Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1.

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

Oral Levodopa Stimulates Copeptin Secretion in Children and Adolescents with Intact Posterior Pituitary Function.

BACKGROUND: Copeptin stimulation tests can be used in the differential diagnosis of polyuria polydipsia syndrome. Current stimulation methods rely on intravenous or subcutaneous administration. Oral stimulus can further simplify the diagnostic approach. The levodopa stimulation test is widely used in the evaluation of growth hormone deficiency (GHD), and the dopamine pathway was reported to be associated with arginine vasopressin secretion. The study aimed to investigate the effect of oral levodopa on copeptin secretion. METHODS: The study was a prospective observational single-center cohort study. Patients < 18 years old with short stature and no symptoms of polyuria or polydipsia undergoing levodopa stimulation test for suspected GHD were recruited from May 2023 to Nov 2023. Copeptin and growth hormone (GH) were measured at 0, 30, 60, 90, and 120min in the levodopa test. The insulin tolerance test with copeptin and GH measured at the same time points was conducted in part of patients. RESULTS: Forty-four participants were included in the final analysis. In the levodopa stimulation test, the median (interquartile range, IQR) copeptin concentration increased from 5.20 (3.51, 8.25) pmol/L to maximum 19.36 (8.97, 108.08) pmol/L (P < 0.001), 3.94 (1.41, 13.88) times of the baseline (P < 0.001). Compared with insulin tolerance test, peak copeptin in the levodopa test was significantly higher (34.61 (13.67, 98.96) vs 8.88 (7.14, 15.42) pmol/L, P = 0.009). Higher copeptin was associated with larger dose of levodopa. CONCLUSIONS: Oral levodopa could be used to stimulate copeptin.

[Value of SOX1 and PAX1 Gene Methylation Detection in Secondary Triage of High-Grade Cervical Lesions].

Objective To evaluate the value of SOX1 and PAX1 gene methylation detection in the secondary triage of high-grade cervical lesions.Methods Exfoliated cervical cells were collected from 122 patients tested positive for human papilloma virus (HPV) and subjected to thin-prep cytologic test (TCT) and SOX1/PAX1 gene methylation tests.Results The HPV test combined with TCT showed the sensitivity of 95.24% and the specificity of 23.75% for detecting cervical intraepithelial neoplasia (CIN) grade 2 and above (CIN2+).After the addition of the SOX1/PAX1 gene methylation detection in secondary triage,the sensitivity for detecting CIN2+ was 83.33%,which had no statistically significant difference from the sensitivity of TCT combined with HPV test (P=0.078).However,the specificity reached 77.50%,which was significantly higher than that of HPV test combined with TCT (P<0.001).The SOX1/PAX1 gene methylation level in the CIN2+ group was higher than those in the normal cervical tissue and the CIN1 group(P<0.001).The cut-off values of SOX1 and PAX1 gene methylation for CIN2+ detection were -11.81 and -11.98,respectively.Conclusion Adding the detection of SOX1/PAX1 gene methylation in secondary triage significantly improves the efficiency and accuracy of CIN2+ detection.

Development of PROTAC degrader probe of CDK4/6 based on DCAF16.

Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.

Research Progress of Nucleic Acid Detection Technology for Genetically Modified Maize.

Genetically modified (GM) maize is one of the earliest GM crops to have achieved large-scale commercial cultivation globally, and it is of great significance to excel in the development and implementation of safety policy regarding GM, and in its technical oversight. This article describes the general situation regarding genetically modified maize, including its varieties, applications, relevant laws and regulations, and so on. From a technical point of view, we summarize and critically analyze the existing methods for detecting nucleic acid levels in genetically modified maize. The nucleic acid extraction technology used for maize is explained, and the introduction of traditional detection techniques, which cover variable-temperature and isothermal amplification detection technology and gene chip technology, applications in maize are described. Moreover, new technologies are proposed, with special attention paid to nucleic acid detection methods using sensors. Finally, we review the current limitations and challenges of GM maize nucleic acid testing and share our vision for the future direction of this field.

Association between prenatal PM2.5 exposure and the risk of large for gestational age.

BACKGROUND: The relationship between particulate matter <2.5 µm (PM2.5) and large for gestational age (LGA) is unclear, and studies conducted in highly polluted areas are lacking. We aimed to explore the association between PM2.5 and the risk of LGA in China. METHODS: Maternal and neonatal characteristics were collected in the National Prepregnancy Examination Project. The definition of LGA was neonates with a weight over the 90th percentile for gestational age. Logistic regression was used to evaluate the relationship between PM2.5 exposure and the risk of LGA. The dose-response relationship was evaluated using a restricted cubic spline model. RESULTS: There were 196,243 mother-neonate pairs included, among which the percentage of LGA was 15.3%. The average PM2.5 concentration was 75.29 µg/m3. A 10 µg/m3 increase in PM2.5 during the whole pregnancy was associated with an increased risk of LGA (odds ratio (OR) 1.097, 95% confidence interval (CI) 1.091-1.103). Pregnant women in the high-exposure group had a higher risk of giving birth to an LGA infant (OR 1.37, 95% CI 1.33-1.41). There was a nonlinear relationship between PM2.5 concentration and the risk of LGA, and the risk increased more rapidly at higher PM2.5 levels. CONCLUSIONS: Prenatal exposure to PM2.5 was linked to an increased risk of LGA. IMPACT: A nation-wide study in a highly polluted country suggested the association between prenatal PM2.5 exposure and LGA. A trimester-specific relationship between PM2.5 exposure and LGA was established. Call for attention on the pregnant women in highly polluted areas who were in high risk of giving birth to LGA.

Synthesis and biological evaluation of a tumor-selective degrader of PARP1.

Poly (ADP-ribose) polymerase (PARP) inhibitors show potent antiproliferative activity in treatment with triple-negative breast cancer (TNBC) when combined with chemotherapeutic drugs. However, the emergence of safety issues and drug-resistance of PARP inhibitors prompt us to search for new strategies. It was proved that Proteolysis Targeting Chimeras (PROTACs) is more effective than traditional small molecule which can induce target proteins degradation rather than inhibition. In this article, based on the Olaparib derivatives and cereblon (CRBN) E3 ligase ligands, a series of PARP1 degraders, with linkers bearing different length and type were designed and synthesized. Among them, compound LB23 showed efficacious antiproliferative activity in various human cancer cells and can induce PARP1 protein degradation effectively. Moreover, LB23 showed 60-fold degradation selectivity in tumor cells with low degradation toxicity in normal cells. This study shows that the PROTAC tumor selectivity can be optimized by tuning the length and composition of the linker.

High prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumors.

PURPOSE: To evaluate the prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumor (iGCT), and to explore the risk factors of it. METHODS: iGCT patients visiting Peking Union Medical College Hospital between Jan 2008 to Oct 2020 were included. The prevalence of overweight/obesity and dyslipidemia was calculated. Mixed-effects models were used to evaluate the relationship between BMI z-scores, concentration of lipid profiles and potential risk factors. RESULTS: One hundred and six patients were included. The median follow-up time was 27 (IQR 5-59) months. The number of patients diagnosed with overweight/obesity and dyslipidemia were 49 (46.2%) and 86 (81.1%) during visits. Higher BMI z-scores were associated with treatment (mean difference (MD) 0.51, 95%CI 0.31-0.72), surgical biopsies (MD 0.71, 95%CI 0.16-1.25), adrenal insufficiency (MD 0.37, 95%CI 0.07-0.68), hypothyroidism (MD 0.35, 95%CI 0.06-0.63), glucocorticoid supplementation (MD 0.64, 95%CI 0.40-0.87), and thyroxine supplementation (MD 0.48, 95%CI 0.24-0.72). Hypothalamus involvement was associated with increased TC (MD 0.52, 95%CI 0.06-0.98), TG (MD 0.36, 95%CI 0.01-0.72), LDL-C (MD 0.60, 95%CI 0.20-0.98), and decreased HDL-C (MD - 0.23, 95%CI - 0.44 to - 0.02). Higher TC (MD 0.53, 95%CI 0.26-0.80) and LDL-C (MD 0.39, 95%CI 0.17-0.62) were observed in patients after treatment. Glucocorticoid supplementation was associated with increased TC (MD 0.70, 95%CI 0.38-1.03), LDL-C (MD 0.51, 95%CI 0.24-0.78), and HDL-C (MD 0.25, 95%CI 0.09-0.40), while sex hormone supplementation was associated with decreased TC (MD - 0.74, 95%CI - 1.2 to - 0.29) and TG (MD - 0.47, 95%CI - 0.86 to - 0.08). CONCLUSION: Overweight/obesity and dyslipidemia were high prevalent in iGCT patients and should be screened during follow-ups.

FAM83A has a pro-tumor function in ovarian cancer by affecting the Akt/Wnt/ß-catenin pathway.

Family with sequence similarity 83, member A (FAM83A) is a tumor-exclusive gene that has a vital role in numerous tumors. However, its role in tumorigenesis remains controversial. This work is dedicated to the study of the role of FAM83A in ovarian cancer. We observed elevated levels of FAM83A in ovarian cancer specimens and cells. Kaplan-Meier survival curves revealed that elevated FAM83A levels predicted a worse overall survival in ovarian cancer patients. The inhibition of FAM83A caused remarkable suppressive effects on the proliferation and invasion of ovarian cancer cells, and enhanced their chemosensitivity. On the contrary, the upregulation of FAM83A had opposite effects. Mechanistically, FAM83A had an effect on the Akt and Wnt/ß-catenin pathways in ovarian cancer cells. The repression of Akt could cancel the regulatory effect of FAM83A overexpression on the Wnt/ß-catenin pathway. Moreover, reactivation of the Wnt/ß-catenin pathway abolished FAM83A-inhibition-evoked antitumor effects. Additionally, FAM83A inhibition weakened the tumorigenic potential of ovarian cancer in vivo. Taken together, this work shows that FAM83A exerts a pro-tumor function in ovarian cancer by affecting the Akt/Wnt/ß-catenin pathway and proposes FAM83A as an effective and possible treatment target for ovarian cancer.

Relationship between the duration of smoking and blood pressure in Han and ethnic minority populations: a cross-sectional study in China.

BACKGROUND: Evidence for correlation between the cigarette use and blood pressure change remains ambiguous. This study modelled relationship between the duration of smoking and systolic blood pressure in a large national multi-ethnic cross-sectional survey in China. METHODS: Participants were selected through a multi-stage probability sampling procedure from 2012 to 2017. Former or current smokers were included in this study, whose smoking behaviour, blood pressure, and other demographic information were collected and measured through a face-to-face interview. Linear and non-linear relationships between the duration of smoking and systolic blood pressure were analysed and differences of the association between Han and minority populations were specially checked. RESULTS: A total of 8801 participants were enrolled in this study. Prevalence of hypertension was 41.3 and 77.8% were current smokers. For every additional year of smoking duration, systolic blood pressure raised by 0.325 mmHg (95% CI 0.296 to 0.354 mmHg, P <  0.001). The Chinese minority populations may suffer more from the elevated blood pressure in long-term smoking than Han populations (0.283 mmHg (95% CI 0.252 to 0.314 mmHg, P <  0.001) versus 0.450 mmHg (95% CI 0.380 to 0.520 mmHg, P <  0.001) raise in systolic blood pressure with each additional year of smoking in minority and Han populations). CONCLUSIONS: Smoking is associated with raised systolic blood pressure in Chinese population. This association is notedly stronger in Chinese minority populations.

Research on Flow Field Perception Based on Artificial Lateral Line Sensor System.

In nature, the lateral line of fish is a peculiar and important organ for sensing the surrounding hydrodynamic environment, preying, escaping from predators and schooling. In this paper, by imitating the mechanism of fish lateral canal neuromasts, we developed an artificial lateral line system composed of micro-pressure sensors. Through hydrodynamic simulations, an optimized sensor structure was obtained and the pressure distribution models of the lateral surface were established in uniform flow and turbulent flow. Carrying out the corresponding underwater experiment, the validity of the numerical simulation method is verified by the comparison between the experimental data and the simulation results. In addition, a variety of effective research methods are proposed and validated for the flow velocity estimation and attitude perception in turbulent flow, respectively and the shape recognition of obstacles is realized by the neural network algorithm.

Efficacy and Safety of Tacrolimus versus Cyclosporine A for Idiopathic Membranous Nephropathy:A Network Meta-analysis.

Objective To compare the efficacy and safety of tacrolimus with those of cyclosporine in treating idiopathic membranous nephropathy (IMN) via network meta-analysis. Methods Databases including PubMed,Embase,CENTRAL (Cochrane),Wanfang Database,CNKI,and VIP citation database were searched for relevant studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Package Meta 4.5.0 and Gemtc 0.8.1 in R 3.3.1 were used to analyze the included studies. Results In this network meta-analysis,the complete remission rate (RR=0.98,95% CI:0.70-1.40)and the total remission rate (RR=1.00,95% CI:0.90-1.20)of idiopathic membranous nephropathy did not differ significantly between IMN patients treated with cyclosporine A or tacrolimusand,nor did the incidences of hepatic dysfunction(RR=1.40,95% CI:0.52-4.00),infection(RR=0.75,95% CI:0.18-3.10),or gastrointestinal syndrome(RR=2.1,95% CI:0.36-28.00). Conclusion Cyclosporine A seems to have similar effectiveness and safety to tacrolimus in treating IMN.

Evaluation of sample preparation and chromatographic separation for the parallel determination of taurine and edaravone in rat tissues using HILIC-MS/MS.

The quantitative analysis of taurine and edaravone in biological sample is critical in pharmaceutical studies. Although each of them can be individually analyzed by different approaches, concurrent quantification is still a highly challenging task with respect to their great polarity variation and the complex composition of tissue sample. In the present study, to simultaneously determine taurine and edaravone in rat tissue, the sample preparation and chromatographic separation conditions were evaluated and discussed in detail. As for the sample preparation, four kinds of solvent and the volume ratio of the optimal solvent to biological sample were both tested and evaluated based on the chromatographic profile, extraction recovery, and matrix effect (ME). The chromatographic separation was performed in a reverse phase (RP) and two hydrophilic interaction liquid chromatography (HILIC) modes, and the corresponding separation efficiencies were assessed using chromatographic parameters like half-width (W 1/2 ), tailing factor (f t), theoretical plates number (N), and ME. Furthermore, adopted composition of two mobile phase systems and the concentrations of the additives in the optimum buffer system were also investigated on an Atlantis HILIC silica column according to the resultant chromatographic profiles and peak areas of the analytes. The optimal results were obtained when the biological samples were deproteined by 4-fold volume of methanol/acetonitrile (1:3, v/v) and separated on a HILIC column with a gradient elution of acetonitrile/water containing 0.2 % formic acid and 10 mM ammonium formate. The proposed approach was validated and successfully applied to the parallel determination of the tissue distribution of edaravone and taurine in rat tissues.

Simultaneous determination of baicalin, oroxylin A-7-O-glucuronide and wogonoside in rat plasma by UPLC-DAD and its application in pharmacokinetics of pure baicalin, Radix Scutellariae and Yinhuang granule.

A novel UPLC-DAD method was developed and validated for the simultaneous determination of baicalin (baicalein-7-glucuronide, BG), oroxylin A-7-O-glucuronide (OAG) and wogonoside (WG) in rat plasma using rutin as the internal standard. Plasma samples were precipitated using acetonitrile containing 0.1% formic acid. Separation was performed on an Agilent Eclipse Plus C18 column (2.1 × 50 mm, 1.8 µm) using gradient acetonitrile and 0.2% formic acid water solution as mobile phase. The flow-rate was set at 0.4 mL/min and the eluate was detected at 275 nm. The method was linear over the ranges of 0.075-17.50, 0.050-12.60 and 0.056-14.10 µg/mL for BG, OAG and WG, respectively. The intra- and inter-day precisions were respectively <4.8% and 6.4%. All of the limits of detection of three analytes in rat plasma were 0.01 µg/mL, whereas the limits of quantification were, respectively, 0.035, 0.025 and, 0.025 µg/mL. This assay has been successfully applied to pharmacokinetics of BG, OAG and WG in rats after oral administration of Yinhuang granule (YHG) and comparative pharmacokinetics of BG in rats following oral administration of the pure BG, Radix Scutellariae (RS) or YHG. We speculate that some co-existing ingredients in RS or YHG may increase the absorption and elimination of BG in rat. This work may be helpful for the quality control of Yinhuang granule.

Synthesis and identification of a selective FGFR2 degrader with potent antiproliferative effects in gastric cancer.

Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib, a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC50 value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation.

Enhancing supercapacitor electrochemical performance through acetate-ion intercalation in layered nickel-cobalt double hydroxides.

Enhancing the performance of layered nickel-cobalt double hydroxides (NiCo-LDH) as electrode materials for supercapacitors represents a promising strategy for optimizing energy storage systems. However, the complexity of the preparation method for electrode materials with enhanced electrochemical performance and the inherent defects of nickel-cobalt LDH remain formidable challenges. In this study, we synthesized acetate-ion-intercalated NiCo-LDH (NCLA) through a simple one-step hydrothermal method. The physical and chemical structural properties and supercapacitor characteristics of the as-prepared NCLA were systematically characterized. The results indicated that the introduction of Ac- engendered a distinctive tetragonal crystal structure in NiCo-LDH, concomitant with a reduced interlayer spacing, thus enhancing structural stability. Electrochemical measurements revealed that NCLA-8 exhibited a specific capacitance of 1032.2 F g-1 at a current density of 1 A g-1 and a high specific capacitance of 922 F g-1 at 10 A g-1, demonstrating a rate performance of 89.3%. Furthermore, NCLA-8 was used to construct the positive electrode of an asymmetric supercapacitor, while the negative electrode was composed of activated carbon. This configuration resulted in an energy density of 67.7 Wh kg-1 at a power density of 800 W kg-1. Remarkably, the asymmetric supercapacitor retained 82.8% of its initial capacitance following 3000 charge-discharge cycles at a current density of 10 A g-1. Thus, this study demonstrates the efficacy of acetate-ion intercalation in enhancing the electrochemical performance of NiCo-LDH, establishing it as a viable electrode material for supercapacitors.

Prospects of yam (Dioscorea) polysaccharides: Structural features, bioactivities and applications.

Yam (Dioscorea) is a tuber crop cultivated for food security, revenue, and medicinal purposes. It has been used to treat diabetes, asthma, diarrhea, and other diseases. The main active ingredients in yam, polysaccharides, are regarded to be the important reason for its widespread applications. Now, a comprehensive review of research developments of yam polysaccharides (YPs) was presented to explore their prospects. We outlined the structural characteristics, biological activities, structure-activity relationships, and potential applications. Around 13 neutral components and 17 acidic components were separated. They exhibited various bioactivities, including immunomodulatory, hypoglycemic, hypolipidemic, antioxidant, gastrointestinal protective, anti-fatigue, and senile disease treatment activities, as well as prebiotic effect. Structure-activity relationships illustrated that unique structural properties, chemical modifications, and carried biopolymers could influence the bioactivities of YPs. The potential applications in medicine, food, and other fields have also been summarized.

A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy.

Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.

Niraparib enhances antitumor immunity and contributes to the efficacy of PD-L1 blockade in cervical cancer.

PURPOSE: With the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can't receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear. METHODS: The alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT-PCR. RESULTS: We found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8+ T cells and the level of IFN-γ, granzyme B in vivo. CONCLUSION: Our findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.

Effects of different sowing dates on biomass allocation of various organs and allometric growth of Fagopyrum esculentum.

Introduction: The sowing date plays a crucial role in influencing the growth and reproduction of plants, with its specific impact on biomass allocation and allometric growth remaining unclear. Understanding these effects is essential for optimizing agricultural practices and enhancing crop productivity. Methods: To investigate the effects of sowing dates on biomass allocation and allometric growth, a field experiment was conducted with sequential sowings of Fagopyrum esculentum from April 12th to August 11th in 2018. Biomass measurements were taken across various plant organs, and corresponding allocation calculations were made. A detailed analysis of the allometric growth relationship involving organ biomass variations was performed. Results: The study revealed that the accumulation and allocation of organ biomass in buckwheat were significantly impacted by the sowing dates. Delayed planting led to reduced vegetative growth and increased biomass allocation towards reproduction. Allometric parameters such as exponent, constant, and individual size of buckwheat were notably affected by delayed planting. Interestingly, the allometric exponents governing the relationships between reproductive vs. vegetative biomass and belowground vs. aboveground biomass exhibited varying trends across different sowing dates. Discussion: Notably, late sowings resulted in significantly higher reproductive biomass compared to early and middle sowings. These findings highlight the nuanced relationship between plant size and reproductive biomass under different sowing dates, emphasizing the critical role of planting timing in shaping mature plant sizes and reproductive outcomes. The study underscores the importance of considering sowing dates in agricultural practices to optimize plant growth and productivity.