Latent profile analysis of benefit finding among family caregivers of Chinese older adults with disabilities and its influencing factors.

OBJECTIVES: The increase in the number of older adults with disability creates new challenges for caregivers. Benefit finding is the positive experience that caregivers get from caregiving, helping to reduce the negative impact on the caregiver's quality of life. However, there is less research on the positive experiences of family caregivers of older adults with disabilities. This study aimed to identify different benefit finding profiles among family caregivers of older adults with disabilities in China and to explore the sociodemographic characteristics and psychosocial factors with different benefit finding profiles. METHODS: A cross-sectional study of 218 family caregivers of Chinese older adults with disabilities using the sociodemographic questionnaire, the Family-APGAR, the Sense of Coherence-13, the Emotion Regulation Scale and Benefit Finding Scale from October 2022 to June 2023 in communities and hospitals of China, Shenyang, Liaoning Province. Latent profile analysis was used to analyze the latent profiles of benefit finding among family caregivers of Chinese older adults with disability. Multiple logistic regression was used to explore the predictors of different profiles. RESULTS: The benefit finding among family caregivers of Chinese older adults with disability can be classified into three potential profiles: Profile 1 - high-level benefit finding group (12.84%), Profile 2 - medium-level benefit finding group (43.58%), Profile 3 - low-level benefit finding group (43.58%). Working status, family function, and cognitive reappraisal of caregiver were predictors of different profiles. CONCLUSIONS: Nurses and community health care staffs should pay attention to the characteristics, family function, and emotion regulation strategies of family caregivers of older adults with different disability. Help family caregivers enhance family cohesion and cognitive reappraisal to improve positive experiences for caregivers in different profiles.

Anti-hepatoma immunotherapy of Pholiota adiposa polysaccharide-coated selenium nanoparticles by reversing M2-like tumor-associated macrophage polarization.

Targeting macrophages to regulate the tumor microenvironment is a promising strategy for treating cancer. This study developed a stable nano drug (PAP-SeNPs) using Se nanoparticles (SeNPs) and the Pholiota adiposa polysaccharide component (PAP-1a) and reported their physical stability, M2-like macrophages targeting efficacy and anti-hepatoma immunotherapy potential, as well as their molecular mechanisms. Furthermore, the zero-valent and well-dispersed spherical PAP-SeNPs were also successfully synthesized with an average size of 55.84 nm and a negative ζ-potential of -51.45 mV. Moreover, it was observed that the prepared PAP-SeNPs were stable for 28 days at 4 °C. Intravital imaging highlighted that PAP-SeNPs had the dual effect of targeting desirable immune organs and tumors. In vitro analyses showed that the PAP-SeNPs polarized M2-like macrophages towards the M1 phenotype to induce hepatoma cell death, triggered by the time-dependent lysosomal endocytosis in macrophages. Mechanistically, PAP-SeNPs significantly activated the Tlr4/Myd88/NF-κB axis to transform tumor-promoting macrophages into tumor-inhibiting macrophages and successfully initiated antitumor immunotherapy. Furthermore, PAP-SeNPs also enhanced CD3+CD4+ T cells and CD3+CD8+ T cells, thereby further stimulating anti-hepatoma immune responses. These results suggest that the developed PAP-SeNPs is a promising immunostimulant that can assist hepatoma therapy.

An Insulin-Modified pH-Responsive Nanopipette Based on Ion Current Rectification.

The properties of nanopipettes largely rely on the materials introduced onto their inner walls, which allow for a vast extension of their sensing capabilities. The challenge of simultaneously enhancing the sensitivity and selectivity of nanopipettes for pH sensing remains, hindering their practical applications. Herein, we report insulin-modified nanopipettes with excellent pH response performances, which were prepared by introducing insulin onto their inner walls via a two-step reaction involving silanization and amidation. The pH response intensity based on ion current rectification was significantly enhanced by approximately 4.29 times when utilizing insulin-modified nanopipettes compared with bare ones, demonstrating a linear response within the pH range of 2.50 to 7.80. In addition, insulin-modified nanopipettes featured good reversibility and selectivity. The modification processes were monitored using the I-V curves, and the relevant mechanisms were discussed. The effects of solution pH and insulin concentration on the modification results were investigated to achieve optimal insulin introduction. This study showed that the pH response behavior of nanopipettes can be greatly improved by introducing versatile molecules onto the inner walls, thereby contributing to the development and utilization of pH-responsive nanopipettes.

A synergistic mechanism of Liquiritin and Licochalcone B from Glycyrrhiza uralensis against COPD.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a refractory respiratory disease mainly attributed to multiple pathological factors such as oxidative stress, infectious inflammation, and idiopathic fibrosis for decades. The medicinal plant Glycyrrhiza uralensis extract (ULE) was widely used to control respiratory diseases in China. However, the regulatory mechanism of scientific evidence to support the therapeutic benefits of ULE in the management of COPD is greatly limited. PURPOSE: This study aims to discover the potential protection mechanism of ULE on COPD via a muti-targets strategy. STUDY DESIGN AND METHODS: The present study set out to determine the potential protective effects of ULE on COPD through a multi-target strategy. In vivo and in vitro models of COPD were established using cigarette smoke and lipopolysaccharide to assess the protective effects of ULE. It was evaluated by measuring inflammatory cytokines and assessing pulmonary pathological changes. HPLC was used to verify the active compounds of the potential compounds that were collected and screened using HERB, works of literature, and ADME tools. The mechanisms of ULE in the treatment of COPD were explored using transcriptomics, connectivity-map, and network pharmacology approaches. The relevant targets were further investigated using RT-PCR, western blot, and immunohistochemistry. The HCK inhibitor (iHCK-37) was used to evaluate the potential mechanism of ULE's active compounds in the prevention of COPD. RESULTS: ULE effectively protected the lungs of COPD mice from oxidative stress, inflammation, and fibrosis damage. After screening and verification using ADME properties and HPLC, 4 active compounds were identified in ULE: liquiritin (LQ), licochalcone B (LCB), licochalcone A (LCA), and echinatin (ET). Network pharmacology integrated with transcriptomics analysis showed that ULE mitigated oxidative stress, inflammation, and fibrosis in COPD by suppressing HCK. The combination of LCB and LQ was optimized for anti-inflammation, antioxidation, and anti-fibrosis activities. The iHCK-37 further validated the preventive treatment of LCB and LQ on COPD by inhibiting HCK to exert antioxidant, anti-inflammatory, and anti-fibrotic effects. The combination of LCB and LQ, in a 1:1 ratio, exerted synergistic antioxidative, anti-inflammatory, and anti-fibrotic effects in the treatment of COPD by downregulating HCK. CONCLUSION: The combination of LCB and LQ performed a significant anti-COPD effect via downregulating HCK.

Comparative analysis of two digestive tract reconstruction methods in total laparoscopic radical total gastrectomy.

BACKGROUND: The incidence of gastric cancer has significantly increased in recent years. Surgical resection is the main treatment, but the method of digestive tract reconstruction after gastric cancer surgery remains controversial. In the current study, we sought to explore a reasonable method of digestive tract reconstruction and improve the quality of life and nutritional status of patients after surgery. To this end, we statistically analyzed the clinical results of patients with gastric cancer who underwent jejunal interposition double-tract reconstruction (DTR) and esophageal jejunum Roux-en-Y reconstruction (RY). AIM: To explore the application effect of DTR in total laparoscopic radical total gastrectomy (TLTG) and evaluate its safety and efficacy. METHODS: We collected the relevant data of 77 patients who underwent TLTG at the Fourth Hospital of Hebei Medical University from October 2021 to January 2023. Among them, 35 cases were treated with DTR, and the remaining 42 cases were treated with traditional RY. After 1:1 propensity score matching, the cases were grouped into 31 cases per group, with evenly distributed data. The clinical characteristics and short- and long-term clinical outcomes of the two groups were statistically analyzed. RESULTS: The two groups showed no significant differences in basic data, intraoperative blood loss, number of lymph node dissections, first defecation time after operation, postoperative hospital stay, postoperative complications, and laboratory examination results on the 1st, 3rd, and 5th days after operation. The operation time of the DTR group was longer than that of the RY group [(307.58 ± 65.14) min vs (272.45 ± 62.09) min, P = 0.016], but the first intake of liquid food in the DTR group was shorter than that in the RY group [(4.45 ± 1.18) d vs (6.0 ± 5.18) d, P = 0.028]. The incidence of reflux heartburn (Visick grade) and postoperative gallbladder disease in the DTR group was lower than that in the RY group (P = 0.033 and P = 0.038). Although there was no significant difference in body weight, hemoglobin, prealbumin, and albumin between the two groups at 1,3 and 6 months after surgery, the diet of patients in the DTR group was better than that in the RY group (P = 0.031). CONCLUSION: The clinical effect of DTR in TLTG is better than that of RY, indicating that it is a more valuable digestive tract reconstruction method in laparoscopic gastric cancer surgery.

Synthesis of Pseudostellaria heterophylla polysaccharide-gold nanocomposites and their antitumor effect through immunomodulation.

Polysaccharides from natural sources have an excellent immune function and low toxicity; however, their limitations such as short half-life and instability limit their sustained pharmacological activity. In this context, the combination of polysaccharides and nanotechnology have been developed to promote the stability and prolong the immune activities of polysaccharides. To synthesize and explore the antitumor effect and immunomodulatory activity of PHP-AuNPs. Polysaccharides extracted from Pseudostellaria heterophylla were used to synthesize gold nanocomposites (PHP-AuNPs), and their physicochemical properties and immunoregulatory effect in vitro and in vivo were analyzed. The PHP-AuNPs were green synthesized with high biosafety. PHP-AuNPs can activate macrophages in vitro and decrease the tumor weight and volume, whereas they increase the immune organ index in vivo. Besides, PHP-AuNPs showed a beneficial effect for maintaining the immune balance of CD4+/CD8+ T cells and modulating the release of cytokines such as TNF-α increase and IL-10 decrease in mice. All these results suggested that PHP-AuNPs exhibit a remarkable antitumor effect and stronger immunomodulatory activity than that of free PHP-1. RESEARCH HIGHLIGHTS: The P. heterophylla polysaccharide-gold nanocomposites (PHP-AuNPs) were synthesized and physicochemical properties were characterized. The cytotoxicity in vitro and immunomodulatory effects of PHP-AuNPs on macrophages were analyzed. The immune-antitumor effects in vivo of PHP-AuNPs have also been confirmed.

CFViSA: A comprehensive and free platform for visualization and statistics in omics-data.

INTRODUCTION: The rapid growth of omics technologies has led to the use of bioinformatics as a powerful tool for unravelling scientific puzzles. However, the obstacles of bioinformatics are compounded by the complexity of data processing and the distinct nature of omics data types, particularly in terms of visualization and statistics. OBJECTIVES: We developed a comprehensive and free platform, CFViSA, to facilitate effortless visualization and statistical analysis of omics data by the scientific community. METHODS: CFViSA was constructed using the Scala programming language and utilizes the AKKA toolkit for the web server and MySQL for the database server. The visualization and statistical analysis were performed with the R program. RESULTS: CFViSA integrates two omics data analysis pipelines (microbiome and transcriptome analysis) and an extensive array of 79 analysis tools spanning simple sequence processing, visualization, and statistics available for various omics data, including microbiome and transcriptome data. CFViSA starts from an analysis interface, paralleling a demonstration full course to help users understand operating principles and scientifically set the analysis parameters. Once analysis is conducted, users can enter the task history interface for figure adjustments, and then a complete series of results, including statistics, feature tables and figures. All the graphic layouts were printed with necessary statistics and a traceback function recording the options for analysis and visualization; these statistics were excluded from the five competing methods. CONCLUSION: CFViSA is a user-friendly bioinformatics cloud platform with detailed guidelines for integrating functions in multi-omics analysis with real-time visualization adjustment and complete series of results provision. CFViSA is available at http://www.cloud.biomicroclass.com/en/CFViSA/.

Sodium alginate hydrogelation mediated paper-based POCT sensor for visual distance reading and smartphone-assisted colorimetric dual-signal determination of L-lactate.

Herein, we present a paper-based POCT sensor based on lactate dehydrogenase-mediated alginate gelation combined with visual distance reading and smartphone-assisted colorimetric dual-signal analysis to determine the concentration of L-lactate in yogurt samples. In this research, L-lactate was transformed into pyruvate by lactate dehydrogenase. Pyruvate then triggered the gelation of a sol mixture, increasing the viscosity (ηs) of the mixture, which was shown as a decrease in the diffusion diameter on the paper-based sensor. In addition, protons from pyruvate accelerated the degradation of Rhodamine B, causing color fading of the mixture, which was analyzed using RGB analysis application software. Under optimal experimental conditions, the linear ranges of visual distance reading and smartphone-assisted colorimetric analysis were 0.1-15 µM and 0.3-15 µM and the detection limits were 0.03 µM and 0.07 µM, respectively. As a proof-of-concept application, we exploited the paper-based sensor to determine the concentration of L-lactate in yogurt samples. The results from the dual-signal paper-based sensor were consistent with the ones from HPLC analysis. In short, this study developed a simple, convenient, cost-effective, and feasible method for the quantitative detection of L-lactate in real samples.

Efficacies of anlotinib monotherapy versus gemcitabine-based chemotherapy for patients with advanced soft tissue sarcoma after the failure of anthracycline-based chemotherapy.

OBJECTIVE: The purpose of this study was to compare the antitumor efficacy of anlotinib with gemcitabine-based chemotherapy as subsequent treatment regimens in patients with advanced non-specific soft tissue sarcoma (STS) after the failure of anthracycline-based chemotherapy. METHODS: Patients diagnosed with advanced STS who were treated with either anlotinib or gemcitabine-based chemotherapy between May 2009 and May 2023 in our center were eligible. All patients experienced disease progression or recurrence after the anthracycline-based chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were disease control rate (DCR), overall survival (OS) and safety. RESULTS: We included 49 patients receiving anlotinib and 45 patients receiving gemcitabine-based chemotherapy. The median follow-up time was 76.9 weeks (range 2.9-678.9 weeks). The DCR (65.3% vs. 57.8%; p = 0.610), PFS (24.0 weeks vs. 18.6 weeks; p = 0.669) and OS (79.4 weeks vs. 87.0 weeks; p = 0.471) of anlotinib and gemcitabine-based chemotherapy indicated similar clinical efficacy. Moreover, exploratory subgroup analyses showed that patients with STS originating from limbs and trunk were inclined to benefit from anlotinib treatment (median PFS: 31.3 weeks vs. 12.4 weeks; p = 0.045). ECOG PS was an independent predictor of the PFS [Hazard Ratio (HR) 0.31; 95% confidence interval (CI) 0.11-0.85; p = 0.023] and OS (HR 0.26, 95%CI 0.10-0.70; p = 0.008) in the anlotinib group. While neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic factor of the PFS (HR 0.33, 95%CI 0.11-0.98; p = 0.045) in the gemcitabine-based chemotherapy group. The incidence of grade 3 or higher related AEs in anlotinib and gemcitabine-based chemotherapy was 20.4% (n = 10) and 20.0% (n = 9), respectively. CONCLUSION: Our research suggested that anlotinib and gemcitabine-based chemotherapy showed similar clinical efficacy and safety in the subsequent treatment of advanced STS after the failure of anthracycline-based chemotherapy.

Ebola virus sequesters IRF3 in viral inclusion bodies to evade host antiviral immunity.

Viral inclusion bodies (IBs) commonly form during the replication of Ebola virus (EBOV) in infected cells, but their role in viral immune evasion has rarely been explored. Here, we found that interferon regulatory factor 3 (IRF3), but not TANK-binding kinase 1 (TBK1) or IκB kinase epsilon (IKKε), was recruited and sequestered in viral IBs when the cells were infected by EBOV transcription- and replication-competent virus-like particles (trVLPs). Nucleoprotein/virion protein 35 (VP35)-induced IBs formation was critical for IRF3 recruitment and sequestration, probably through interaction with STING. Consequently, the association of TBK1 and IRF3, which plays a vital role in type I interferon (IFN-I) induction, was blocked by EBOV trVLPs infection. Additionally, IRF3 phosphorylation and nuclear translocation induced by Sendai virus or poly(I:C) stimulation were suppressed by EBOV trVLPs. Furthermore, downregulation of STING significantly attenuated VP35-induced IRF3 accumulation in IBs. Coexpression of the viral proteins by which IB-like structures formed was much more potent in antagonizing IFN-I than expression of the IFN-I antagonist VP35 alone. These results suggested a novel immune evasion mechanism by which EBOV evades host innate immunity.

Synthesis of 9-Cinnamyl-9H-purine Derivatives as Novel TLR4/MyD88/NF-κB Pathway Inhibitors for Anti-inflammatory Effects.

The novel 9-cinnamyl-9H-purine skeleton, inspired by resveratrol and curcumin, was developed to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). It replaced the phenol group with purine analogues, the building blocks of DNA and RNA. Alterations to the hydroxyl group in the cinnamyl group, such as H, Me, or F substitutions, were made to impede its oxidation to a PAINS-associated quinone. Among the compounds tested, 5e significantly inhibited nitric oxide production in LPS-induced macrophages (IC50: 6.4 vs 26.4 µM for resveratrol). 5e also reduced pro-inflammatory cytokine levels (IL-6, TNF-α, IL-1ß) and lowered iNOS and COX-2 protein levels. Mechanistically, 5e disrupted the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway suppression. In an atopic dermatitis mouse model, 5e reduced ear edema and inflammation. These findings indicate that the novel 9-cinnamyl-9H-purine skeleton provides therapeutic insight into treating various human diseases by regulating inflammation.

Stereoselective Synthesis of ß-glycosyl Esters via 1-Hydroxybenzotriazole Mediated Acylation of Glycosyl Hemiacetals.

Highly stereoselective access to ß-glycosyl esters was disclosed, employing 1-hydroxybenzotriazole (HOBt) mediated esterification of glycosyl hemiacetals in the presence of EDCI and 1,4-diazabicyclo[2.2.2]octane (DABCO). Mechanistic studies indicated a dynamic kinetic acylation pathway. In addition, a stereoretentive esterification of glycosyl hemiacetals with tert-butyloxycarbonyl ortho-hexynylbenzoate and DMAP was also reported.

Effects of intrauterine and post-natal exposure to air pollution on children's pneumonia: Key roles in different particulate matters exposure during critical time windows.

BACKGROUND: Despite mounting evidence linked pneumonia with air pollution, it is unclear what main pollutant(s) exposure in which critical window(s) play a key role in pneumonia. OBJECTIVE: To examine effects of intrauterine and post-natal exposure to air pollution on children's doctor-diagnosed pneumonia (DDP). METHODS: A combination of cross-sectional and retrospective cohort study was conducted at Changsha, China during 2019-2020. Personal exposure to outdoor air pollutants at each child's home address was estimated using inverse distance weighted (IDW) method based on data from 10 air quality monitoring stations. Associations between personal air pollution exposure and DDP were evaluated. RESULTS: Children's DDP was associated with intrauterine and post-natal exposure to PM2.5, PM2.5-10, and PM10, adjusted ORs (95% CI) of 1.17 (1.04-1.30), 1.09 (1.01-1.17), and 1.07 (1.00-1.14) for IQR increase in intrauterine exposure and 1.12 (1.02-1.22), 1.13 (1.06-1.21), and 1.28 (1.16-1.41) for post-natal exposure. Intrauterine PM2.5 exposure and post-natal PM10 exposure were associated with a higher risk of pneumonia. We identified the 2nd trimester, 3rd trimester, and first year as critical windows respectively for PM2.5, PM2.5-10, and PM10 exposure. Daytime exposure to traffic-related air pollution especially during early life increased DDP. CONCLUSION: Intrauterine and post-natal exposure to particulate matters played a dominant role in children's DDP.

Intrauterine and early postnatal exposure to air pollution associated with childhood allergic rhinitis.

BACKGROUND: Despite mounting evidence linking allergic rhinitis (AR) to air pollution, it remains unclear which major air pollutant(s) and critical window(s) of exposure play important roles in children's AR. OBJECTIVE: To examine the effects of intrauterine and early postnatal exposure to outdoor air pollution on children with doctor-diagnosed allergic rhinitis (DDAR). METHODS: A retrospective cohort study involving 8689 kindergarten children was conducted in Changsha, China, from 2019 to 2020. A questionnaire survey was conducted to collect information on the health status of children and their family members, as well as their living habits and home environment. Personal exposure to daily outdoor air pollutants (PM2.5, PM2.5-10, PM10, SO2, NO2, and CO) was estimated during 40 gestational weeks, three trimesters, the entire pregnancy, and the first year after birth. Multiple logistic regression models were used to assess the associations between air pollution and children's DDAR. RESULTS: Children's DDAR was associated with intrauterine CO exposure, with adjusted ORs (95% CI) of 1.18 (1.03-1.34) for each IQR increase in CO exposure. The second and third trimesters were critical windows for PM2.5 and CO exposure in relation to DDAR. Furthermore, early postnatal exposure to PM2.5-10 and PM10 in first year of life was associated with DDAR development, with adjusted ORs (95% CI) of 1.11 (1.01-1.22) and 1.27 (1.09, 1.47). The entire pregnancy and the first year of life were critical windows for CO and PM10 exposure. Some children were predisposed to DDAR risk due to exposure to traffic-related air pollution (TRAP). CONCLUSION: Our findings support the hypothesis of "fetal origin of allergic rhinitis" by demonstrating that intrauterine and early postnatal exposure to air pollution plays an important role in children's DDAR.

A case series of 10 patients undergone linear cutter/stapler guiding device-led overlapped esophagojejunostomy: a preliminary study.

Background: In laparoscopic total gastrectomy with overlap esophagojejunostomy (EJS), esophageal 'false track' is easily formed during EJS. In this study, a linear cutter/stapler guiding device (LCSGD) was used in EJS, so that the linear cutting stapler can complete the technical action with high speed and high efficiency in a narrow space, while avoiding the formation of 'false passage', optimizing the quality of common opening and shortening the anastomosis time. The LCSGD is safe and feasible in laparoscopic total gastrectomy overlap EJS, and the clinical effect is satisfactory. Methods: A retrospective, descriptive design was adopted. The clinical data of 10 gastric cancer patients admitted to the Third Department of Surgery of the Fourth Hospital of Hebei Medical University from July 2021 to November 2021 were collected. The cohort comprised 8 males and 2 females aged 50-75 years. Results: (I) The intra-operative conditions: 10 patients received LCSGD-guided overlap EJS after radical laparoscopic total gastrectomy. Both D2 lymphadenectomy and R0 resection were achieved in these patients. No combined multiple organ resection was performed. There was neither conversion to an open thoracic or abdominal procedure nor conversion to other EJS approaches. The average time from the entry of the LCSGD into the abdominal cavity to the completion of the firing of the stapler was 1.8±0.4 minutes, the average time for manual suturing of the EJS common opening was 14.4±2.1 minutes (mean: 18±2 stitches), and the average operative time was 255±52 minutes. (II) The postoperative outcomes: the time to the first ambulation was 1.9±1.4 days, the average time to the first postoperative exhaust/defecation was 3.5±1.3 days, the average time to a semi-liquid diet was 3.6±0.7 days, and the average postoperative hospital stay was 10.4±4.1 days. All patients were smoothly discharged, without any secondary surgery, bleeding, anastomotic fistula, or duodenal stump fistula. (III) Follow-up: The telephone follow-up lasted 9-12 months. No eating disorders or anastomotic stenosis was reported. One patient experienced Visick grade II heartburn, and the condition of the remaining 9 patients was Visick grade I. Conclusions: Application of the LCSGD in overlap EJS after laparoscopic total gastrectomy is safe and feasible, with satisfactory clinical effectiveness.

Chinese Giant Salamander Iridovirus 025L Is a Viral Essential Gene.

Ranavirus is a large nucleocytoplasmic DNA virus. Chinese giant salamander iridovirus (CGSIV) belongs to the ranavirus genus, and its replication involves a series of essential viral genes. Viral PCNA is a gene closely associated with viral replication. CGSIV-025L also encodes PCNA-like genes. We have described the function of CGSIV-025L in virus replication. The promoter of CGSIV-025L is activated during viral infection, and it is an early (E) gene that can be effectively transcribed after viral infection. CGSIV-025L overexpression promoted viral replication and viral DNA replication. siRNA interfered with CGSIV-025L expression and attenuated viral replication and viral DNA replication. The Δ025L-CGSIV strain with the deletion of CGSIV-025L could not replicate normally and could be rescued by the replenishment of 025L. CGSIV-025L was proven to be an essential gene for CGSIV by overexpression, interference, and deletion mutation experiments. CGSIV-025L was found to interact with CGSIV-062L by yeast two-hybrid, CoIP, and GST pulldown. Thus, the current study demonstrated that CGSIV-025L is an essential gene of CGSIV, which may be involved in viral infection by participating in viral DNA replication and interacting with replication-related proteins.

Direct Production of Bio-Recalcitrant Carboxyl-Rich Alicyclic Molecules Evidenced in a Bacterium-Induced Steroid Degradation Experiment.

Carboxyl-rich alicyclic molecules (CRAM) are highly unsaturated compounds extensively distributed throughout aquatic environments and sediments. This molecular group is widely referred to as a major proxy of recalcitrant organic materials, but its direct biosynthesis remains unclear. Steroids are a typical anthropogenic contaminant and have been previously suggested to be precursors of CRAM; however, experimental evidence to support this hypothesis is lacking. Here, a steroid-degrading bacterium, Comamonas testosteroni ATCC 11996, was incubated in a liquid medium supplemented with testosterone (a typical steroid) as the sole carbon source for 90 days. Testosterone-induced metabolites (TIM) were extracted for molecular characterization and to examine the bioavailability during an additional 90-day incubation after inoculation with a natural coastal microbial assemblage. The results showed that 1,775 molecular formulas (MFs) were assigned to TIM using ultrahigh-resolution mass spectrometry, with 66.99% categorized as CRAM-like constituents. A large fraction of TIM was respired or transformed during the additional 90-day seawater incubation; nevertheless, 638 MFs of the TIM persisted or increased during incubation. Among the 638 MFs, 394 were commonly assigned in natural deep seawater samples (depths of 500 to 2,000 m) from the South China Sea. Compared to the catabolites of the well-established testosterone degradation pathway, we compiled a list of bio-refractory MFs and potential chemical structures, some of which shared structural homology with CRAM. These results demonstrated direct microbial production of bio-refractory CRAM from steroid hormones and indicated that some of the biogenic CRAM resisted microbial decomposition, potentially contributing to the aquatic refractory dissolved organic matter (DOM) pool. IMPORTANCE CRAM are an operationally defined DOM group comprising a complex mixture of carboxylated and fused alicyclic structures. This DOM group is majorly characterized as refractory DOM in the marine environment. However, the origins of the complex CRAM remain unclear. In this study, we demonstrated that testosterone (a typical steroid) could be transformed into bio-refractory CRAM by a single bacterial strain and observed that some of the CRAM highly resisted microbial degradation. Through molecular comparison and screening, potential chemical structures of steroid-induced CRAM were suggested. This study established the biological connection between steroids and bio-refractory CRAM, and it provides a novel perspective explaining the fate of terrestrial contaminants in aquatic environments.

Efficacy and safety of immune checkpoint inhibitors with or without radiotherapy in metastatic non-small cell lung cancer: A systematic review and meta-analysis.

Background and purpose: Although immune checkpoint inhibitors (ICIs) have become the first-line treatment for metastatic non-small cell lung cancer (mNSCLC), their efficacy is limited. Meanwhile, recent reports suggest that radiotherapy (RT) can activate the systemic antitumor immune response by increasing the release of antigens from tumor tissues. Therefore, in patients with mNSCLC treated with ICIs, investigations were performed to determine whether the addition of RT improved the outcomes. Furthermore, the adverse events rate was evaluated. Methods and materials: Pubmed, Embase, and Cochrane Library were searched using the keywords "radiotherapy," "immune checkpoint inhibitors," and "non-small cell lung cancer" from the date of inception to 2 May 2022. Randomized controlled trials (RCTs) and nonRCTs (NRCTs) comparing the efficacy and safety of RT combined with ICIs versus ICIs alone in metastatic NSCLC were assessed. The primary outcomes were progression-free survival (PFS) and overall survival (OS), and the secondary outcomes were abscopal response rate (ARR), abscopal control rate (ACR), adverse events rate, and pneumonia rate. The analyses were conducted using the Mantel-Haenszel fixed-effects or random-effects model. The I2 statistic was used to determine heterogeneity, whereas funnel plots and Egger's test were used to assess publication bias. Results: In 15 clinical studies, 713 patients received RT combined with ICIs and 1,275 patients received only ICIs. With regard to PFS and OS, the hazard ratios of RT combined with ICIs were 0.79 (0.70, 0.89) and 0.72 (0.63, 0.82), respectively. In terms of ARR and ACR, the odds ratios (ORs) of RT combined with ICIs were 1.94 (1.19, 3.17) and 1.79 (1.08, 2.97), respectively. Subgroup analyses based on study type (RCT/NRCT), RT target (intracranial/extracranial), number of RT sites (single site), previous ICI resistance (yes/no), and sequencing of RT and ICIs (concurrent/post-RT ICIs) revealed that the addition of RT significantly prolonged PFS and OS. However, subgroup analyses based on radiation dose/fractionation indicated that the addition of hypofractionated RT significantly prolonged OS but not PFS. When grouped according to the level of PD-L1 expression, the addition of RT prolonged PFS only in patients who were PD-L1-negative. Furthermore, subgroup analyses of ARR and ACR signified that the combination therapy resulted in better local control of lesions outside the irradiation field in the hypofractionated RT, extracranial RT, and ICI-naïve subgroups. In terms of adverse events, the addition of RT did not significantly increase the adverse events rate but was associated with a higher pneumonia rate [OR values were 1.24 (0.92, 1.67) and 1.76 (1.12, 2.77), respectively]. Conclusion: Meta-analysis of existing data suggests that the addition of RT can significantly prolong PFS and OS in patients with metastatic NSCLC receiving ICIs. In addition to lesions in the irradiation field, RT can improve the local control rate of lesions outside the irradiation field via immune activation. Combination therapy does not increase the overall risk of adverse reactions, except for pneumonia.