Human striatal organoids derived from pluripotent stem cells recapitulate striatal development and compartments.

The striatum links neuronal circuits in the human brain, and its malfunction causes neuronal disorders such as Huntington's disease (HD). A human striatum model that recapitulates fetal striatal development is vital to decoding the pathogenesis of striatum-related neurological disorders and developing therapeutic strategies. Here, we developed a method to construct human striatal organoids (hStrOs) from human pluripotent stem cells (hPSCs), including hStrOs-derived assembloids. Our hStrOs partially replicated the fetal striatum and formed striosome and matrix-like compartments in vitro. Single-cell RNA sequencing revealed distinct striatal lineages in hStrOs, diverging from dorsal forebrain fate. Using hStrOs-derived assembloids, we replicated the striatal targeting projections from different brain parts. Furthermore, hStrOs can serve as hosts for striatal neuronal allografts to test allograft neuronal survival and functional integration. Our hStrOs are suitable for studying striatal development and related disorders, characterizing the neural circuitry between different brain regions, and testing therapeutic strategies.

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3-5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Layered Ferromagnetic Structure Caused by the Proximity Effect and Interlayer Charge Transfer for LaNiO3/LaMnO3 Superlattices.

Magnetic proximity-induced magnetism in paramagnetic LaNiO3 (LNO) has spurred intensive investigations in the past decade. However, no consensus has been reached so far regarding the magnetic order in LNO layers in relevant heterostructures. This paper reports a layered ferromagnetic structure for the (111)-oriented LNO/LaMnO3 (LMO) superlattices. It is found that each period of the superlattice consisted of an insulating LNO-interfacial phase (five unit cells in thickness, ∼1.1 nm), a metallic LNO-inner phase, a poorly conductive LMO-interfacial phase (three unit cells in thickness, ∼0.7 nm), and an insulating LMO-inner phase. All four of these phases are ferromagnetic, showing different magnetizations. The Mn-to-Ni interlayer charge transfer is responsible for the emergence of a layered magnetic structure, which may cause magnetic interaction across the LNO/LMO interface and double exchange within the LMO-interfacial layer. This work indicates that the proximity effect is an effective means of manipulating the magnetic state and associated properties of complex oxides.

Effects of CYP3A5*3 genetic polymorphisms on the pharmacokinetics of perampanel in Chinese pediatric patients with epilepsy.

PURPOSE: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. RESULTS: The plasma concentration showed a linear correlation with the daily dose taken ( r  = 0.17; P  < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ±â€…297.1 vs. 633.8 ±â€…305.5 µg/ml; P  = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ±â€…1.7 vs. 3.8 ±â€…2.0; P  = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ±â€…293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ±â€…165.6 ng/ml and 260.0 ±â€…36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ±â€…285.6 vs. 433.0 ±â€…227.2 ng/ml; P  = 0.042). CONCLUSION: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.

Proteomic analysis of mitochondria associated membranes in renal ischemic reperfusion injury.

BACKGROUND: The mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes. METHODS: A 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein-Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms. RESULTS: A total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value < 0.05 and HR/N > 1.5 or HR/N < 0.66 set as the threshold criteria. Enrichment analysis of differentially expressed proteins unveiled biological processes such as mRNA splicing, apoptosis regulation, and cell division, while molecular functions were predominantly associated with energy metabolic activity. These proteins play key roles in the cellular responses during HR, offering insights into the IRI mechanisms and potential therapeutic targets. The validation of hub genes MFN2 and BNIP3 both in vitro and vivo was consistent with the proteomic findings. MFN2 demonstrated a protective role in maintaining the integrity of mitochondria associated membranes (MAMs) and mitigating mitochondrial damage following hypoxia/reoxygenation injury, this protective effect may be associated with the activation of the PI3K/AKT pathway. CONCLUSIONS: The proteins located in mitochondria associated membranes (MAMs) are implicated in crucial roles during renal ischemic reperfusion injury (IRI), with MFN2 playing a pivotal regulatory role in this context.

Association Between Preeclampsia and Blood Pressure in Offspring: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Pregnancy-induced preeclampsia is a severe pregnancy complication and preeclampsia has been associated with an increased risk of chronic hypertension for offspring. However, the magnitude of the overall effect of exposure to preeclampsia in pregnancy on blood pressure (BP) in offspring is unknown. This systematic review and meta-analysis was sought to systematically assess the effects of preeclampsia on the BP of the offspring. RECENT FINDINGS: Of 2550 publications identified, 23 studies were included. The meta-analysis indicated that preeclampsia increases the potential risk of hypertension in offspring. Systolic blood pressure (SBP) was 2.0 mm Hg (95% CI: 1.2, 2.8) and diastolic blood pressure (DBP) was 1.4 mm Hg (95% CI: 0.9, 1.9) higher in offspring exposed to pre-eclampsia in utero, compared to those born to normotensive mothers. The correlations were similar in stratified analyses of children and adolescents by sex, geographic area, ages, and gestational age. During childhood and young adulthood, the offspring of pregnant women with preeclampsia are at an increased risk of high BP. It is crucial to monitor their BP.

Plasma Concentration, Efficacy, and Tolerability of Perampanel in Chinese Pediatric Patients with Epilepsy: Real-World Clinical Experience.

BACKGROUND: Information on the efficacy and plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy is limited. Therefore, this real-world retrospective study aimed to assess the efficacy, tolerability, and plasma concentration of the maximum dose of PER for epilepsy treatment in Chinese pediatric patients. METHODS: A total of 107 pediatric patients from 2 hospitals in China were enrolled in this study. The plasma concentration of PER was determined using ultrahigh-performance liquid chromatography. The primary efficacy endpoint was the seizure reduction rate after PER treatment at the last follow-up. RESULTS: The response rate to PER therapy was 59.8% (64/107). The authors observed that patients younger than 6 years of age (n = 49) showed a significantly lower concentration-to-dose ratio than patients with ages between 6 and 14 years (n = 58) (2.2 ± 1.7 vs. 3.0 ± 1.8 mcg·mL -1 ·kg·mg -1 , respectively; P < 0.05). Patients who received enzyme-inducing antiseizure medication had significantly lower concentration-to-dose ratios than those who did not receive enzyme-inducing antiseizure medication (EIASM) (2.1 ± 1.8 vs. 3.1 ± 2.0 mcg·mL -1 ·kg·mg -1 , P < 0.05). A total of 37 patients (34.6%) reported treatment adverse events. Patients with somnolence and irritability had a significantly higher PER plasma concentration than the "no treatment-emergent adverse effect" groups ( P < 0.05). CONCLUSIONS: PER is an effective and well-tolerated treatment option for patients with epilepsy. To ensure the clinical efficacy and safety of PER in pediatric patients, it is necessary to monitor its plasma concentrations.

Mechanochemical Formation of Poly(melamine-formaldehyde) Microplastic Fibers During Abrasion of Cleaning Sponges.

The abrasion of synthetic textile fibers is a significant factor in the generation of environmental microplastic fibers (MPFs). The extent to which polymer sponges designed specifically for surface cleaning have a tendency to release MPFs during normal use remains unknown. Here, the tribological behaviors of melamine cleaning sponges (also known as "magic erasers") with different strut densities against metal surfaces of different roughness were investigated using a reciprocating abrader. The MPFs formed by sponge wear under various conditions were characterized in terms of their morphology, composition, and quantity. They were mainly composed of poly(melamine-formaldehyde) polymer with linear or branched fiber morphologies (10-405 µm in length), which were formed through deformation and fracture of the struts within open cells of the sponges, facilitated by friction-induced polymer decomposition. The rate and capability of MPF production generally increased with increasing roughness of the metal surface and density of the struts, respectively. The sponge wear could release 6.5 million MPFs/g, which could suggest a global overall emission of 4.9 trillion MPFs due to sponge consumption. Our study reveals a hitherto unrecognized source of the environmental MPF contamination and highlights the need to evaluate exposure risks associated with these new forms of MPFs.

Composition, Release, and Transformation of Earthworm Tissue-Bound Residues of Tetrabromobisphenol A in Soil.

Earthworms accumulate organic pollutants to form earthworm tissue-bound residues (EBRs); however, the composition and fate of EBRs in soil remain largely unknown. Here, we investigated the fate of tetrabromobisphenol A (TBBPA)-derived EBRs in soil for 250 days using a 14C-radioactive isotope tracer and the geophagous earthworm Metaphire guillelmi. The EBRs of TBBPA in soil were rapidly transformed into nonextractable residues (NERs), mainly in the form of sequestered and ester-linked residues. After 250 days of incubation, 4.9% of the initially applied EBRs were mineralized and 69.3% were released to extractable residues containing TBBPA and its transformation products (TPs, generated mainly via debromination, O-methylation, and skeletal cleavage). Soil microbial activity and autolytic enzymes of earthworms jointly contributed to the release process. In their full-life period, the earthworms overall retained 24.1% TBBPA and its TPs in soil and thus prolonged the persistence of these pollutants. Our study explored, for the first time, the composition and fate of organic pollutant-derived EBRs in soil and indicated that the decomposition of earthworms may release pollutants and cause potential environmental risks of concern, which should be included in both environmental risk assessment and soil remediation using earthworms.

Maize (Zea mays L.) Plants Alter the Fate and Accumulate Nonextractable Residues of Sulfamethoxazole in Farmland Soil.

The fate of sulfonamide antibiotics in farmlands is crucial for food and ecological safety, yet it remains unclear. We used [phenyl-U-14C]-labeled sulfamethoxazole (14C-SMX) to quantitatively investigate the fate of SMX in a soil-maize system for 60 days, based on a six-pool fate model. Formation of nonextractable residues (NERs) was the predominant fate for SMX in unplanted soil, accompanied by minor mineralization. Notably, maize plants significantly increased SMX dissipation (kinetic constant kd = 0.30 day-1 vs 0.17 day-1), while substantially reducing the NER formation (92% vs 58% of initially applied SMX) and accumulating SMX (40%, mostly bound to roots). Significant NERs (maximal 29-42%) were formed via physicochemical entrapment (determined using silylation), which could partially be released and taken up by maize plants. The NERs consisted of a considerable amount of SMX formed via entrapment (1-8%) and alkali-hydrolyzable covalent bonds (2-12%, possibly amide linkage). Six and 10 transformation products were quantified in soil extracts and NERs, respectively, including products of hydroxyl substitution, deamination, and N-acylation, among which N-lactylated SMX was found for the first time. Our findings reveal the composition and instability of SMX-derived NERs in the soil-plant system and underscore the need to study the long-term impacts of reversible NERs.

Genome-Centric Metatranscriptomic Characterization of a Humin-Facilitated Anaerobic Tetrabromobisphenol A-Dehalogenating Consortium.

Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant in electronics manufacturing, has caused global contamination due to improper e-waste disposal. Its persistence, bioaccumulation, and potential carcinogenicity drive studies of its transformation and underlying (a)biotic interactions. This study achieved an anaerobic enrichment culture capable of reductively dehalogenating TBBPA to the more bioavailable bisphenol A. 16S rRNA gene amplicon sequencing and quantitative PCR confirmed that successive dehalogenation of four bromide ions from TBBPA was coupled with the growth of both Dehalobacter sp. and Dehalococcoides sp. with growth yields of 5.0 ± 0.4 × 108 and 8.6 ± 4.6 × 108 cells per µmol Br- released (N = 3), respectively. TBBPA dehalogenation was facilitated by solid humin and reduced humin, which possessed the highest organic radical signal intensity and reducing groups -NH2, and maintained the highest dehalogenation rate and dehalogenator copies. Genome-centric metatranscriptomic analyses revealed upregulated putative TBBPA-dehalogenating rdhA (reductive dehalogenase) genes with humin amendment, cprA-like Dhb_rdhA1 gene in Dehalobacter species, and Dhc_rdhA1/Dhc_rdhA2 genes in Dehalococcoides species. The upregulated genes of lactate fermentation, de novo corrinoid biosynthesis, and extracellular electron transport in the humin amended treatment also stimulated TBBPA dehalogenation. This study provided a comprehensive understanding of humin-facilitated organohalide respiration.

Stimulated Raman Scattering Microscopy Reveals Bioaccumulation of Small Microplastics in Protozoa from Natural Waters.

Microplastics (MPs) are pollutants of global concern, and bioaccumulation determines their biological effects. Although microorganisms form a large fraction of our ecosystem's biomass and are important in biogeochemical cycling, their accumulation of MPs has never been confirmed in natural waters because current tools for field biological samples can detect only MPs > 10 µm. Here, we show that stimulated Raman scattering microscopy (SRS) can image and quantify the bioaccumulation of small MPs (<10 µm) in protozoa. Our label-free method, which differentiates MPs by their SRS spectra, detects individual and mixtures of different MPs (e.g., polyethylene, polypropylene, polyvinyl chloride, polyethylene terephthalate, polystyrene, and poly(methyl methacrylate)) in protozoa. The ability of SRS to quantify cellular MP accumulation is similar to that of flow cytometry, a fluorescence-based method commonly used to determine cellular MP accumulation. Moreover, we discovered that protozoa in water samples from Yangtze River, Xianlin Wastewater Treatment Plant, Lake Taihu and the Pearl River Estuary accumulated MPs < 10 µm, but the proportion of MP-containing cells was low (∼2-5%). Our findings suggest that small MPs could potentially enter the food chain and transfer to organisms at higher trophic levels, posing environmental and health risks that deserve closer scrutiny.

Network pharmacology, molecular docking, and molecular dynamics simulation analysis reveal the molecular mechanism of halociline against gastric cancer.

Halociline, a derivative of alkaloids, was isolated from the marine fungus Penicillium griseofulvum by our group. This remarkable compound exhibits promising antineoplastic activity, yet the precise molecular mechanisms underlying its anticancer properties remain enigmatic. To unravel these mechanisms, we employed an integrated approach of network pharmacology analysis, molecular docking simulations, and molecular dynamics simulations to explore halociline therapeutic targets for gastric cancer. The data from network pharmacology indicate that halociline targets MAPK1, MMP-9, and PIK3CA in gastric cancer cells, potentially mediated by diverse pathways including cancer, lipid metabolism, atherosclerosis, and EGFR tyrosine kinase inhibitor resistance. Notably, molecular docking and dynamics simulations revealed a high affinity between halociline and these targets, with free binding energies (ΔEtotal) of - 20.28, - 27.94, and - 25.97 kcal/mol for MAPK1, MMP-9, and PIK3CA, respectively. This study offers valuable insights into the potential molecular mechanism of halociline's inhibition of gastric cancer cells and serves as a valuable reference for future basic research efforts.

Direct Observation of Magnetic Skyrmions and Their Current-Induced Dynamics in Epitaxial Single-Crystal Oxide Films.

Magnetic skyrmions are scarcely investigated for single-crystal quality films, for which skyrmions may have a remarkable performance. Even in the limited studies in this aspect, the skyrmions are usually probed by the topological Hall effect, missing important information on dynamic properties. Here, we present a comprehensive investigation on the generation/manipulation of magnetic skyrmions in La0.67Ba0.33MnO3 single-crystal films. Using the technique of magnetic force microscopy, the current-driven skyrmion dynamics are directly observed. Unlike isolated skyrmions produced by magnetic field alone, closely packed skyrmions can be generated by electric pulses in a magnetic background, with a high density (∼60/µm2) and a small size (dozens of nanometers). The threshold current moving skyrmions is ∼2.3 × 104 A/cm2, 2-3 orders of magnitude lower than that required by metallic multilayers or van der Waals ferromagnetic heterostructures. Our work demonstrates the great potential of single-crystal oxide films in developing skyrmion-based devices.

[Prediction of quality markers of Angong Niuhuang Pills based on LC-MS and pull-down with SPR chips].

Elucidating the quality markers(Q-markers) of traditional Chinese medicines is essential for understanding the mechanisms of action and promoting the rational use of traditional Chinese medicines as well as for developing traditional Chinese medicine-derived drugs. Studies have shown that surface plasmon resonance(SPR) is promising in this field. This study proposed a method based on pull-down with SPR chips to predict the Q-markers of Angong Niuhuang pills(AGNHP). Firstly, 71 main chemical components of AGNHP were analyzed by UPLC-Q-TOF-MS, and then network pharmacology was employed to predict the potential targets of AGNHP against stroke. Secondly, the STAT3 protein chip was constructed, and the extract of AGNHP was recovered by pull-down of the SPR system for STAT3 ligand. The potential active ingredients were collected, enriched, and identified as coptisine, palmatine, epiberberine, berberine, worenine, demethyleneberberine, jatrorrhizine, tetrahydrocoptisine, baicalein, and baicalin methyl ester. Next, the affinity constants of the 10 active ingredients were determined as 44.7, 44, 58.1, 51.3, 39.7, 32.1, 49.2, 69.1, 19.7, and 24.9 µmol·L~(-1), respectively. The molecular docking results showed that the 10 compounds could compete for binding with STAT3. This is the first report that SPR combined with UPLC-Q-TOF-MS is reliable and feasible for determining the active ingredients of AGNHP at the molecular level from complex systems. STAT3 could be used as a potential target for the biological quality evaluation of AGNHP.

Label-Free Imaging of Humic Substance Bioaccumulation by Pump-Probe Microscopy.

Humic substances (HS) are the most abundant forms of natural organic matter on the earth surface. Comprised of decomposed plant and animal materials rich in carbon, oxygen, hydrogen, nitrogen, and sulfur complexes, HS facilitate global carbon and nitrogen cycling and the transport of anthropogenic contaminants. While it is known that HS also interact with organisms at different trophic levels to produce beneficial and harmful effects whether HS exert these biological effects through accumulation remains unknown. Current radiolabeling techniques, which only detect the amount of accumulated radiolabels, cannot visualize the transport and accumulation behavior of HS. Here, using a label-free method based on pump-probe microscopy, we show HS entered the protozoan Tetrahymena thermophila, zebrafish embryos, and human cells and exerted direct effects on these organisms. HS accumulated in the nucleus of T. thermophila, chorion pore canals of zebrafish embryos, and nucleus of intestinal and lung cells in a concentration- and time-dependent way. Epigenetic and transcriptomics assays show HS altered chromatin accessibility and gene transcription in T. thermophila. In zebrafish larvae, HS induced neurotoxicity, altering spontaneous muscle contraction and locomotor activity. Detailed images showing HS accumulation in our study reveal new insights on the ecological and environmental behavior of HS.

PDK1 regulates the progression of esophageal squamous cell carcinoma through metabolic reprogramming.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest human malignancies characterized by late-stage diagnosis, drug resistance, and poor prognosis. Pyruvate dehydrogenase kinase 1 (PDK1) plays an important role in regulating the metabolic reprogramming of cancer cells. However, its expression, function, and regulatory mechanisms of PDK1 in ESCC have not been reported. In this study, we found that PDK1 silence and dichloroacetic acid (DCA) significantly inhibited the growth of ESCC cells and induced cell apoptosis. Interestingly, PDK1 is a direct target of miR-6516-5p, and miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and cisplatin (cis-diammine-dichloroplatinum, DDP) synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress via the inhibition of the Keap1/Nrf2 signaling pathway. And, Tert-butylhydroquinone (TBHQ), a specific activator of the Keap1/Nrf2 signaling, could diminish the synergic antitumor effects of DCA and DDP on ESCC cells. Collectively, our findings indicate that PDK1 may regulate the progression of ESCC by metabolic reprogramming, which provides new strategy for the treatment of ESCC.

Phytoremediation of isoproturon-contaminated sites by transgenic soybean.

The widespread application of isoproturon (IPU) can cause serious pollution to the environment and threaten ecological functions. In this study, the IPU bacterial N-demethylase gene pdmAB was transferred and expressed in the chloroplast of soybean (Glycine max L. 'Zhonghuang13'). The transgenic soybeans exhibited significant tolerance to IPU and demethylated IPU to a less phytotoxic metabolite 3-(4-isopropylphenyl)-1-methylurea (MDIPU) in vivo. The transgenic soybeans removed 98% and 84% IPU from water and soil within 5 and 14 days, respectively, while accumulating less IPU in plant tissues compared with the wild-type (WT). Under IPU stress, transgenic soybeans showed a higher symbiotic nitrogen fixation performance (with higher total nodule biomass and nitrogenase activity) and a more stable rhizosphere bacterial community than the WT. This study developed a transgenic (TS) soybean capable of efficiently removing IPU from its growing environment and recovering a high-symbiotic nitrogen fixation capacity under IPU stress, and provides new insights into the interactions between rhizosphere microorganisms and TS legumes under herbicide stress.

A cross-neutralizing antibody between HIV-1 and influenza virus.

Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.

Insights into Health Risks of Face Paint Application to Opera Performers: The Release of Heavy Metals and Stage-Light-Induced Production of Reactive Oxygen Species.

Face paints used by opera performers have been shown to contain high levels of heavy metals. However, whether frequent exposure, via dermal contact and inadvertent oral ingestion, results in occupational diseases is unknown, as is the potential exacerbation of toxicity by high-intensity irradiation from stage lights. In this study, we examined the release of Cr, Cu, Pb, and Zn from 40 face paints and the consequent health risks posed by different practical scenarios involving their use. The results showed that the in vitro bioaccessibility (IVBA) of Cr, Cu, Pb, and Zn in the tested products was, on average, 7.0, 5.5, 19.9, and 7.9% through oral ingestion and 1.1, 2.2, 1.6, and 1.2% through dermal contact, respectively. Stage light irradiation significantly increased the IVBA associated with dermal contact, to the average of 4.8, 34.9, 5.7, and 1.9% for Cr, Cu, Pb, and Zn, respectively. The increase was mainly due to the light-induced generation of reactive oxygen species, particularly hydroxyl free radicals. The vitality and transcriptional response of 3D skin models as well as a quantitative risk assessment of skin sensitization indicated that dermal contact with face paints may induce predictable skin damage and potentially other skin diseases. Long-term exposure to face paints on stage may also pose a non-carcinogenic health risk. The demonstrated health risks to opera performers of face paint exposure should lead to strict regulations regarding the content of theatrical face paints.