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Objectives: The present study aimed to investigate the relationship between male hormones and metabolic dysfunction-associated fatty liver disease (MAFLD) in males. Methods: Data from the Fangchenggang Area Male Health and Examination Survey (FAMHES) were used to analyze the male hormone levels between MAFLD patients and controls. Univariate and multivariate logistic regression analyses were performed to identify risk factors for MAFLD. Receiver operating characteristic curve analysis was used to assess the diagnostic performance of male hormones for MAFLD. Result: A total of 1578 individuals were included, with 482 individuals (30.54%) of MAFLD, including 293 (18.57%) with mild disease and 189 (11.98%) with moderate-to-severe disease. The MAFLD patients were significantly older than those without MAFLD. The LH, FSH, and SHBG levels in the MAFLD patients were significantly greater than those in the control group. Age, FSH, LH, SHBG, and estradiol were all risk factors for MAFLD. Age, FSH, and LH were risk factors for moderate-to-severe MAFLD. FSH was an independent risk factor for MAFLD and moderate-to-severe MAFLD. FSH showed an excellent diagnostic value, with an AUC of 0.992 alone and 0.996 after adjusting age. Conclusions: Our findings indicate that FSH may be a potential diagnostic and predictive biomarker for MAFLD. [ABSTRACT FROM AUTHOR]

A superhydrophobic surface is an ideal choice to enhance the corrosion resistance of aluminum (Al) and Al-based alloys which are widely used in various industrial fields. However, there are limitations in the complex fabrication process, high cost, and easy damage of micro-nano structures for processing superhydrophobic Al surface. To address the aforementioned limitations, we presented an efficient and facile method via acid wet blasting method to fabricate micro-nano composite structures on the Al substrate and subsequently low surface energy modification to obtain superhydrophobic Al surface (SHP-AWBM-Al), which had a water contact angle of 162° and rolling angle of 3°. The fabricated SHP-AWBM-Al had excellent self-cleaning performance, anti-fouling ability, and good fog collection ability. Tape peeling test, sandpaper friction test, acidic solution corrosion test, alkaline solution corrosion test, and natural environment corrosion test showed that the SHP-AWBM-Al had good mechanical stability and chemical stability compared with the superhydrophobic Al surface (SHP-H-Al) obtained by chemical etching. In addition, the electrochemical corrosion test showed that the SHP-AWBM-Al was more corrosion-resistant than the SHP-H-Al. This finding could enhance the technology for fabricating superhydrophobic Al surfaces. [ABSTRACT FROM AUTHOR]

Purpose: 11β-Hydroxylase deficiency (11β-OHD) is the second leading cause of congenital adrenal hyperplasia (CAH), a rare autosomal recessive disease caused by mutations in the CYP11B1 gene. We previously reported the case of a male Chinese patient with typical 11β-OHD symptoms. Sanger sequencing revealed that the patient carried a splice-site mutation, c.595+1G>A in the CYP11B1 gene. His mother and sister harbored the heterozygous mutation, c.595+1G>A. Paradoxically, Sanger sequencing did not detect any abnormality in the CYP11B1 gene of his father and brother. Therefore, in this study, we aimed to further explore the exact genetic etiology of 11β-OHD in this pedigree and analyze the functional consequence of the c.595+1G>A mutation. Methods: Gemomic DNA was extracted from the peripheral blood leukocytes of the family members and normal control individuals, followed by quantitative real-time polymerase chain reaction (qPCR) to detect the copy number of the target CYP11B1 gene fragment. Mutation analysis was also performed via whole-exome sequencing (WES) followed by Sanger sequencing validation. In vitro minigene assay was also performed to investigate the impact of the c.595+1G>A mutation on pre-mRNA splicing. Results: qPCR results suggested a heterozygous deletion encompassing position c.595+1 along with flanking exonic and intronic sequences in the CYP11B1 gene of the patient and his father. WES followed by Sanger sequencing verified that the patient carried compound heterozygous mutations in the CYP11B1 gene, including a novel 2840-bp deletion (c.395+661_c.1121+180del) and c.595+1G>A, while his father carried the heterozygous c.395+661_c.1121+180del mutation. No other novel CYP11B1 mutations were found in the rest of the family members. Furthermore, minigene assay revealed that the c.595+1G>A mutation resulted in a 70-bp deletion of exon 3 in the mRNA, and this altered the reading frame at amino acid 176 and created a premature stop codon at amino acid 197. Conclusion: We identified a novel 2840-bp-sized large deletion and confirmed that the c.595+1G>A mutation disrupts normal pre-mRNA splicing. Either mutation could significantly alter the reading frame and abolish CYP11B1 enzyme activity. Therefore, our findings widen the mutation spectrum of CYP11B1 and provide an accurate diagnosis of 11β-OHD at a molecular genetic level. [ABSTRACT FROM AUTHOR]

The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis. Oral microbes in non-oral locations are noted across various cancers. This study highlights the abnormal translocation of oral microbes to the nasopharynx, raising the risk of nasopharyngeal cancer by remodeling the tumor microenvironment and potentially influencing EBV infection. [ABSTRACT FROM AUTHOR]

Data hierarchy, as a hidden property of data structure, exists in a wide range of machine learning applications. A common practice to classify such hierarchical data is first to encode the data in the Euclidean space, and then train a Euclidean classifier. However, such a paradigm leads to a performance drop due to distortion of data embedding in the Euclidean space. To relieve this issue, hyperbolic geometry is investigated as an alternative space to encode the hierarchical data for its higher ability to capture the hierarchical structures. Those methods cannot explore the full potential of the hyperbolic geometry, in the sense that such methods define the hyperbolic operations in the tangent plane, causing the distortion of data embeddings. In this paper, we develop two novel kernel formulations in the hyperbolic space, with one being positive definite (PD) and another one being indefinite, to solve the classification tasks in hyperbolic space. The PD one is defined via mapping the hyperbolic data to the Drury-Arveson (DA) space, which is a special reproducing kernel Hilbert space (RKHS). To further increase the discrimination of the classifier, an indefinite kernel is further defined in the Kreĭn spaces. Specifically, we design a 2-layer nested indefinite kernel which first maps hyperbolic data into the DA spaces, followed by a mapping from the DA spaces to the Kreĭn spaces. Extensive experiments on real-world datasets demonstrate the superiority of the proposed kernels. [ABSTRACT FROM AUTHOR]

Context: 2,4,6,8,10, 12-hexanitro-2,4,6,8,10, 12-hexazepane (CL-20) is a new energetic material with high performance and low sensitivity. In-depth study of the thermal decomposition mechanism of CL-20 is a necessary condition to improve its performance, ensure its safety, and optimize its application. On the basis of a large number of empirical force fields used in molecular dynamics simulation in the past, the machine learning augmented first-principles molecular dynamics method was used for the first time to simulate the thermal decomposition reaction of CL-20 at 2200 K, 2500 K, 2800 K, and 3000 K isothermal temperature. The main stable resulting compounds are N2, CO2, CO, H2O, andH2, where CO2 and H2O continue to decompose at higher temperatures. The initial decomposition pathways are denitration by N–N fracture, ring-opening by C–N bond fracture, and redox reaction involving NO2 and CL-20. After ring opening, two main compounds, fused tricyclic pyrazine and azadicyclic, were formed, which were decomposed continuously to form monocyclic pyrazine and pyrazole ring structures. The most common fragments formed during decomposition are those containing two, three, four, and six carbons. The formation rule and quantity of main small molecule intermediates and resulting stable products under different simulated temperatures were analyzed. Methods: Based on ab initio Bayesian active learning algorithm, efficient and accurate prediction of CL-20 is made using the dynamic machine learning function of Vienna Ab-Initio Simulation Package (VASP), which constructs the energy potential surface by learning a large number of data based on AIMD calculations. The result is a machine learning force field (MLFF). Then the molecular dynamics of CL-20 was simulated using the trained MLFF model. PAW pseudopotentials and generalized gradient approximation (GGA), namely, Perdew-Burke-Ernzerhof (PBE) functional, are used in the calculation. The plane wave truncation energy (ENCUT) is set to 550 eV, and using the Gaussian broadening, the thermal broadening size of the single-electron orbital is 0.05 eV. A van der Waals revision of the system with Grimme Version 3. The energy convergence accuracy (EDIFF) of electron self-consistent iteration is set to 1E-5 eV and 1E-6 eV, respectively. The two-step structure optimization is carried out using 1′1′1 k point grid and conjugate gradient method. The ENCUT was changed to 500 eV and EDIFF to 1E-5 eV, and NVT integration (ISIF = 2) of Langevin thermostat was used for machine learning force field training and AIMD simulation of the system. [ABSTRACT FROM AUTHOR]

Huperzia crispata is a traditional Chinese herb plant and has attracted special attention in recent years for its products Hup A can serve as an acetylcholinesterase inhibitor (AChEI). Although the chloroplast (cp) genome of H. crispata has been studied, there are no reports regarding the Huperzia mitochondrial (mt) genome since the previously reported H. squarrosa has been revised as Phlegmariurus squarrosus. The mt genome of H. crispata was sequenced using a combination of long-read nanopore and Illumina sequencing platforms. The entire H. crispata mt genome was assembled in a circular with a length of 412,594 bp and a total of 91 genes, including 45 tRNAs, 6 rRNAs, 37 protein-coding genes (PCGs), and 3 pseudogenes. Notably, the rps8 gene was present in P. squarrosus and a pseudogene rps8 was presented in H. crispata, which was lacking in most of Pteridophyta and Gymnospermae. Intron-encoded maturase (mat-atp9i85 and mat-cobi787) genes were present in H. crispata and P. squarrosus, but lost in other examined lycophytes, ferns, and Gymnospermae plants. Collinearity analysis showed that the mt genome of H. crispata and P. squarrossus is highly conservative compared to other ferns. Relative synonymous codon usage (RSCU) analysis showed that the amino acids most frequently found were phenylalanine (Phe) (4.77%), isoleucine (Ile) (4.71%), lysine (Lys) (4.26%), while arginine (Arg) (0.32%), and histidine (His) (0.42%) were rarely found. Simple sequence repeats (SSR) analysis revealed that a total of 114 SSRs were identified in the mt genome of H. crispata and account for 0.35% of the whole mt genome. Monomer repeats were the majority types of SSRs and represent 91.89% of the total SSRs. In addition, a total of 1948 interspersed repeats (158 forward, 147 palindromic, and 5 reverse repeats) with a length ranging from 30 bp to 14,945 bp were identified in the H. crispata mt genome and the 30–39-bp repeats were the most abundant type. Gene transfer analysis indicated that a total of 12 homologous fragments were discovered between the cp and mt genomes of H. crispata, accounting for 0.93% and 2.48% of the total cp and mt genomes, respectively. The phylogenetic trees revealed that H. crispata was the sister of P. squarrosus. The Ka/Ks analysis results suggested that most PCGs, except atp6 gene, were subject to purification selection during evolution. Our study provides extensive information on the features of the H. crispata mt genome and will help unravel evolutionary relationships, and molecular identification within lycophytes. [ABSTRACT FROM AUTHOR]

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Introduction: This study examined the cost-effectiveness of first-line toripalimab plus chemotherapy (TC) for patients with advanced non-small cell lung cancer (NSCLC), excluding patients with nonsquamous NSCLC and EGFR/ALK mutations. It further analyzed the cost-effectiveness of this strategy in biomarker-based subgroups, all within the context of the Chinese healthcare system. Methods: Eighteen Markov models with 21-day Markov cycle lengths and 30-year time horizons were constructed in this study. Clinical effectiveness data were derived from the CHOICE-01 trial. Health state utilities and costs data were obtained from various sources. The primary outputs were the calculation of incremental cost-effectiveness ratios (ICERs), which were then compared to a willingness-to-pay (WTP) threshold of $17,961 per quality-adjusted life-year (QALY). This comparison was used to determine the treatment that offered greater cost-effectiveness. To account for uncertainty in the model, sensitivity analyses were conducted. Results: For the overall patient population, the estimated ICER between first-line TC and placebo plus chemotherapy (PC) was $9445/QALY, significantly lower than the WTP threshold used in the model. In subgroups based on pathologic types, first-line TC had an ICER of $16,757/QALY for patients with nonsquamous NSCLC, slightly below the WTP threshold; first-line TC demonstrated dominance in patients with squamous NSCLC, indicating both better effectiveness and lower costs compared to first-line PC. In biomarkers-based subgroups, first-line TC was dominant over first-line PC in the subgroups with programmed cell death ligand 1 (PD-L1) expression ≥ 50% and SMARCA4 mutations. Moreover, first-line TC had ICERs lower than the WTP threshold in other subgroups, except for the subgroup with RB1 mutations. Sensitivity analysis confirmed the robustness of these findings. Conclusion: From the perspective of the Chinese healthcare system, this study's findings suggested that first-line TC represents a cost-effective strategy for patients with advanced NSCLC. However, the cost-effectiveness of first-line TC varied across different subgroups when considering predictive biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Sugemalimab is the first China-developed programmed death-ligand 1 inhibitor that has proved to be effective as a first-line treatment for both metastatic squamous and non-squamous non-small cell lung cancer (NSCLC) when used in combination with chemotherapy. This study compared the cost-effectiveness of sugemalimab plus chemotherapy (sugema + chemo) with placebo plus chemotherapy (placebo + chemo) among metastatic squamous and nonsquamous NSCLC, respectively. Methods: Separate Markov models were constructed to generate the cumulative healthcare costs and quality-adjusted life-years (QALYs) associated with two treatment strategies over a 20-year time horizon. Transition probabilities were estimated using survival data reported in the GEMSTONE-302 trial. Health state utilities and costs were derived from published literature, national databases, and local general hospitals. Sensitivity analyses were performed to test the robustness of our conclusions. Results: Compared with first-line placebo + chem, sugema + chemo achieved an incremental cost-effectiveness ratio (ICER) of $57,842/QALY for patients with metastatic squamous NSCLC and achieved an ICER of $78,249/QALY for patients with metastatic non-squamous NSCLC. In our sensitivity analyses of a willingness-to-pay (WTP) threshold of $35,663 per QALY, the first-line sugema + chemo was only cost-effective for patient groups when the price of sugemalimab decreased. Conclusion: Sugema + chemo was not cost-effective as a first-line treatment for either metastatic squamous or metastatic nonsquamous NSCLC in Chinese patients compared with placebo + chemo. However, we found that sugema + chemo would be cost-effective in patients with metastatic squamous and non-squamous NSCLC when sugemalimab's price was decreased by > 39.0% and 64.8%, respectively. [ABSTRACT FROM AUTHOR]

The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention. ETS transcription factor ERG has been implicated in numerous cancers, including leukemia. Here, the authors show that ERG interaction with the NCoR-HDAC3 co-repressor complex is essential for its leukemogenic activity. Highlighting this interaction as a potential therapeutic target, HDAC3 inhibition led to reduced growth of ERG-dependent leukemia cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Key message: In total, 17 QTLs for lint percentage in short-season cotton, including three stable QTLs, were detected. Twenty-eight differentially expressed genes located within the stable QTLs were identified, and two genes were validated by qRT-PCR. The breeding and use of short-season cotton have significant values in addressing the question of occupying farmlands with either cotton or cereals. However, the fiber yields of short-season cotton varieties are significantly lower than those of middle- and late-maturing varieties. How to effectively improve the fiber yield of short-season cotton has become a focus of cotton research. Here, a high-density genetic map was constructed using genome resequencing and an RIL population generated from the hybridization of two short-season cotton accessions, Dong3 and Dong4. The map contained 4960 bin markers across the 26 cotton chromosomes and spanned 3971.08 cM, with an average distance of 0.80 cM between adjacent markers. Based on the genetic map, quantitative trait locus (QTL) mapping for lint percentage (LP, %), an important yield component trait, was performed. In total, 17 QTLs for LP, including three stable QTLs, qLP-A02, qLP-D04, and qLP-D12, were detected. Three out of 11 non-redundant QTLs overlapped with previously reported QTLs, whereas the other eight were novel QTLs. A total of 28 differentially expressed genes associated with the three stable QTLs were identified using RNA-seq of ovules and fibers at different seed developmental stages from the parental materials. The two genes, Ghir_A02G017640 and Ghir_A02G018500, may be related to LP as determined by further qRT-PCR validation. This study provides useful information for the genetic dissection of LP and promotes the molecular breeding of short-season cotton. [ABSTRACT FROM AUTHOR]

We study regularity criteria of weak solutions to the three dimensional (3d) incompressible Navier–Stokes equations, and provide several Prodi-Serrin type regularity criteria involving only partial components of the velocity or its gradient on framework of the anisotropic Lebesgue spaces. [ABSTRACT FROM AUTHOR]

Auxin response factor (ARF) is an important transcription factor that regulates the expression of auxin-responsive genes by direct binding to their promoters, which play a central role in plant growth, development, and response to abiotic stresses. The availability of the entire Coix (Coix lacryma-jobi L.) genome sequence provides an opportunity to investigate the characteristics and evolutionary history of the ARF gene family in this medicine and food homology plant for the first time. In this study, a total of 27 ClARF genes were identified based on the genome-wide sequence of Coix. Twenty-four of the 27 ClARF genes were unevenly distributed on 8 chromosomes except Chr 4 and 10, and the remaining three genes (ClARF25-27) were not assigned to any chromosome. Most of the ClARF proteins were predicted to be localized to the nucleus, except ClARF24, which was localized to both the plasma membrane and nucleus. Twenty-seven ClARFs were clustered into six subgroups based on the phylogenetic analysis. Duplication analysis showed that segmental duplication, rather than tandem duplications promoting the expansion of the ClARF gene family. Synteny analysis showed that purifying selection might have been a primary driving force in the development of the ARF gene family in Coix and other investigated cereal plants. The prediction of the cis element of the promoter showed that 27 ClARF genes contain several stress response elements, suggesting that ClARFs might be involved in the abiotic stress response. Expression profile analysis shows that 27 ClARF genes were all expressed in the root, shoot, leaf, kernel, glume, and male flower of Coix with varying expression levels. Furthermore, qRT-PCR analyses revealed that the majority of ClARFs members were upregulated or downregulated in response to hormone treatment and abiotic stress. The current study expands our understanding of the functional roles of ClARFs in stress responses and provides basic information for the ClARF genes. [ABSTRACT FROM AUTHOR]

In this paper, we consider the singular points of suitable weak solutions to the 3D co-rotational Beris–Edwards system modeling the hydrodynamical motion of nematic liquid crystal flows, which is a coupled system with the Navier–Stokes equations for the fluid and a parabolic system of Q-tensor for the liquid average orientation. We prove that if (u , Q) defined on R 3 × (0 , T) is a suitable weak solution to the 3D co-rotational Beris–Edwards system, and satisfies ‖ (u , ∇ Q) ‖ L q , ∞ (0 , T ; L p (R 3)) < ∞ with 3 < p < ∞ and 2 q + 3 p = 1 , then for a given open subset Ω ⊆ R 3 and for a given moment of time t 0 ∈ (0 , T) , the number of points of the set Σ (t 0) ∩ Ω is finite, where Σ (t 0) ≡ { (x , t 0) ∈ Σ } and Σ is the set of singular points for (u , Q) . Moreover, if T 1 ∈ (0 , T) is the first time for singularity appears, and if (u , Q) satisfies ‖ (u , ∇ Q) (· , t) ‖ L p (R 3) ≤ c 0 (T 1 - t) p - 3 2 p for all 0 < t < T 1 , with 3 < p ≤ ∞ and c 0 is a postive constant, then we show that (u , Q) preserves the energy equality on the closed interval [ 0 , T 1 ] including the first blow-up time T 1 . [ABSTRACT FROM AUTHOR]

Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis. [ABSTRACT FROM AUTHOR]

In this remark, we consider regularity criterion for weak solutions to the 3d incompressible Navier–Stokes equations via pressure. It is proved that if the corressponding pressure P satisfies ∇ h ˜ P ∈ L β (0 , T ; L p (R x 1 ; L q (R x 2 ; L r (R x 3)))) with 2 β + 1 p + 1 q + 1 r = 3 , 6 5 < p , q , r ≤ 3 and 2 − (1 p + 1 q + 1 r) ≥ 0 , then the weak solution remains smooth on (0 , T ] . Here, ∇ h ˜ = (0 , ∂ 2 , ∂ 3) . [ABSTRACT FROM AUTHOR]

Differential diagnosis of pulmonary nodules detected by computed tomography (CT) remains a challenge in clinical practice. Here, we characterize the global metabolomes of 480 serum samples including healthy controls, benign pulmonary nodules, and stage I lung adenocarcinoma. The adenocarcinoma demonstrates a distinct metabolomic signature, whereas benign nodules and healthy controls share major similarities in metabolomic profiles. A panel of 27 metabolites is identified in the discovery cohort (n = 306) to distinguish between benign and malignant nodules. The discriminant model achieves an AUC of 0.915 and 0.945 in the internal validation (n = 104) and external validation cohort (n = 111), respectively. Pathway analysis reveals elevation in glycolytic metabolites associated with decreased tryptophan in serum of lung adenocarcinoma vs benign nodules and healthy controls, and demonstrates that uptake of tryptophan promotes glycolysis in lung cancer cells. Our study highlights the value of the serum metabolite biomarkers in risk assessment of pulmonary nodules detected by CT screening. Detection of lung adenocarcinoma through serum sampling could be an alternative to CT scanning. Here, the authors use global metabolomics to create a 27 metabolite signature, which showed accuracy in detection in an external validation cohort. [ABSTRACT FROM AUTHOR]

Pinus elliottii used as rootstock instead of homologous rootstock, have been proved to accelerate early growth of the scion (Pinus massoniana), for cultivation of large diameter wood. However, the basal diameter of scions in heterologous grafts was significantly smaller than self-graft 10 years later, according to field investigation, which was opposed to cultivation objectives. Although advantage of heterologous grafts has been reported, less is known about the long term effect of heterologous rootstock on scions of P. massoniana. The aim of present study was to investigate the mechanism of the above difference. Toward this aim, the growth traits and physiological characteristics of scions in the two graft groups were studied, and the underlying mechanism was preliminarily explored through transcriptome sequencing technology. Results showed that scions of heterologous grafts had less TSCA compared to self-grafts, while no significant difference of plant height, number of branches and canopy volume between two graft groups. Besides, scion leaves of heterologous grafts displayed higher antioxidant enzyme activity and lower chlorophyll content. And interactions between rootstocks and scions had also changed the mineral element composition of scion leaves. Compared with homologous grafts, scion leaves of heterologous grafts accumulated more K+, Mg2+ and Zn2+, but less Ca2+,which have been proved to be conducive to the growth of stem diameter of P. massoniana. Moreover, a comparative transcriptome analysis of two graft groups showed that DEGs between them were mainly caused by the specificity of rootstock. GO and KEGG analysis found that heterologous rootstock had different gene expression preferences, and the gene expression level between rootstocks and scions were significantly different, such as auxin auxin-related genes and stress responsive genes. That may imply that auxin pathway played an important role not only in grafting healing process, but also in maintaining the growth between scion and stock. Summary of all above results, we concluded that the long term effect of heterologous rootstock on scions may be unsatisfactory with the later rapidly growth of scion, probably due to delayed graft incompatibility between scion and stock of heterologous grafts. This study may remind us that the long-term growth of the scion deserves attention as well as the healing process, which could also provide a basis for delayed graft incompatibility. [ABSTRACT FROM AUTHOR]

Globally, air pollution is amongst the most significant causes of premature death. Nevertheless, studies on the relationship between fine particulate matter (PM2.5) exposure and blood lipids have typically not been population-based. In a large, community-based sample of residents in Yixing city, we assessed the relationship between short-term outdoor PM2.5 exposure and blood lipid concentrations. Participants who attended the physical examination were enrolled from Yixing People's hospital from 2015 to 2020. We collected general characteristics of participants, including gender and age, as well as test results of indicators of blood lipids. Data on daily meteorological factors were collected from the National Meteorological Data Sharing Center (http://data.cma.cn/) and air pollutant concentrations were collected from the China Air Quality Online Monitoring and Analysis Platform (https://www.aqistudy.cn/) during this period. We applied generalized additive models to estimate short-term effects of ambient PM2.5 exposure on each measured blood lipid-related indicators and converted these indicators into dichotomous variables (non- hyperlipidemia and hyperlipidemia) to calculate risks of hyperlipidemia associated with PM2.5 exposure. A total of 197,957 participants were included in the analysis with mean age 47.90 years (± SD, 14.28). The increase in PM2.5 was significantly associated with hyperlipidemia (odds ratio (OR) 1.003, 95% CI 1.001–1.004), and it was still significant in subgroups of males and age < 60 years. For every 10 μg/m3 increase in PM2.5, triglyceride levels decreased by 0.5447% (95% CI − 0.7873, − 0.3015), the low-density lipoprotein cholesterol concentration increased by 0.0127 mmol/L (95% CI 0.0099, 0.0156), the total cholesterol concentration increased by 0.0095 mmol/L (95% CI 0.0053, 0.0136), and no significant association was observed between PM2.5 and the high-density lipoprotein cholesterol concentration. After excluding people with abnormal blood lipid concentrations, the associations remained significant except for the high-density lipoprotein cholesterol concentration. PM2.5 was positively correlated with low-density lipoprotein cholesterol and total cholesterol, and negatively correlated with triglyceride, indicating PM2.5 can potentially affect health through blood lipid levels. [ABSTRACT FROM AUTHOR]

When dealing with complex thermal infrared (TIR) tracking scenarios, the single category feature is not sufficient to portray the appearance of the target, which drastically affects the accuracy of the TIR target tracking method. In order to address these problems, we propose an adaptively multi-feature fusion model (AMFT) for the TIR tracking task. Specifically, our AMFT tracking method adaptively integrates hand-crafted features and deep convolutional neural network (CNN) features. In order to accurately locate the target position, it takes advantage of the complementarity between different features. Additionally, the model is updated using a simple but effective model update strategy to adapt to changes in the target during tracking. In addition, a simple but effective model update strategy is adopted to adapt the model to the changes of the target during the tracking process. We have shown through ablation studies that the adaptively multi-feature fusion model in our AMFT tracking method is very effective. Our AMFT tracker performs favorably on PTB-TIR and LSOTB-TIR benchmarks compared with state-of-the-art trackers. [ABSTRACT FROM AUTHOR]

On 05 September 2022, an Ms 6.8 (Mw 6.6) earthquake occurred in Luding County, Sichuan Province, China, with the epicenter at 29.59°N, 102.08°E and a focal depth of approximately 16.0 km. Combining field investigations, high-resolution satellite images and multiple datatpes characterizing the seismogenic structure, topography and geology, this study attempts to discuss the influence of geomorphic and tectonic indexes on landslide distribution. The results show that the 2022 Luding earthquake with seismogenic fault at the Moxi fault, was a sinistral strike-slip event that triggered at least 4528 landslides over an area of ∼2000 km2. These landslides span a total area of 28.1 km2, and the western section of the seismogenic fault, which serves as the active wall area, is characterized by a higher landslide concentration, especially in the Wandong Basin. The seismogenic fault and lithology influence the regional distribution of landslides, and more landslides occurred closer to the seismogenic fault and in the controlling lithologies of granite and dolomite. Local topography influences the landslide occurrence position on the slope; the eastern section is prone to form landslides in the lower gorge section, and the western section is prone to form landslides in the upper-top section of the gorge. For coseismic landslides in the eastern Baryan Har block, the eastern boundary (Longmenshan fault), where the earthquakes are characterized by thrusts with slight dextral strike-slip movement, could be the primary landslide-prone area; the southern boundary, the Moxi fault and the southern segment of the Xianshuihe fault, with more intensive strike-slip movement, may be the secondary landside-prone area; and the northern boundary is the tertiary landside-prone area. Additionally, the current landslide inventory may be underestimated although this underestimation has limited influence on the results. [ABSTRACT FROM AUTHOR]

Background: Huperzia crispata, belonging to the Huperziaceae family, is one of the most essential resources of huperzine A for candidate drugs to treat Alzheimer's diseases. However, there is very limited information about H. crispat, and its taxonomic status and interspecific relationships between Huperzia species are still unclear. To investigate the taxonomic classification of Huperzia species and identify species discrimination markers, the complete chloroplast (cp) genome of H. crispata was sequenced and characterized for the first time. Methods and Results: Total genomic DNA was isolated and sequenced using the next-generation Illumina NovaSeq 6000 platform. The data were filtered, assembled and annotated by a series software and web service. The results were as follows: the cp genome of H. crispata was 154,320 bp long with a large single-copy (LSC) region of 104,023 bp, a small single-copy (SSC) region of 19,671 bp, and a pair of inverted repeat (IRa and IRb) regions of 15,313 bp. A total of 131 genes, including 87 protein-coding genes, 36 transfer RNA genes (tRNAs), and eight ribosome RNA genes (rRNAs), were annotated in the cp genome. The contraction and expansion of the inverted repeat (IR) regions were relatively conserved in the Huperzia genus. Codon usage bias analysis showed that the encoding rate at the 3-end of codon A/T (74.34%) was significantly higher than that of C/G (25.66%). A total of 8 hotspot loci with high Pi values (> 0.06) were identified in the four Huperzia species based on nucleic acid diversity analysis. Ka/Ks selective pressure analysis demonstrated that the cemA gene is the most common gene undergoing positive selection among Huperzia. In addition, a total of 261 simple sequence repeats and 179 interspersed repeats were identified in the cp genome. Phylogenetic tree analysis based on the complete protein sequences of 23 related species of H. crispata indicated that H. serrata f. longipetiolata is a sister of H. crispata, suggesting that H. serrata f. longipetiolata and H. crispata are more closely related than H. serrata and H. lucidula. Conclusions: The results strongly supported that H. crispata was more closely related to H. serrata f. longipetiolata than to H. serrata and H. lucidula within the Huperzia genus. The outcome provided important information for the phylogenetic analysis of the subsequent specific molecular species identification in Huperzia. The present results will provide valuable information for further research into the classification, phylogeny and species identification of Huperzia plants. [ABSTRACT FROM AUTHOR]

Gills are the location of gas exchange and also the first target organ of fish response for environmental stress. As a multifunctional organ, its energy supply, when faced with insufficient dissolved oxygen in the water, remains unclear. In this study, largemouth bass was subjected to hypoxia stress (1.2 mg/L) for 24 h and 12 h reoxygenation (R12) to evaluate energy supply strategy of gills. Under hypoxia exposure, the respiratory rate of largemouth bass increased by an average of 20 breaths per minute. A total of 2026, 1744, 1003, 579, 485, and 265 differentially expressed genes (DGEs) were identified at 0 h, 4 h, 8 h, 12 h, 24 h, and R12h in gills after hypoxia exposure. KEGG functional analysis of DEGs revealed that the glycolysis/gluconeogenesis pathway was enriched across all the sampling points (0, 4, 8, 12, 24 h, R12). The gene expression and enzyme activity of three rate-limiting enzymes (hexokinase, phosphofructokinase-6, pyruvate kinase) in glycolysis pathway were significantly increased. Increased levels of glycolysis products pyruvate and lactic acid, as well as the number of mitochondria (1.8-fold), suggesting an enhancement of aerobic and anaerobic metabolism of glucose in gills. These results suggest that the gill of largemouth bass enhanced the energy supply during acute exposure to hypoxia stress. [ABSTRACT FROM AUTHOR]

The diagnosis and disease management of chronic hepatitis B (CHB) remain challenging due to the elusive assessment of disease severity. Recently, soluble receptor for advanced glycation end-products (sRAGE) has been implicated in the inflammatory-immune response initiated by liver injury. Nonetheless, its natural behavior and clinical importance in CHB remain elusive. One hundred and twenty CHB patients and forty healthy controls (HCs) were enrolled, and the serum sRAGE as well as RAGE expression in biopsy specimens from these subjects was analyzed, and correlation of sRAGE with clinical features as well as its potential predictive value for monitoring the CHB was also evaluated. Reduced serum sRAGE levels and decreased tissular RAGE expression were observed in CHB patients. sRAGE and RAGE were inversely correlated with gradually increased grades of hepatic necroinflammation as well as the routine indicator ALT. Furthermore, receiver operating characteristic (ROC) analysis showed that combination of ALT and sRAGE exerted better predictive power (area under the ROC curve (AUC) of 0.86) for hepatic necroinflammation than that of ALT (AUC of 0.82), sRAGE (AUC of 0.81), or sRAGE-to-ALT ratio (sRAGE/ALT) (AUC of 0.85) alone. More importantly, circulating sRAGE alone exerted valuable predictive power for hepatic moderate-to-severe necroinflammation in CHB patients but with normal ALT (AUC of 0.81) or minimally elevated ALT (AUC of 0.85). In conclusion, reduced serum sRAGE levels may imply an increased severity for necroinflammation, and it may serve as a potential alternative biomarker for monitoring hepatic necroinflammation in CHB. [ABSTRACT FROM AUTHOR]

Methane is supersaturated in surface seawater and shallow coastal waters dominate global ocean methane emissions to the atmosphere. Aerobic methane oxidation (MOx) can reduce atmospheric evasion, but the magnitude and control of MOx remain poorly understood. Here we investigate methane sources and fates in the East China Sea and map global MOx rates in shallow waters by training machine-learning models. We show methane is produced during methylphosphonate decomposition under phosphate-limiting conditions and sedimentary release is also source of methane. High MOx rates observed in these productive coastal waters are correlated with methanotrophic activity and biomass. By merging the measured MOx rates with methane concentrations and other variables from a global database, we predict MOx rates and estimate that half of methane, amounting to 1.8 ± 2.7 Tg, is consumed annually in near-shore waters (<50 m), suggesting that aerobic methanotrophy is an important sink that significantly constrains global methane emissions. Aerobic oxidation is a biological sink of methane that can reduce oceanic emissions to the atmosphere. This study estimates that half of methane from total loss, amounting to 1.8 ± 2.7 Tg, is oxidized annually in global 0–50 m near-shore waters [ABSTRACT FROM AUTHOR]

On 5th September 2022, a magnitude Ms-6.8 earthquake occurred nearby Mt. Gongga, western Sichuan. The stability of the glaciers in east Mt. Gongga close to the epicenter was widely concerned due to the strong shake triggered by the earthquake. Using multi-source observations (including in-situ photographs, remote sensing datasets before and after the event), we carried out a preliminary assessment of the stability and hazard risks of the Hailuogou (HLG) glacier. Triggered by the earthquake, a small block of fractured ice at the lowest part of icefall collapsed. The magnitude of the coseismic ice avalanche was relatively small, which is comparable in size to most ice avalanches over the past seven years, but much less than the previous mapped largest one (03 April 2018, runout ∼699 m). One most recent large (runout ∼608 m) ice avalanche occurred between 01 and 04 September, just before the earthquake, likely unloaded large amount of ice mass and made a larger ice avalanche avoided during the earthquake shake. Nevertheless, the momentum of collapsed snow-ice-rock mass could be safely unloaded over a wide and gentler-slope ice tongue area, limiting its mobility and the risk of a cascading hazard. Glacier-wide surface flow dynamics monitored by Sentinel-1 satellite SAR time series (12 September 2021–19 September 2022) show that HLG glacier velocity was generally consistent before and after the earthquake. The entire HLG glacier exhibited more stable than expected, with almost no abnormal features detected in its upper accumulation part, the lower ice tongue, and its lateral paraglacial slopes. Since the glacier valley has experienced remarkable downwasting and the paraglacial environment has been strongly disturbed and destabilized, we suggested that, to efficiently evaluate glacier-related cascading hazard risks, it is also necessary to systematically combine multi-source observations (e.g., high-resolution UAV survey, radar/Lidar scan, ground investigation, monitoring and warning systems) to continuously monitor the regional glacier anomalies in the post-earthquake seismic active areas. [ABSTRACT FROM AUTHOR]

The largemouth bass (Micropterus salmoides) has become a cosmopolitan species due to its widespread introduction as game or domesticated fish. Here a high-quality chromosome-level reference genome of M. salmoides was produced by combining Illumina paired-end sequencing, PacBio single molecule sequencing technique (SMRT) and High-through chromosome conformation capture (Hi-C) technologies. Ultimately, the genome was assembled into 844.88 Mb with a contig N50 of 15.68 Mb and scaffold N50 length of 35.77 Mb. About 99.9% assembly genome sequences (844.00 Mb) could be anchored to 23 chromosomes, and 98.03% assembly genome sequences could be ordered and directed. The genome contained 38.19% repeat sequences and 2693 noncoding RNAs. A total of 26,370 protein-coding genes from 3415 gene families were predicted, of which 97.69% were functionally annotated. The high-quality genome assembly will be a fundamental resource to study and understand how M. salmoides adapt to novel and changing environments around the world, and also be expected to contribute to the genetic breeding and other research. Measurement(s) genome assemble Technology Type(s) Illumina paired-end sequencing, PacBio single molecule sequencing technique (SMRT) and High-through chromosome conformation capture (Hi-C) technologies Sample Characteristic - Organism Micropterus floridanus [ABSTRACT FROM AUTHOR]

In this paper, we consider the 3d axisymmetric MHD-Boussinesq system with nonzero swirl, and prove that the system, with initial data (u 0 , h 0 , ρ 0) = (u 0 r e r + u 0 θ e θ + u 0 z e z , h 0 θ e θ , ρ 0) which satisfies some small nonlinear condition, admits a global unique solution (u , h , ρ) . Furthermore, some continuation criteria that imply regularity of axisymmetric solutions are also obtained. [ABSTRACT FROM AUTHOR]

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a GTPase exclusively expressed in hematopoietic cells that acts as a pivotal regulator of several aspects of cell behavior via various cellular processes. RAC2 undergoes a tightly regulated GTP-binding/GTP-hydrolysis cycle, enabling it to function as a molecular switch. Mutations in RAC2 have been identified in 18 patients with different forms of primary immunodeficiency, ranging from phagocyte defects caused by dominant negative mutations to common variable immunodeficiency resulting from autosomal recessive loss-of-function mutations, or severe combined immunodeficiency due to dominant activating gain-of-function mutations. Here, we describe an 11-year-old girl with combined immunodeficiency presenting with recurrent respiratory infections and bronchiectasis. Immunological investigations revealed low T-cell receptor excision circle/K-deleting recombination excision circles numbers, lymphopenia, and low serum immunoglobulin G. Targeted next-generation sequencing identified a novel heterozygous mutation in RAC2, c.86C > G (p.P29R), located in the highly conserved Switch I domain. The mutation resulted in enhanced reactive oxygen species production, elevated F-actin content, and increased RAC2 protein expression in neutrophils, as well as increased cytokine production and a dysregulated phenotype in T lymphocytes. Furthermore, the dominant activating RAC2 mutation led to accelerated apoptosis with augmented intracellular active caspase 3, impaired actin polarization in lymphocytes and neutrophils, and diminished RAC2 polarization in neutrophils. We present a novel RAC2 gain-of-function mutation with implications for immunodeficiency and linked to functional dysregulation, including abnormal apoptosis and cell polarization arising from altered RAC2 expression. Thus, our findings broaden the spectrum of known RAC2 mutations and their underlying mechanisms. [ABSTRACT FROM AUTHOR]

Gallstones were examined for 58 patients in Jilin, Jilin. It was found that gallstones from only one who suffered from cholecystectomy were composed of 20 spheroidal stones and they rarely exhibited three different types of surface appearances. Six representative powder samples were analyzed for gallstones compositions and Mn2+ using X-ray diffraction (XRD)/Infrared (IR) and electron spin resonance (ESR), respectively. The results suggested that all gallstones from this patient were identified by XRD to be gallstones consisting mainly of cholesterol and CaCO3 (GCCC). They rarely exhibited three different kinds of surface appearances corresponding to different concentration of trace Mn2+ in calcite (CMn2+/CCal): 18 dark/light brown spheres with smooth surfaces and CMn2+/CCal = 0–6 μg/g/%, a yellowish-brown huge sphere with a rougher surface and CMn2+/CCal = 30 μg/g/%, and an ashy sphere composed of tens of microspheres with the roughest surface and CMn2+/CCal = 60 μg/g/%. The difference in surface appearance showed significant association with CMn2+/CCal, and its increase made the gallstone's surface change from smooth to rough and to fade in color. The unbalanced and competitive Mn2+ accumulation could occur occasionally in individual stones owing to different affinities to Mn2+, resulting in the formation of a huge stone and an ashy sphere. These two aberrations caused by higher CMn2+/CCal played an important role in suppressing the crystalline growth of the majority of dark/light brown spheres. GCCC from a patient might have a prominent Mn2+ partitioning feature corresponding to different surface appearances. [ABSTRACT FROM AUTHOR]

With the improvement of people's living standards and rice trade worldwide, the demand for high-quality rice is increasing. Therefore, breeding high quality rice is critical to meet the market demand. However, progress in improving rice grain quality lags far behind that of rice yield. This might be because of the complexity of rice grain quality research, and the lack of consensus definition and evaluation standards for high quality rice. In general, the main components of rice grain quality are milling quality (MQ), appearance quality (AQ), eating and cooking quality (ECQ), and nutritional quality (NQ). Importantly, all these quality traits are determined directly or indirectly by the structure and composition of the rice seeds. Structurally, rice seeds mainly comprise the spikelet hull, seed coat, aleurone layer, embryo, and endosperm. Among them, the size of spikelet hull is the key determinant of rice grain size, which usually affects rice AQ, MQ, and ECQ. The endosperm, mainly composed of starch and protein, is the major edible part of the rice seed. Therefore, the content, constitution, and physicochemical properties of starch and protein are crucial for multiple rice grain quality traits. Moreover, the other substances, such as lipids, minerals, vitamins, and phytochemicals, included in different parts of the rice seed, also contribute significantly to rice grain quality, especially the NQ. Rice seed growth and development are precisely controlled by many genes; therefore, cloning and dissecting these quality-related genes will enhance our knowledge of rice grain quality and will assist with the breeding of high quality rice. This review focuses on summarizing the recent progress on cloning key genes and their functions in regulating rice seed structure and composition, and their corresponding contributions to rice grain quality. This information will facilitate and advance future high quality rice breeding programs. [ABSTRACT FROM AUTHOR]

The melanocortin-3 receptor (MC3R) is an important regulator of energy homeostasis and inflammation in mammals. However, its function in teleost fish needs to be further explored. In this study, we characterized rainbow trout MC3R (rtMC3R), which encoded a putative protein of 331 amino acids. Phylogenetic and chromosomal synteny analyses showed that rtMC3R was closely related to bony fishes. Quantitative PCR (qPCR) revealed that the transcripts of rtMC3R were highly expressed in the brain and muscle. The cellular function of rtMC3R was further verified by the signal-pathway-specific luciferase reporter assays. Four agonists such as α-MSH, β-MSH, ACTH (1–24), and NDP-MSH can active rtMC3R, increasing the production of intracellular cAMP and upregulating MAPK/ERK signals. Moreover, we found that rtMC3R stimulated with α-MSH and NDP-MSH can significantly inhibit the NF-κB signaling pathway. This research will be helpful for further studies on the function of MC3R in rainbow trout, especially the role of energy metabolism and immune regulation. [ABSTRACT FROM AUTHOR]

Physical erosion and chemical weathering rates beneath glaciers are expected to increase in a warming climate with enhanced melting but are poorly constrained. We present a global dataset of cations in meltwaters of 77 glaciers, including new data from 19 Asian glaciers. Our study shows that contemporary cation denudation rates (CDRs) beneath glaciers (2174 ± 977 Σ*meq+ m−2 year−1) are ~3 times higher than two decades ago, up to 10 times higher than ice sheet catchments (~150-2000 Σ*meq+ m−2 year−1), up to 50 times higher than whole ice sheet means (~30-45 Σ*meq+ m−2 year−1) and ~4 times higher than major non-glacial riverine means (~500 Σ*meq+ m−2 year−1). Glacial CDRs are positively correlated with air temperature, suggesting glacial chemical weathering yields are likely to increase in future. Our findings highlight that chemical weathering beneath glaciers is more intense than many other terrestrial systems and may become increasingly important for regional biogeochemical cycles. Global glacial chemical denudation is one of the largest contributors to global elemental cycles and, amplified by climate warming, will significantly impact nutrient loads in downstream ecosystems. [ABSTRACT FROM AUTHOR]

Gypsums played a vital role in the building materials, and gypsum whiskers were fiber-like crystals with small diameters and high aspect ratios, which performed lightweight, high strength, and green. The traditional methods of anhydrous gypsum whiskers through high temperature mostly involve high energy consumption and have potential environmental impacts. New methods of anhydrous gypsum whiskers even nano-whiskers had faced many challenges now. In this study, acetic acid and dilute sulfuric acid formed mixed acid, and anhydrous calcium sulfate nano-whiskers were directly fabricated by calcium carbonate slurry in a microemulsion solution. After modification, the anhydrous calcium sulfate nano-whiskers were modified with organosilicon quaternary ammonium salt and ion-exchanged with fatty acid methyl ester sulfonate. The particle performed phase evolution and surface structure changes. When 1% modified calcium sulfate was added into the cement slurry, the compressive strength of the cement slurry increased at 28 d. This method pointed out a new way to develop different technologies for building materials. [ABSTRACT FROM AUTHOR]

Organic dyes had caused many environmental problems. It penetrated underground water and caused widespread and long-term pollution. Although many works had been reported, there were still challenges for developing novel technologies of dyes eliminations. In this work, polydopamine/Ag microspheres were synthesized immediately through a convenient synthesis approach in emulsion solutions. Polydopamine microspheres were obtained through the microemulsion method at room temperature. Ag nanoparticles in-situ grew on the surface of modified microspheres. Through the MB solution test, polydopamine/Ag microspheres removed the MB from the solution quickly. Polydopamine/Ag microspheres also eliminated the MB at different temperatures, as well as concentrations and pH values. This method pointed out a new way to develop new materials for dyes elimination. [ABSTRACT FROM AUTHOR]

Introduction: The JAVELIN Bladder 100 trial showed that maintenance avelumab therapy after chemotherapy improved the survival of patients with advanced or metastatic urothelial carcinoma. We analyzed the cost-effectiveness of maintenance therapy with avelumab plus best supportive care (BSC) in patients with advanced or metastatic urothelial carcinoma after receiving first-line platinum-based chemotherapy from the US payer perspective. Methods: A Markov model was used to analyze the economic outcomes of maintenance avelumab plus BSC (avelumab strategy) in the treatment of urothelial carcinoma. The clinical data were derived from the JAVELIN Bladder 100 trial. All cost information was obtained from Medicare and published literature. The total cost, total life years (LYs), total quality-adjusted LYs (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefit (INHB) were calculated. One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. Results: Our results showed that avelumab strategy versus BSC strategy cost US $176,352 and $238,661 and yielded an additional 0.465 and 1.007 QALY in all patients with unknown programmed-death ligand 1 (PD-L1) status and the PD-L1-positive subpopulation, respectively, which led to an ICER of $102,365/QALY and $106,253/QALY gained. In all patients with unknown PD-L1 status, maintenance avelumab plus BSC therapy guiding by PD-L1 expression testing (PD-L1-guided strategy) compared with the avelumab strategy and BSC strategy resulted in ICER of $105,360/QALY and $122,653/QALY, respectively. The probabilities of the avelumab strategy and the PD-L1-guided strategy being cost-effective in the simultaneous competition of the three strategies were 38.49% and 48.82%. In patients with PD-L1-positive status, the avelumab strategy had an 87.51% probability of cost-effectiveness. The most influential parameter for the model was the cost of avelumab and pembrolizumab. Conclusions: This analysis demonstrated that maintenance therapy with avelumab plus BSC may be a cost-effective option for patients with advanced or metastatic urothelial carcinoma at a willingness-to-pay (WTP) threshold of $150,000/QALY, especially for patients with PD-L1-positive status. [ABSTRACT FROM AUTHOR]

Pheretima has been used as an animal-derived traditional Chinese medicine for thousands of years in Asian countries due to its multi-activities. However, more than half of the commercial Pheretima are adulterants according to the previous research. Besides, the standards of Pheretima are still inadequate in the identification of Pheretima species. In this study, an amino acids (AAs) analytical method established based on the ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS) in multiple reaction monitoring (MRM) mode through derivatization with 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) was used for qualitative and quantitative analysis of the total AAs of three main commercial Pheretima (two major Pheretima species, Amynthas aspergillum, Metaphire vulgaris, and one main counterfeit, M. magna). As a result, 16 AAs were detected and quantitated in their hydrolyzed samples. Then, multivariate statistical analysis was applied to distinguish the three commercial Pheretima based on their AAs level. Finally, four AAs (Thr, Glu, Asp, and Arg) were screened as species-differential AAs, which may be used as chemical markers to distinguish the three commercial Pheretima. This study deeply described the outline of AAs in Pheretima and offered a good reference for its species authentication. [ABSTRACT FROM AUTHOR]

Infectious microbes that spread easily in healthcare facilities remain as the severe threat for the public health, especially among immunocompromised populations. Given the intricate problem of dramatic increase in resistance to common biocides, the development of safe and efficient biocide formulated agents to alleviate drug resistance is highly demanding. In this study, Schiff-base ligands were successfully formed on natural biopolymer of epsilon-poly-L-lysine (ε-PL) decorated aldehyde functionalized mesoporous silica SBA-15 (CHO-SBA-15) for the selective coordination of silver ions, which was affirmed by various physicochemical methods. Besides the identified broad-spectrum antibacterial activities, the as-prepared Schiff-base silver nanocomplex (CHO-SBA-15/ε-PL/Ag, CLA-1) exhibited an improved inhibitory effect on infectious pathogen growth typified by Escherichia coli and Staphylococcus aureus in comparison with two control silver complexes without Schiff-base conjugates, SBA-15/ε-PL/Ag and CHO-SBA-15/Ag, respectively. In addition, CLA-1 remarkably inhibited the growth of Mycobacterium tuberculosis due to the excellent antimicrobial activity of silver species. Significantly, CLA-1 kills Candida albicans cells, inhibits biofilm formation, and eliminates preformed biofilms, with no development of resistance during continuous serial passaging. The antifungal activity is connected to disruption of bacterial cell membranes and increased levels of intracellular reactive oxygen species. In mouse models of multidrug-resistant C. albicans infection, CLA-1 exhibited efficient in vivo fungicidal efficacy superior to two antifungal drugs, amphotericin B and fluconazole. Moreover, CLA-1 treatment induces negligible toxicity against normal tissues with safety. Therefore, this study reveals the pivotal role of the molecular design of Schiff-base silver nanocomplex formation on biopolymer surface-functionalized silica mesopores as a green and efficient nanoplatform to tackle infectious microbes. [ABSTRACT FROM AUTHOR]

Identification of novel functional domains and characterization of detailed regulatory mechanisms in cancer-driving genes is critical for advanced cancer therapy. To date, CRISPR gene editing has primarily been applied to defining the role of individual genes. Recently, high-density mutagenesis via CRISPR tiling of gene-coding exons has been demonstrated to identify functional regions in genes. Furthermore, breakthroughs in combining CRISPR library screens with single-cell droplet RNA sequencing (sc-RNAseq) platforms have revealed the capacity to monitor gene expression changes upon genetic perturbations at single-cell resolution. Here, we present "sc-Tiling," which integrates a CRISPR gene-tiling screen with single-cell transcriptomic and protein structural analyses. Distinct from other reported single-cell CRISPR screens focused on observing gene function and gene-to-gene/enhancer-to-gene regulation, sc-Tiling enables the capacity to identify regulatory mechanisms within a gene-coding region that dictate gene activity and therapeutic response. Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization. [ABSTRACT FROM AUTHOR]

Introduction: The effectiveness of nivolumab plus ipilimumab with two cycles of chemotherapy (NIC) for advanced non-small cell lung cancer (NSCLC) has been demonstrated. We aimed to evaluate the cost-effectiveness of NIC for advanced NSCLC from the US payer perspective. Methods: A Markov model has been established to predict the disease course of previously untreated advanced NSCLC. The clinical data were derived from the CheckMate 9LA trial. Cost and utility were obtained from the literature. Model outputs included the incremental cost-effectiveness ratios (ICERs), incremental monetary benefit (INMB), and incremental net-health benefit (INHB). A series of sensitivity analyses were performed to analyze the uncertainty of the model. Results: Our results showed that NIC versus chemotherapy alone cost $264,278 and yielded an additional 0.80 quality-adjusted life-years (QALYs), which led to an ICER of $202,275/QALY gained. The INHB was − 0.28 QALY, and the INMB was − $41,865 at the threshold of $150,000/QALY. The results of one-way sensitivity analysis showed that the hazard ratio of overall survival was the most sensitive parameter. Conclusion: NIC was unlikely to be cost-effective as a first-line treatment for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Persons living with diabetes (PLWD) with newly diagnosed tuberculosis are at greater risk of poor treatment outcomes. Identifying and prioritizing high-risk subgroups of PLWD and tuberculosis for tuberculosis programs to target has been rarely performed. We investigated risk factors for poor tuberculosis treatment outcomes among PLWD and developed a predictive risk score for tuberculosis control prioritization. Among PLWD diagnosed with tuberculosis, demographic, clinical, and tuberculosis treatment outcome data were collected. Poor treatment outcomes included treatment failure, death, default, and transfer. Multivariable logistic regression modeling was used to analyze risk factors of poor treatment outcomes. Risk scores were derived based on regression coefficients to classify participants at low-, intermediate-, and high-risk of poor treatment outcomes. Among 335 PLWD newly diagnosed with tuberculosis, 109 were cured and 172 completed treatment. Multivariable logistic regression found that risk factors of poor treatment outcomes included bacteriologically-positivity, low body mass index, no physical activity, and pulmonary cavitation. Rates of poor treatment outcomes in low- (0–2), intermediate- (3–4), and high-risk (5–8) groups were 4.2%, 10.5%, and 55.4% (Ptrend < 0.0001), respectively. The risk score accurately discriminated poor and successful treatment outcomes (C-statistic, 0.85, 95% CI 0.78–0.91). We derived a simple predictive risk score that accurately distinguished those at high- and low-risk of treatment failure. This score provides a potentially useful tool for tuberculosis control programs in settings with a double burden of both tuberculosis and diabetes. [ABSTRACT FROM AUTHOR]