A novel neuroprotective peptide YVYAETY identified and screened from Flammulina velutipes protein hydrolysates attenuates scopolamine-induced cognitive impairment in mice.

Flammulina velutipes protein hydrolysates are known for their abundant amino acids and excellent developmental values. This study aimed to identify and screen neuroprotective peptides from F. velutipes protein hydrolysates in vitro and validate the protective effects of YVYAETY on memory impairment in scopolamine-induced mice. The F. velutipes protein was hydrolyzed by simulated gastrointestinal digestion, followed by purification through ultrafiltration and gel chromatography. The fraction exhibiting the strongest neuroprotective activity was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main identified peptides (SDLKPADF, WNDHYY, YVYAETY, and WFHPLF) effectively mitigated excessive ROS production by increasing SOD and GSH-px activities while inhibiting cell apoptosis and mitochondrial membrane potential (MMP) collapse against oxidative stress in Aß25-35-induced HT22 cells. By molecular docking, the interaction between peptides and the active site of the Keap1-Kelch domain reveals their capacity to regulate the Keap1/Nrf2/HO-1 pathway. In vitro, the peptide YVYAETY had the best effect and can be further validated in vivo. The behavioral tests showed that YVYAETY improved scopolamine-induced cognitive impairment in mice. YVYAETY also alleviated neuron damage including neuron vacuolation and pyknotic nuclei in the hippocampus. Furthermore, it significantly inhibited oxidative stress and suppressed the activation of the Nrf2 pathway. Therefore, this study revealed that YVYAETY had the potential to serve as a novel neuroprotective agent.

MicroRNA164 Affects Plant Responses to UV Radiation in Perennial Ryegrass.

Increasing the ultraviolet radiation (UV) level, particularly UV-B due to damage to the stratospheric ozone layer by human activities, has huge negative effects on plant and animal metabolism. As a widely grown cool-season forage grass and turfgrass in the world, perennial ryegrass (Lolium perenne) is UV-B-sensitive. To study the effects of miR164, a highly conserved microRNA in plants, on perennial ryegrass under UV stress, both OsmiR164a overexpression (OE164) and target mimicry (MIM164) transgenic perennial ryegrass plants were generated using agrobacterium-mediated transformation, and UV-B treatment (~600 µw cm-2) of 7 days was imposed. Morphological and physiological analysis showed that the miR164 gene affected perennial ryegrass UV tolerance negatively, demonstrated by the more scorching leaves, higher leaf electrolyte leakage, and lower relative water content in OE164 than the WT and MIM164 plants after UV stress. The increased UV sensitivity could be partially due to the reduction in antioxidative capacity and the accumulation of anthocyanins. This study indicated the potential of targeting miR164 and/or its targeted genes for the genetic manipulation of UV responses in forage grasses/turfgrasses; further research to reveal the molecular mechanism underlying how miR164 affects plant UV responses is needed.

Advances in the Design of Functional Cellulose Based Nanopesticide Delivery Systems.

The advancement of science and technology, coupled with the growing environmental consciousness among individuals, has led to a shift in pesticide development from traditional methods characterized by inefficiency and misuse toward a more sustainable and eco-friendly approach. Cellulose, as the most abundant natural renewable resource, has opened up a new avenue in the field of biobased drug carriers by developing cellulose-based drug delivery systems. These systems offer unique advantages in terms of deposition rate enhancement, modification facilitation, and environmental impact reduction when designing nanopesticides. Consequently, their application in the field of nanoscale pesticides has gained widespread recognition. The present study provides a comprehensive review of cellulose modification methods, carrier types for cellulose-based nanopesticides delivery systems (CPDS), and various stimulus-response factors influencing pesticide release. Additionally, the main challenges in the design and application of CPDS are summarized, highlighting the immense potential of cellulose-based materials in the field of nanopesticides.

Fibrosis and steatotic liver disease in US adolescents according to the new nomenclature.

OBJECTIVE: To apply the new nomenclature for steatotic liver diseases (SLD), replacing nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD), in adolescents using National Health and Nutrition Examination Survey (NHANES) data. METHODS: Among 1410 adolescents (12-19 years) in NHANES (2017-March, 2020), the controlled attenuation parameter (CAP) of transient elastography (TE) was used to define steatosis and fibrosis (TE ≥ 7.4 kPa). Obesity and alanine aminotransferase (ALT) ≥ 80 U/L were used to identify adolescents qualifying for hepatology referral according to practice guidelines. NAFLD was defined as liver steatosis without a specific exposure; it has no cardiometabolic risk factor requirement, unlike MASLD. RESULTS: Steatosis (yes/no) is the first decision point in the new diagnostic protocol; however, criteria for steatosis are undefined. At the supplier (EchoSens)-recommended CAP threshold of 240 dB/m, 30.5% (95% confidence interval [CI]: 27.1%-34.0%) of adolescents had SLD and about 85% of adolescents with NAFLD met criteria for MASLD. The other 15% would receive an ambiguous diagnosis of either cryptogenic SLD or possible MASLD. At higher CAP thresholds, MASLD/NAFLD concordance increased and approached 100%. Among adolescents with MASLD-fibrosis, only 8.8% (95% CI: 0%-19.3%) had overweight/obese and ALT ≥ 80 U/L. CONCLUSIONS: The new nomenclature highlights the high prevalence of liver steatosis. At the CAP threshold of 240 dB/m, however, approximately 15% of adolescents would receive an ambiguous diagnosis, which could lead to confusion and worry. Fewer than 10% of adolescents with MASLD-fibrosis had overweight/obese and ALT ≥ 80 U/L. Revised guidelines are needed to ensure that the other 90% receive appropriate referral and liver disease care.

A global dataset of terrestrial evapotranspiration and soil moisture dynamics from 1982 to 2020.

Quantifying terrestrial evapotranspiration (ET) and soil moisture dynamics accurately is crucial for understanding the global water cycle and surface energy balance. We present a novel, long-term dataset of global ET and soil moisture derived from the newly developed Simple Terrestrial Hydrosphere model, version 2 (SiTHv2). This ecohydrological model, driven by multi-source satellite observations and hydrometeorological variables from reanalysis data, provides daily global ET-related estimates (e.g., total ET, plant transpiration, soil evaporation, intercepted evaporation) and three-layer soil moisture dynamics at a 0.1° spatial resolution. Validation with in-situ measurements and comparisons with mainstream global ET and soil moisture products demonstrate robust performance of SiTHv2 in both magnitude and temporal dynamics of ET and soil moisture at multiple scales. The comprehensive water path characterization in the SiTHv2 model makes this seamless dataset particularly valuable for studies requiring synchronized water budget and vegetation response to water constraints. With its long-term coverage and high spatiotemporal resolution, the SiTHv2-derived ET and soil moisture product will be suitable to support analyses related to the hydrologic cycle, drought assessment, and ecosystem health.

Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice.

BACKGROUND: Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. MATERIALS AND METHODS: To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. RESULTS: Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. CONCLUSIONS: Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

Effects of phoxim on antibacterial infection of silver carp.

The efficacy of phoxim in treating bacterial sepsis in silver carp is significant, yet its underlying mechanism remains elusive. This study aimed to establish a model of Aeromonas veronii infection in silver carp and subsequently treat the infected fish with 10 µg/L phoxim. Kidney and intestine samples from silver carp were collected for transcriptome analysis and assessment of intestinal microbial composition, with the aim of elucidating the mechanism underlying the efficacy of phoxim in treating bacterial sepsis in silver carp. The results of transcriptome and intestinal microbial composition analysis of silver carp kidney indicated that A. veronii infection could up-regulate the expression of il1ß, il6, nos2, ctsl, casp3 et al., which means, signifying that the kidney of silver carp would undergo inflammation, induce apoptosis, and alter the composition of intestinal microorganisms. Phoxim immersion might enhance the energy metabolism of silver carp and change its intestinal microbial composition, potentially elevating the antibacterial infection resistance of silver carp. These findings may contribute to an understanding of how phoxim can effectively treat bacterial sepsis in silver carp.

Effects of herbal dregs supplementation of Salvia miltiorrhiza and Isatidis Radix residues improved production performance and gut microbiota abundance in late-phase laying hens.

The present study was designed to evaluate the effect of a mixture of Chinese medicinal residues (CMRs) consisting of Salvia miltiorrhiza residues (SMR) and Isatidis Radix residues (IRR) on productive performance, egg quality, serum lipid and hormone levels, liver and blood antioxidant capacity, oviduct inflammation levels, and gut microbiota in the late-laying stage. A total of 288 fifty-four-week-old BaShang long-tailed hens were divided into four groups. The feed trial period was 8 weeks. The control group was fed the basic diet as a CCMR group, supplemented with 3, 4, and 6% for the experimental groups LCMR, MCMR, and HCMR. The egg production rate of the MCMR group was 8.1% higher than that of the CCMR group (p < 0.05). Serum triglyceride (TG) levels of hens of the CMR-supplemented group were significantly decreased than those of the CCMR group (p < 0.05). The group supplemented with different levels of CMR had significantly higher serum HDL-C levels compared with the control group (p < 0.05). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were remarkably increased for the LCMR and MCMR groups and significantly decreased for the HCMR group compared to CCMR (p < 0.05). Serum and liver glutathione peroxidase (GSH-PX) activities were significantly increased, and malondialdehyde (MDA) levels were significantly decreased in the MCMR group compared to the CCMR group (p < 0.05). The expression levels of tubal inflammatory factor markers (IL-4, IL-1ß, TNF-α) in the MCMR and HCMR groups were consistent with the pathological findings of the sections. As for cecal microbiota, supplementation with CMR affected the alpha diversity of the cecum microbiome at the genus level. The Shannon index was significantly higher in the MCMR group than in the CCMR and HCMR groups (p < 0.05). Supplementation with different levels of CMR mainly regulated the ratio of intestinal Firmicutes to Bacteroidetes and the abundance of phyla such as Proteobacteria. In addition, CMR supplementation at different levels in the diet enriched lipid-metabolizing bacteria, such as Bacteroides and Ruminococcus_gnavus_group. Furthermore, according to linear discriminant analysis (LDA) effect size (LEfSe) analysis, the MCMR group showed an increase in the number of short-chain fatty acid-producing bacteria Romboutsia and fiber-degrading specialized bacteria Monoglobus. Therefore, supplementation of appropriate amounts of CMR to the diet of laying hens enhanced reproductive hormone levels, hepatic antioxidant capacity, and lipid metabolism, alleviated the levels of oviductal inflammatory factors, and modulated the abundance structure of bacterial flora to improve the late-laying performance and egg quality. The results of the current study showed that CMR is a beneficial feed supplement for chickens when added in moderation.

Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling.

Cooperative interactions in protein-protein interfaces demonstrate the interdependency or the linked network- like behavior and their effect on the coupling of proteins. Cooperative interactions also could cause ripple or allosteric effects at a distance in protein-protein interfaces. Although they are critically important in protein-protein interfaces, it is challenging to determine which amino acid pair interactions are cooperative. In this work we have used Bayesian network modeling, an interpretable machine learning method, combined with molecular dynamics trajectories to identify the residue pairs that show high cooperativity and their allosteric effect in the interface of G protein coupled receptor (GPCR) complexes with Gα subunits. Our results reveal six GPCR:Gα contacts that are common to the different Gα subtypes and show strong cooperativity in the formation of interface. Both the C-terminus helix5 and the core of the G protein are codependent entities and play an important role in GPCR coupling. We show that a promiscuous GPCR coupling to different Gα subtypes, makes all the GPCR:Gα contacts that are specific to each Gα subtype (Gαs, Gαi and Gαq). This work underscores the potential of data-driven Bayesian network modeling in elucidating the intricate dependencies and selectivity determinants in GPCR:G protein complexes, offering valuable insights into the dynamic nature of these essential cellular signaling components.

Quantitative lipidomics reveals the changes of lipids and antioxidant capacity in egg yolk from laying hens with fatty liver hemorrhagic syndrome.

In laying hens, fatty liver hemorrhagic syndrome (FLHS) is a common metabolic disorder, which can affect egg production and nutritional value. However, the impact of FLHS on the lipid content in egg yolks was not clear. In this study, FLHS model was induced by using high-energy low-protein diet, and the egg quality was evaluated. Egg yolk lipids were quantitatively analyzed by using ultra-performance liquid chromatography-mass spectrometry combined with multivariate statistical analysis. Gene expressions of the lipoprotein were determined by qRT-PCR and antioxidant capacity of the egg yolk were determined by kits. The elevated blood lipids and extensive lipid droplets observed indicated successful establishment of the FLHS model in laying hens. Measurements of egg quality showed that egg yolk weight was increased in the FLHS group. Lipidomics revealed that 1,401 lipids, comprising 27 lipid subclasses in the egg yolk. According to score plots of principal component analysis and orthogonal partial least squares discriminant analysis, different lipid profile was observed between the control and FLHS groups. A total of 97 different lipid species were screen out. Sphingolipid and glycerophospholipid metabolism were identified as key pathways. Free polyunsaturated fatty acids (PUFA) exhibited an increase in the FLHS group (P < 0.05). Notably, the form of PUFAs was changed that the FLHS group showed an increase in triacylglycerol-docosahexenoic acid and triacylglycerol-arachidonic acid in the egg yolk, while triacylglycerol-α-linolenic acid was decreased (P < 0.05). Total superoxide dismutase was decreased in the egg yolks affected by FLHS. Gene expressions of vitellogenin 2 (VTG2), VTG3, very low-density apolipoprotein II and apolipoprotein B were increased in the liver of laying hens with FLHS (P < 0.05). In conclusion, FLHS promoted the lipid transport from the liver to the yolk by upregulating lipoprotein expression, which altered lipid profile, and reduced antioxidant capacity in the yolk. This study provided a foundation for understanding the changes in lipids, lipid transport and lipid antioxidation capacity in egg yolk from laying hens with FLHS.

Identification of Hsp20 gene family in Malus domestica and functional characterization of Hsp20 class I gene MdHsp18.2b.

Heat shock protein 20 (Hsp20) is a small molecule heat shock protein that plays an important role in plant growth, development, and stress resistance. Little is known about the function of Hsp20 family genes in apple (Malus domestica). Here, we performed a genome-wide analysis of the apple Hsp20 gene family, and a total of 49 Hsp20s genes were identified from the apple genome. Phylogenetic analysis revealed that the 49 genes were divided into 11 subfamilies, and MdHsp18.2b, a member located in the CI branch, was selected as a representative member for functional characterization. Treatment with NaCl and Botryosphaeria dothidea (B. dothidea), the causal agent of apple ring rot disease, significantly induced MdHsp18.2b transcription level. Further analysis revealed that overexpressing MdHsp18.2b reduced the resistance to salt stress but enhanced the resistance to B. dothidea infection in apple calli. Moreover, MdHsp18.2b positively regulated anthocyanin accumulation in apple calli. Physiology assays revealed that MdHsp18.2b promoted H2O2 production, even in the absence of stress factors, which might contribute to its functions in response to NaCl and B. dothidea infection. Hsps usually function as homo- or heterooligomers, and we found that MdHsp18.2b could form a heterodimer with MdHsp17.9a and MdHsp17.5, two members from the same branch with MdHsp18.2b in the phylogenetic tree. Therefore, we identified 49 Hsp20s genes from the apple genome and found that MdHsp18.2b was involved in regulating plant resistance to salt stress and B. dothidea infection, as well as in regulating anthocyanin accumulation in apple calli.

Highly Sensitive and Stable Flexible Smart Sensors Based on Commercial Carbon Fiber Powder Inks.

With the fast development of the smart lifestyle in recent years, simple and flexible body condition monitoring has become more and more important. However, currently, commercially available motion-sensing devices always lack flexibility or at a high cost. This article has fully explored the merits of a commercial and easily available material of carbon fiber powder (CFP) and prepared CFP-based screen printing inks. This conductive ink can be directly and quickly printed onto a variety of different flexible common substrates, such as paper, cotton fabrics, etc., to prepare flexible sensors. At the same time, as a result of the good photothermal performance and conductivity of CFP, the printed flexible sensors have fast and stable performance on thermal and human motion detection. The use of CFP as the smart element to construct a wearable device will offer a choice for the intelligent industry.

Characterization and removal mechanism of fluoroquinolone-bioremediation by fungus Cladosporium cladosporioides 11 isolated from aquacultural sediments.

Antibiotics have been widely detected in aquatic environments, and fungal biotransformation receives considerable attention for antibiotic bioremediation. Here, a fungus designated Cladosporium cladosporioides 11 (CC11) with effective capacity to biotransform fluoroquinolones was isolated from aquaculture pond sediments. Enrofloxacin (ENR), ciprofloxacin (CIP) and ofloxacin (OFL) were considerably abated by CC11, and the antibacterial activities of the fluoroquinolones reduced significantly after CC11 treatment. Transcriptome analysis showed the removal of ENR, CIP and OFL by CC11 is a process of enzymatic degradation and biosorption which consists well with ligninolytic enzyme activities and sorption experiments under the same conditions. Additionally, CC11 significantly removed ENR in zebrafish culture water and reduced the residue of ENR in zebrafish. All these results evidenced the potential of CC11 as a novel environmentally friendly process for the removal of fluoroquinolones from aqueous systems and reduce fluoroquinolone residues in aquatic organisms.

Scalable Fabrication of Ionic-Conductive Covalent Organic Framework Fibers for Capturing of Sustainable Osmotic Energy.

High-performance covalent organic framework (COF) fibers are demanded for an efficient capturing of blue osmotic power because of their excellent durability, simple integration, and large scalability. However, the scalable production of COF fibers is still very challenging due to the poor solubility and fragile structure of COFs. Herein, for the first time, it is reported that COF dispersions can be continuously processed into macroscopic, meter-long, and pure COF fibers using a wet spinning approach. The two presented COF fibers can be directly used for capturing of osmotic energy, avoiding the production of composite materials that require other additives and face challenges such as phase separation and environmental issues induced by the additives. A COF fiber exhibits power densities of 70.2 and 185.3 W m-2 at 50-fold and 500-fold salt gradients, respectively. These values outperform those of most reported systems, which indicate the high potential of COF fibers for capturing of blue osmotic energy.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1ß, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566 µM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 µM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

A systematic review and meta-analysis of the association between air pollutants and the incidence of tuberculosis.

Objective: To investigate the association between air pollutants and the incidence of tuberculosis (TB) through a systematic review and meta-analysis, and to provide directions for future research and prevention of TB. Methods: A search was conducted for all literature related to the incidence of TB and air pollution in the database. We screened the retrieved articles and proceeded statistical analyses using random effects models to investigate the relationships between five air pollutants (PM2.5, PM10, SO2, NO2 and O3) and the incidence of TB. Results: The initial search identified 100 pieces of literature and 9 studies met the screening criteria after the screening. The single-day lagged risk ratio (RR) and 95% Confidence Intervals (CIs) for the combined effects estimates are as follows: PM2.5: 1.059 (0.966, 1.160); PM10: 1.000 (0.996, 1.004); SO2: 0.980 (0.954, 1.007); NO2: 1.011 (0.994, 1.027); O3: 0.994 (0.980,1.008). The cumulative lagged results for these five pollutants are listed like this: PM2.5: 1.095 (0.983, 1.219); PM10: 1.035 (1.006, 1.066); SO2: 0.964 (0.830, 1.121); NO2: 1.037 (1.010, 1.065); O3: 0.982 (0.954, 1.010). Conclusion: The single-day lag effects of PM2.5, PM10, SO2, NO2, and O3 are not statistically significantly relevant for the occurrence of TB. However, the cumulative lag results show that both PM10 and NO2 contribute to the prevalence of TB, while the statistical relationship between the cumulative lag effects of PM2.5, SO2, and O3 and the onset of TB remains unknown.

The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

Multiplex dependence analysis of China's interprovincial virtual water based on an ecological network.

The interprovincial circulation of goods and services has formed virtual water flows between regions, which can redistribute water resources. Based on previous virtual water trade research, this study further explored the multiple dependencies of virtual water, i.e., direct, indirect, and complete dependence. This study examined the direct, indirect, and complete dependence of virtual water between provinces in China by constructing multilayer dependence networks and identified the key regions and paths of virtual water trade network. The results showed direct dependence was the densest and had the largest overall dependence degree, but indirect dependence was the most stable and orderly. Second, the dominant provinces were Guangxi, Hunan, Sichuan, Xinjiang, and Anhui, referred to as "core‒five‒region," and the flow relevant to them accounted for approximately 30% of the virtual water. The seven provinces of Shanxi, Zhejiang, Shandong, Hubei, Guangdong, Shaanxi, and Gansu depend both directly and indirectly on the "core‒five‒region." Shanxi and Zhejiang have close direct and indirect dependence, with more than one of the "core‒five‒region." Guangdong was the province with the most direct and indirect input of virtual water from the "core‒five‒region." The study provides a scientific basis for multiregional identification for the collaborative management of water resources in China from the perspective of dependence.