, CLIC1, LPCAT4, MAST3, and DOCK9. Furthermore, differential gene expression analysis of monocytes showed that the downregulated gene LPCAT4 could be used as a marker to prevent menopausal gliomas in women. Our findings regarding the association of menopause with the risk of gliomas are consistent with several extensive cohort studies. In view of the available evidence, postmenopausal status is likely to represent a significant risk factor for gliomas.

PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates.

Tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory mechanism for exocytosis. However, the participation of protein tyrosine phosphatases (PTPs) in different exocytosis stages has not been defined. Here we demonstrate that PTP-MEG2 controls multiple steps of catecholamine secretion. Biochemical and crystallographic analyses reveal key residues that govern the interaction between PTP-MEG2 and its substrate, a peptide containing the phosphorylated NSF-pY83 site, specify PTP-MEG2 substrate selectivity, and modulate the fusion of catecholamine-containing vesicles. Unexpectedly, delineation of PTP-MEG2 mutants along with the NSF binding interface reveals that PTP-MEG2 controls the fusion pore opening through NSF independent mechanisms. Utilizing bioinformatics search and biochemical and electrochemical screening approaches, we uncover that PTP-MEG2 regulates the opening and extension of the fusion pore by dephosphorylating the DYNAMIN2-pY125 and MUNC18-1-pY145 sites. Further structural and biochemical analyses confirmed the interaction of PTP-MEG2 with MUNC18-1-pY145 or DYNAMIN2-pY125 through a distinct structural basis compared with that of the NSF-pY83 site. Our studies thus provide mechanistic insights in complex exocytosis processes.

Responses of soil phosphorus cycling and bioavailability to plant invasion in river-lake ecotones.

The invasion of exotic plants in the river-lake ecotone has seriously affected the nutrient cycling processes in wetland soil. The South American species Alternanthera philoxeroides (Mart.) Griseb. is rapidly invading the river-lake ecotone in subtropical China, and has become the dominant species in the river-lake ecotone. However, there have been few studies on the effects of A. philoxeroides invasion on soil phosphorus (P) cycling and bioavailability in this ecotone. Here, we measured the bioavailable P fractions, physicochemical properties and nutrient content in the surface soils of the native plant (Zizania latifolia (Griseb.) Turcz and Nelumbo nucifera Gaertn.) communities and the adjacent invasive A. philoxeroides communities in three river-lake ecotones with different nutrient substrates in the subtropical Dongting Lake basin over a 3-year period to reveal the effects of A. philoxeroides invasion on the morphology and concentrations of soil bioavailable P. The principal coordinate analysis results showed that the A. philoxeroides invasion significantly altered the bioavailable P concentrations in the soil of native plant communities in the different river-lake ecotones, and this effect was not disturbed by the heterogeneity of the soil matrix. However, the effects of invasion into different native plant communities on the fractions of soil bioavailable P were different. Compared with native Z. latifolia and N. nucifera communities, A. philoxeroides invasion increased the concentration of inorganic P by 39.5% and 3.7%, respectively, and the concentration of organic P decreased by 32.7% and 31.9%, respectively. In addition, the invasion promoted P cycling and accumulation in the river-lake ecotone, which resulted in average decreases in the soil N:P and C:P ratios of 7.9% and 12.5%, respectively. These results highlight the impact of exotic plant invasions on nutrient cycling in wetland ecosystems in the river-lake ecotone, and this process may be detrimental to the late recovery of native plants.

Association of Insulin-Like Growth Factor-1 With Polycystic Ovarian Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: Circulating concentration of insulin-like growth factor (IGF)-1 in patients with polycystic ovary syndrome (PCOS) is still unclear. Therefore, we aimed to investigate the association of IGF-1 with PCOS through this meta-analysis. METHODS: Literature search was conducted through PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (up to July 2022). A manual search was performed on the references of related original research. Then, we applied the random-effects model to evaluate the overall effect size by calculating the standard mean difference and its 95% CI. Subgroup analyses were used to explore the sources of heterogeneity. In addition, a sensitivity analysis was performed and publication bias was assessed. RESULTS: Twenty studies were included in this meta-analysis involving 657 individuals: 362 patients with PCOS and 295 normal controls. The results of meta-analysis showed that serum IGF-1 levels were significantly higher in patients with PCOS than in controls (standard mean difference, 0.89; 95% CI, 0.34-1.45; P = .002). The final pooled data were determined by the random-effects model because a significant high heterogeneity (I2 = 89%) was found. A subgroup analysis based on body mass index showed that elevated IGF-1 level was associated with normal-weight and overweight patients in the PCOS group, but there was no significant association with obesity. The sensitivity analysis indicated that no individual study significantly affected the overall pooled result and no publishing bias was observed. CONCLUSION: These data suggest that elevated serum IGF-1 levels may not be a major cause of PCOS pathogenesis. Body mass index may be a major determinant of serum IGF-1.

How I do it? Uniportal full-endoscopic transforaminal lumbar interbody fusion with a complete reduction for L5 isthmic grade 2 spondylolisthesis.

BACKGROUND: Endoscopic transforaminal lumbar interbody fusion (endo-TLIF) with bilateral percutaneous pedicle screw fixation is an emerging option for low-grade spondylolisthesis. However, uniportal full endo-TLIF with a complete reduction for high-grade spondylolisthesis is challenging. METHODS: We attempted uniportal endo-TLIF for L5 isthmic grade 2 spondylolisthesis with a complete reduction, and have described the procedures, with a discussion of the indications, limitations, potential complications, and ways to avoid complications. CONCLUSION: We had successfully completed a perfect reduction of L5 isthmic grade 2 spondylolisthesis via uniportal endo-TLIF with bilateral pedicle screw fixation. Uniportal endo-TLIF is suitable for isthmic grade 2 spondylolisthesis.

Caregiver burden among family caregivers of patients with advanced cancer in a palliative context: A mixed-method study.

AIM: To examine the multidimensional properties of caregiver burden among family caregivers of patients with advanced cancer in a palliative context. DESIGN: A sequential, explanatory, mixed-method study was performed. METHODS: Family caregivers of patients diagnosed with advanced cancer were recruited from a palliative care department of a third-level hospital in Sichuan Province, China. The Caregiver Burden Inventory, Social Support Rating Scale and Connor-Davidson Resilience Scale were used to collect quantitative data, and a total of 150 caregivers were recruited from January 2022 to September 2022. Qualitative data were collected through semi-structured interviews, and a total of 22 caregivers were interviewed from October 2022 to November 2022. Survey data were analysed using descriptive statistics, and the factors of caregiver burden were identified using the Mann-Whitney U test, Kruskal-Wallis H test and Spearman correlations. Interpretative phenomenological analysis was performed to analyse the interview data to initially explore the multidimensions of caregiver burden. The following-a-thread method and convergence coding matrix were used for triangulation to examine the multidimensional properties of caregiver burden. RESULTS: The participants experienced a moderate level of caregiver burden (32.97 ± 13.09). Through triangulation, six meta-themes and nine meta-subthemes were identified as multidimensional properties of caregiver burden, including physical (too many caring tasks and poor health condition), emotional (strong negative emotions resulting from patients' suffering and insufficient and ineffective family communication), social (less social interaction and social role conflict) and economic burdens, factors that aggravate burden (prevention and control of COVID-19 and spousal relationship with patients) and factors that mitigate burden (social support). CONCLUSION: Multiple dimensions of caregiver burden were experienced by family caregivers of patients with advanced cancer in the palliative context. Family-centred palliative care must be further developed. IMPLICATIONS FOR THE PROFESSION: It is important to develop family-centred palliative care. Therefore, the focus must be on developing a rational understanding of palliative care in public and a culture-oriented death education in palliative units. IMPACT: This study adopted a mixed-method approach to comprehensively understand the phenomenon of and factors in caregiver burden in the Chinese palliative oncology context. Our findings suggest that family caregivers in palliative oncology experience a moderate level of caregiver burden, with dimensions including physical, emotional, social and economic burdens, among which emotional burden is the most prominent. The findings of this study provide policy makers and nurse practitioners with targets to be addressed in family-centred care in Chinese palliative units. REPORTING METHOD: The results of this study are reported based on the guidelines of the Mixed-Methods Article Reporting Standards. PATIENT OR PUBLIC CONTRIBUTION: Eligible caregivers were invited to participate in the study and semi-structured interviews. Nurse managers of the palliative unit helped us access the patient-management system.

Notch1 Is Involved in Physiologic Cardiac Hypertrophy of Mice via the p38 Signaling Pathway after Voluntary Running.

Appropriate exercise such as voluntary wheel-running can induce physiological cardiac hypertrophy. Notch1 plays an important role in cardiac hypertrophy; however, the experimental results are inconsistent. In this experiment, we aimed to explore the role of Notch1 in physiological cardiac hypertrophy. Twenty-nine adult male mice were randomly divided into a Notch1 heterozygous deficient control (Notch1+/- CON) group, a Notch1 heterozygous deficient running (Notch1+/- RUN) group, a wild type control (WT CON) group, and a wild type running (WT RUN) group. Mice in the Notch1+/- RUN and WT RUN groups had access to voluntary wheel-running for two weeks. Next, the cardiac function of all of the mice was examined by echocardiography. The H&E staining, Masson trichrome staining, and a Western blot assay were carried out to analyze cardiac hypertrophy, cardiac fibrosis, and the expression of proteins relating to cardiac hypertrophy. After two-weeks of running, the Notch1 receptor expression was decreased in the hearts of the WT RUN group. The degree of cardiac hypertrophy in the Notch1+/- RUN mice was lower than that of their littermate control. Compared to the Notch1+/- CON group, Notch1 heterozygous deficiency could lead to a decrease in Beclin-1 expression and the ratio of LC3II/LC3I in the Notch1+/- RUN group. The results suggest that Notch1 heterozygous deficiency could partly dampen the induction of autophagy. Moreover, Notch1 deficiency may lead to the inactivation of p38 and the reduction of ß-catenin expression in the Notch1+/- RUN group. In conclusion, Notch1 plays a critical role in physiologic cardiac hypertrophy through the p38 signaling pathway. Our results will help to understand the underlying mechanism of Notch1 on physiological cardiac hypertrophy.

Polygonum orientale L. Alleviates Myocardial Ischemia-Induced Injury via Activation of MAPK/ERK Signaling Pathway.

Although Polygonum orientale L. (PO) has a beneficial effect on treatment of myocardial ischemia (MI), its mechanism remains unclear. This study aimed to explore the pharmacological mechanism of PO against MI through MAPK signaling pathways. Firstly, the therapeutic effect of PO was evaluated for treatment of MI mice. Using Western blot and immunohistochemistry, the influence of PO on MAPK signaling pathways and cell apoptosis was investigated. Subsequently, one key pathway (ERK) of MAPK signaling pathways was screened out, on which PO posed the most obvious impact. Finally, an inhibitor of ERK1/2 was utilized to further verify the regulatory effect of PO on the MAPK/ERK signaling pathway. It was found that PO could reduce the elevation of the ST segment; injury of heart tissue; the activity of LDH, CK, NOS, cNOS and iNOS and the levels of NO, BNP, TNF-α and IL-6. It is notable that PO could significantly modulate the protein content of p-ERK/ERK in mice suffering from MI but hardly had an effect on p-JNK/JNK and p-p38/p38. Additionally, the expressions of bax, caspase3 and caspase9 were inhibited in heart tissue in the PO-treated group. To evaluate whether ERK1/2 inhibitor (PD98059) could block the effect of PO on treatment of MI, both PO and PD98059 were given to mice with MI. It was discovered that the inhibitor indeed could significantly reverse the regulatory effects of PO on the above indicators, indicating that PO could regulate p-ERK/ERK. This study provides experimental evidence that PO extenuates MI injury, cardiomyocyte apoptosis and inflammation by activating the MAPK/ERK signaling pathway.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.