Search

Bisphenol A (BPA) as an endocrine disrupting chemical has been shown to alter reproductive endocrine function, but little is known on its analogues such as bisphenol F (BPF) and bisphenol S (BPS) with increasing usage and exposure.To explore the associations between exposures to BPA, BPF and BPS and serum reproductive hormones among reproductive-aged Chinese men.We measured BPA, BPF and BPS concentrations in repeated urine samples and multiple reproductive hormones in the serum samples collected from 462 men attending an infertility clinic in Wuhan, China. Linear regression models were applied to assess the associations between averaged urinary BPA, BPF and BPS levels and serum hormone concentrations, and restricted cubic spline (RCS) models were further utilized to explore potential non-linear associations. We also examined potential modifying effects by age and body mass index (BMI).There was little evidence of associations between BPA exposure and altered reproductive hormones. However, we found that elevated BPF and BPS exposures were in negative associations with estrogen (E2) levels and E2/T (total testosterone) ratio (all P for trends 0.05), and that elevated BPS exposure was negatively associated with SHBG levels (P for trend = 0.09). Based on the RCS models, these linear negative associations except that between BPS exposure and E2/T ratio were further confirmed. In stratified analyses, BPF and BPS exposures in relation to reduced E2 and E2/T ratio were more pronounced among men aged 30 years, whereas their associations with reduced SHBG levels were more pronounced among men aged ≤ 30. Also, BPS exposure in negative association with FSH only emerged among men with BMI ≥ 24 kg/mBPF and BPS exposures were negatively associated with male serum E2, E2/T ratio and SHBG levels, and these associations varied by age and BMI.

We investigate the magnetic ground state of Sm$_3$BWO$_9$ with the distorted kagome lattice. A magnetic phase transition is identified at $T_N=0.75$ K from the temperature dependence of specific heat. From $^{11}$B nuclear magnetic resonance (NMR) measurements, an incommensurate magnetic order is shown by the double-horn type spectra under a $c$-axis magnetic field. While, absence of line splitting is observed for field oriented within the $ab$-plane, indicating the incommensurate modulation of the internal field strictly along $c$-axis. From the spin dynamics, the critical slowing down behavior is observed in the temperature dependence of $1/T_1$ with $\mu_0H\perp c$-axis, which is completely absent in that with $\mu_0H||c$-axis. Based on the local symmetry of $^{11}$B sites, we analyze the hyperfine coupling tensors and propose two constraints on the possible magnetic structure. The single ion anisotropy should play an important role in the determination of the contrasting ground states of Sm$_3$BWO$_9$ and Pr$_3$BWO$_9$., Comment: 7 pages, 5 figures

Crystalline porous materials (CPMs) not only present the precise integration of molecular building blocks into extensible structures with periodic frameworks and regular pores, but also provide limited molecular spaces for the interactions of guest molecules, electrons and photons. Incorporating aggregation-induced emission (AIE)-based units into crystalline porous frameworks can result in unique luminescent properties. AIE-based CPMs have widely tunable composition, high luminescent efficiency and good photo-stability, which make them useful for biomedical applications involving bio-sensing, bio-imaging and imaging-guided therapies. This review focused on structure design and luminescent property modulation of AIE-based CPMs with highlights on their applications in biomedical fields. The prospect and challenges in the development of AIE-based CPMs from chemistry, materials to biomedical applications were also discussed.

Introduction: Intraocular foreign bodies (IOFBs) are a serious subset of open-globe injury that can result in visual loss. This study analyzed the epidemiology, clinical characteristics, and visual outcomes of patients with IOFBs in Southwest China. Methods: This retrospective study comprised 1,176 patients with the primary diagnosis of IOFBs who resided in Sichuan Province over a 10-year period. All data were collected from medical records and analyzed statistically. Results: The annual incidence for IOFBs was 0.14 per 100,000 (95% confidence interval 0.12–0.16 per 100,000) people in Southwest China. In that period, IOFBs accounted for 22.3% of all open-globe injuries. Working-age male patients accounted for 79.1% of all IOFBs patients and there had significant differences in age distributions between genders (p < 0.001). Metallic IOFBs were the most common (74.6%) IOFB, but there were significant differences in the materials of IOFBs between adults and children of different age-groups (p < 0.001). At discharge, 277 (23.6%) patients had increased visual acuity (VA) and 95 (8.0%) had no light perception. Initial VA p < 0.001), increasing wound size (OR, 1.3; p = 0.004), IOFBs in the posterior segment (OR, 2.6; p = 0.002) and existing complications (traumatic cataract, endophthalmitis, retinal detachment, or retinal break) were independent risk factors for final VA Conclusion: The incidence of IOFBs in Southwest China differed from global statistics. Adults and children had different clinical characteristics. Thus, their prevention strategies should be different.

Covalent organic frameworks (COFs) are an emerging kind of crystalline porous polymers which present the precise integration of organic building blocks into extensible structures with regular pores and periodic skeletons. The diversity of organic units and covalent linkages makes COFs a rising materials platform for the design of structure and functionality. In this review, we summarize the recent research progress in developing COFs for photoluminescent materials. We highlight structural and functional design strategies, and identify fundamental problems that need to be solved in conjunction with potential applications from perspectives of photoluminescent materials.

China’s rapid economic development has initiated the deterioration of its ecological environment, posing a threat to the sustainable development of human society. As a result, an assessment of regional sustainability is critical. This paper researches China’s most forested province, Fujian Province, as the study area. We proposed a grid-based approach to assess the regional carbon footprint in accordance with the Intergovernmental Panel on Climate Change’s (IPCC) carbon emission guidelines. Our method of assessment also introduced carbon emission indicators with our improved and published Net Primary Production (NPP) based on process simulation. The carbon footprint in Fujian Province from 2005–2017 was calculated and examined from a spatiotemporal perspective. Ecological indicators were used in the sustainability assessment. The research draws the following conclusions: 1) the carbon footprint in the eastern regions of Fujian Province was higher due to rapid economic development; 2) that of the western regions was lower; 3) an uptrend in the carbon footprint of Fujian Province was observed. All five ecological indicators based on carbon emissions and economic and social data showed an ecologically unsustainable trend over 13 years in the research area due to unsustainable economic development. Therefore, it is urgent to balance the relationship between economic development and environmental protection. Our research provides scientific references for achieving ecological civilization and sustainability in a similar region.

OBJECTIVES This study aimed to investigate the relationships among islet function, the Nrf2 pathway, and insulin receptor substrate 2 (IRS2) in type 2 diabetes mellitus (T2DM), prediabetes mellitus (IGR), and normal glucose tolerance (NGT) populations. METHODS Three hundred cases each were selected for the NGT, IGR, and T2DM groups; FBG, 2hPG, HbA1 c, FINS, TG, TC, HDL-C, and LDL-C levels and serum levels of nuclear factor in E2-related factor 2 (Nrf2), insulin receptor substrate 2 (IRS2), tumor necrosis factor alpha (TNF-α), and heme oxygenase 1 (HO-1) were evaluated. RESULTS The T2DM group had lower islet β-cell function index and insulin sensitivity index than the NGT and IGR groups (P

Hypertriglyceridemia (HTG) can aggravate acute pancreatitis (AP), but its pathogenesis remains unclear. As autophagic activity is closely related to lipid metabolism and AP, we investigated the autophagic response in models of AP aggravated by HTG and explored whether rapamycin has a protective effect against HTG-related pancreatitis. HTG-associated AP models were established in vivo in rats and in vitro. The degree of inflammation, pancreatic injury, the expression of endoplasmic reticulum (ER) stress, and autophagy markers (P62, LC3) were compared. Autophagic flux were assessed using immunostaining, electron microscopy, and immunoblotting. Compared with the normal diet group, the high-fat diet (HFD) AP group exhibited more severe pancreatic injury, apoptosis, and blocked autophagic flux. In addition, the three branches (PERK-eIF2α, ATF-6-GRP78, and IRE1-sXBP1) of the unfolded protein response and mTORC1/S6K1 pathway were activated in HFD AP models. Moreover, the same phenomena were confirmed in vitro in palmitic acid-stimulated pancreatic acinar cells. Preincubation with the mTOR inhibitor rapamycin restored the autophagic flux and markedly reduced the adverse effects of HTG. In conclusion, the autophagic flux is impaired in HFD-induced AP models and is strongly associated with ER stress. Rapamycin could prevent the aggravation of HTG-associated AP via inhibiting mTORC1/S6K1 pathway.

Based on Gray mapping, the properties of the autocorrelation sum of quadriphase Z-complementary pairs (QZCPs) are investigated. It is proved that both the real and imaginary parts of the sum equal zero modulo 2. Additionally, a novel construction that transforms binary ZCPs (BZCPs) into QZCPs is presented. The proposed construction can produce QZCPs, which are different to the ones from existing constructions, with the same zero-correlation-zone (ZCZ) width-length ratios (ZWLRs) as the employed BZCPs.

Remote sensing can be used to monitor cropland phenological characteristics; however, tradeoffs between the spatial and temporal resolutions of cloudless satellite images limit the accuracy of their retrieval. In this study, an improved enhanced spatial and temporal adaptive reflectance fusion model (ESTARFM) was applied to human-dominated Xiong'an New Area to develop a self-adapting algorithm automating the extraction of main phenological transition points (greenup, maturity, senescence, and dormancy). The analyses of cropland phenological characteristics were performed utilizing the Softmax classification method. By examining three different phases of fusion images, it was found that the improved ESTARFM was more accurate than the original ESTARFM (correlation coefficient 0.76; relative root mean square error 0.25; structural similarity index 0.79). The reconstructed normalized difference vegetation indexes were consistent with that acquired by the Moderate Resolution Imaging Spectroradiometer (average discrepancy: 0.1136, median absolute deviation: 0.0110). The greenup, maturity, senescence, and dormancy points were monitored in 5-day resolution and 50-day length on a 30-m grid scale, and their average day of year (DOY) were 67, 119, 127, and 166 for wheat; 173, 224, 232, and 283 for single-season corn; and 189, 227, 232, and 285 for rotation corn, respectively. The corresponding median absolute deviations were 2, 3, 2, and 2 days for wheat; 2, 5, 3, and 4 days for single-season corn; and 2, 5, 2, and 2 days for rotation corn, respectively, while all coefficients of variation did not exceed 6%. The proposed self-adapting approach can be used for identifying the planting modes at grid level in rotation agroecosystems and cropland phenological dynamics on a global or regional scale.

Remote sensing spatiotemporal fusion models blend multi-source images of different spatial resolutions to create synthetic images with high resolution and frequency, contributing to time series research where high quality observations are not available with sufficient frequency. However, existing models are vulnerable to spatial heterogeneity and land cover changes, which are frequent in human-dominated regions. To obtain quality time series of satellite images in a human-dominated region, this study developed the Modified Flexible Spatial-temporal Data Fusion (MFSDAF) approach based on the Flexible Spatial-temporal Data Fusion (FSDAF) model by using the enhanced linear regression (ELR). Multiple experiments of various land cover change scenarios were conducted based on both actual and simulated satellite images, respectively. The proposed MFSDAF model was validated by using the correlation coefficient (r), relative root mean square error (RRMSE), and structural similarity (SSIM), and was then compared with the Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model (ESTARFM) and FSDAF models. Results show that in the presence of significant land cover change, MFSDAF showed a maximum increase in r, RRMSE, and SSIM of 0.0313, 0.0109 and 0.049, respectively, compared to FSDAF, while ESTARFM performed best with less temporal difference of in the input images. In conditions of stable landscape changes, the three performance statistics indicated a small advantage of MFSDAF over FSDAF, but were 0.0286, 0.0102, 0.0317 higher than for ESTARFM, respectively. MFSDAF showed greater accuracy of capturing subtle changes and created high-precision images from both actual and simulated satellite images.

This paper investigates the construction of QAM Golay complementary sequence pairs (CSPs) based on standard binary Golay–Davis–Jedwab (GDJ) CSPs. In order to guarantee that the proposed construction produces QAM Golay CSPs, a sufficient condition that the coefficients of offsets should satisfy is developed, which is fit for finding all the coefficients by a computer. In particular, all the coefficients of offsets over the 64- and 256-QAM constellations are given. The proposed construction includes Zeng’s and Ma et al. ’s ones as special cases. The inputs of resultant sequence pairs are binary signals rather than quaternary ones, which means that the resulting sequences are fit for such QAM systems that merely depend on binary inputs. The obtained QAM Golay CSPs can be applied to orthogonal frequency division multiplexing systems so as to reduce peak envelope power of their signals.

Extracellular vesicles (EVs) are a promising new therapeutic platform. However, the low cargo-loading efficiency limits their clinical translation. In this study, we developed a high-yield EV cargo-loading device and explored its ability to encapsulate gene editing proteins. A series of fusion protein-based systems were constructed and their cargo loading efficiencies were compared by a NanoGlo luciferase assay. A myristoylated (Myr) peptide tag cloned from the N-terminal region of charged multivesicular body protein 6 (CHMP6), termed Myr(CHMP6), outcompeted CD9, ARRDC1, and other short polypeptides as an active packaging device. As determined by nanoparticle tracking analysis and transmission electron microscopy, the overexpression of Myr(CHMP6) increased small EV (sEV) production in Lenti-X 293T cells without altering sEV morphology. The high passive packaging efficiency of Myr(CHMP6) was also elucidated for unmodified cargo loading. Western blotting revealed that Myr(CHMP6) facilitated the loading of Cre and Cas9 into sEVs without the generation of packaging device-cargo fusion proteins. Furthermore, Myr(CHMP6)-modified sEVs loaded with Cre or Cas9 promoted gene-editing in recipient cells, as observed using a fluorescence reporter system. Subsequent investigation demonstrated a dose-dependent effect of Myr(CHMP6) tag-induced cargo-loading. Mechanistically, N-myristoylation alone was necessary but not sufficient for the effective packaging of proteins into EVs. Thus, our results indicated that Myr(CHMP6) induces sEV production and may be effective in loading gene editing proteins into sEVs for therapeutic purposes.

Yingying Sun,1 Jie Jin,2 Aying Zhu,1 Hong Hu,1 Yingying Lu,1 Yue Zeng,1 Dadao Jing1 1Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, People’s Republic of China; 2Department of Geriatrics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of ChinaCorrespondence: Dadao JingDepartment of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, NO. 650 Xinsongjiang Road, Shanghai, 201600, People’s Republic of China, Tel +86-13816958050, Email dadaojing@126.comBackground: In recent years, the cure rate of acute pancreatitis (AP) has increased gradually, but the morbidity of recurrent acute pancreatitis (RAP) has not decreased. Patients with RAP have a poor quality of life and are more likely to develop into chronic pancreatitis. To investigate the risk factors of RAP after first pancreatitis attack is very necessary.Methods: Patients with first episode AP admitted to Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2018 to May 2021 were included in this retrospective study, and follow-up was 3– 45 months after discharge. The patients information were collected from medical records including laboratory tests and auxiliary inspection of their hospitalization. Univariate and multivariate Cox regression analysis were used to explore the risk factors of RAP. Cumulative risk of RAP was plotted using Kaplan–Meier curves.Results: A total of 592 patients were enrolled in the study and 81 (13.7%) of the patients developed RAP. Among those RAP patients, the majority (67.9%) were men, with a median age of 43 years. The most common etiology of RAP was hypertriglyceridemia (38.3%). Multivariate Cox analysis showed that smoking history (p < 0.001), infected pancreatic necrosis occurred during first admission (p = 0.005), and high low-density lipoprotein cholesterol (LDLc) level (p < 0.001) were significant independent risk factors for RAP. Patients with the above independent risk factors had increased 3-year cumulative risk of recurrence (32.2%, 45.5%, 28.9%, respectively).Conclusion: Smoking history, infected pancreatic necrosis, and high LDLc level were the most decisive risk factors for RAP. Attention should be paid to the patients with the above factors.Keywords: first episode pancreatitis, recurrent acute pancreatitis, risk factors, low-density lipoprotein cholesterol, infected pancreatic necrosis

Studies have documented the impact of childhood socioeconomic status (SES) on cognition. However, research that simultaneously considers SES in varied life stages, the multidimensional mechanisms, and racial differences is relatively understudied. This study examines the intersectionality across age, SES, and race and its impact on cognitive trajectories.Using 8376 respondents aged 65+ from the 1998-2016 Health and Retirement Study, we used latent growth curve modeling to examine the effects of four life course models (latency, pathway, accumulation, and mobility) on 18-year trajectories of mental status and episodic memory. We further tested for differences in the links between SES and cognitive trajectories between black and white respondents.Cognitive function declines with age and is interrelated with SES and race. Adulthood has a stronger effect on cognitive performance than childhood. However, linked positive childhood and adulthood SES contributes to positive cognition. Accumulated SES disadvantages were associated with lower cognition. Older adults with downward mobility and low SES throughout their lifespans had the lowest cognition scores. Life course models operated differently on trajectories of cognitive decline, yet the effects were particularly evident among older black respondents. Overall, those with socioeconomic advantages tended to have a slower decline in cognition, while a faster decline occurred for those with accrued disadvantages.Cognitive performance is a complex, longitudinal process intertwined with socioeconomic conditions and population heterogeneity shaped by life course contexts. Policies that facilitate healthy cognitive performance and address SES inequality could equalize health opportunities and address racial cognitive disparities later in life.

Carbon neutrality is increasingly broadly recognized as a vehicle for climate action and sustainable development. Photosynthesis contributes to maintaining a suitable carbon-oxygen balance for survival and plays an irreplaceable role in mitigating the greenhouse effect. However, the energy conversion efficiency of photosynthesis is only about 1%, far below the theoretical maximum. With the ecological demand of carbon neutrality, it is wise and necessary to further improve the efficiency of photosynthesis. Among methods to do so, the most direct and original one is improving the utilization of photosynthetic pigments to the weak absorption region of the spectrum and thus enhancing the solar energy utilization efficiency.This Account summarizes our group's work on constructing conjugated polymer-photosynthetic organism interfaces to augment photosynthetic efficiency. Side chain modification of ionic groups or preparation of nanoparticles makes conjugated polymers water-soluble and electrically charged, which allows them to bind to the surface of photosynthetic microorganisms through electrostatic interactions or be absorbed by plant roots. Owing to the designable and unparalleled light capture and emission capabilities, funnel-like excitation energy transfer mode, and enviable biocompatibility, organic semiconductor conjugated polymers can be used as "artificial antennas" to make up for the lack of natural antenna pigments and expand the photosynthetically active radiation (PAR) range. With this strategy, we achieved enhancement of the photosynthetic efficiency of a broad range of organisms, including oxygenic photosynthetic organisms, from organelle to prokaryotic cyanobacteria, eukaryotic lower plants, and higher plants, as well as anoxygenic photosynthetic organisms. Unlike conventional semiconductors, conjugated polymers have not only electronic conductivity but also ionic conductivity, which is the main means of bioelectrical signal transduction. Therefore, they are able to act as "electron bridges" to accelerate the electron transfer rate at the material-organism interface. On this basis, we introduced conjugated polymers into artificial photosynthesis systems, including biological photovoltaics and artificial carbon sequestration, to increase energy conversion efficiency. These studies open a new frontier for functional studies of conjugated molecules and provide inspirations for the design of photosynthesis systems in the future.

Photosynthetic biohybrid systems exhibit promising performance in biosynthesis; however, these systems can only produce a single metabolite and cannot further transform carbon sources into highly valuable chemical production. Herein, a photosynthetic biohybrid system integrating biological and chemical cascade synthesis was developed for solar-driven conversion of glucose to value-added chemicals. A new ternary cooperative biohybrid system, namely bacterial factory, was constructed by self-assembling of enzyme-modified light-harvesting donor-acceptor conjugated polymer nanoparticles (D-A CPNs) and genetically engineered Escherichia coli ( E. coli ). The D-A CPNs coating on E. coli could effectively generate electrons under light irradiation, which were transferred into E. coli to promote the 37% increment of threonine production by increasing the ratio of nicotinamide adenine dinucleotide phosphate (NADPH). Subsequently, the metabolized threonine was catalyzed by threonine deaminase covalently linking with D-A CPNs to obtain 2-oxobutyrate, which is an important precursor of drugs and chemicals. The 2-oxobutyrate yield under light irradiation is increased by 58% in comparison to that in dark. This work provides a new organic semiconductor-microorganism photosynthetic biohybrid system for biological and chemical cascade synthesis of highly valuable chemicals by taking advantage of renewable carbon sources and solar energy.

Cucurbitacins have a variety of bioactivities, such as anticancer, anti-inflammatory, antidepressant-like, and antiviral effects, but their pharmacological effect in ulcerative colitis (UC) has not been reported until now. Thus, this study aims to investigate the preventive effects of Xuedan sustained release pellets (XSPs) on UC rats and the underlying mechanisms. XSPs were prepared by extracting cucurbitacins from Hemsleya. Experimental UC rats were induced by the intake of 4% dextran sulfate sodium (DSS) for a week and treated with different doses of XSP (0.95, 1.90, and 3.8 mg/kg). The body weight, colon length, disease activity index (DAI), and histological changes of colonic tissue were measured. In addition, the expressions of pro-inflammatory cytokines were detected by using the enzyme-linked immunosorbent assay. Pathways involved in the intestinal inflammation were targeted by RNA-sequencing. Moreover, the changes of gut microbial diversity and composition were analyzed by the 16SrNA analysis and the contents of short-chain fatty acids (SCFAs) were detected by GC-MS. The results revealed that XSP intervention greatly restored the weight loss and colonic shortening (p < 0.05) and reduced the raised DAI scores, myeloperoxidase, and nitric oxide activities in UC in rats (p < 0.05). XSP administration also downregulated the protein levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α. Notably, it was found that XSP considerably suppressed the activation of the MAPK signaling pathway. In addition, XSP treatment improved the balance of gut microbiota that was disturbed by DSS. The beneficial bacteria Lachnospiraceae_NK4A136 group and Lactobacillus at the genus level significantly increased in the XSP group, which had decreased with the use of DSS (p < 0.05). Pathogenic bacteria including Escherichia–Shigella and Bacteroides in UC in rats were reduced by XSP intervention. Furthermore, XSP significantly elevated the production of SCFAs in UC in rats (p < 0.05). These alterations in inflammatory status were accompanied with changes in gut microbiota diversity and SCFA production. In conclusion, XSP exhibited protective effects against DSS-induced UC in rats. XSP treatment decreased inflammation via modulation of gut microbiota composition and SCFA production.

Immunotherapy has become the standard of care for non-small cell lung cancer (NSCLC), either in combination or monotherapy. However, there are still some patients who cannot benefit from it. Immunization strategies for NSCLC are based on the expression of PD-L1 on tumor cells and TMB, and although these indicators have a certain predictive effect, their predictive performance is not good. Therefore, clinicians must make adjustments to recognize markers. This is a review article that summarized immunotherapeutic biomarkers according to the “seed-soil-environment”, generalizes primary resistance to immunotherapy, and summarizes the integration of markers.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Background Immunotherapy has unequal efficacies in different populations. This study aims to explore inter-subgroup differences in responses to immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and find the optimal treatments for each subgroup. Methods We performed (network) meta-analyses of phase III random controlled trials, in which efficacies of 10 immunotherapy-based treatments were compared with each other and chemotherapy, including anti-programmed death receptor-1 (PD-1) (+chemotherapy), anti-programmed death ligand-1 (PD-L1) (+chemotherapy), anti-PD-L1+anti-cytotoxic T-lymphocyte protein 4 (CTLA-4), anti-PD-1+anti-CTLA-4 (+chemotherapy), anti-CTLA-4+chemotherapy, anti-PD-1+anti-angiogenic therapy (AT)+chemotherapy, and anti-PD-L1+AT+chemotherapy, for 19 subgroups by sex, age, smoking status, metastatic site, histological type, and PD-L1 expression, using subgroup-level hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and their 95% confidence intervals (CIs). Results 22 studies comprised of 12678 patients were included in our analyses. The results showed survival advantages of immunotherapy-based treatments in 16 out of 19 subgroups comparing with chemotherapy. In patients with PD-L1 tumor proportion score (TPS)

Disinfection byproducts (DBPs) have been shown to alter ovarian steroidogenesis and cause estrous cyclicity disturbance and prolongation in experimental studies, however human studies are lacking. We aimed to evaluate the cross-sectional associations between drinking water DBPs and menstrual cycle characteristics. A total of 1078 women attending an infertility clinic in Wuhan, China were included between December 2018 and January 2020. Characteristics of menstrual cycle were collected by questionnaires. Concentrations of dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) were measured in urine as biomarkers of drinking water DBPs. Multivariate logistic and linear regression models were used to evaluate the associations between urinary DCAA and TCAA concentrations and menstrual cycle characteristics. Higher urinary DCAA concentrations were associated with increased odds ratios (ORs) of irregular menstrual cycle (OR = 1.80; 95% CI: 0.97, 3.33 for the highest vs. lowest quartile; P for trend = 0.05) and long menstrual cycle (OR = 1.62; 95% CI: 0.97, 2.70 for the highest vs. lowest quartile; P for trend = 0.06), as well as prolonged variation in cycle length (β = 1.27 days; 95% CI: -0.11, 2.66 for the highest vs. lowest quartile; P for trend = 0.04). Higher urinary TCAA concentrations were associated with prolonged bleeding duration (β = 0.23 days; 95% CI: -0.06, 0.51 for the highest vs. lowest quartile; P for trend = 0.07). These results suggest that exposure to drinking water DBPs is associated with menstrual cycle disturbances. These findings are warranted to confirm in other studies.

Stool is the most commonly used sample for gut microbiota analysis in humans and animals. Cryopreservation of stool at - 80 °C is a feasible and simple method in clinics and researches, especially in large-scale cohort studies. However, the viability of bacteria in stool after freezing has yet well-demonstrated quantitatively and compositionally. This study determined the viable microbiota of samples under cryopreservation at - 80 °C, relative to fresh samples and that stored at ambient. Stool samples were collected from three healthy adults. Propidium monoazide treatment combined with quantitative PCR and 16S rRNA gene sequencing was performed to target viable microbiota. After freezing, the number of viable bacteria decreased, though inter-individual difference existed. Notably, the alpha diversity of viable microbiota after freezing did not change significantly, while its composition changed. Freezing significantly reduced the viable bacteria in Gram-negative genera of Bacteroidetes and Firmicutes, and proportionally increased Gram-positive bacteria in genera of Actinobacteria and Firmicutes, including Bifidobacterium, Collinsella and Blautia, implying that the cell envelope structure associated with the bacterial sensitivity to freezing. On the contrary, the room temperature storage not only decreased the number of viable bacteria, but also decreased the microbial alpha diversity, and remarkably enriched facultative anaerobes of Escherichia-Shigella, Enterococcus and Lactococcus, some of which are opportunistic pathogens. Our findings suggested that changes in viable microbiota in stool samples caused by cryopreservation should be paid enough attention for downstream utilization.

The lung is the prophylaxis target against SARS-CoV-2 infection, and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen. In this study, we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle (VRP) delivery system, to prevent SARS-CoV-2 infections. First, a modified VEEV replicon with two subgenomic (sg) promoters was engineered to translate the light and heavy chains of antibody simultaneously, for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6. Second, the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays. The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice. Overall, our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.

Purpose of review This review aims to introduce the resistance mechanisms to osimertinib, discuss the therapeutic strategies, and make clinical updates in overcoming resistance to osimertinib. Recent findings Osimertinib has shown favorable efficacy on second-line and first-line treatments in EGFR-mutant advanced nonsmall cell lung cancer (NSCLC). However, the presence of primary and acquired resistance to osimertinib restricts its clinical benefits. The primary resistance mainly consists of BIM deletion polymorphism and EGFR exon 20 insertions. Meanwhile, the heterogeneous mechanisms of acquired resistance include EGFR-dependent (on-target) and EGFR-independent (off-target) mechanisms. EGFR C797S mutation, MET amplification, HER2 amplification, and small cell lung cancer transformation were identified as frequent resistance mechanisms. Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. With the results of completed and on-going clinical trials, the emerging therapeutic strategies of postosimertinib progression are summarized. Summary The resistance mechanisms to osimertinib are heterogeneous and gradually perfected. The combination of osimertinib with bypass targeted therapy and other therapeutic approaches emerge as promising strategies.

Background Duck plague virus (DPV), belonging to herpesviruses, is a linear double-stranded DNA virus. There are many reports about the outbreak of the duck plague in a variety of countries, which caused huge economic losses. Recently, increasing reports revealed that multiple long non-coding RNAs (lncRNAs) can possess great potential in the regulation of host antiviral immune response. Furthermore, it remains to be determined which specific molecular mechanisms are responsible for the DPV-host interaction in host immunity. Here, lncRNAs and mRNAs in DPV infected duck embryonic fibroblast (DEF) cells were identified by high-throughput RNA-sequencing (RNA-seq). And we predicted target genes of differentially expressed genes (DEGs) and formed a complex regulatory network depending on in-silico analysis and prediction. Result RNA-seq analysis results showed that 2921 lncRNAs were found at 30 h post-infection (hpi). In our study, 218 DE lncRNAs and 2840 DE mRNAs were obtained in DEF after DPV infection. Among these DEGs and target genes, some have been authenticated as immune-related molecules, such as a Macrophage mannose receptor (MR), Anas platyrhynchos toll-like receptor 2 (TLR2), leukocyte differentiation antigen, interleukin family, and their related regulatory factors. Furthermore, according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis, we found that the target genes may have important effects on biological development, biosynthesis, signal transduction, cell biological regulation, and cell process. Also, we obtained, the potential targeting relationship existing in DEF cells between host lncRNAs and DPV-encoded miRNAs by software. Conclusions This study revealed not only expression changes, but also the possible biological regulatory relationship of lncRNAs and mRNAs in DPV infected DEF cells. Together, these data and analyses provide additional insight into the role of lncRNAs and mRNAs in the host's immune response to DPV infection.

Glycosite-specific antibody‒drug conjugatess (gsADCs), harnessing Asn297

Disinfection by-products (DBPs) have been shown to impair female reproductive function. However, epidemiological evidence on reproductive hormones is scarce.To investigate the associations between DBP exposures and reproductive hormones among women undergoing assisted reproductive technology.We included 725 women from the Tongji Reproductive and Environmental (TREE) Study, an ongoing cohort conducted in Wuhan, China during December 2018 and January 2020. Urine samples collected at recruitment were quantified for dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) as biomarkers of DBP exposures. At day 2-5 of menstruation, serum reproductive hormones including luteinizing hormone (LH), estradiol (EAfter adjusting for relevant confounders, we observed that higher urinary DCAA levels were associated with increased serum PRGE (9.2%; 95% CI: -0.55%, 19.8% for the highest vs. lowest tertile; P for trend = 0.06). Based on NCS models, we observed U-shaped associations of urinary DCAA with serum PRGE and PRL; each ln-unit increment in urinary DCAA concentrations above 3.61 μg/L and 6.30 μg/L was associated with 18.9% (95% CI: 4.8%, 34.7%) and 23.3% (95% CI: -0.92%, 53.5%) increase in serum PRGE and PRL, respectively. The U-shaped associations were further confirmed in RCS models (P for overall association ≤0.01 and P for non-linear associations ≤0.04). We did not observe evidence of associations between urinary TCAA and reproductive hormones.Urinary DCAA but not TCAA was associated with altered serum PRGE and PRL levels among women undergoing assisted reproductive technology.

Gut microbiome is considered as a crucial regulator of human health. Alteration of gut microbiome has been reported in acute pancreatitis (AP) and probably contributes to the severity of disease. Explore the precise role of gut microbiome in the pathogenesis of AP could offer new strategies to improve the clinical outcomes of AP. This review summarizes the role of gut microbiome in AP, lists possible mechanisms associated with it and offers an overview of current treatments based on gut microbiome.

Transducin-like enhancer of Split3 (TLE3) serves as a transcriptional corepressor during cell differentiation and shows multiple roles in different kinds of cancers. Recently, TLE3 together with many other genes involved in Wnt/β-catenin pathway were detected hyper-methylated in colorectal cancer (CRC). However, the potential role and the underlying mechanism of TLE3 in CRC progression remain scarce. Gene expression profiles were analyzed in The Cancer Genome Atlas (TCGA) microarray dataset of 41 normal colorectal intestine tissues and 465 CRC tissues. Western blot and Real-time Quantitative PCR (RT-qPCR) were respectively performed to detect protein and mRNA expression in 8 pairs of CRC tissue and matched adjacent normal mucosa. Immunohistochemistry (IHC) was conducted to evaluate TLE3 protein expression in 105 paraffin-embedded, archived human CRC tissues from patients, whose survival data were analyzed with Kaplan-Meier method. In vitro experiments including MTT assay, colony formation assay, and soft agar formation assay were used to investigate the effects of TLE3 on CRC cell growth and proliferation. Additionally, subcutaneous tumorigenesis assay was performed in nude mice to confirm the effects of TLE3 in vivo. Furthermore, gene set enrichment analysis (GSEA) was run to explore potential mechanism of TLE3 in CRC, and then we measured the distribution of CRC cell cycle phases and apoptosis by flow cytometry, as well as the impacts of TLE3 on MAPK and AKT signaling pathways by Western blot and RT-qPCR. TLE3 was significantly down-regulated in 465 CRC tissues compared with 41 normal tissues. Both protein and mRNA expressions of TLE3 were down-regulated in CRC compared with matched adjacent normal mucosa. Lower expression of TLE3 was significantly associated with poorer survival of patients with CRC. Besides, knock down of TLE3 promoted CRC cell growth and proliferation, while overexpression of TLE3 showed suppressive effects. Furthermore, overexpression of TLE3 caused G1-S phase transition arrest, inhibition of MAPK and AKT pathways, and up-regulation of p21Cip1/WAF1 and p27Kip1. This study indicated that TLE3 repressed CRC proliferation partly through inhibition of MAPK and AKT signaling pathways, suggesting the possibility of TLE3 as a biomarker for CRC prognosis.

The associations of organochlorine pesticides (OCPs) with semen quality from human studies are conflicting, and also it is largely unknown whether the associations are modified by genetic polymorphisms. We aimed to evaluate the associations between serum concentrations of 18 OCPs and semen quality among 387 Chinese men, and further to examine the modifying effects by genetic polymorphisms in cytochrome P450 (CYP2E1) and glutathione S-transferase (GSTT1). Multivariable linear regressions were used to evaluate the relationships between serum OCP concentrations and semen quality, and the role of CYP2E1 and GSTT1 polymorphisms in modifying the associations were assessed. Multiple testing was adjusted using the false discovery rate (FDR). We observed that men with detectable concentrations of serum ɤ-HCH had a decrease in sperm motility of 7.07% (95% CI: -10.9%, -3.24%) compared to those with undetectable concentrations (FDR-P value = 0.02). Men with TT of CYP2E1 rs 915906 genotypes had higher median concentrations of serum dieldrin compared with those with CT/CC of CYP2E1 rs 915906 genotypes. There were interactions between CYP2E1 and GSTT1 polymorphisms and certain OCPs namely ɤ-HCH, δ-HCH, dieldrin, endosulfan I, and endrin aldehyde on semen quality. For example, elevated dieldrin levels in relation to decreased sperm concentration, sperm count, and sperm motility were only observed among men with CC of CYP2E1 rs2031920 genotypes (all P

DNA methylation, an epigenetic modification, regulates gene transcription and maintains genome stability. DNA methyltransferase (DNMT) inhibitors can activate silenced genes at low doses and cause cytotoxicity at high doses. The ability of DNMT inhibitors to reverse epimutations is the basis of their use in novel strategies for cancer therapy. In this review, we examined the literature on DNA methyltransferase inhibitors. We summarized the mechanisms underlying combination therapy using DNMT inhibitors and clinical trials based on combining hypomethylation agents with other chemotherapeutic drugs. We also discussed the efficacy of such compounds as antitumor agents, the need to optimize treatment schedules and the regimens for maximal biologic effectiveness. Notably, the combination of DNMT inhibitors and chemotherapy and/or immune checkpoint inhibitors may provide helpful insights into the development of efficient therapeutic approaches.