Search

Abstract Background Pulmonary nuclear protein in testis (NUT) carcinoma is a rare and aggressive malignancy that often exhibits clinical and pathological features overlapping with other thoracic malignancies, posing significant challenges for accurate diagnosis and leading to poor treatment outcomes. Method We conducted a retrospective analysis of five patients diagnosed with pulmonary NUT carcinoma between 2020 and 2023. Comprehensive clinical, imaging, histopathological, and molecular data and survival outcomes were collected. Results The cohort included three females and two males, with a median age of 44 years. Clinical features commonly involved centrally located masses with mediastinal invasion. Distant metastases to bones, pleura, and lungs were confirmed in 60% of cases. Diagnostic confirmation was achieved through NUT protein positivity via IHC and FISH rearrangements in all five patients. RNA sequencing identified BRD3-NUTM1 fusions in 60% (3/5) patients. Chemotherapy was employed as the initial treatment strategy but showed limited efficacy in advanced stages. Among two patients undergoing surgical resection, better outcomes were achieved in the patient receiving adjuvant therapy with overall survival (OS) exceeding 36 months. Immunotherapy demonstrated limited benefit, likely attributable to low PD-L1 expression and an immunologically “cold” tumor microenvironment. Despite multimodal treatment approaches, three out of five patients in advanced pulmonary NUT carcinoma died to the disease, with OS ranging from 6 to 15 months. Conclusion Advanced molecular techniques are critical for diagnosing pulmonary NUT carcinoma, but survival outcomes remain poor. Surgical resection with adjuvant therapy offers better outcomes for early-stage patients, while chemotherapy and immunotherapy show limited efficacy in metastatic cases due to the tumor’s aggressive behavior. Early detection and innovative therapies are essential for improving outcomes.

Abstract Magnetic resonance imaging and circulating molecular testing are potential methods for diagnosing and treating Parkinson’s disease (PD). However, their relationships remain insufficiently studied. Using genome-wide association summary statistics, we found in the general population a genetic negative correlation between white matter tract mean diffusivity and PD (-0.17 < Rg 0.8), including SH2B1 and TRIM10. Our study bridges the gap between molecular genetics, neuroimaging, and PD pathology, and suggests novel targets for diagnosis and treatment.

Abstract Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Lung cancer accounts for the highest proportion of cancer deaths in the world and poses a great threat to human health. About 30% to 40% of non-small cell lung cancer (NSCLC) is caused by point mutations, exon insertion and exon deletion of the epidermal growth factor receptor (EGFR). In addition to the common exon 19 deletion mutation and exon 21 L858R mutation, exon 18 G719X mutation, exon 21 L861Q mutation and exon 20 S768I mutation are the most important rare mutations. At present, the diagnostic methods for major rare mutations are mainly next-generation sequencing (NGS), digital polymerase chain reaction (dPCR), droplet digital PCR (ddPCR), etc. Regarding the targeted therapy of G719X/L861Q/S768I mutant NSCLC, the first generation EGFR-tyrosine kinase inhibitors (TKIs) have poor efficacy, while the second and third generation EGFR-TKIs have similar efficacy. The novel third generation EGFR-TKIs and combination therapy show a good therapeutic prospect. This article summarized the progress in the diagnosis and targeted therapy of G719X/L861Q/S768I mutant NSCLC, so as to provide reference for subsequent clinical drug use and research.

Honey is a natural substance produced by honeybees and is widely consumed as food worldwide. Honey has anti-inflammatory effects, which are related to its antibacterial and antioxidant functions. The anti-inflammatory properties of honey can be explored from two aspects: Basic research studies that reveal the molecular mechanisms underlying the biological functions of honey and identify its effective components, and clinical research studies that evaluate the healing effects of honey in inflammatory diseases. Basic research studies are indicated that honey has anti-inflammatory properties and further elucidated the relevant molecular mechanisms. The anti-inflammatory functions of honey are highly related to its components, specifically flavonoids, phenolic acids, glucose oxidase, hydrogen peroxide, and methylglyoxal. These effective constituents exhibit anti-inflammatory effects by regulating immune cell function, affecting inflammatory cytokines, inhibiting the growth of pathogenic bacteria, and acting as antioxidants. Honey can attenuate gastrointestinal inflammation, aid the recovery of intestinal microbiota, relieve symptoms of chronic sinusitis, and prevent radiation-induced oral mucositis. Based on honey-related basic and clinical research studies conducted over the past five years, this article reviews the anti-inflammatory mechanisms of honey, the functions of its effective constituents, and the applications of honey in inflammatory diseases.

ABSTRACT: Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) binding contributes to immune evasion mechanisms responsible for B lymphocyte exhaustion and apoptosis. This facilitates immunosuppression in chronic viral infections, including infectious bursal disease virus (IBDV). Our previous study showed that PD-1 and PD-L1 expression increases in the peripheral blood mononuclear cells of chickens infected with IBDV. However, due to their high production costs and immune-related adverse events, monoclonal antibodies targeting PD-1 or PD-L1 are unsuitable therapeutic agents. Thus, in the current study, we designed peptides with optimized binding sites for PD-1 and investigated their ability to disrupt PD-1/PD-L1 binding and restore B lymphocyte function in vitro. The peptide gCK-16 exhibited a high affinity for PD-1 (KD: 3.37 nM) and effectively inhibited the PD-1/PD-L1 interaction in vitro. Moreover, gCK-16 significantly enhanced B lymphocyte proliferation. Remarkably, gCK-16 treatment abrogated the IBDV-induced upregulation of PD-1/PD-L1, NF-κB activation, and B lymphocyte apoptosis. Additionally, IBDV infection attenuated PI3K/AKT pathway activation in B lymphocytes, while gCK-16 treatment increased immunoglobulin M (IgM) production in IBDV-infected B lymphocytes. Together, these results demonstrate that gCK-16 treatment can potentially enhance B lymphocyte function against IBDV infection, guiding the development of vaccine adjuvants to effectively prevent IBDV-induced avian immunosuppression.

BackgroundChimeric antigen receptor (CAR) engineered natural killer (NK) cells exhibit advantages such as MHC-independent recognition and strong anti-tumor functions. However, allogeneic CAR-NK cells derived from human tissues are heterogeneous and susceptible to clearance by hosts.MethodsWe generated a B2M knockout, HLA-E and CD19 CAR ectopic expressing embryonic stem cell (ESC) line, which differentiated normally and gave rise to homogeneous CD19 CAR-NK (CD19 CAR-UiNK) cells using an organoid aggregate induction method. The CD19 CAR-UiNK were co-cultured with T cells or NK cells derived from peripheral blood mononuclear cells (PBMC) with the mismatched HLA to evaluate the immunogenicity of CD19 CAR-UiNK cells. We further assessed the therapeutic effects of CD19 CAR-UiNK cells on CD19+ tumor cells through in vitro cytotoxicity assays and in vivo animal models.ResultsThe CD19 CAR-UiNK cells exhibited typical expression patterns of activating and inhibitory receptors, and crucial effector molecules of NK cells, similar to those of unmodified NK cells. In co-culture assays, the CD19 CAR-UiNK cells evaded allogeneic T cell response and suppressed allogeneic NK cell response. Functionally, the CD19 CAR-UiNK cells robustly secreted IFN-γ and TNF-α, and upregulated CD107a upon stimulation with Nalm-6 tumor cells. The CD19 CAR-UiNK cells effectively eliminated CD19+ tumor cells in vitro, including B-cell cancer cell lines and primary tumor cells from human B-cell leukemia and lymphoma. Further, the CD19 CAR-UiNK cells exhibited strong anti-tumor activity in xenograft animals.ConclusionWe offer a strategy for deriving homogeneous and hypoimmunogenic CD19 CAR-iNK cells with robust anti-tumor effects from ESCs. Our study has significant implications for developing hypoimmunogenic CD19 CAR-NK cell therapy using human ESC as an unlimited cell source.

ABSTRACT Background The incidence of small cell lung cancer (SCLC) among Asian patients is on the rise. Nevertheless, there remains a deficiency in precise prognostic models tailored to the specific needs of this patient population. It is imperative to develop a novel nomogram aimed at forecasting the prognosis of Asian SCLC patients. Methods The SEER database supplied data on 661 Asian SCLC patients, who were then divided into training and internal validation sets through a random selection process. In addition, we identified 212 patients from a Chinese medical institution for the purpose of creating an external validation cohort. To forecast survival, we employed both univariate and multivariate analyses. The performance of our nomogram was assessed through calibration plots, the concordance index (C‐index), and decision curve analysis (DCA). Results Five independent prognostic factors were determined and integrated into the nomogram. C‐index values for the training and internal validation cohorts were 0.774 (95% confidence interval [CI] = 0.751–0.797) and 0.731 (95%CI = 0.690–0.772), respectively. In the external validation cohort, the C‐index is 0.712 (95% CI = 0.655–0.7692). Calibration curves demonstrated highly accurate predictions. When compared to the AJCC staging system, our model exhibited improved net benefits in DCA. Furthermore, the risk stratification system effectively differentiated patients with varying survival risks. Conclusion We have created a novel nomogram for predicting the survival of Asian patients with SCLC. This nomogram has been subjected to external validation and has shown its superiority over the conventional TNM staging system. It offers a more precise and reliable means of forecasting the prognosis of Asian SCLC patients.

Abstract Most electrocatalysts are known to experience structural change during the oxygen evolution reaction (OER) process. Considerable endeavors have been dedicated thus far to comprehending the catalytic process and uncovering the underlying mechanism. During the dynamic evolution of catalyst structure, component leaching of electrocatalysts is the most common phenomenon. This article offers a concise overview of recent findings and developments related to the leaching phenomena in the OER process in terms of fundamental understanding of leaching, advanced characterization techniques used to investigate leaching, leaching of inactive components, and leaching of active components. Leaching behaviors and the induced effects in various kinds of OER catalysts are discussed, progress in manipulating leaching amount/degree toward a tunable surface evolution is spotlighted, and finally, three representative types of structure transformations induced by leaching metastable species in OER condition are proposed. By understanding the process of component leaching in the OER, it will provide more guidance for the rational design of superior electrocatalysts.

ABSTRACT Microorganisms can produce a vast diversity of volatile organic compounds of different chemical classes that are capable of mediating intra- and inter-kingdom interactions. In this study, we showed that the soil-dwelling bacterium Streptomyces venezuelae can produce alkaline volatiles under multiple growth conditions, which we discovered through investigation of the S. venezuelae mutant strain MU-1. Strain MU-1 has a defective morphology and exhibits a bald phenotype due to the lack of aerial mycelia and spores, as confirmed by scanning electron microscopy. Using physical barriers to separate the strains on culture plates, we determined that volatile compounds produced by wild-type S. venezuelae could rescue the phenotype of strain MU-1, and pH analysis of the growth medium indicated that these volatile compounds were alkaline. Ultra-high-performance liquid chromatography, combined with mass spectrometry analysis, showed that wild-type S. venezuelae produced abundant levels of the alkaline volatile trimethylamine (TMA) and the oxide form TMAO; however, the levels of these compounds were much lower in strain MU-1. Notably, exposure to TMA alone could rescue the phenotype of this mutant strain, restoring the production of aerial mycelia and spores. We also showed that the rescue effect by alkaline volatiles is mostly species-specific, suggesting that the volatiles may aid particular mutants or other less-fit variants of closely related species to resume normal physiological status and to compete more effectively in complex communities such as soil. Our study reveals a new and intriguing role for bacterial volatiles, including volatiles that may have toxic effects on other species.IMPORTANCEBacterial volatiles have a wide range of biological roles at intra- or inter-kingdom levels. The impact of volatiles has mainly been observed between producing bacteria and recipient bacteria, mostly of different species. In this study, we report that the wild-type, soil-dwelling bacterium Streptomyces venezuelae, which forms aerial hypha and spores as part of its normal developmental cycle, also produces the alkaline volatile compound trimethylamine (TMA) under multiple growth conditions. We showed that the environmental dispersion of TMA produced by S. venezuelae promotes the growth and differentiation of growth-deficient mutants of the same species or other slowly growing Streptomyces bacteria, and thus aids in their survival and their ability to compete in complex environmental communities such as soil. Our novel findings suggest a potentially profound biological role for volatile compounds in the growth and survival of communities of volatile-producing Streptomyces species.

Abstract Background The occurrence of severe intraventricular hemorrhage (sIVH) was high in the very preterm infants (VPIs) in China. The management strategies significantly contributed to the occurrence of sIVH in VPIs. However, the status of the perinatal strategies associated with sIVH for VPIs was rarely described across the multiple neonatal intensive care units (NICUs) in China. We aim to investigate the characteristics of the perinatal strategies associated with sIVH for VPIs across the multiple NICUs in China. Methods This was a retrospective analysis of data from a prospective cohort of Chinese Neonatal Network (CHNN) dataset, enrolling infants born at 24+0—31+6 from 2019 to 2021. Eleven perinatal practices performed within the first 3 days of life were investigated including antenatal corticosteroids use, antenatal magnesium sulphate therapy, intubation at birth, placental transfusion, need for advanced resuscitation, initial inhaled gas of 100% FiO2 in delivery room, initial invasive respiratory support, surfactant and caffeine administration, early enteral feeding, and inotropes use. The performances of these practices across the multiple NICUs were investigated using the standard deviations of differences between expected probabilities and observations. The occurrence of sIVH were compared among the NICUs. Results A total of 24,226 infants from 55 NICUs with a mean (SD) gestational age of 29.5 (1.76) and mean (SD) birthweight of 1.31(0.32) were included. sIVH was detected in 5.1% of VPIs. The rate of the antenatal corticosteroids, MgSO4 therapy, and caffeine was 80.0%, 56.4%, and 31.5%, respectively. We observed significant relationships between sIVH and intubation at birth (AOR 1.52, 95% CI 1.13 to 1.75) and initial invasive respiratory support (AOR 2.47, 95% CI 2.15 to 2.83). The lower occurrence of sIVH (4.8%) was observed corresponding with the highest utility of standard antenatal care, the lowest utility of invasive practices, and early enteral feeding administration. Conclusions The current evidence-based practices were not performed in each VPI as expected among the studied Chinese NICUs. The higher utility of the invasive practices could be related to the occurrence of sIVH.

We demonstrated herein an electrochemical dearomatizative alkylation of Katritzky salts, wherein Katritzky salts were harnessed as both radical acceptors and donors. A wide range of privileged dihydropyridine scaffolds was constructed with good to excellent yields. Cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) results confirmed the key intermediates-dihydropyridine radicals and gram-scale reaction highlighted the practical and sustainable feature of the newly developed protocol.

Rechargeable zinc-air batteries (ZABs) have gained extensive research attention as a promising sustainable energy technology due to their considerable theoretical specific energy density, low toxicity, abundant availability, and robust safety features. However, the practical implementation of ZABs still faces challenges, primarily attributed to the sluggish kinetics of oxygen-involved reactions, including oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) during the discharge and charge process. Therefore, searching for efficient bifunctional oxygen electrocatalysts is crucial to address these challenges. Dual-atom catalysts (DACs), an extension of single-atom catalysts (SACs), exhibit flexible architectures that allow for the combination of homogeneous and/or heterogeneous active sites, making them highly attractive for improving bifunctional activity. In this review, we first introduce the basic framework of ZABs and the structural characteristics of DACs. Subsequently, we organize the research progress on applying DACs in liquid and solid-state ZABs and elaborate on their unique catalytic mechanism. Finally, we highlight the challenges and future research directions for further innovation of DACs in ZABs. In summary, this review highlights the advantages of DACs compared with SACs used as bifunctional oxygen electrocatalysts and provides a reference for the broad applications of DACs in energy conversion and storage.

Identifying ecosystem service functions, clarifying the spatiotemporal trade-offs and synergies of terrestrial ecosystem services and their driving mechanisms, and exploring differentiated ecological functional zoning are crucial steps in achieving healthy regional ecosystem management, and are conducive to developing diversified ecological restoration strategies, establishing a robust cross-regional collaborative management mechanism, implementing differentiated ecological management strategies, and contributing to the construction of a Beautiful China. This paper, based on the InVEST model, Pearson correlation, GeoDetector, and Spatiotemporal Geographically Weighted Regression models, constructs a spatial quantification model of the trade-offs and synergies among five key ecosystem service functions—habitat quality, soil retention, water conservation, food supply, and carbon sequestration—of China’s terrestrial ecosystems from 2000 to 2020. It explores the influencing factors of terrestrial ecosystem services in China and their spatiotemporal heterogeneity, thereby investigating the future strategies for ecological functional zoning and management of China’s national land space. The results indicate that: (1) during 2000–2020, China’s food supply and soil conservation have increased. However, the habitat quality, water conservation, and carbon sequestration have decreased. (2) Significant spatial and temporal heterogeneities exist in the key ecosystem services of China’s terrestrial ecosystems. (3) Natural, economic, and social factors all impact China’s terrestrial key ecosystem services. Among them, slope, annual average precipitation, land development intensity, and vegetation coverage are the main influencing factors, and different factors exhibit significant spatial heterogeneity. (4) Significant trade-offs/synergy effects among critical terrestrial ecosystem services exist in China. (5) China’s national territory is divided into four ecological protection functional zones: ecological restoration areas, ecological control areas, resilient development areas, and ecological conservation areas, and explores differentiated zoning optimization control paths.

A convenient and efficient method for the synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with excellent yield and enantioselectivity.

Abstract The demand for milk has increased globally, accompanied by an increase in waste milk. Here, we provide an artificial humification technology to recycle waste milk into an agricultural nano-fertilizer. We use KOH-activated persulfate to convert waste milk into fulvic-like acid and humic-like acid. We mix the product with attapulgite to obtain a slow-release nano fulvic-like acid fertilizer. We apply this nano-fertilizer to chickweeds growing in pots, resulting in improved yield and root elongation. These results indicate that waste milk could be recycled for agricultural purposes, however, this nano-fertilizer needs to be tested further in field experiments.

To address the limitations of traditional footstep vibration signal localization algorithms, such as limited accuracy, single feature extraction, and cumbersome parameter adjustment, a motion target localization method for step vibration signals based on deep learning is proposed. Velocity vectors are used to describe human motion and adapt it to the nonlinear motion and complex interactions of moving targets. In the feature extraction stage, a one-dimensional residual convolutional neural network is constructed to extract the time–frequency domain features of the signals, and a channel attention mechanism is introduced to enhance the model’s focus on different vibration sensor signal features. Furthermore, a bidirectional long short-term memory network is built to learn the temporal relationships between the extracted signal features of the convolution operation. Finally, regression operations are performed through fully connected layers to estimate the position and velocity vectors of the moving target. The dataset consists of footstep vibration signal data from six experimental subjects walking on four different paths and the actual motion trajectories of the moving targets obtained using a visual tracking system. Experimental results show that compared to WT-TDOA and SAE-BPNN, the positioning accuracy of our method has been improved by 37.9% and 24.8%, respectively, with a system average positioning error reduced to 0.376 m.

Abstract The crack pattern of steel reinforced ultrahigh performance concrete (UHPC) beam is usually characterized by many densely distributed fine cracks (i.e., multiple microcracks) along with localized macrocrack, and the crack width development rate along the beam height is smaller than that of normal concrete since steel fibers and steel reinforcement bars are supposed to be effective in controlling crack width propagation of the UHPC beam. However, an effective crack width prediction formula is still underdeveloped for steel reinforced UHPC beam. The present study aims to formulate a crack width prediction equation based on the equations in Chinese code GB50010 where the parameters can be regressed and calibrated. Ten UHPC beams with different steel fiber volumes and reinforcing ratios are experimentally tested to collect crack width and spacing data for comparison and validation purposes. Nonuniformity distribution coefficient of rebar strain and average crack spacing are calibrated by the test data. Also, rebar stress is calculated with considering residual tensile strength of UHPC based on a sectional analysis. The modified crack width equation is validated with the test results, showing the best prediction accuracy of 0.97 and standard deviation of 0.11 for the test beams in this study compared to those predicted by JTG 3362, CECS 38, MC and AFGC. This study is emphasizing crack width prediction and control in designing UHPC structures.

Abstract Background The interferon-induced protein known as guanylate-binding protein 2 (GBP2) has been linked to multiple different cancer types as an oncogenic gene. Although the role of GBP2 in cancer has been preliminarily explored, it is unclear how this protein interacts with tumor immunity in gastric cancer. Methods The expression, prognostic value, immune-correlations of GBP2 in gastric cancer was explored in multiple public and in-house cohorts. In addition, the pan-cancer analysis was performed to investigate the immunological role of GBP2 based on The Cancer Genome Atlas (TCGA) dataset, and the predictive value of GBP2 for immunotherapy was also examined in multiple public cohorts. Results GBP2 was highly expressed in tumor tissues and associated with poor prognosis in gastric cancer. In addition, GBP2 was associated with the immune-hot phenotype. To be more specific, GBP2 was positively related to immuno-modulators, tumor-infiltrating immune cells (TIICs), immunotherapy biomarkers, and even well immunotherapeutic response. In addition to gastric cancer, GBP2 was expected to be an indicator of high immunogenicity in most cancer types. Importantly, GBP2 could predict the immunotherapeutic responses in at least four different cancer types, including melanoma, urothelial carcinoma, non-small cell lung cancer, and breast cancer. Conclusions To sum up, GBP2 expression is a promising pan-cancer biomarker for estimating the immunological characteristics of tumors and may be utilized to detect immuno-hot tumors in gastric cancer.

Summary: Background: The optimal treatment strategy for patent ductus arteriosus (PDA) in extremely preterm infants is currently highly controversial. This study aimed to evaluate the association between PDA treatment and short-term outcomes among extremely preterm infants. Methods: This cohort study included all extremely preterm infants (≤27 and 6/7 weeks) who were admitted to hospitals participating in the Chinese Neonatal Network from January 2019 to December 2021, and were diagnosed to have PDA by echocardiogram. PDA treatment was defined as medical treatment and/or surgical ligation of PDA during hospitalization. Short-term outcomes included death, bronchopulmonary dysplasia (BPD), death/BPD, retinopathy of prematurity, necrotizing enterocolitis, and severe brain injury. Multivariate logistic regression was used to evaluate the association between PDA treatment and outcomes. Subgroup analysis were performed among infants with different respiratory support on 3 and 7 days of life. Findings: A total of 2494 extremely preterm infants with the diagnosis of PDA were enrolled, of which 1299 (52.1%) received PDA treatment. PDA treatment was significantly associated with lower risk of death (adjusted odds ratio, 0.48; 95% confidence interval, 0.38–0.60). The decreased risk of death was accompanied by increased risk of BPD and death/BPD. In subgroup analysis according to respiratory support, PDA treatment was associated with lower risk of death among infants who required invasive ventilation. However, the beneficial effect on death was not significant among infants who did not require invasive ventilation. Interpretation: PDA treatment was associated with reduced mortality in extremely preterm infants, but this beneficial effect was mainly present among infants who required invasive ventilation. Funding: This study was funded by the Shanghai Science and Technology Commission's Scientific and Technological Innovation Action Plan (21Y21900800) and the Canadian Institutes of Health Research (CTP87518).

Abstract Mutations in glucocerebrosidase cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Therapies to restore the enzyme’s function in the brain hold great promise for treating the neurological implications. Thus, we developed blood-brain barrier penetrant therapeutic molecules by fusing transferrin receptor-binding moieties to β-glucocerebrosidase (referred to as GCase-BS). We demonstrate that these fusion proteins show significantly increased uptake and lysosomal efficiency compared to the enzyme alone. In a cellular disease model, GCase-BS rapidly rescues the lysosomal proteome and lipid accumulations beyond known substrates. In a mouse disease model, intravenous injection of GCase-BS leads to a sustained reduction of glucosylsphingosine and can lower neurofilament-light chain plasma levels. Collectively, these findings demonstrate the potential of GCase-BS for treating GBA1-associated lysosomal dysfunction, provide insight into candidate biomarkers, and may ultimately open a promising treatment paradigm for lysosomal storage diseases extending beyond the central nervous system.

Image super-resolution (SR) is a research field focusing on image degradation techniques. The High-order Deterioration Model (HDM) implemented in Real-ESRGAN has proven more effective in simulating the degradation of real-world images compared to conventional bicubic kernel interpolation. However, images reconstructed by Real-ESRGAN suffer from two significant weaknesses. Firstly, the rebuilt image is overly smooth and suffers from substantial texture information loss, resulting in a worse performance than classical models such as SRGAN and ESRGAN. Secondly, the reconstructed images exhibit better visualization effects but are entirely different from the original image, violating the principle of image reconstruction. To address these issues, this paper presents an improved image SR model based on the HDM implemented in Real-ESRGAN. The first-order degradation modeling of HDM was removed, and only the second-order degradation modeling was kept to reduce the degree of visual deterioration. PatchGAN was used as the fundamental structure of the discriminator, and a channel attention mechanism was added to the generator’s dense block to enhance texture details in the reconstructed images. The L1 loss function was also replaced with the SmoothL1 loss function to improve convergence speed and model performance. The proposed model, IRE, was evaluated on various benchmark datasets and compared to Real-ESRGAN. The results show that the proposed model outperforms Real-ESRGAN regarding visual quality and measures such as RankIQA and NIQE. The study also indicates that PatchGAN, as the discriminator, reduces the average training time by approximately 28%.

ObjectiveEndometrial cancer recurrence is one of the main factors leading to increased mortality, and there is a lack of predictive models. Our study aimed to establish a nomogram predictive model to predict recurrence in endometrial cancer patients.MethodScreen 517 endometrial cancer patients who came to Nanjing Drum Tower Hospital from 2008 to 2018. All these data are listed as the training group, and then 70% and 60% are randomly divided into verification groups 1 and 2. Univariate, Multivariate logistic regression, stepwise regression were used to select variables for nomogram. Nomogram identification and calibration were evaluated by concordance index (c-index), area under receiver operating characteristic curve (AUC) over time and calibration plot Function. By decision curve analysis (DCA), net reclassification index (NRI), integrated discrimination improvement (IDI), we compared and quantified the net benefit of nomogram and ESMO-ESGO-ESTRO model-based prediction of tumor recurrence.ResultsA nomogram predictive model of endometrial cancer recurrence was established with the eight variables screened. The c-index (for the training cohort and for the validation cohort) and the time-dependent AUC showed good discriminative power of the nomogram. Calibration plots showed good agreement between nomogram predictions and actual observations in both the training and validation sets.ConclusionsWe developed and validated a predictive model of endometrial cancer recurrence to assist clinicians in assessing recurrence in endometrial cancer patients.

Abstract Background Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized. Methods To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS. Results Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS. Conclusion Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS. Graphical Abstract

A novel zero-reference low-light image-enhancement approach based on noise estimation (ZLEN) is proposed to mitigate noise interference in image-enhancement processes, while the tenets of zero-reference and lightweight network architecture are maintained. ZLEN improves the high-order curve expression governing the mapping of low-light images to their enhanced counterparts, addressing image noise through a meticulously designed noise-estimation module and a zero-reference noise loss function. First, the higher-order curve expression with a noise term is defined, and then the noise map undergoes feature extraction through the semantic-aware attention module; following this, the resulting features are integrated with the low-light image. Ultimately, a lightweight convolutional neural network is adjusted to estimate higher-order curve parameters that link the low-light image to its enhanced version. Notably, ZLEN achieves luminance enhancement and noise reduction without paired or unpaired training data. Rigorous qualitative and quantitative evaluations were conducted on diverse benchmark datasets, demonstrating that ZLEN attained state-of-the-art (SOAT) status among existing zero-reference and unpaired-reference image-enhancement methodologies, while it exhibited comparable performance to full-reference image-enhancement methods. To confirm the practicality and robustness of ZLEN, the luminance enhancement was applied to mine images, which yielded satisfactory results.

Summary GlnR activates nitrogen metabolism genes under nitrogen‐limited conditions, whereas MtrA represses these genes under nutrient‐rich conditions in Streptomyces. In this study, we compared the transcription patterns of nitrogen metabolism genes in a double deletion mutant (ΔmtrA‐glnR) lacking both mtrA and glnR and in mutants lacking either mtrA (ΔmtrA) or glnR (ΔglnR). The nitrogen metabolism genes were expressed similarly in ΔmtrA‐glnR and ΔglnR under both nitrogen‐limited and nutrient‐rich conditions, with patterns distinctly different from that of ΔmtrA, suggesting a decisive role for GlnR in the control of nitrogen metabolism genes and further suggesting that regulation of these genes by MtrA is GlnR‐dependent. MtrA and GlnR utilize the same binding sites upstream of nitrogen metabolism genes, and we showed stronger in vivo binding of MtrA to these sites under nutrient‐rich conditions and of GlnR under nitrogen‐limited conditions, consistent with the higher levels of MtrA or GlnR under those respective conditions. In addition, we showed that both mtrA and glnR are self‐regulated. Our study provides new insights into the regulation of nitrogen metabolism genes in Streptomyces.

This study aims to explore bond capacity between monolayer graphene and cementitious composites for the first time through a pullout test. The low-pressure chemical vapor deposition method was used to synthesize monolayer graphene on the copper substrate to be embedded in the mortar made by the briquette mold. The bond capacity between them was higher than the tensile strength of the copper sheet with as-grown monolayer graphene on the surface since all specimens failed in fracture with embedment length of more than 30 mm. The monolayer graphene enhanced the copper tensile fracture stress and normalized energy during the test as the copper sheet width increased. This short communication explores a new path to quantify the bond between the monolayer graphene and the mortar to promote the understanding of the behavior of graphene-enhanced cementitious composites.

Abstract Background Silica nanoparticles (SiO2 NPs) are extensively applied in the biomedical field. The increasing medical application of SiO2 NPs has raised concerns about their safety. However, studies on SiO2 NP-induced retinal toxicity are lacking. Methods We investigated the retinal toxicity of SiO2 NPs with different sizes (15 and 50 nm) in vitro and in vivo along with the underlying mechanisms. The cytotoxicity of SiO2 NPs with different sizes was assessed in R28 human retinal precursor cells by determining the ATP content and LDH release. The cell morphologies and nanoparticle distributions in the cells were analyzed by phase-contrast microscopy and transmission electron microscopy, respectively. The mitochondrial membrane potential was examined by confocal laser scanning microscopy. The retinal toxicity induced by SiO2 NPs in vivo was examined by immunohistochemical analysis. To further investigate the mechanism of retinal toxicity induced by SiO2 NPs, reactive oxygen species (ROS) generation, glial cell activation and inflammation were monitored. Results The 15-nm SiO2 NPs were found to have higher cytotoxicity than the larger NPs. Notably, the 15-nm SiO2 NPs induced retinal toxicity in vivo, as demonstrated by increased cell death in the retina, TUNEL-stained retinal cells, retinal ganglion cell degeneration, glial cell activation, and inflammation. In addition, The SiO2 NPs caused oxidative stress, as demonstrated by the increase in the ROS indicator H2DCF-DA. Furthermore, the pretreatment of R28 cells with N-acetylcysteine, an ROS scavenger, attenuated the ROS production and cytotoxicity induced by SiO2 NPs. Conclusions These results provide evidence that SiO2 NPs induce size-dependent retinal toxicity and suggest that glial cell activation and ROS generation contribute to this toxicity. Graphical Abstract

Laser-induced fluorescence technology is an effective method for detecting oil pollutants. The laser induced fluorescence detection system was developed, and four parallel microchannel sample pools were designed to improve the detection accuracy of fluorescence signals. The grating scanning system is improved by introducing grating feedback link to improve the wavelength scanning accuracy of the system.The experimental results show that the wavelength scanning resolution of the microchannel laser-induced fluorescence detection system is improved by 0.4 nm. Aiming at the defects of the traditional parallel factor algorithm which is sensitive to the sample components, slow operation speed and easy to fall into local convergence, the generalized inverse singular value decomposition is used to improve the parallel factor algorithm. Configure different concentrations of diesel, gasoline and kerosene solution samples. The experimental verification shows that the excitation-emission spectra of each component obtained by the improved parallel factor algorithm are highly consistent with the measured spectral characteristics, indicating that the microchannel laser-induced fluorescence detection system combined with the improved parallel factor analysis method can accurately identify oil pollutants.

Abstract Electrocatalytic water splitting involves the breaking/formation of chemical bonds and the concomitant dynamic reconstruction of catalyst structure, both of which, in a conventional view, are directly driven by the applied bias. However, some latest reports have demonstrated that the chemical driving force can also govern electrocatalytic water splitting. This finding provides a transformative approach to designing advanced energy materials, which calls for a thorough understanding of the underlying correlation between the chemical driving force and the corresponding water splitting performance. This review timely summarizes chemical driving force in three different scenarios. Effects of chemical driving forces on surface reconstruction, reaction rate/mechanism, and interfacial redox reactions are discussed. Finally, an outlook on the chemical driving force is provided. We aim to raise the energy community's awareness of this new vision and hope it could contribute to material design for energy storage and conversion applications.

Thermal maturity of the shales from the Ziliujing Formation of the Jurassic age in the Sichuan Basin is in the hydrocarbon generation window, which makes it a candidate for shale oil and gas development. The meso- and macropore characteristics and heterogeneity of shales are important factors affecting the occurrence and development of oil and gas. However, the meso- and macropores of the Ziliujing shales have not been systematically studied. Thus, the mineral compositions and total organic carbon (TOC) of samples from this formation, as well as its pore structure, are analyzed by low-temperature N2 adsorption technique. Moreover, the heterogeneity of the pores was determined by multifractal analysis. The results show that the Ziliujing shales can be classified into three types according to the distributions of mineral compositions of carbonate and mixed and argillaceous shales. Results revealed that the smallest meso- and macropore volume (PV), the smallest specific surface area (SSA), and the largest average pore diameter (APD) occur in the carbonate shales. However, the largest PV and SSA and the smallest APD are observed in the argillaceous shales. The porosity of carbonate shales is mainly concentrated between 5 nm and 30 nm. Compared with carbonate shales, the porosity with pore sizes less than 30 nm of mixed and argillaceous shales shows a rapid increase. Furthermore, inorganic minerals are the main factors affecting the pore distributions, while TOC shows a weak effect. Herein, clay minerals significantly increase the mesopore volume and the pore number with a size of less than 30 nm. The Dq-q curves reveal that the meso- and macropore distributions of Ziliujing shales show multifractal behavior, but the multifractal characteristics of pores of various shales are distinctly different. The information dimension D1, the Hurst exponent H, and the width of the right side D0–D10 are key indicators to distinguish the local variations within the pore structure of different types of shales. The carbonate shales have the largest multifractal spectra width and the smallest D1 and H, while the opposite trend is found for the argillaceous shales. Clay minerals reduce the heterogeneity of the meso- and macropore distributions and increase the pore connectivity. Nevertheless, the carbonate minerals exhibit a reverse trend. Finally, it was found that TOC does not impact pore complexity as much. Collectively, this study supports our understanding of the occurrence of shale oil within various reservoir facies, thereby providing a guideline for future explorations in the Ziliujing Formation of the Jurassic age in the Sichuan Basin.

Although the precast segmental construction (PSC) technique can relieve age-dependent difficulties and accelerate bridge construction as compared to the cast-in-situ construction (CSC) technique for long-span prestressed concrete box-girder bridges (LSPCBB), the ordinary concrete joints between adjacent precast segments are risky. In order to improve the bond strength at the joint interface and enhance structural reliability, ultra-high-performance concrete (UHPC) can be used to fill joints as a new cementitious material with high strength, ductility, and durability. Thus, the effect of the naturally cured UHPC shrinkage and creep on the bridge's long-term performance should be evaluated. The present study numerically investigates the long-term bridge performance constructed by the PSC technique with wet UHPC joints. One cast-in-place segment using the CSC technique is replaced by one precast segment and one cast-in-place UHPC joint using the PSC technique in the bridge model. A creep coefficient equation in an existing code and a shrinkage strain equation fitted from the test data for the UHPC are verified, and an equivalent temperature drop method is used for simulating pretension forces of the prestressing strands in the numerical model. Through comparison with the CSC technique, the technical advantages in reducing long-term deflection, rotation, prestress losses, and improving normal cross-sectional stresses are quantitatively highlighted for the UHPC enhanced PSC bridge.

The long-term creep and shrinkage behavior of a recently proposed normal concrete (NC) filled ultra-high-performance concrete (UHPC) tube (abbreviated as NFUT) composite column has been rarely investigated. The present study aims to propose an analytical solution for calculating the restrained stress and initial axial stress of NC core based on elastic mechanics knowledge. The nominal creep coefficient or strain of the NFUT composite column is analytically calculated as well, based on the age-adjusted effective modulus method. The perfect bond between the UHPC and NC is assumed and the shrinkage of the UHPC tube subjected to steam curing is negligible during the calculation. Moreover, a finite element model is established, and the numerical restrained stress and initial axial stress are compared with the analytical ones. Also, the effect of the Poisson’s ratio and reinforcement ratio in the UHPC tube on these stresses is investigated. The analytical nominal creep coefficients or strains of the specimens are compared with the test ones and the previous numerical parametric analysis results. It is found that the numerical restrained stress and initial axial stress show good agreement with the analytical ones with errors smaller than 10 % The restrained stress factor and initial axial stress are linearly proportional with the Poisson’s ratio difference between the UHPC and NC. Also, the analytical nominal creep coefficients generally show good agreement with the test ones, and the errors between the analytical and the numerical final strain predictions are within 1 %, which demonstrates the applicability and accuracy of the age-adjusted effective modulus method based nominal creep coefficient calculation.

Petroleum refineries are one of the main sources of hazardous air pollutants, so the accurate determination of petroleum pollutants is of great significance to maintain ecological balance. In this study, three-dimensional (3D) fluorescence spectroscopy combined with pattern recognition algorithm is adopted to distinguish the composition and content of oil pollutants efficiently and accurately. Three hundred samples of kerosene, diesel, and gasoline mixed solutions with different concentrations are prepared. The principal component analysis is used to extract the optimal feature variables, and the correlation coefficient method is used to obtain eight groups of principal component features in the spectra. The dimension is selected as 8, and the principal component score is calculated, which is used as the input data of the extension neural network. Next, the pattern recognition method is improved, and the designed neural network has functions of both resolution and measurement. The results of neural network pattern recognition are used as the input of the concentration network. The first 270 samples are used as the training samples to train the network model, and the remaining 30 samples are used as test samples, which are applied to the input layer of the trained neural network. The relative fluorescence intensity, relative slope, and comprehensive background parameters are used as the input parameters, and the extension neural network is used for pattern recognition and evaluation of oil pollutants. The experimental results show that the average recognition rate of the improved pattern recognition algorithm for oil pollutants is 98.43%, and the average recovery rate of concentration is 98.67%. Further, the average time for pattern recognition is 1.53 s, while the parallel factor analysis algorithm takes 2.89 s. This suggests that the improved extension neural network is an effective and reliable pattern recognition method for the identification of mixed oil pollutants.

This study compared 3 commonly used quenching agents for dechlorinating samples prior to disinfection byproduct (DBP) analysis under typical drinking water sampling conditions for a representative suite of chlorination byproducts. Ascorbic acid and sodium sulfite quenched the residual free chlorine to below detection within 5 seconds. Ammonium chloride did not quench the chlorine to below detection with up to a 70% molar excess, which agrees with published ammonium chloride-chlorine chemistry. With respect to the DBPs, ascorbic acid worked well for the trihalomethanes and haloacetic acids, except for dibromoiodomethane, which exhibited 2.6–28% error when using ascorbic acid compared to non-quenched control samples. Sodium sulfite also worked well for the trihalomethanes (and performed similarly to ascorbic acid for dibromoiodomethane) and was the best performing quenching agent for MX and the inorganic DBPs, but contributed to the decay of several emerging DBPs, including several halonitromethanes and haloacetamides. Ammonium chloride led to considerable errors for many DBPs, including 27–31% errors in chloroform concentrations after 24 hours of storage. This work shows that ascorbic acid is suitable for many of the organic DBPs analyzed by gas chromatography-electron capture detection and that sodium sulfite may be used for simultaneous chlorite, chlorate, and bromate analysis. HIGHLIGHTS Low ascorbic acid and sodium sulfite doses quenched chlorine within 5 seconds.; Ascorbic acid had minimal effect on most of the organochlorine byproducts tested.; Sodium sulfite was the best-performing quenching agent for the inorganic byproducts.; Ammonium chloride led to errors for chloroform and several nitrogenous byproducts.;

PurposeThis study aimed to determine the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in critically ill trauma patients.MethodsThis retrospective study involved adult trauma patients from 335 intensive care units (ICUs) at 208 hospitals stored in the eICU database. The primary outcome was ICU mortality. The lengths of ICU and hospital stay were calculated as the secondary outcomes. The multivariable logistic regression model was used to identify independent predictors of mortality. To identify the effect of the NLR on survival, a 15-day survival curve was used.ResultsA total of 3,865 eligible subjects were enrolled in the study. Univariate analysis showed that patients in the group with a higher NLR were more likely to receive aggressive methods of care delivery: mechanical ventilation, vasopressor, and antibiotics ( P 7.44 was an independent risk factor for ICU death in patients with TBI (OR: 1.837, 95% CI: 1.045–3.229) and TBI victims whose NLR > 7.44 had a 15-day survival disadvantage (P = 0.005).ConclusionA high NLR is associated with a poor prognosis in trauma patients, even worse in patients with TBI. An NLR > 7.44 is an independent risk factor for death in patients with TBI.

With the development of renewable energy technology, distributed power supply mode with multi energy and multi-directional power flow including utility grid, renewable energy and energy storage unit has gradually become a research hotspot. An AC/DC hybrid multi-port power routing (MPPR) system which based on partial power conversion (PPC) of dual DC buses is proposed in this paper. The photovoltaic (PV) port, the battery port and two DC voltage buses form a power router. PV maximum power point tracking (MPPT) and high-voltage ride through (HVRT) of the grid-tied inverter are implemented by the same auxiliary port voltage modulation. The PPC based PV conversion features that only the power determined by voltage difference between PV panel and the series connected DC bus is dealt with, which significantly reduces the loss compared to the full power conversion (FPC) for PV. The detailed control schemes of all converters and energy transmit are given. The simulation and experimental results verify the effectiveness of the proposed scheme.

The spike protein of coronaviruses (S-protein) is an envelope-anchored trimeric type I transmembrane glycoprotein that mediates receptor binding and the fusion of the viral and host cell membranes. Here the authors report the conformational states of HCoV-229E S trimer and observe the conformational changes in S1 subunit from closed state to activated state for receptor binding.

ABSTRACT The global regulator MtrA controls development and primary and secondary metabolism in Streptomyces species. However, residues critical for its function have not yet been characterized. In this study, we identified residue D53 as the potential phosphorylation site of MtrA from Streptomyces venezuelae, a model Streptomyces strain. MtrA variants with amino acid substitutions at the D53 site were generated, and the effects of these substitutions were evaluated in vitro and in vivo. We showed that, although substitutions at D53 did not alter MtrA’s secondary structure, the MtrA D53 protein variants lost the ability to bind known MtrA recognition sequences (MtrA sites) in electrophoretic mobility shift assays. Complementation of the ΔmtrA strain with MtrA D53 protein variants did not affect overall strain growth. However, in comparison to the wild-type strain, chloramphenicol and jadomycin production were aberrant in the D53 variant strains, with levels similar to the levels in the ΔmtrA strain. Transcriptional analysis showed that the expression patterns of genes were also similar in the ΔmtrA strain and the D53 variant strains. Although the D53 protein variants and wild-type MtrA were produced at similar levels in S. venezuelae, chromatin immunoprecipitation-quantitative PCR results indicated that replacing the D53 residue rendered the altered proteins unable to bind MtrA sites in vivo, including MtrA sites that regulate genes involved in nitrogen metabolism and in chloramphenicol and jadomycin biosynthesis. In conclusion, our study demonstrates that the predicted phosphorylation site D53 is critical for the role of MtrA in regulation and suggests that MtrA functions in a phosphorylated form in the genus Streptomyces. IMPORTANCE Although phosphorylation has been shown to be essential for the activation of many response regulator proteins of two-component systems, the role of the phosphorylation site in the function of the global regulator MtrA in the genus Streptomyces has not been reported. In this study, we generated Streptomyces mutants that had amino acid substitutions at the predicted phosphorylation site of MtrA, and the effects of the substitutions were investigated by comparing the phenotypes of the resulting strains and their gene expression patterns with those of the wild-type strain and an MtrA deletion mutant. The ability of the altered proteins to bind known promoter targets in vitro was also evaluated. Our analyses showed that the predicted phosphorylation site D53 is critical for MtrA binding in vitro and for the normal functioning of MtrA in vivo. These studies further demonstrate the importance of MtrA as a global regulator in the genus Streptomyces.

Natural fractures are of paramount importance in storing carbon in shale oil reservoirs, where ultra-low porosity and permeability necessitate their essentiality for enhanced oil recovery. Therefore, comprehensively clarifying the characteristics of natural fractures in shale oil reservoirs is imperative. This paper focuses on investigating the microscopic features of natural fractures in organic-rich continental shale oil reservoirs that are commonly found in the Lower Jurassic strata of the Sichuan Basin, employing them as a representative example. Multiple methods were utilized, including mechanical testing, Kaiser testing, multi-scale CT scanning (at 2 mm, 25 mm, and 100 mm scales), and a numerical simulation of fluid seepage in fracture models. The results revealed that the in situ stress of the target seam displays the characteristic of σH > σv > σh, with σv and σh being particularly similar. The relatively high lateral stress coefficient (ranging from 1.020 to 1.037) indicates that the horizontal stresses are higher than the average level. Although the 2 mm CT scan provides a more detailed view of fractures and connected pores, it primarily exhibited more pore information due to the high resolution, which may not fully unveil additional information about the fractures. Thus, the 25 mm shale core is a better option for studying natural fractures. The tortuosity of the different fractures indicated that the morphology of larger fractures is more likely to remain stable, while small-scale fractures tend to exhibit diverse shapes. The simulations demonstrated that the stress sensitivity of fracture permeability is approximately comparable across different fracture scales. Therefore, our research can enhance the understanding of the properties of natural fractures, facilitate predicting favorable areas for shale oil exploration, and aid in evaluating the carbon storage potential of shale oil reservoirs.

Background and AimTo investigate the short-term dynamic changes and the factors associated with regression of glucose metabolism disorders in patients with hepatitis flare of chronic hepatitis B virus (HBV) infection.MethodsIn this study, 118 patients with severe hepatitis flare of chronic HBV infection were prospectively studied. Oral glucose tolerance test was performed on admission and during follow-up to evaluate dynamic changes in glucose metabolism disorders. The factors associated with regression of glucose metabolism disorders were identified using univariate and multivariate logistic regression analyses.ResultsThe prevalence of diabetes was significantly higher in 70 (47.1%) patients with liver cirrhosis than that in 48 (16.8%) patients without liver cirrhosis. The prevalence of impaired glucose tolerance in patients with liver cirrhosis (35.7%) was significantly lower than that in patients without liver cirrhosis (47.8%). After a follow-up of 20.0 ± 18.7 days, 28 of 31 (90.3%) patients without liver cirrhosis experienced regression of glucose metabolism disorders. Additionally, 30 (54.5%) patients with liver cirrhosis experienced regression of glucose metabolism disorders after 42.0 ± 36.2 days. In patients with liver cirrhosis, those with regression of glucose metabolism disorders had significantly higher levels of homeostasis model assessment-β-cell function, albumin (ALB), and a significantly lower level of fibrosis-4 score. ALB was identified as an independent factor associated with the regression of glucose metabolism disorders in patients with liver cirrhosis.ConclusionSevere acute liver inflammation aggravates glucose metabolism disorders in patients with hepatitis B-related liver cirrhosis and high ALB level is associated with regression of glucose metabolism disorders upon resolution of acute liver inflammation.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a serious public health crisis worldwide, and considering the novelty of the disease, preventative and therapeutic measures alike are urgently needed. To accelerate such efforts, the development of JS016, a neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein, was expedited from a typical 12- to 18-month period to a 4-month period. During this process, transient Chinese hamster ovary cell lines are used to support preclinical, investigational new drug-enabling toxicology research, and early Chemistry, Manufacturing and Controls development; mini-pool materials to supply Phase 1 clinical trials; and a single-clone working cell bank for late-stage and pivotal clinical trials were successively adopted. Moreover, key process performance and product quality investigations using a series of orthogonal and state-of-the-art techniques were conducted to demonstrate the comparability of products manufactured using these three processes, and the results indicated that, despite observed variations in process performance, the primary and high-order structures, purity and impurity profiles, biological and immunological functions, and degradation behaviors under stress conditions were largely comparable. The study suggests that, in particular situations, this strategy can be adopted to accelerate the development of therapeutic biopharmaceuticals and their access to patients.

A practical method was developed for the convenient synthesis of isoxazole-fused tricyclic quinazoline alkaloids. This procedure accesses diverse isoxazole-fused tricyclic quinazoline alkaloids and their derivatives via intramolecular cycloaddition of methyl azaarenes with tert-butyl nitrite (TBN). In this method, TBN acts as the radical initiator and the source of N–O. Moreover, this protocol forms new C–N, C–C, and C–O bonds via sequence nitration and annulation in a one-pot process with broad substrate scope and functionalization of natural products.

Pedestrian inertial navigation technology plays an important role in indoor positioning technology. However, low-cost inertial sensors in smart devices are affected by bias and noise, resulting in rapidly increasing and accumulating errors when integrating double acceleration to obtain displacement. The data-driven class of pedestrian inertial navigation algorithms can reduce sensor bias and noise in IMU data by learning motion-related features through deep neural networks. Inspired by the RoNIN algorithm, this paper proposes a data-driven class algorithm, RBCN-Net. Firstly, the algorithm adds NAM and CBAM attention modules to the residual network ResNet18 to enhance the learning ability of the network for channel and spatial features. Adding the BiLSTM module can enhance the network’s ability to learn over long distances. Secondly, we construct a dataset VOIMU containing IMU data and ground truth trajectories based on visual inertial odometry (total distance of 18.53 km and total time of 5.65 h). Finally, the present algorithm is compared with CNN, LSTM, ResNet18 and ResNet50 networks in VOIMU dataset for experiments. The experimental results show that the RMSE values of RBCN-Net are reduced by 6.906, 2.726, 1.495 and 0.677, respectively, compared with the above networks, proving that the algorithm effectively improves the accuracy of pedestrian navigation.

Abstract In this paper, a type of phycocyanin (PC)-functionalized and curcumin (CUR)-loaded biotin-chitosan oligosaccharide-dithiodipropionic acid-curcumin (BCSC) nanoparticles, called CUR-BCSC@PCs, were designed to enhance the biocompatibility of CUR. The structure of BCSC was confirmed using 1H-NMR. In CUR-BCSC@PCs with an average hydrodynamic diameter of 160.3 ± 9.0 nm, the biomimetic protein corona gave the nanoparticles excellent stability and the potential to avoid protein adsorption in blood circulation. The in vitro release experiment verified that CUR-BCSC@PCs with redox responsive shells were sensitive to high concentrations of glutathione. In addition, CUR-BCSC@PCs were effective at increasing the inhibitory activity on the proliferation of A549 cells by enhancing the intracellular uptake of CUR. These results indicated that CUR-BCSC@PCs have great application prospects in cancer therapy as effective drug delivery carriers.

Objectives: We investigated the impact of obesity (proxied as body mass index (BMI)), on short- and long-term mortality in sepsis patients. Methods: We conducted a retrospective analysis with adult sepsis ICU patients in a US medical institution from 2001 to 2012 in the MIMIC-III database. The WHO BMI categories were used. Multivariate logistic regression assessed the relationships between BMI and 30-day and 1-year mortality. Results: In total, 5563 patients were enrolled. Obese patients tended to be younger (P

Abstract Background Esophageal cancer (EC) is one of the malignant tumors with a poor prognosis. The early stage of EC is asymptomatic, so identification of cancer biomarkers is important for early detection and clinical practice. Methods In this study, we compared the protein expression profiles in esophageal squamous cell carcinoma (ESCC) tissues and adjacent normal esophageal tissues from five patients through high-resolution label-free mass spectrometry. Through bioinformatics analysis, we found the differentially expressed proteins of ESCC. To perform the rapid identification of biomarkers, we adopted a high-throughput protein identification technique of Quantitative Dot Blot (QDB). Meanwhile, the QDB results were verified by classical immunohistochemistry. Results In total 2297 proteins were identified, out of which 308 proteins were differentially expressed between ESCC tissues and normal tissues. By bioinformatics analysis, the four up-regulated proteins (PTMA, PAK2, PPP1CA, HMGB2) and the five down-regulated proteins (Caveolin, Integrin beta-1, Collagen alpha-2(VI), Leiomodin-1 and Vinculin) were selected and validated in ESCC by Western Blot. Furthermore, we performed the QDB and IHC analysis in 64 patients and 117 patients, respectively. The PTMA expression was up-regulated gradually along the progression of ESCC, and the PTMA expression ratio between tumor and adjacent normal tissue was significantly increased along with the progression. Therefore, we suggest that PTMA might be a potential candidate biomarker for ESCC. Conclusion In this study, label-free quantitative proteomics combined with QDB revealed that PTMA expression was up-regulated in ESCC tissues, and PTMA might be a potential candidate for ESCC. Since Western Blot cannot achieve rapid and high-throughput screening of mass spectrometry results, the emergence of QDB meets this demand and provides an effective method for the identification of biomarkers.

On-time monitoring and condition assessments of steel cables provide mission-critical data for informed decision making, ensuring the structural safety of post-tensioned concrete structures. This study aimed to develop a spiral deployment scheme of distributed fiber optic sensors (DFOS) and to monitor/assess the post-tensioned force in seven-wire twisted steel cables, based on the pulse-pre-pump Brillouin optical time domain analysis. Each DFOS was placed in a spiral shape between two surface wires of a steel cable and glued to the steel cable by epoxy. Image observations were conducted to investigate the entireness and bonding condition between the optical fiber and the steel wires. Eight concrete bar specimens were cast, each with a pre-embedded plastic or metal duct at its center and each was post-tensioned by a steel strand through the duct once they were instrumented with two strain and two temperature sensors. The strand was loaded/unloaded and monitored by measuring the Brillouin frequency shifts and correlating them with the applied strains and the resulting cable force after temperature compensation. The maximum, minimum, and average cable forces integrated from the measured stain data were compared and validated with those from a load cell. The maximum (or average) cable force was linearly related to the ground truth data with a less than 10% error between them, after any initial slack had been removed from the test setup. The post-tensioned force loss was bounded by approximately 30%, using the test setup designed in this study.

Pyroptosis, a newly discovered form of programmed cell death, is characterized by cell swelling, the protrusion of large bubbles from the plasma membrane and cell lysis. This death pathway is mediated by the pore formation of gasdermin D (GSDMD), which is activated by human caspase-1/caspase-4/caspase-5 (or mouse caspase-1/caspase11), and followed with the releasing of both cell contents and proinflammatory cytokines. Pyroptosis was initially found to function as an innate immune effector mechanism to facilitate host defense against pathogenic microorganisms, and subsequent studies revealed that pyroptosis also plays an eventful role in inflammatory immune diseases and tumor resistance. Recent studies have also shown that pyroptosis is involved in the initiation, the progression and complications of atherosclerosis. Here, we provide an overview of the role of pyroptosis in atherosclerosis by focusing on three important participating cells: ECs, macrophages, and SMCs. In addition, we also summarized drugs and stimuli that regulate the progression of atherosclerosis by influencing cell pyroptosis.

With the development of modern industry, small UAVs have been widely used in agriculture, mapping, meteorology, and other fields. There is an increasing demand for the core attitude-solving algorithm of UAV flight control. In this paper, at first, a novel attitude solving algorithm is proposed by using quaternions to represent the attitude matrix and using Allan variance to analyze the gyroscope error and to quantify the trend of the error over time, so as to improve the traditional Mahony complementary filtering. Simulation results show that the six-axis data from the initial sensors (gyroscope and accelerometer) agree well with the measured nine-axis data with an extra magnetometer, which reduces the complexity of the system hardware. Second, based on the hardware platform, the six-axis data collected from MPU6050 are sent to FPGA for floating-point operation, transcendental function operation, and attitude solution module for processing through IIC communication, which effectively validates the attitude solution by using the proposed method. Finally, the proposed algorithm is applied to a practical scenario of a quadrotor UAV, and the test results show that the RMSE does not exceed 2° compared with the extended Kalman filter method. The proposed system simplifies the hardware but keeps the accuracy and speed of the solution, which may result in application in UAV flight control.