Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Design-build-test of recombinant Bacillus subtilis chassis cell by lifespan engineering for robust bioprocesses.

Microbial cell factories utilize renewable raw materials for industrial chemical production, providing a promising path for sustainable development. Bacillus subtilis is widely used in industry for its food safety properties, but challenges remain in the limitations of microbial fermentation. This study proposes a novel strategy based on lifespan engineering to design robust B. subtilis chassis cells to supplement traditional metabolic modification strategies that can alleviate cell autolysis, tolerate toxic substrates, and get a higher mass transfer efficiency. The modified chassis cells could produce high levels of l-glutaminase, and tolerate hydroquinone to produce α-arbutin efficiently. In a 5 L bioreactor, the l-glutaminase enzyme activity of the final strain CRE15TG was increased to 2817.4 ± 21.7 U mL-1, about 1.98-fold compared with that of the wild type. The α-arbutin yield of strain CRE15A was increased to 134.7 g L-1, about 1.34-fold compared with that of the WT. To our knowledge, both of the products in this study performed the highest yields reported so far. The chassis modification strategy described in this study can Improve the utilization efficiency of chassis cells, mitigate the possible adverse effects caused by excessive metabolic modification of engineered strains, and provide a new idea for the future design of microbial cell factories.

Synthesis of cis-(8b,14a)-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones via photo cascade reaction.

A concise method for the synthesis of cis-(8b,14a)-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones 2 via photo-induced 3-([1,1'-biphenyl]-2-yl)-1-(2-hydroxyethyl)pyridin-2(1H)-ones 1 was developed. Irradiation of 1 in the solution of toluene with a 313 nm UV light in the presence of HCl gave cis-(8b,14a)-9a-α-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinoli n-14-ones and cis-(8b,14a)-9a-ß-hexahydro-14H-dibenzo[f,h]oxazolo[3,2-b]isoquinolin-14-ones 2 (2-α and 2-ß) in good yields. The protocol simultaneously constructs dearomatized phenanthrene ring and oxindolizidinones ring by photo cascade reaction to achieve high bonding efficiency and high atomic efficiency. Additionally, the antitumor activities of 2 was evaluated and compounds 2b-α, 2b-ß, 2j-ß and 2 k-α showed similar or better activity compared to the cisplatin against tumor cell lines of Leukemia HL-60, lung cancer A594, liver cancer SMMC-7721 and breast cancer MDA-MB-231.

Microeukaryotic plankton evolutionary constraints in a subtropical river explained by environment and bacteria along differing taxonomic resolutions.

Microeukaryotic plankton communities are keystone components for keeping aquatic primary productivity. Currently, variations in microeukaryotic plankton diversity have often been explained by local ecological factors but not by evolutionary constraints. We used amplicon sequencing of 100 water samples across five years to investigate the ecological preferences of the microeukaryotic plankton community in a subtropical riverine ecosystem. We found that microeukaryotic plankton diversity was less associated with bacterial abundance (16S rRNA gene copy number) than bacterial diversity. Further, environmental effects exhibited a larger influence on microeukaryotic plankton community composition than bacterial community composition, especially at fine taxonomic levels. The evolutionary constraints of microeukaryotic plankton community increased with decreasing taxonomic resolution (from 97% to 91% similarity levels), but not significant change from 85% to 70% similarity levels. However, compared with the bacterial community, the evolutionary constraints were shown to be more affected by environmental variables. This study illustrated possible controlling environmental and bacterial drivers of microeukaryotic diversity and community assembly in a subtropical river, thereby indirectly reflecting on the quality status of the water environment by providing new clues on the microeukaryotic community assembly.

On-chip octave-spanning flat supercontinuum in all-normal-dispersion silicon nitride waveguides.

On-chip supercontinuum generators have emerged as an attractive optical source with small size, broad spectrum and high power efficiency. Nevertheless, there has long been a trade-off between spectral uniformity and bandwidth. We propose a novel silicon nitride waveguide with flat saddle-shaped all-normal dispersion, particularly for enhancing the nonlinear interactions over a wide band. By launching a 250-fs 30-kW input pulse, an ultra-flat (-6 dB) octave-spanning supercontinuum extending from 638 nm to 1477 nm can be generated. We analyze the performance of the supercontinuum generator in terms of spectral flatness and bandwidth under different input pulse conditions. Thanks to mature dispersion engineering, the pump wavelength can be flexibly selected within the flat dispersion region. The generated supercontinuum, therefore, can be applied to different spectral regions by shifting the center wavelength.

The association between intensity-specific physical activity and the number of multiple chronic diseases among Chinese elderly: A study based on the China Health and Retirement Longitudinal study (CHARLS).

Background: With ageing, the elderly are facing a complex situation where multiple chronic diseases coexist. This paper aims to investigate the effect of intensity-specific physical activity on the number of multiple chronic diseases in the elderly. Methods: Our data came from wave 4 of the China Health and Retirement Longitudinal Survey (CHARLS), which involved 10,341 residents aged ≥ 60 years. The intensity-specific physical activity was divided into two categories: moderate-intensity physical activity (MPA) lasting ≥ 150 min/week and vigorous-intensity physical activity (VPA) lasting ≥ 75 min/week. Data on 14 types of chronic diseases were collected. Propensity score matching (PSM) with controlling nine confounding factors were used to analyse the effects of intensity-specific physical activity. Results: Among 10,341 samples, 40.12% of the elderly often participated in MPA and 25.72% participated in VPA. The PSM results showed that performing 150 min/week of MPA leads to 0.0675(P<0.05) fewer multiple chronic diseases than not achieving this standard, and VPA up to 75 min/week leads to 0.0785(P<0.05) fewer multiple chronic disease than that does not meet this criterion. Additionally, VPA is more effective than MPA. Conclusion: Both MPA of at least 150 min/week and VPA of at least 75 min/week can significantly reduce the number of multiple chronic diseases in elderly. Elderly people should increase their exercise intensity as much as possible while ensuring safety.

A colorimetric and SERS dual-mode aptasensor for the detection of Shiga toxin type II based on Mn/Fe-MIL(53)@AuNSs.

Shiga toxin type II (Stx2), the major virulence component of enterohemorrhagic Escherichia coli, is strongly associated with the life-threatening hemolytic uremic syndrome thus posing a substantial risk to food safety and human health. In this work, a dual-mode aptasensor with colorimetric and surface-enhanced Raman scattering was developed for Stx2 specific detection based on noble metal nanoparticles and Raman reporter loaded metal-organic framework (Mn/Fe-MIL(53)@AuNSs-MBA). The Mn/Fe-MIL(53)@AuNSs could catalyze the H2O2-mediated oxidation of 3,3',5,5'-tetramethylbenzidine (TMB), thereby enabling visual detection. Meanwhile, the SERS signal from MBA can be enhanced by the decorated AuNSs. Under optimal conditions, a linear range of 0.05-500 ng/mL with limit of detection (LOD) of 26 pg/mL was achieved in colorimetric mode and a linear range of 5-1000 ng/mL with LOD of 0.82 ng/mL in SERS mode, in which the dual-mode results complement each other, widening the linear range, increasing the accuracy and reliability of the detection. The method was further applied to the detection of Stx2 in milk with average recovery of 101.1 %, demonstrating its superior potential for bacterial toxin monitoring.

Dual Heterojunctions and Nanobowl Morphology Engineered BiVO4 Photoanodes for Enhanced Solar Water Splitting.

Photoelectrochemical (PEC) water splitting represents an attractive strategy to realize the conversion from solar energy to hydrogen energy, but severe charge recombination in photoanodes significantly limits the conversion efficiency. Herein, a unique BiVO4 (BVO) nanobowl (NB) heterojunction photoanode, which consists of [001]-oriented BiOCl underlayer and BVO nanobowls containing embedded BiOCl nanocrystals, is fabricated by nanosphere lithography followed by in situ transformation. Experimental characterizations and theoretical simulation prove that nanobowl morphology can effectively enhance light absorption while reducing carrier diffusion path. Density functional theory (DFT) calculations show the tendency of electron transfer from BVO to BiOCl. The [001]-oriented BiOCl underlayer forms a compact type II heterojunction with the BVO, favoring electron transfer from BVO through BiOCl to the substrate. Furthermore, the embedded BiOCl nanoparticles form a bulk heterojunction to facilitate bulk electron transfer. Consequently, the dual heterojunctions engineered BVO/BiOCl NB photoanode exhibits attractive PEC performance toward water oxidation with an excellent bulk charge separation efficiency of 95.5%, and a remarkable photocurrent density of 3.38 mA cm-2 at 1.23 V versus reversible hydrogen electrode, a fourfold enhancement compared to the flat BVO counterpart. This work highlights the great potential of integrating dual heterojunctions engineering and morphology engineering in fabricating high-performance photoelectrodes toward efficient solar conversion.

A brief history of metal recruitment in protozoan predation.

Metals and metalloids are used as weapons for predatory feeding by unicellular eukaryotes on prokaryotes. This review emphasizes the role of metal(loid) bioavailability over the course of Earth's history, coupled with eukaryogenesis and the evolution of the mitochondrion to trace the emergence and use of the metal(loid) prey-killing phagosome as a feeding strategy. Members of the genera Acanthamoeba and Dictyostelium use metals such as zinc (Zn) and copper (Cu), and possibly metalloids, to kill their bacterial prey after phagocytosis. We provide a potential timeline on when these capacities first evolved and how they correlate with perceived changes in metal(loid) bioavailability through Earth's history. The origin of phagotrophic eukaryotes must have postdated the Great Oxidation Event (GOE) in agreement with redox-dependent modification of metal(loid) bioavailability for phagotrophic poisoning. However, this predatory mechanism is predicted to have evolved much later - closer to the origin of the multicellular metazoans and the evolutionary development of the immune systems.

Prognostic significance of the systemic immune-inflammation index in patients with extranodal natural killer/T-cell lymphoma.

Background: The systemic immune-inflammation index (SII) is based on the neutrophil, platelet, and lymphocyte counts, and has been identified as a prognostic marker in multiple types of cancer. However, the potential value of the SII for predicting survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTCL) has not been investigated thus far. Method: This study included 382 patients with ENKTCL treated with asparaginase-base regimens from 2021 to 2017 in West China Hospital (Chengdu, China). Clinical and demographic variables, as well as the prognostic value of the SII, were analyzed using Cox proportional hazards regression analysis. Results: The complete and objective response rates were 55.8% and 74.9%, respectively. Patients with high SII were associated with a lower rate of complete response, higher rate of B symptoms, and serum lactate dehydrogenase levels above or equal to the upper limits of normal (p < 0.01). Patients with low SII were linked to better overall survival and progression-free survival than those with high SII (p < 0.01). Patients with early-stage disease or prognostic model for natural killer lymphoma with Epstein-Barr virus, defined as the low-risk group, could be further stratified according to the SII (p < 0.01). Negative prognostic factors were determined using the Cox proportional hazards regression analysis, which identified four variables: Eastern Cooperative Oncology Group performance status score ≥2, Stage III/IV disease, positivity for Epstein-Barr virus DNA in plasma, and high SII. Predictive nomograms for the prediction of 3- and 5-year overall survival, as well as progression-free survival, were constructed based on those four variables. The nomograms demonstrated favorable discriminating power. Conclusion: The SII is a novel prognostic marker for ENKTCL, which may be used for the prediction of poorer survival in low-risk patients.

Corrigendum: Tetraploidy in Citrus wilsonii enhances drought tolerance via synergistic regulation of photosynthesis, phosphorylation, and hormonal changes.

[This corrects the article DOI: 10.3389/fpls.2022.875011.].

Unveiling the tribological potential of MXenes-current understanding and future perspectives.

Reducing energy consumption and CO2 emissions by improving the tribological performance of mechanical systems relies on the development of new lubrication concepts. Two-dimensional (2D) materials have been the subject of extensive tribological research due to their unique physical and chemical properties. 2D transition metal carbides, nitrides, and carbonitrides (MXenes), with their tuneable chemistry and structure, are a relatively new addition to the family of 2D materials. MXenes' good strength and stiffness, easy-to-shear ability, capability to form wear-resistant tribofilms, and the possibility to control their surface chemistry make them appealing candidates to be explored for tribological purposes. This review provides a comprehensive overview of MXenes' tribology, covering their structure-property relationship, synthesis approaches, deposition methods to generate MXene coatings for tribological purposes, and their fundamental tribological mechanisms. Furthermore, detailed insights into studies exploring MXenes' tribological performance from the nano- to the macro-scale are presented with special emphasis on their use as self-lubricating solid lubricants, lubricant additives, and reinforcement phases in composites.

Phagotrophic protists preserve antibiotic-resistant opportunistic human pathogens in the vegetable phyllosphere.

Food safety of leafy greens is an emerging public health issue as they can harbor opportunistic human pathogens (OHPs) and expose OHPs to consumers. Protists are an integral part of phyllosphere microbial ecosystems. However, our understanding of protist-pathogen associations in the phyllosphere and their consequences on public health remains poor. Here, we examined phyllosphere protists, human pathogen marker genes (HPMGs), and protist endosymbionts from four species of leafy greens from major supermarkets in Xiamen, China. Our results showed that Staphylococcus aureus and Klebsiella pneumoniae were the dominant human pathogens in the vegetable phyllosphere. The distribution of HPMGs and protistan communities differed between vegetable species, of which Chinese chive possessed the most diverse protists and highest abundance of HPMGs. HPMGs abundance positively correlated with the diversity and relative abundance of phagotrophic protists. Whole genome sequencing further uncovered that most isolated phyllosphere protists harbored multiple OHPs which carried antibiotic resistance genes, virulence factors, and metal resistance genes and had the potential to HGT. Colpoda were identified as key phagotrophic protists which positively linked to OHPs and carried diverse resistance and virulence potential endosymbiont OHPs including Pseudomonas nitroreducens, Achromobacter xylosoxidans, and Stenotrophomonas maltophilia. We highlight that phyllosphere protists contribute to the transmission of resistant OHPs through internalization and thus pose risks to the food safety of leafy greens and human health. Our study provides insights into the protist-OHP interactions in the phyllosphere, which will help in food safety surveillance and human health.

Functional characterization and structural basis of a reversible glycosyltransferase involves in plant chemical defence.

Plants experience numerous biotic stresses throughout their lifespan, such as pathogens and pests, which can substantially affect crop production. In response, plants have evolved various metabolites that help them withstand these stresses. Here, we show that two specialized metabolites in the herbaceous perennial Belamcanda chinensis, tectorigenin and its glycoside tectoridin, have diverse defensive effects against phytopathogenic microorganisms and antifeeding effects against insect pest. We further functionally characterized a 7-O-uridine diphosphate glycosyltransferase Bc7OUGT, which catalyses a novel reversible glycosylation of tectorigenin and tectoridin. To elucidate the catalytic mechanisms of Bc7OUGT, we solved its crystal structure in complex with UDP and UDP/tectorigenin respectively. Structural analysis revealed the Bc7OUGT possesses a narrow but novel substrate-binding pocket made up by plentiful aromatic residues. Further structure-guided mutagenesis of these residues increased both glycosylation and deglycosylation activities. The catalytic reversibility of Bc7OUGT was also successfully applied in an one-pot aglycon exchange reaction. Our findings demonstrated the promising biopesticide activity of tectorigenin and its glycosides, and the characterization and mechanistic study of Bc7OUGT could facilitate the design of novel reversible UGTs to produce valuable glycosides with health benefits for both plants and humans.

Alginate: Microbial production, functionalization, and biomedical applications.

Alginates are natural polysaccharides widely participating in food, pharmaceutical, and environmental applications due to their excellent gelling capacity. Their excellent biocompatibility and biodegradability further extend their application to biomedical fields. The low consistency in molecular weight and composition of algae-based alginates may limit their performance in advanced biomedical applications. It makes microbial alginate production more attractive due to its potential for customizing alginate molecules with stable characteristics. Production costs remain the primary factor limiting the commercialization of microbial alginates. However, carbon-rich wastes from sugar, dairy, and biodiesel industries may serve as potential substitutes for pure sugars for microbial alginate production to reduce substrate costs. Fermentation parameter control and genetic engineering strategies may further improve the production efficiency and customize the molecular composition of microbial alginates. To meet the specific needs of biomedical applications, alginates may need functionalization, such as functional group modifications and crosslinking treatments, to achieve enhanced mechanical properties and biochemical activities. The development of alginate-based composites incorporated with other polysaccharides, gelatin, and bioactive factors can integrate the advantages of each component to meet multiple requirements in wound healing, drug delivery, and tissue engineering applications. This review provided a comprehensive insight into the sustainable production of high-value microbial alginates. It also discussed recent advances in alginate modification strategies and alginate-based composites for representative biomedical applications.

SceneDirector: Interactive Scene Synthesis by Simultaneously Editing Multiple Objects in Real-Time.

Intelligent tools for creating synthetic scenes have been developed significantly in recent years. Existing techniques on interactive scene synthesis only incorporate a single object at every interaction, i.e., crafting a scene through a sequence of single-object insertions with user preferences. These techniques suggest objects by considering existent objects in the scene instead of fully picturing the eventual result, which is inherently problematic since the sets of objects to be inserted are seldom fixed during interactive processes. In this article, we introduce SceneDirector, a novel interactive scene synthesis tool to help users quickly picture various potential synthesis results by simultaneously editing groups of objects. Specifically, groups of objects are rearranged in real-time with respect to a position of an object specified by a mouse cursor or gesture, i.e., a movement of a single object would trigger the rearrangement of the existing object group, the insertions of potentially appropriate objects, and the removal of redundant objects. To achieve this, we first propose an idea of coherent group set which expresses various concepts of layout strategies. Subsequently, we present layout attributes, where users can adjust how objects are arranged by tuning the weights of the attributes. Thus, our method gives users intuitive control of both how to arrange groups of objects and where to place them. Through extensive experiments and two applications, we demonstrate the potentiality of our framework and how it enables concurrently effective and efficient interactions of editing groups of objects.

A controlling nutritional status score is an independent predictor for patients with newly diagnosed nasal-type extranodal NK/T-cell lymphoma based on asparaginase-containing regimens.

BACKGROUND: The controlling nutritional status (CONUT) score is a nutritional index that combines serum albumin, total cholesterol, and lymphocyte counts. The potential value of CONUT score for predicting clinical outcomes in patients with nasal-type extranodal NK/T-cell lymphoma (ENKTL) has not been explored. METHODS: This study included 374 ENKTL patients treated with asparaginase-containing regimens from September 2012 to September 2017. Clinical characteristics, treatment efficacy, prognostic factors, and the predictive value of CONUT score were analyzed. RESULTS: The complete response (CR) and overall response rate (ORR) were 54.8% and 74.6%, respectively. Patients with CONUT scores <2 had higher CR and ORR compared to patients with scores ≥2 (69.1% vs. 48.9% for CR, p = 0.001; 90.0% vs. 74.6% for ORR, p < 0.001). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 61.9% and 57.3%, respectively. Patients with CONUT scores <2 had better survival outcomes than those with scores ≥2 (5-year OS, 76.1% vs. 56.0%, p < 0.001; 5-year PFS, 74.4% vs. 50.1%, p < 0.001). CONUT score ≥2 was identified as an independent poor prognostic factor for both OS and PFS. A CONUT score ≥2 was also associated with poorer survival outcomes in low-risk ENKTL patients. CONCLUSION: A CONUT score ≥2 is a prognostic marker for poor survival in patients with ENKTL and could be used to stratify risk in low-risk patients.

Comparison of the clinical efficacies of two L-asparaginase-based chemotherapy regimens for newly diagnosed nasal-type extranodal NK/T-cell lymphoma.

BACKGROUND: Nasal-type extranodal natural killer (NK)/T cell lymphoma (ENKTL) is a rare and aggressive type of lymphoma. The optimal chemotherapy regimen for ENKTL has not yet been established. In this study, we compared the LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) and GLIDE (gemcitabine, L-asparaginase, ifosfamide, dexamethasone, and etoposide) chemotherapy regimens for the treatment of ENKTL. METHODS: A total of 267 patients with newly diagnosed ENKTL were included in this retrospective study. Propensity score matching (PSM) was used to adjust for confounders between the LVDP and GLIDE groups. Treatment responses, survival outcomes, and toxicities between the two groups were compared before and after PSM. RESULTS: At the end of therapy, the objective response rate (ORR) and complete response (CR) were 83.5% and 62.2%, respectively, for all patients. The ORR and CR were 85.5% and 62.2% for the LVDP group compared with 79.3% and 62.2% for the GLIDE group, respectively, and no differences between the two groups were found (ORR, p = 0.212; CR, p = 0.996). With a median 71 months follow-up, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 64.3% and 68.5%, respectively. The 5-year PFS and OS were 65.6% and 70.1% for the LVDP group compared with 61.6% and 64.6% for the GLIDE group, respectively (PFS, p = 0.478; OS, p = 0162). After PSM, no significant differences in short-term efficacy (ORR, p = 0.696; CR, p = 0.264) or long-term efficacy (PFS, p = 0.794; OS, p = 0.867) between the two groups were identified. However, treatment-related toxicities were milder in the LVDP group compared to the GLIDE group, even after adjusting for confounders via PSM. CONCLUSION: In conclusion, both LVDP and GLIDE regimens are effective for the treatment of ENKTL. However, the LVDP regimen is safer than the GLIDE regimen, with milder treatment-related toxicities. Therefore, the LVDP regimen could be a preferable option for patients with ENKTL.

Quadriwave lateral shearing interferometry based on double birefringent crystals of beam displacer.

A quadriwave lateral shearing interferometry (QWLSI) is proposed based on double birefringent crystals of a beam displacer (DBCs-BD). The DBCs-BD is formed by adopting two birefringent crystals of a polarization beam displacer (PBD), which can generate the lateral shearing interference waves of four beams of overlapped replicas in the DBCs-BD orthogonal directions. When the replica waves are overlapped incident to the analyzer, and the direction of the transmission axis is set as 45° or 135°, the QWLSI's polarization interferogram can be obtained. The high-precision phase can be obtained by simple spectrum denoising and performing the Fourier transform of the resulting interferogram. We deduce the principle of QWLSI in detail, and the wavefront distribution can be achieved by the phase calculation. The experiment shows that the DBCs-BD-QWLSI exhibits feasibility and high precision.