Genome-Wide Identification and Expression Analysis of BrBASS Genes in Brassica rapa Reveals Their Potential Roles in Abiotic Stress Tolerance.

The bile acid sodium symporter (BASS) family plays an important role in transporting substances and coordinating plants' salt tolerance. However, the function of BASS in Brassica rapa has not yet been elucidated. In this study, eight BrBASS genes distributed on five chromosomes were identified that belonged to four subfamilies. Expression profile analysis showed that BrBASS7 was highly expressed in roots, whereas BrBASS4 was highly expressed in flowers. The promoter element analysis also identified several typical homeopathic elements involved in abiotic stress tolerance and stress-related hormonal responses. Notably, under salt stress, the expression of BrBASS2 was significantly upregulated; under osmotic stress, that of BrBASS4 increased and then decreased; and under cold stress, that of BrBASS7 generally declined. The protein-protein interaction analysis revealed that the BrBASS2 homologous gene AtBASS2 interacted with Nhd1 (N-mediated heading date-1) to alleviate salt stress in plants, while the BrBASS4 homologous gene AtBASS3 interacted with BLOS1 (biogenesis of lysosome-related organelles complex 1 subunit 1) via co-regulation with SNX1 (sorting nexin 1) to mitigate an unfavorable growing environment for roots. Further, Bra-miR396 (Bra-microRNA396) targeting BrBASS4 and BrBASS7 played a role in the plant response to osmotic and cold stress conditions, respectively. This research demonstrates that BrBASS2, BrBASS4, and BrBASS7 harbor great potential for regulating abiotic stresses. The findings will help advance the study of the functions of the BrBASS gene family.

Dolutegravir/Lamivudine Efficacy and Safety Outcomes in People With HIV-1 With or Without Historical Resistance Results at Screening: 48-Week Pooled Analysis.

Background: Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated the impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in adults who were virologically suppressed with or without historical resistance results at screening. Methods: Adults who were virologically suppressed (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n = 369; SALSA, n = 246) or continue their current antiretroviral regimen (CAR; TANGO, n = 372; SALSA, n = 247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm, Food and Drug Administration; intention-to-treat exposed), CD4+ cell count, and safety were analyzed by availability of historical resistance results. Results: Overall, 294 of 615 (48%) participants in the DTG/3TC group and 277 of 619 (45%) participants in the CAR group had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%-95%) maintained virologic suppression through week 48, regardless of results availability. Across both subgroups of results availability, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No participants taking DTG/3TC had confirmed virologic withdrawal, regardless of historical resistance results availability. One participant undergoing CAR without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal. Conclusions: Findings support DTG/3TC as a robust switch option for adults who are virologically suppressed with HIV-1 and no prior virologic failure, regardless of historical resistance results availability. Clinical trial registration: TANGO: NCT03446573, https://clinicaltrials.gov/study/NCT03446573. SALSA: NCT04021290, https://clinicaltrials.gov/study/NCT04021290.

Molecular basis for the activation of PAF receptor by PAF.

Platelet-activating factor (PAF) is a potent phospholipid mediator crucial in multiple inflammatory and immune responses through binding and activating the PAF receptor (PAFR). However, drug development targeting the PAFR has been limited, partly due to an incomplete understanding of its activation mechanism. Here, we present a 2.9-Å structure of the PAF-bound PAFR-Gi complex. Structural and mutagenesis analyses unveil a specific binding mode of PAF, with the choline head forming cation-π interactions within PAFR hydrophobic pocket, while the alkyl tail penetrates deeply into an aromatic cleft between TM4 and TM5. Binding of PAF modulates conformational changes in key motifs of PAFR, triggering the outward movement of TM6, TM7, and helix 8 for G protein coupling. Molecular dynamics simulation suggests a membrane-side pathway for PAF entry into PAFR via the TM4-TM5 cavity. By providing molecular insights into PAFR signaling, this work contributes a foundation for developing therapeutic interventions targeting PAF signal axis.

Dolutegravir + Lamivudine vs. Dolutegravir + Tenofovir Disoproxil Fumarate/Emtricitabine: Very-Low-Level HIV-1 Replication through 144 Weeks in the GEMINI-1 and GEMINI-2 Studies.

In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott's RealTime HIV-1 assay provides quantitative VL (40-10,000,000 copies/mL) and qualitative target detected or target not detected (TND) for VL < 40 copies/mL. This post hoc analysis assessed very-low-level viremia and "blips" through Week 144. Proportions with VL < 40 copies/mL and TND are presented overall and by baseline VL and CD4+ cell count. "Blips" (single VL ≥ 50 to <200 copies/mL with adjacent values < 50 copies/mL) were assessed from Day 1 after VL suppression and from Weeks 48 through to 144. Proportions with TND increased through Week 48 and were similar between groups at all visits (Week 144: dolutegravir + lamivudine, 451/716 [63%]; dolutegravir + TDF/FTC, 465/717 [65%]). By observed analysis, TND rates were similar between groups across baseline subgroups. Through Week 144, proportions with ≥1 "blip" were generally comparable for dolutegravir + lamivudine vs. dolutegravir + TDF/FTC from Day 1 (15% vs. 20%) and from Week 48 (7% vs. 11%). Through 144 weeks, the proportions with TND or "blips" were similar between dolutegravir + lamivudine and the three-drug comparator, reinforcing the efficacy and durability of dolutegravir + lamivudine.

The endoplasmic reticulum stress-related genes and molecular typing predicts prognosis and reveals characterization of tumor immune microenvironment in lung squamous cell carcinoma.

BACKGROUND: Endoplasmic reticulum stress (ERS) acts critical roles on cell growth, proliferation, and metastasis in various cancers. However, the relationship between ERs and lung squamous cell carcinoma (LUSC) prognoses still remains unclear. METHODS: The consensus clustering analysis of ERS-related genes and the differential expression analysis between clusters were investigated in LUSC based on TCGA database. Furthermore, ERS-related prognostic risk models were constructed by LASSO regression and Cox regression analyses. Then, the predictive effect of the risk model was evaluated by Kaplan-Meier, Cox regression, and ROC Curve analyses, as well as validated in the GEO cohort. According to the optimal threshold, patients with LUSC were divided into high- and low- risk groups, and somatic mutations, immune cell infiltration, chemotherapy response and immunotherapy effect were systematically analyzed. RESULTS: Two ERS-related clusters were identified in patients with LUSC that had distinct patterns of immune cell infiltration. A 5-genes ERS-related prognostic risk model and nomogram were constructed and validated. Kaplan-Meier curves and Cox regression analysis showed that ERS risk score was an independent prognostic factor (p < 0.001, HR = 1.317, 95% CI = 1.159-1.496). Patients with low-risk scores presented significantly lower TIDE scores and significantly lower IC50 values for common chemotherapy drugs such as cisplatin and gemcitabine. CONCLUSION: ERS-related risk signature has certain prognostic value and may be a potential therapeutic target and prognostic biomarker for LUSC patients.

Durable Efficacy of Switching From a 3- or 4-Drug Tenofovir Alafenamide-Based Regimen to the 2-Drug Regimen Dolutegravir/Lamivudine in the TANGO Study Through Week 196.

BACKGROUND: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO. SETTING: 134 centers, 10 countries. METHODS: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196. RESULTS: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term. CONCLUSION: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.

A novel method for identifying aerobic granular sludge state using sorting, densification and clarification dynamics during the settling process.

Aerobic granular sludge is one of the most promising biological wastewater treatment technologies, yet maintaining its stability is still a challenge for its application, and predicting the state of the granules is essential in addressing this issue. This study explored the potential of dynamic texture entropy, derived from settling images, as a predictive tool for the state of granular sludge. Three processes, traditional thickening, often overlooked clarification, and innovative particle sorting, were used to capture the complexity and diversity of granules. It was found that rapid sorting during settling indicates stable granules, which helps to identify the state of granules. Furthermore, a relationship between sorting time and granule heterogeneity was identified, helping to adjust selection pressure. Features of the dynamic texture entropy well correlated with the respirogram, i.e., R2 were 0.86 and 0.91 for the specific endogenous respiration rate (SOURe) and the specific quasi-endogenous respiration rate (SOURq), respectively, providing a biologically based approach for monitoring the state of granules. The classification accuracy of models using features of dynamic texture entropy as an input was greater than 0.90, significantly higher than the input of conventional features, demonstrating the significant advantage of this approach. These findings contributed to developing robust monitoring tools that facilitate the maintenance of stable granular sludge operations.

Usenamine A triggers NLRP3/caspase-1/GSDMD-mediated pyroptosis in lung adenocarcinoma by targeting the DDX3X/SQSTM1 axis.

BACKGROUND: Usenamine A (C18H17NO6) is a newly developed, natural anticancer drug that reportedly exerts low toxicity. The therapeutic efficacy and underlying mechanisms of usenamine A in lung adenocarcinoma (LUAD) remain poorly understood. We aimed to explore the therapeutic effects and molecular mechanisms through which usenamine A inhibits LUAD tumorigenesis. METHODS: We used LUAD cell lines H1299 and A549 in the present study. CCK-8 and colony formation assays were performed to analyze cell proliferation. Cell migration, invasion, and apoptosis were evaluated using wound-healing, transwell, and flow cytometric assays, respectively. Levels of reactive oxygen species were measured using a DCFH-DA probe. Inflammatory factors (lactate dehydrogenase, interleukin [IL]-1ß, and IL-18) were detected using enzyme-linked immunosorbent assays. Western blotting was performed to determine the expression of NOD-like receptor pyrin 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway-related proteins. Pyroptosis was detected using transmission electron microscopy. The interaction and co-localization of DDX3X and sequestosome 1 (SQSTM1) were identified using co-immunoprecipitation and immunofluorescence assays, respectively. For in vivo assessment, we established a xenograft model to validate the usenamine A-mediated effects and mechanisms of action in LUAD. RESULTS: Usenamine A inhibited the proliferation, migration, and invasion of LUAD cells. Furthermore, usenamine A induced NLRP3/caspase-1/GSDMD-mediated pyroptosis in LUAD cells. Usenamine A upregulated DDX3X expression to trigger pyroptosis. DDX3X interacted with SQSTM1, which is responsible for inducing pyroptosis. In vivo, usenamine A suppressed LUAD tumorigenesis by triggering NLRP3/caspase-1/GSDMD-mediated pyroptosis via the upregulation of the DDX3X/SQSTM1 axis. CONCLUSIONS: Usenamine A was found to induce NLRP3/caspase-1/GSDMD-mediated pyroptosis in LUAD by upregulating the DDX3X/SQSTM1 axis.

Very-Low-Level Viremia, Inflammatory Biomarkers, and Associated Baseline Variables: Three-Year Results of the Randomized TANGO Study.

Background: We compared proportions of participants with target detected, target not detected (TND), and elevated viral load (VL) and assessed baseline variables associated with week 144 inflammatory biomarker levels between dolutegravir-lamivudine (DTG/3TC) and tenofovir alafenamide-based regimens (TBRs) in the TANGO study (post hoc). Methods: TANGO is an open-label, multicenter, phase 3 study that randomized adults with VL <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or continue TBR. At baseline and each study visit, the VL was measured. Elevated VL event frequencies were assessed, including "blips." Interleukin 6, D-dimer, high-sensitivity C-reactive protein, soluble CD14, and soluble CD163 were measured at baseline and at week 144. Loge-transformed week 144 biomarker levels were compared between treatment groups using an analysis of covariance model adjusting for baseline variables. Results: High, comparable proportions of participants had VL <40 copies/mL and TND at week 144 (DTG/3TC, 279 of 369 [76%]; TBR, 267 of 372 [72%], intention-to-treat exposed Snapshot analysis; adjusted difference, 3.9% [95% confidence interval, -2.5% to 10.2%]), with similar TND proportions at all postbaseline visits (123 of 369 [33%] vs 101 of 372 [27%], respectively). Similar proportions of DTG/3TC participants had ≥1 postbaseline VL ≥50 copies/mL (28 of 369 [8%] vs 42 of 372 [11%] for TBR), primarily blips (18 of 369 [5%] and 26 of 372 [7%], respectively). Week 144 inflammatory biomarker levels were low and comparable between groups and associated with multiple demographic and baseline characteristics, including baseline biomarker levels, indicating a multifactorial inflammatory response. Conclusions: Week 144 biomarker levels were low and generally comparable between treatment groups, reflecting similar, robust, and durable viral suppression observed using the stringent TND end point. Trial registration:  ClinicalTrials.gov, NCT03446573.

Clinical significance of immunotherapy-associated oxidative stress gene expression in lung adenocarcinoma and its relationship with immune cell infiltration and drug sensitivity / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探究肺腺癌中与免疫治疗相关氧化应激基因（IROSG）及其与肿瘤组织免疫浸润和患者预后的关系。方法：从TCGA数据库和GEO数据库下载肺腺癌患者IROSG表达数据及相关临床信息。对非小细胞肺癌免疫治疗队列进行差异基因表达分析以获取免疫治疗相关基因，然后与从GeneCards数据库筛选的氧化应激相关基因取交集得到IROSG。基于得到的IROSG对肺腺癌患者进行分型，对亚型的差异表达基因进行单因素COX、LASSO和多因素COX回归分析以构建预后模型。使用模型公式计算每个患者的风险评分，并将患者划分为高、低风险组。从多个层面验证模型的预测效能，并进行肿瘤微环境（TME）分析、免疫治疗反应预测和药物敏感性分析。结果：通过数据库分析获取82个IROSG，IROSG高表达的肺腺癌患者预后较好（P<0.05）。基于IROSG表达水平分型和风险评分构建的肺腺癌患者预后模型预测能力好，基于风险评分和病例特征等预后因子构建的列线图和校正曲线能较好地预测肺腺癌患者的总生存率。低风险组主要富集于同种异体移植物排斥和自身免疫性疾病等通路，而高风险组主要富集在细胞周期和DNA复制等通路上，且低风险组肺腺癌组织中免疫细胞浸润水平较高。高、低风险评分结合肿瘤突变负荷（TMB）、TME、肿瘤免疫功能障碍和排斥（TIDE）评分和免疫检查点分子表达水平能较好地预测肺腺癌患者预后、免疫治疗反应和对化疗药物的敏感性。结论：本研究构建了一个可以预测肺腺癌患者预后和免疫治疗反应的模型，可为肺腺癌患者个体化治疗提供了理论依据。

Developing a multi-epitope vaccine candidate to combat porcine epidemic diarrhea virus and porcine deltacoronavirus co-infection by employing an immunoinformatics approach.

Coinfection of porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV) is common in pig farms, but there is currently no effective vaccine to prevent this co-infection. In this study, we used immunoinformatics tools to design a multi-epitope vaccine against PEDV and PDCoV co-infection. The epitopes were screened through a filtering pipeline comprised of antigenic, immunogenic, toxic, and allergenic properties. A new multi-epitope vaccine named rPPMEV, comprising cytotoxic T lymphocyte-, helper T lymphocyte-, and B cell epitopes, was constructed. To enhance immunogenicity, the TLR2 agonist Pam2Cys and the TLR4 agonist RS09 were added to rPPMEV. Molecular docking and dynamics simulation were performed to reveal the stable interactions between rPPMEV and TLR2 as well as TLR4. Additionally, the immune stimulation prediction indicated that rPPMEV could stimulate T and B lymphocytes to induce a robust immune response. Finally, to ensure the expression of the vaccine protein, the sequence of rPPMEV was optimized and further performed in silico cloning. These studies suggest that rPPMEV has the potential to be a vaccine candidate against PEDV and PDCoV co-infection as well as a new strategy for interrupting the spread of both viruses.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings.

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings.

Genome-Wide Identification and Expression Analysis of BrGeBP Genes Reveal Their Potential Roles in Cold and Drought Stress Tolerance in Brassica rapa.

The GLABROUS1 Enhancer Binding Protein (GeBP) gene family is pivotal in regulating plant growth, development, and stress responses. However, the role of GeBP in Brassica rapa remains unclear. This study identifies 20 BrGeBP genes distributed across 6 chromosomes, categorized into 4 subfamilies. Analysis of their promoter sequences reveals multiple stress-related elements, including those responding to drought, low temperature, methyl jasmonate (MeJA), and gibberellin (GA). Gene expression profiling demonstrates wide expression of BrGeBPs in callus, stem, silique, and flower tissues. Notably, BrGeBP5 expression significantly decreases under low-temperature treatment, while BrGeBP3 and BrGeBP14 show increased expression during drought stress, followed by a decrease. Protein interaction predictions suggest that BrGeBP14 homolog, At5g28040, can interact with DES1, a known stress-regulating protein. Additionally, microRNA172 targeting BrGeBP5 is upregulated under cold tolerance. These findings underscore the vital role of BrGeBPs in abiotic stress tolerance. Specifically, BrGeBP3, BrGeBP5, and BrGeBP14 show great potential for regulating abiotic stress. This study contributes to understanding the function of BrGeBPs and provides valuable insights for studying abiotic stress in B. rapa.

Nitrogen Addition Affects Interannual Variation in Seed Production in a Tibetan Perennial Herb.

The variability observed in the annual seed production of perennial plants can be seen as an indication of changes in the allocation of resources between growth and reproduction, which can be attributed to fluctuations in the environment. However, a significant knowledge gap exists concerning the impacts of nitrogen addition on the interannual seed production patterns of perennial plants. We hypothesized that the addition of nitrogen would impact the annual variations in the seed production of perennial plants, ultimately affecting their overall reproductive efficiency. A multiyear field experiment was conducted to investigate the effects of varying nitrogen supply levels (e.g., 0, 4, and 8 kg N ha-1 yr-1 of N0, N4, and N8) on vegetative and floral traits, pollinator visitation rates, and seed traits over a period of four consecutive years. The results showed that the N0 treatment exhibited the highest levels of seed production and reproductive efficiency within the initial two years. In contrast, the N4 treatment displayed its highest level of performance in these metrics in the second and third years, whereas the N8 treatment showcased its most favorable outcomes in the third and fourth years. Similar patterns were found in the number of flowers per capitulum and the number of capitula per plant. There exists a positive correlation between aboveground biomass and several factors, including the number of flowers per capitulum, the number of capitula per plant, the volume of nectar per capitulum, and the seed production per plant. A positive correlation was found between pollinator visitation and the number of flowers per capitulum or the number of capitula per plant. This implies that the addition of N affected the maintenance of plant aboveground biomass, flower trait stability, pollinator visitation, and, subsequently, the frequency of seed production and reproductive efficiency. Our results suggest that augmenting the nitrogen content in the soil may have the capacity to modify the inherent variability in seed production that is observed across various years and enhance the effectiveness of reproductive processes. These findings have the potential to enhance our comprehension of the impact of nitrogen addition on the reproductive performance of perennial herbaceous plants and the underlying mechanisms of biodiversity in the context of global environmental changes.

Nitrogen addition affects floral and vegetative traits, reproduction, and pollinator performance in Capsicum annuum L.

BACKGROUND AND AIMS: It has been demonstrated that nitrogen (N) addition alters flower morphology, floral rewards and pollinator performance. However, little is known about the effects of N addition on plant reproduction, including fruit set and seed set during selfing and outcrossing, floral and vegetative traits, and pollinator performance. We hypothesized that N addition would influence fruit set, seed set in selfed and outcrossed flowers, the relationship between vegetative and flower traits, and pollinator performance. METHODS: A 2-year pot experiment was conducted in which Capsicum annuum was exposed to three levels of relatively short-term N supply, i.e. 0 g m-2 (no N addition, as a control), 4 g m-2 (4N) and 16 g m-2 (16N), which are equivalent to about 0-, 1- and 4-fold of the peak local N deposition. We measured flower rewards, flower morphology, flowering phenology, as well as pollinator visitation rate, fruit set and seed set by self- and outcross-fertilization of C. annuum. RESULTS: The four levels of N addition increased plant biomass, biomass allocation to flowers, flower size, stigma-anther separation, nectar production and pollen production, resulting in an increase in pollinator visitation and fruit set. Nevertheless, the control and 16 levels of N addition reduced plant biomass, biomass allocation to flowers, flower size and stigma-anther separation, and nectar and pollen production, and consequently decreased pollinator visitation and fruit set. Exclusion of pollinators and hand-pollination experiments revealed that low levels of N addition were associated with high seed set in outcrossed flowers; however, this trend was reversed in flowers grown in the control and 16N treatments. CONCLUSION: Our results suggest that an optimal level of 4N can enhance the correlation between flower traits, pollinator performance and plant reproduction. Our findings cast new light on the underlying mechanisms of plant-pollinator interactions and plant adaptation to nitrogen deposition.

Low transplacental transfer of PFASs in the small-for-gestational-age (SGA) new-borns: Evidence from a Chinese birth cohort.

Early life in utero exposure to per- and polyfluoroalkyl substances (PFASs) and infiltration through the placenta into cord blood pose significant risk to fetal development. Accumulating knowledge suggests that PFASs pass through the placenta in multiple transportation ways, not limiting to passive transport but also active transport or facilitated diffusion. Therefore, we propose that the transplacental transfer efficiency (TTE) could be re-evaluated as traditional cord to maternal ratio-based method might overlook certain biological or health information from the mother and fetus. In this study, we investigated 30 PFAS chemicals in paired maternal and cord serum from 195 births classified as small-for-gestational-age (SGA) and matched appropriate-for-gestational-age (AGA). PFASs were ubiquitously detected in the maternal and serum samples, with PFOA, PFOS, 6:2 Cl-PFESA and other dominant compounds. We adopted a modified TTE estimation method (TTEm), taking into consideration of the total burden mass of PFASs in the blood from mother to fetus. Using the modified TTEm, a significant (p < 0.05) decrease was observed in the PFAS transplacental transfer potential in SGA (1.6%-11.3%) compared to AGA (2.3%-21.1%), suggesting a reverse association between TTE and SGA birth risk. This is the first study attempted to re-evaluate the TTE of PFAS and indicates that TTEm might be more advantageous to reflect the transplacental transfer potency of chemicals particularly when transportation mechanisms are multi-faceted.

Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144.

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

Nucleophosmin promotes lung adenocarcinoma cell proliferation, migration and invasion by activating the EGFR/MAPK signaling pathway.

Lung adenocarcinoma (LUAD) is the main cause of death globally. The present study investigated the prognostic value and functional verification of nucleophosmin (NPM1) in LUAD. LUAD and normal samples from The Cancer Genome Atlas were analyzed to identify whether NPM1 is associated with LUAD prognosis. NPM1 protein expression level was verified by western blotting. Cell proliferation, migration and invasion were detected by Cell Counting Kit­8, wound healing and Transwell assays, respectively. EGFR/MAPK pathway­related proteins [phosphorylated (p)­EGFR/EGFR, p­MEK/MEK, and p­ERK/ERK] expression was measured through western blotting. A xenograft tumor mice model was constructed to perform the in vivo verification. NPM1 was upregulated in LUAD cells, and high­level NPM1 indicated poor prognosis in patients with LUAD. In vitro experiments revealed that NPM1 knockdown inhibited LUAD cell proliferation, migration and invasion. Moreover, protein expression of p­EGFR/EGFR, p­MEK/MEK and p­ERK/ERK was reduced with the NPM1 silencing. Furthermore, EGF, an activator of the EGFR/MAPK pathway, reversed the effects of NPM1. In vivo experiments showed that NPM1 knockdown inhibited tumor growth and protein levels of p­EGFR/EGFR, p­MEK/MEK and p­ERK/ERK. NPM1 is related to the poor prognosis of LUAD and promotes the malignant progression of LUAD by activating the EGFR/MAPK pathway. This discovery provides a new potential therapeutic target for the diagnosis and treatment of LUAD.

Investigation of Poly(MM-EM-BM) as Nanosealing Materials in Oil-Based Drilling Fluids: Synthesis and Evaluation.

Nanosealing technology has become the key to overcoming the wellbore instability problem in deep and ultradeep shale formations. In this Article, the terpolymer poly(MM-EM-BM) was synthesized from methyl methacrylate, ethyl methacrylate, and butyl methacrylate by a Michael addition reaction. The poly(MM-EM-BM) nanoparticles were investigated by Fourier transform infrared spectroscopy, laser scattering analysis, and thermogravimetric analysis. The results imply that the particle size range of poly(MM-EM-BM) is between 33.90 and 135.62 nm and the average diameter is about 85.95 nm at room temperature, which can maintain excellent stability at 382.75 °C. The effects of poly(MM-EM-BM) on the properties of oil-based drilling fluids (OBDFs) were ascertained through experiments on the rheological performance, electrical stability, and high-temperature and high-pressure (HTHP) filtration loss. The results suggested that when the amount of added poly(MM-EM-BM) increases, the apparent viscosity, plastic viscosity, dynamic shear force, and demulsification voltage of the drilling fluids will increase correspondingly; in contrast, the HTHP filtration loss gradually decreased. When poly(MM-EM-BM) is added at 0.75%, the kinetic-to-plastic ratio of the drilling fluids is 0.24 and the filtration loss is 0.6 mL, showing excellent overall performance. The drilling fluids have a good rock-carrying ability and water loss wall-building property. The sealing performance and mechanism of poly(MM-EM-BM) were researched by the method of a sealing performance test under high temperature. The results indicated that the more poly(MM-EM-BM) used, the higher the sealing efficiency of the mud cake and the core as the sealing medium. When poly(MM-EM-BM) was added at 0.75%, the sealing rates of the mud cake and the core as the sealing medium reached the maximum sealing rates of 40.30% and 91.48%, respectively. When poly(MM-EM-BM) enters the core nanopore joint for a certain distance under formation pressure, a tight sealing layer will be formed to effectively prevent the entry of filtrate. Poly(MM-EM-BM) as a potential oil-based nanosealing agent is expected to solve the problem caused by wellbore instability in shale horizontal wells.

Tongue-Brain-Transported ZnO Nanoparticles Induce Abnormal Taste Perception.

Nanoparticles (NPs) can be transported to the brain, especially through nerves, because of their small size and high biological activity. Previous studies confirmed that zinc oxide (ZnO) NPs can enter the brain through the tongue-brain pathway, but it is unclear whether they will further affect synaptic transmission and brain perception. In this study, it is found that tongue-brain-transported ZnO NPs can cause a decrease in taste sensitivity and taste aversion learning ability, indicating abnormal taste perception. Moreover, the release of miniature excitatory postsynaptic currents, the frequency of action potential release, and the expression of c-fos are decreased, suggesting that the synaptic transmission is reduced. To further explore the mechanism, protein chip detection of inflammatory factors is carried out and it is found that neuroinflammation occurs. Importantly, it is found that neuroinflammation originated from neurons. The JAK-STAT signaling pathway is activated, which inhibits the Neurexin1-PSD95-Neurologigin1 pathway and c-fos expression. Blocking the activation of the JAK-STAT pathway prevents neuroinflammation and the reduction in Neurexin1-PSD95-Neurologigin1. These results indicate that ZnO NPs can be transported by the tongue-brain pathway and lead to abnormal taste perception by neuroinflammation-induced deficits in synaptic transmission. The study reveals the influence of ZnO NPs on neuronal function and provides a novel mechanism.