Growth of Size-Tunable Ag2O Polyhedra and Revelation of Their Bulk and Surface Lattices.

By primarily adjusting the reagent amounts, particularly the volume of AgNO3 solution introduced, Ag2O cubes with decreasing sizes from 440 to 79 nm, octahedra from 714 to 106 nm, and rhombic dodecahedra from 644 to 168 nm are synthesized. 733 nm cuboctahedra are also prepared for structural analysis. With in-house X-ray diffraction (XRD) peak calibration, shape-related peak shifts are recognizable. Synchrotron XRD measurements at 100 K reveal the presence of bulk and surface layer lattices. Bulk cell constants also deviate slightly. They show a negative thermal expansion behavior with shrinking cell constants at higher temperatures. The Ag2O crystals exhibit size- and facet-dependent optical properties. Bandgaps red-shift continuously with increasing particle sizes. Optical facet effect is also observable. Moreover, synchrotron XRD peaks of a mixture of Cu2O rhombicuboctahedra and edge- and corner-truncated cubes exposing all three crystal faces can be deconvoluted into three components with the bulk and the [111] microstrain phase as the major component. Interestingly, while the unheated Cu2O sample shows clear diffraction peak asymmetry, annealing the sample to 450 K yields nearly symmetric peaks even when returning the sample to room temperature, meaning even moderately high temperatures can permanently change the crystal lattice.

RsaL is a self-regulatory switch that controls alternative biosynthesis of two AHL-type quorum sensing signals in Pseudomonas aeruginosa PA1201.

Pseudomonas aeruginosa is a ubiquitous and metabolically versatile microorganism naturally found in soil and water. It is also an opportunistic pathogen in plants, insects, animals, and humans. In response to increasing cell density, P. aeruginosa uses two acyl-homoserine lactone (AHL) quorum-sensing (QS) signals (i.e., N-3-oxo-dodecanoyl homoserine lactone [3-oxo-C12-HSL] and N-butanoyl-homoserine lactone [C4-HSL]), which regulate the expression of hundreds of genes. However, how the biosynthesis of these two QS signals is coordinated remains unknown. We studied the regulation of these two QS signals in the rhizosphere strain PA1201. PA1201 sequentially produced 3-oxo-C12-HSL and C4-HSL at the early and late growth stages, respectively. The highest 3-oxo-C12-HSL-dependent elastase activity was observed at the early stage, while the highest C4-HSL-dependent rhamnolipid production was observed at the late stage. The atypical regulator RsaL played a pivotal role in coordinating 3-oxo-C12-HSL and C4-HSL biosynthesis and QS-associated virulence. RsaL repressed lasI transcription by binding the -10 and -35 boxes of the lasI promoter. In contrast, RsaL activated rhlI transcription by binding the region encoding the 5'-untranslated region of the rhlI mRNA. Further, RsaL repressed its own expression by binding a nucleotide motif located in the -35 box of the rsaL promoter. Thus, RsaL acts as a molecular switch that coordinates the sequential biosynthesis of AHL QS signals and differential virulence in PA1201. Finally, C4-HSL activation by RsaL was independent of the Las and Pseudomonas quinolone signal (PQS) QS signaling systems. Therefore, we propose a new model of the QS regulatory network in PA1201, in which RsaL represents a superior player acting at the top of the hierarchy.

Correlative Super-resolution Optical and Electron Microscopic Imaging of Intracellular Ribosomal RNA by a Terpyridine Iridium(III) Complex.

Ribosomal RNA (rRNA) plays a vital role in binding amino acids together, which dictates the primary structure of a protein. Visualization of its intracellular distribution and dynamics during protein synthesis enables a better understanding of the correlated biological essence. However, appropriate tools targeting live cell rRNA that are capable of multimodal imaging at the nanoscale are still lacking. Here, we rationally designed a series of terpyridine ammonium iridium(III) complexes, one of which is capable of selectively labeling rRNA in living cells. Its metal core and photostable nature allow further super-resolution STED imaging of rRNA found on the rough endoplasmic reticulum at a ∼40 nm resolution that is well correlated under correlative light and electron microscopy (CLEM). Interestingly, the Ir(III) complex demonstrated rRNA dynamics in living cells while boosting protein synthesis at the nanoscale. Our work offers a versatile tool to visualize rRNA synchronously under optical and electron microscopy, which provides a better understanding of rRNA evolution in living systems.

Relationships between minerals' intake and blood homocysteine levels based on three machine learning methods: a large cross-sectional study.

BACKGROUND: Blood homocysteine (Hcy) level has become a sensitive indicator in predicting the development of cardiovascular disease. Studies have shown an association between individual mineral intake and blood Hcy levels. The effect of mixed minerals' intake on blood Hcy levels is unknown. METHODS: Data were obtained from the baseline survey data of the Shanghai Suburban Adult Cohort and Biobank(SSACB) in 2016. A total of 38273 participants aged 20-74 years met our inclusion and exclusion criteria. Food frequency questionnaire (FFQ) was used to calculate the intake of 10 minerals (calcium, potassium, magnesium, sodium, iron, zinc, selenium, phosphorus, copper and manganese). Measuring the concentration of Hcy in the morning fasting blood sample. Traditional regression models were used to assess the relationship between individual minerals' intake and blood Hcy levels. Three machine learning models (WQS, Qg-comp, and BKMR) were used to the relationship between mixed minerals' intake and blood Hcy levels, distinguishing the individual effects of each mineral and determining their respective weights in the joint effect. RESULTS: Traditional regression model showed that higher intake of calcium, phosphorus, potassium, magnesium, iron, zinc, copper, and manganese was associated with lower blood Hcy levels. Both Qg-comp and BKMR results consistently indicate that higher intake of mixed minerals is associated with lower blood Hcy levels. Calcium exhibits the highest weight in the joint effect in the WQS model. In Qg-comp, iron has the highest positive weight, while manganese has the highest negative weight. The BKMR results of the subsample after 10,000 iterations showed that except for sodium, all nine minerals had the high weights in the joint effect on the effect of blood Hcy levels. CONCLUSION: Overall, higher mixed mineral's intake was associated with lower blood Hcy levels, and each mineral contributed differently to the joint effect. Future studies are available to further explore the mechanisms underlying this association, and the potential impact of mixed minerals' intake on other health indicators needs to be further investigated. These efforts will help provide additional insights to deepen our understanding of mixed minerals and their potential role in health maintenance.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Stapokibart in Healthy Volunteers and Adult Subjects with Atopic Dermatitis.

INTRODUCTION: Stapokibart, a novel humanized anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits the signaling of IL-4 and IL-13, which are key drivers of type 2 inflammation in atopic dermatitis (AD). This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of stapokibart in a randomized, double-blind, placebo-controlled single ascending dose (SAD) study and a multiple ascending dose (MAD) study. METHODS: The SAD study enrolled 33 healthy male adults aged 18-65 years at a single center. The MAD study enrolled 39 patients with moderate-to-severe AD aged 18-70 years at seven centers. Enrolled subjects were randomized to subcutaneous (SC) doses of stapokibart (75-600 mg) or placebo. Serum thymus and activation-regulated chemokine (TARC) and total immunoglobulin E (IgE) were measured as PD biomarkers for stapokibart. RESULTS: Similar PK characteristics were observed in healthy volunteers and subjects with AD after the initial administration. Stapokibart exhibited non-linear pharmacokinetics in both types of subjects. Following single doses, the mean maximum serum concentration (Cmax) ranged from 5.3 to 63.0 µg/mL, median Tmax ranged from 3.0 to 7.0 days, mean terminal half-life (t1/2z) ranged from 2.39 to 7.43 days, and mean apparent volume (Vz/F) ranged from 3.64 to 6.73 L in healthy subjects. The mean AUC accumulation ratio was 2.29 in subjects with AD after three doses of stapokibart 300 mg administered every 2 weeks. The median serum total IgE and TARC levels on day 43 decreased from baseline by 14.9-25.2% and 48.6-77.0%, respectively, among subjects with AD receiving three doses of stapokibart. No subjects developed grade ≥ 3 adverse events (AEs) or serious AEs or discontinued the study because of AEs. The incidence of AEs was similar between stapokibart and placebo groups. CONCLUSION: Stapokibart showed favorable pharmacokinetics, pharmacodynamics, safety, and tolerability in the SAD and MAD studies. Based on these results, phase II and phase III trials of stapokibart have been performed in subjects with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06161090 (29 November, 2023), NCT04893941 (15 May, 2021).

Motion-aware Dynamic Graph Neural Network for Video Compressive Sensing.

Video snapshot compressive imaging (SCI) utilizes a 2D detector to capture sequential video frames and compress them into a single measurement. Various reconstruction methods have been developed to recover the high-speed video frames from the snapshot measurement. However, most existing reconstruction methods are incapable of efficiently capturing long-range spatial and temporal dependencies, which are critical for video processing. In this paper, we propose a flexible and robust approach based on the graph neural network (GNN) to efficiently model non-local interactions between pixels in space and time regardless of the distance. Specifically, we develop a motion-aware dynamic GNN for better video representation, i.e., represent each node as the aggregation of relative neighbors under the guidance of frame-by-frame motions, which consists of motion-aware dynamic sampling, cross-scale node sampling, global knowledge integration, and graph aggregation. Extensive results on both simulation and real data demonstrate both the effectiveness and efficiency of the proposed approach, and the visualization illustrates the intrinsic dynamic sampling operations of our proposed model for boosting the video SCI reconstruction results. The code and model will be released.

Superparamagnetic iron oxide nanoparticle regulates microbiota-gut-inner ear axis for hearing protection.

Noise-induced hearing loss (NIHL) is a highly prevalent form of sensorineural hearing damage that has significant negative effects on individuals of all ages and there are no effective drugs approved by the US Food and Drug Administration. In this study, we unveil the potential of superparamagnetic iron oxide nanoparticle assembly (SPIOCA) to reshape the dysbiosis of gut microbiota for treating NIHL. This modulation inhibits intestinal inflammation and oxidative stress responses, protecting the integrity of the intestinal barrier. Consequently, it reduces the transportation of pathogens and inflammatory factors from the bloodstream to the cochlea. Additionally, gut microbiota-modulated SPIOCA-induced metabolic reprogramming in the gut-inner ear axis mainly depends on the regulation of the sphingolipid metabolic pathway, which further contributes to the restoration of hearing function. Our study confirms the role of the microbiota-gut-inner ear axis in NIHL and provides a novel alternative for the treatment of NIHL and other microbiota dysbiosis-related diseases.

Cation Modulation in AgSbTe2 Realizes Carrier Optimization, Defect Engineering, and a 7% Single-Leg Thermoelectric Efficiency.

AgSbTe2 plays a pivotal role in mid-temperature thermoelectric generators (TEGs). Leveraging the seminal advances in cation manipulation within AgSbTe2, this study demonstrates an enhanced TE power factor (PF = S2σ) of 1.5 mWm-1 K-2 and a peak zT of 1.5 at 583 K in an off-stoichiometric Ag1.04Sb0.96Te2 crystal. The introduction of Ge in place of Ag leads to an increased nH as evidenced by the detection of trace Ge4+ through XPS analysis. Further chemical state analysis reveals the simultaneous presence of Ag+, Sb3+, and Ge4+, elucidating the effect of cation modulations. TEM characterizations validate the presence of superlattice structure, and the linear defects discerned within the AgSbTe2 matrix. Consequently, the lattice thermal conductivity κL is substantially reduced in the Ag1.02Ge0.02Sb0.96Te2 crystal, yielding a peak zT of 1.77 at 623 K. This notable advancement is attributed to the counterbalance achieved between the enhanced PF and the reduced κL, facilitated by cation modulation. Additionally, a single-leg TE device incorporating Ag1.02Ge0.02Sb0.96Te2 demonstrates a conversion efficiency of 7% across a temperature gradient (ΔT) of 350 K. This study corroborates the efficacy of cation modulation through thermodynamic approaches and establishes a relationship between transport properties and the presence of defects.

miR-92a-3p promotes pulmonary fibrosis progression by regulating KLF2-mediated endothelial-to-mesenchymal transition.

Pulmonary fibrosis (PF) is a chronic lung disease that has a poor prognosis and a serious impact on the quality of life of patients. Here, we investigated the potential role of miR-92a-3p in PF. The mRNA level of miR-92a-3p was significantly increased in both the lung tissues of bleomycin (BLM)--treated mice and pulmonary microvascular endothelial cells (PMVECs). Overexpressing miR-92a-3p increased the mRNA and protein levels of α­SMA, vimentin, and Col-1 but downregulated E-cadherin. Additionally, the protein and mRNA expression levels of KLF2 were significantly decreased in the lung tissues of BLM-treated mice, suggesting that KLF2 participated in the progression of BLM-induced PF. Downregulating miR-92a-3p upregulated the expression of KLF2 and inhibited the endothelial-to-mesenchymal transition (EndoMT) process, thus alleviating PF in vivo. Altogether, a miR-92a-3p deficiency could significantly reduce the development of myofibroblasts and ameliorate PF progression.

Symmetry-breaking of Dibenzo[b,d]thiophene Sulfone Enhancing Polaron Generation for Boosted Photocatalytic Hydrogen Evolution.

The current bottleneck in the development of efficient photocatalysts for hydrogen evolution is the limited availability of high-performance acceptor units. Over the past nine years, dibenzo[b,d]thiophene sulfone (DBS) has been the preferred choice for the acceptor unit. Despite extensive exploration of alternative structures as potential replacements for DBS, a superior substitute remains elusive. In this study, a symmetry-breaking strategy was employed on DBS to develop a novel acceptor unit, BBTT-1SO. The asymmetric structure of BBTT-1SO proved beneficial for increasing multiple moment and polarizability. BBTT-1SO-containing polymers showed higher efficiencies for hydrogen evolution than their DBS-containing counterparts by up to 166%. PBBTT-1SO exhibited an excellent hydrogen evolution rate (HER) of 222.03 mmol g-1 h-1 and an apparent quantum yield of 27.5% at 500 nm. Transient spectroscopic studies indicated that the BBTT-1SO-based polymers facilitated electron polaron formation, which explains their superior HERs. PBBTT-1SO also showed 14% higher HER in natural seawater splitting than that in deionized water splitting. Molecular dynamics simulations highlighted the enhanced water-PBBTT-1SO polymer interactions in salt-containing solutions. This study presents a pioneering example of a substitute acceptor unit for DBS in the construction of high-performance photocatalysts for hydrogen evolution.

Dynamic impact of delivery modes on gut microbiota in preterm infants hospitalized during the initial 4 weeks of life.

Preterm infants face a high risk of various complications, and their gut microbiota plays a pivotal role in health. Delivery modes have been reported to affect the development of gut microbiota in term infants, but its impact on preterm infants remains unclear. Here, we collected fecal samples from 30 preterm infants at five-time points within the first four weeks of life. Employing 16 S rRNA sequencing, principal coordinates analysis, the analysis of similarities, and the Wilcoxon rank-sum test, we examined the top dominant phyla and genera, the temporal changes in specific taxa abundance, and their relationship with delivery modes, such as Escherichia-Shigella and Enterococcus based on vaginal delivery and Pluralibacter related to cesarean section. Moreover, we identified particular bacteria, such as Taonella, Patulibacter, and others, whose proportions fluctuated among preterm infants born via different delivery modes at varying time points, as well as the microbiota types and functions. These results indicated the influence of delivery mode on the composition and function of the preterm infant gut microbiota. Importantly, these effects are time-dependent during the early stages of life. These insights shed light on the pivotal role of delivery mode in shaping the gut microbiota of preterm infants and have significant clinical implications for their care and management.

Research in revealing the effects on Cuscuta chinensis to diarrhea type irritable bowel syndrome based on network pharmacology and molecular docking potential mechanism.

To explore the potential mechanism in Cuscuta sinensis on diarrhea-type irritable bowel syndrome using network pharmacology and molecular docking techniques. First, the active components and related targets of Cuscuta were found setting oral utilization >30% and drug-like properties greater than or equal to 0.18 as filter information from TCMSP database. The targets of diarrheal irritable bowel syndrome were compiled by searching DrugBank, GeneCards, OMIM, PharmGkb, and TTD databases. The intersections of drugs and targets related to the disease were taken for gene ontology enrichment and Kyoto encyclopedia of genes and genomes enrichment analyses, to elucidate the potential molecular mechanisms and pathway information of Cuscuta sinensis for the treatment of diarrheal irritable bowel syndrome. The protein-protein interaction network was constructed by using the STRING database and visualized with Cytoscape_v3.10.0 software to find the protein-protein interaction network core At last, molecular docking was performed to validate the combination of active compounds with the core target. The target information of Cuscuta and diarrhea-type irritable bowel syndrome was compiled, which can be resulted in 11 active compounds such as quercetin, kaempferol, isorhamnetin, ß-sitosterol, and another 17 core targets such as TP53, IL6, AKT1, IL1B, TNF, EGFR, etc, whose Kyoto encyclopedia of genes and genomes was enriched in the pathways of lipids and atherosclerosis, chemical carcinogenesis-receptor activation, PI3K-Akt signaling pathway, and fluid shear stress and atherosclerosis, etc. Docking demonstrated that the core targets and the active compounds were able to be better combined. Cuscuta chinensis may exert preventive effects on diarrhea-type irritable bowel syndrome by reducing intestinal inflammation, protecting intestinal mucosa, and playing an important role in antioxidant response through multi-targets and multi-pathways.

Investigating the molecular mechanism of Mori Cortex against osteosarcoma by bioinformatics analysis and in vitro experimental.

OBJECTIVE: To explore the therapeutic mechanism of Mori Cortex against osteosarcoma (OS), we conducted bioinformatics prediction followed by in vitro experimental validation. METHODS: Gene expression data from normal and OS tissues were obtained from the GEO database and underwent differential analysis. Active Mori Cortex components and target genes were extracted from the Traditional Chinese Medicine System Pharmacology database. By intersecting these targets with differentially expressed genes in OS, we identified potential drug action targets. Using the STRING database, a protein-protein interaction network was constructed. Subsequent analyses of these intersected genes, including Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, were performed using R software to elucidate biological processes, molecular functions, and cellular components, resulting in the simulation of signaling pathways. Molecular docking assessed the binding capacity of small molecules to signaling pathway targets. In vitro validations were conducted on U-2 OS cells. The CCK8 assay was used to determine drug-induced cytotoxicity in OS cells, and Western Blotting was employed to validate the expression of AKT, extracellular signal-regulated kinases (ERK), Survivin, and Cyclin D1 proteins. RESULTS: Through differential gene expression analysis between normal and OS tissues, we identified 12,364 differentially expressed genes. From the TCSMP database, 39 active components and 185 therapeutic targets related to OS were derived. The protein-protein interaction network indicated that AKT1, IL-6, JUN, VEGFA, and CASP3 might be central targets of Mori Cortex for OS. Molecular docking revealed that the active compound Morusin in Mori Cortex exhibits strong binding affinity to AKT and ERK. The CCK8 assay showed that Morusin significantly inhibits the viability of U-2 OS cells. Western Blot demonstrated a reduction in the p-AKT/AKT ratio, the p-ERK/ERK ratio, Survivin, and Cyclin D1. CONCLUSION: Mori Cortex may exert its therapeutic effects on OS through multiple cellular signaling pathways. Morusin, the active component of Mori Cortex, can inhibit cell cycle regulation and promote cell death in OS cells by targeting AKT/ERK pathway.

Insight into the evolution of textural properties and juiciness of ready-to-eat chicken breasts upon different thermal sterilization: From the perspective of protein degradation.

Texture deterioration of meat products upon high-temperature sterilization is a pressing issue in the meat industry. This study evaluated the effect of different thermal sterilization temperatures on the textural and juiciness of ready-to-eat (RTE) chicken breast. In this study, by dynamically monitoring the texture and juiciness of chicken meat products during the process of thermal sterilization, it has been observed that excessively high sterilization temperatures (above 100°C) significantly diminish the shear force, springiness and water-holding capacity of the products. Furthermore, from the perspective of myofibrillar protein degradation, molecular mechanisms have been elucidated, unveiling that the thermal sterilization treatment at 121°C/10 min triggers the degradation of myosin heavy chains and F-actin, disrupting the lattice arrangement of myofilaments, compromising the integrity of sarcomeres, and resulting in an increase of approximately 40.66% in the myofibrillar fragmentation index, thus diminishing the quality characteristics of the products. This study unravels the underlying mechanisms governing the dynamic changes in quality of chicken meat products during the process of thermal sterilization, thereby providing theoretical guidance for the development of high-quality chicken products.

The spatiotemporal variations of microbial community in relation to water quality in a tropical drinking water reservoir, Southmost China.

It is well-known that water quality has great significance on microbial community composition in aquatic environments. In this study, we detected water column indicates the microbial community composition of nine sampling sites over two seasons using Illumina TruSeq sequencing in Songtao Reservoir, Hainan Province, Southmost China. The study indicated that the dominant phylum was Actinobacteria, Proteobacteria, Bacteroidetes, and Cyanobacteria. The diversity parameters showed that the microbial community composition had significant spatiotemporal variations, including the significantly higher Shannon index and Simpson index upstream than those midstream and downstream. Besides, there were significantly higher Chao1 index, Shannon index, and Simpson index in winter than in summer. Principal coordinates analysis (PCoA) showed the microbial structural composition had significant seasonal differences. The results of microbial community composition further revealed that the eutrophication level upstream was higher than that of midstream and downstream. The redundancy analysis (RDA) diagram indicated that the abundance of microbiology species significantly correlated with temperature, total phosphorus, Se, and Ni. Furthermore, the mantel's test showed that the temperature and total phosphorus significantly affected the community composition of archaea and bacteria. Overall, our finding here partially validated our hypothesis that the spatiotemporal variations of microbial community composition are significantly related to nutrients, physicochemical factors and metals, which has been unknown previously in tropical drinking waterbodies. This study substantially contributed to understanding of the composition of microbial community in tropical drinking water reservoirs and the main environmental driving factors in tropical zones. It also provided a reference for the management of reservoir operation to ensure drinking water safe.

Hybrid Microneedle-Mediated Transdermal Delivery of Atorvastatin Calcium-Loaded Polymeric Micelles for Hyperlipidemia Therapy.

Hyperlipidemia has been a huge challenge to global health, leading to the cardiovascular disease, hypertension, and diabetes. Atorvastatin calcium (AC), a widely prescribed drug for hyperlipidemia, faces huge challenges with oral administration due to poor water solubility and hepatic first-pass effects, resulting in low therapeutic efficacy. In this work, we designed and developed a hybrid microneedle (MN) patch system constructed with soluble poly(vinyl alcohol) (PVA) and AC-loaded polymeric micelles (AC@PMs) for transdermal delivery of AC to enhance the hyperlipidemia therapy. We first prepared various AC@PM formulations self-assembled from mPEG-PLA and mPEG-PLA-PEG block copolymers using a dialysis method and evaluated the physicochemical properties in combination with experiment skills and dissipative particle dynamics (DPD) simulations. Then, we encapsulated the AC@PMs into the PVA MN patch using a micromold filling method, followed by characterizing the performances, especially the structural stability, mechanical performance, and biosafety. After conducting in vivo experiments using a hyperlipidemic rat model, our findings revealed that the hybrid microneedle-mediated administration exhibited superior therapeutic efficacy when compared to oral delivery methods. In summary, we have successfully developed a hybrid microneedle (MN) patch system that holds promising potential for the efficient transdermal delivery of hydrophobic drugs.

Study on the Separation Performance of a Two Cylindrical Section Hydrocyclone under Various Height Ratios.

Two cylindrical section hydrocyclones can suppress particle misplacement by regulating the circulation flow, but few researchers have investigated the effect of the cylindrical height ratio. In this paper, numerical simulations and physical tests were conducted to investigate the effect of height ratio on the particle motion behavior and separation performance of the two cylindrical section hydrocyclone. According to the numerical simulation results, with increasing height ratio, the separation cut size decreased, the separation accuracy and recovery rate of medium and coarse particles in the underflow increased, the coarse particle misplacement in overflow decreased significantly, and the proportion of medium particle circulation flow gradually increased. According to the test results, the number of misplaced fine particles in underflow could be effectively reduced when H1/H0 = 0.30. With increasing height ratio, the number of misplaced coarse particles in the overflow decreased and the classification efficiency of fine particles increased. The maximum separation efficiencies of medium and coarse particles could be obtained at H1/H0 values of 0.47 and 0.17, respectively. Therefore, increasing the height ratio could inhibit coarse particle misplacement in overflow and improve the separation performance of two cylindrical section hydrocyclones.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

Introduction: CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. Methods: The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. Results: There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. Discussion: CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Evolution and adaptation of terrestrial plant-associated Plantibacter species into remote marine environments.

Microbes are thought to be distributed and circulated around the world, but the connection between marine and terrestrial microbiomes remains largely unknown. We use Plantibacter, a representative genus associated with plants, as our research model to investigate the global distribution and adaptation of plant-related bacteria in plant-free environments, particularly in the remote Southern Ocean and the deep Atlantic Ocean. The marine isolates and their plant-associated relatives shared over 98% whole-genome average nucleotide identity (ANI), indicating recent divergence and ongoing speciation from plant-related niches to marine environments. Comparative genomics revealed that the marine strains acquired new genes via horizontal gene transfer from non-Plantibacter species and refined existing genes through positive selection to improve adaptation to new habitats. Meanwhile, marine strains retained the ability to interact with plants, such as modifying root system architecture and promoting germination. Furthermore, Plantibacter species were found to be widely distributed in marine environments, revealing an unrecognized phenomenon that plant-associated microbiomes have colonized the ocean, which could serve as a reservoir for plant growth-promoting microbes. This study demonstrates the presence of an active reservoir of terrestrial plant growth-promoting bacteria in remote marine systems and advances our understanding of the microbial connections between plant-associated and plant-free environments at the genome level.