Search

Abstract The present study aims to explore the etiology of Diabetic osteoporosis (DOP), a chronic complication associated with diabetes mellitus. Specifically, the research seeks to identify potential miRNA biomarkers of DOP and investigated role in regulating osteoblasts. To achieve this, an animal model of DOP was established through the administration of a high-sugar and high-fat diet, and then injection of streptozotocin. Bone microarchitecture and histopathology analysis were analyzed. Rat calvarial osteoblasts (ROBs) were stimulated with high glucose (HG). MiRNA profiles of the stimulated osteoblasts were compared to control osteoblasts using sequencing. Proliferation and mineralization abilities were assessed using MTT assay, alkaline phosphatase, and alizarin red staining. Expression levels of OGN, Runx2, and ALP were determined through qRT-PCR and Western blot. MiRNA-sequencing results revealed increased miRNA-702-5p levels. Luciferase reporter gene was utilized to study the correlation between miR-702-5p and OGN. High glucose impaired cell proliferation and mineralization in vitro by inhibiting OGN, Runx2, and ALP expressions. Interference with miR-702-5p decreased OGN, Runx2, and ALP levels, which were restored by OGN overexpression. Additionally, downregulation of OGN and Runx2 in DOP rat femurs was confirmed. Therefore, the miRNA-702-5p/OGN/Runx2 signaling axis may play a role in DOP, and could be diagnostic biomarker and therapeutic target for not only DOP but also other forms of osteoporosis.

Abstract The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson’s disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. l-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.

Abstract Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

Abstract The discovery of various primary ferroic phases in atomically-thin van der Waals crystals have created a new two-dimensional wonderland for exploring and manipulating exotic quantum phases. It may also bring technical breakthroughs in device applications, as evident by prototypical functionalities of giant tunneling magnetoresistance, gate-tunable ferromagnetism and non-volatile ferroelectric memory etc. However, two-dimensional multiferroics with effective magnetoelectric coupling, which ultimately decides the future of multiferroic-based information technology, has not been realized yet. Here, we show that an unconventional magnetoelectric coupling mechanism interlocked with heterogeneous ferrielectric transitions emerges at the two-dimensional limit in van der Waals multiferroic CuCrP2S6 with inherent antiferromagnetism and antiferroelectricity. Distinct from the homogeneous antiferroelectric bulk, thin-layer CuCrP2S6 under external electric field makes layer-dependent heterogeneous ferrielectric transitions, minimizing the depolarization effect introduced by the rearrangements of Cu+ ions within the ferromagnetic van der Waals cages of CrS6 and P2S6 octahedrons. The resulting ferrielectric phases are characterized by substantially reduced interlayer magnetic coupling energy of nearly 50% with a moderate electric field of 0.3 V nm−1, producing widely-tunable magnetoelectric coupling which can be further engineered by asymmetrical electrode work functions.

Objective: To undertake a comprehensive assay of PDCD11 expression in colorectal cancer (CRC) and its association with prognosis and immune cell infiltration (ICIN) utilizing bioinformatics tools. Methods: The PDCD11 expression in CRC and pan-cancer was quantified through datasets from TCGA and GEO databases, and the assay was conducted through R software and the GEPIA database. Moreover, mRNA and protein expression data of PDCD11 were attained from the HPA database. It was attempted to establish protein-protein interaction networks of PDCD11 via the STRING and GeneMANIA databases. The association of PDCD11 expression with CRC staging was evaluated through R software, while its association with CRC and pan-cancer prognosis was figured out via the GEPIA database. Furthermore, the relationship of PDCD11 expression with ICIN was assayed using R software and the TIMER database. Additionally, the influences of PDCD11 knockdown on the proliferation, apoptosis, and migration of colon cancer RKO cell lines was evaluated. Results: PDCD11 exhibited elevated expression in CRC and various other malignancies, potentially indicating a promotive role in cancer progression. Overexpression of PDCD11 was found to correlate with attenuated overall survival in CRC and other malignancies. Moreover, PDCD11 demonstrated promising predictive capabilities for distinguishing between tumor and non-tumor tissues. The positive association of high PDCD11 expression with the infiltration of neutrophils, dendritic cells, CD8+ T cells, CD4+ T cells, and macrophages, as well as with the expression of immune checkpoint molecules CTLA4 and PD-1 was noteworthy. Lentivirus-mediated PDCD11 knockdown suppressed RKO cell proliferation, colony formation, and migration, while triggered apoptosis in these cells. Conclusion: The outcomes unveiled the noticeable function of PDCD11 in CRC and various other malignancies, emphasizing its potential as a prognostic biomarker and therapeutic target.

Summary: Ribosomopathies arise from the disruptions in ribosome biogenesis within the nucleolus, which is organized via liquid-liquid phase separation (LLPS). The roles of LLPS in ribosomopathies remain poorly understood. Here, we generated human induced pluripotent stem cell (hiPSC) models of ribosomopathy caused by mutations in small nucleolar RNA (snoRNA) gene SNORD118. Mutant hiPSC-derived neural progenitor cells (NPCs) or neural crest cells (NCCs) exhibited ribosomopathy hallmark cellular defects resulting in reduced organoid growth, recapitulating developmental delay in patients. SNORD118 mutations in NPCs disrupted nucleolar morphology and LLPS properties coupled with impaired ribosome biogenesis and a translational downregulation of fibrillarin (FBL), the key LLPS effector acting via the intrinsically disordered region (IDR) motif. IDR-depleted FBL failed to rescue NPC defects, whereas a chimeric FBL with swapped IDR motif from an unrelated protein mitigated ribosomopathy and organoid growth defects. Thus, SNORD118 human iPSC models revealed aberrant phase separation and nucleolar functions as potential pathogenic mechanisms in ribosomopathies.

BackgroundThe existing evidence regarding the joint effect of heavy metals on blood pressure (BP) in children and adolescents is insufficient. Furthermore, the impact of factors such as body weight, fish consumption, and age on their association remains unclear.MethodsThe study utilized original data from the National Health and Nutrition Examination Survey, encompassing 2,224 children and adolescents with complete information on 12 urinary metals (barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, uranium, mercury and arsenic), BP, and core covariates. Various statistical methods, including weighted multiple logistic regression, linear regression, and Weighted Quantile Sum regression (WQS), were employed to evaluate the impact of mixed metal exposure on BP. Sensitivity analysis was conducted to confirm the primary analytical findings.ResultsThe findings revealed that children and adolescents with low-level exposure to lead (0.40 μg/L, 95%CI: 0.37, 0.42), mercury (0.38 μg/L, 95%CI: 0.35, 0.42) and molybdenum (73.66 μg/L, 95%CI: 70.65, 76.66) exhibited reduced systolic blood pressure (SBP) and diastolic blood pressure (DBP). Conversely, barium (2.39 μg/L, 95%CI: 2.25, 2.54) showed a positive association with increased SBP. A 25th percentile increase in the WQS index is significantly associated with a decrease in SBP of 0.67 mmHg (95%CI, −1.24, −0.10) and a decrease in DBP of 0.59 mmHg (95% CI, −1.06, −0.12), which remains statistically significant even after adjusting for weight. Furthermore, among individuals who consume fish, heavy metals have a more significant influence on SBP. A 25 percentile increase in the WQS index is significantly associated with a decrease of 3.30 mmHg (95% CI, −4.73, −1.87) in SBP, primarily attributed to mercury (27.61%), cadmium (27.49%), cesium (17.98%), thallium (8.49%). The study also identified a declining trend in SBP among children aged 10–17, whereas children aged 11–18 exhibited lower levels of systolic and diastolic blood pressure, along with a reduced risk of hypertension.ConclusionSome heavy metals demonstrate an inverse association with the BP of children and adolescents, particularly notable in groups with fish consumption and older children and adolescents. Future studies are warranted to validate these findings and delve deeper into the interplay of heavy metals.

In multi-alternative elections, messages in support of or against alternatives spread across online social media. To make decisions, individuals integrate various sources of information, including information from their friends in online social networks. As information may continuously update online, opinions of individuals also become dynamic, making it challenging to predict voting outcomes. In this paper, we propose a novel voting metric named minimal influence gap, which is based on the information structure induced within a social network, to predict voting outcomes in multi-alternative elections. We evaluate this metric as a predictor of voting outcomes across three popular models of voting behaviours: the Maximising Expected Utility model, the Local Dominance model, and the K-Pragmatist model. We test our metric on synthetic networks with a scale-free feature or a community structure, and on a real-world social network. Experimental results demonstrate that the minimal influence gap strongly correlates with voting outcomes in the three models, particularly in the Local Dominance model when voters persist in supporting their favourite alternative.

Abstract Objective To analyze the clinical characteristics and types of congenital heart defect (CHD) in mild congenital anorectal malformation (CARM), namely the rectoperineal and rectovestibular fistulas. Methods The retrospective study of 183 patients with mild CARM was conducted with assessments of demographic information, color Doppler echocardiography results, and follow-up data. We performed an analysis of the clinical characteristics of CHD, grouping them based on sex and type of mild CARM. Results Of the 183 patients, rectoperineal fistula occurred in 133 patients (72.7%), while the frequency of CHD was 79.8% (146/183). Ventricular septal defects (VSDs) occur more frequently in patients with rectoperineal fistula compared to those with rectovestibular fistula (1.5% vs. 10%), while the opposite trend was observed for patent ductus arteriosus (PDAs) (39.8% vs. 22.0%). Additionally, males presented higher frequency of PDA (42.7% vs. 26.4%) and self-healing (6 months: 87.2% vs. 42.6%; 12 months: 91.0% vs. 63.2%) than females. However, males had a lower rate of undergoing cardiac surgery (6.4% vs. 17.6%) and a younger median diagnosis age (1 day vs. 9 days). Conclusion Our study indicates that there is a necessity for meticulous cardiac assessment and follow-up in neonates diagnosed with mild CARM.

Abstract The forthcoming generation of materials, including artificial muscles, recyclable and healable systems, photochromic heterogeneous catalysts, or tailorable supercapacitors, relies on the fundamental concept of rapid switching between two or more discrete forms in the solid state. Herein, we report a breakthrough in the “speed limit” of photochromic molecules on the example of sterically-demanding spiropyran derivatives through their integration within solvent-free confined space, allowing for engineering of the photoresponsive moiety environment and tailoring their photoisomerization rates. The presented conceptual approach realized through construction of the spiropyran environment results in ~1000 times switching enhancement even in the solid state compared to its behavior in solution, setting a record in the field of photochromic compounds. Moreover, integration of two distinct photochromic moieties in the same framework provided access to a dynamic range of rates as well as complementary switching in the material’s optical profile, uncovering a previously inaccessible pathway for interstate rapid photoisomerization.

Deoxynivalenol (DON) is a mycotoxin produced by Fusarium fungi widespread in wheat, corn, barley and other grain crops, posing the potential for being toxic to human and animal health, especially in the small intestine, which is the primary target organ for defense against the invasion of toxins. This study firstly investigated DON contamination in a local area of a wheat production district in China. Subsequently, the mechanism of DON toxicity was analyzed through cellular molecular biology combining with intestinal flora and gene transcription analysis; the results indicated that DON exposure can decrease IPEC−J2 cell viability and antioxidant capacity, stimulate the secretion and expression of proinflammatory factors, destroy the gut microbiota and affect normal functions of the body. It is illustrated that DON could induce intestinal damage through structural damage, functional injury and even intestinal internal environment disturbance, and, also, these intestinal toxicity effects are intrinsically interrelated. This study may provide multifaceted information for the treatment of intestinal injury induced by DON.

The aim of the study was to investigate the expression levels of ACE2 in ocular glands and to investigate the effect of S protein on them. Male C57BL/6J mice were used for the experiments. The expression levels of ACE2 are highest in the Meibomian glands, followed by the conjunctiva, the cornea, and the lacrimal glands. Co-immunoprecipitation assays confirmed direct binding between ACE2 and S protein in ocular surface epithelia and Meibomian glands. CD45+ cell infiltration was found in the S protein treatment group, which was accompanied by upregulation of inflammation-related cytokines. There was also prominent cell apoptosis in the S protein treatment group. In conclusion, not only the cornea and the conjunctiva, but also the Meibomian glands express ACE2, and S protein could induce ocular surface epithelial cell and Meibomian gland cell inflammation and apoptosis.

Based on the three-dimensional (3D) linear elasticity theory of piezoelectric semiconductor (PS) structures, inspired by the variational principle and the Mindlin plate theory, a two-dimensional (2D) higher-order theory and equations for thin-film devices are established for a rectangular coordinate system, in which Newton’s law (i.e., stress equation of motion), Gauss’s law (i.e., charge equation of electrostatics), Continuity equations (i.e., conservation of charge for holes and electrons), drift–diffusion theory for currents in semiconductors, and unavoidable thermo-deformation-polarization-carrier coupling response in external stimulus field environment are all considered. As a typical application of these equations, the static characteristic analysis of electromechanical fields for the extensional deformation of a PS thin-film device with thermal field excitations is carried out by utilizing established zeroth-order equations and the double trigonometric series solution method. It is revealed that the extensional deformations, electric potential, electron and hole concentration perturbations, and their current densities can be controlled actively via artificially tuning thermal fields of external stimuli. Especially, a higher temperature rise can induce a deeper potential well and a higher potential barrier, which can play a vital role in driving effectively motions and redistributions of electrons and holes. Overall, the derived 2D equations as well as the quantitative results provide us some useful guidelines for investigating the thermal regulation behavior of PS thin-film devices.

To discover novel and effective potential anticancer agents, a series of azophenol derivatives containing 1,3,4-oxadiazoles moiety was synthesized and investigated for their anticancer activities against several human cancer cell lines by MTT method. Their structures were characterized by 1H NMR, 13C NMR, IR and HRMS spectral analyses. Among the prepared compounds, 5df displayed significant anti-proliferative activity against HCT116 cancer cells with an IC50 value of 4.09 ± 0.04 µM. Moreover, this compound had low cytotoxicity against normal cells. Flow cytometric analysis indicated that compound 5df arrested the cell cycle at S phase and induced apoptosis in a dose-dependent manner. Additionally, network pharmacology analysis calculated that 5df might target several key proteins, including AKT serine/threonine kinase 1 (AKT1), SRC proto-oncogene, non-receptor tyrosine kinase (SRC). Furthermore, molecular docking study indicated that 5df exhibited potentially high binding affinity to these target proteins with binding energies lower than −8 kcal/mol. These findings provide valuable insights for the development of azophenol derivatives as potential anticancer agents.

Abstract Background Glioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified. Methods The highly enriched circRNAs in glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT–PCR) was used to determine the expression of circRNF10 in glioma and normal brain tissue. Both gain-of-function and loss-of-function studies were used to assess the effects of circRNF10 on ferroptosis using in vitro and in vivo assays. The hypothesis that ZBTB48 promotes ferroptosis defense was established using bioinformatics analysis and functional assays. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between circRNF10 and target proteins including ZBTB48, MKRN3 and IGF2BP3. The posttranslational modification mechanism of ZBTB48 was verified using coimmunoprecipitation (co-IP) and ubiquitination assays. The transcription activation of HSPB1 and IGF2BP3 by ZBTB48 was confirmed through luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The stabilizing effect of IGF2BP3 on circRNF10 was explored by actinomycin D assay. Finally, a series of in vivo experiments were performed to explore the influences of circRNF10 on the glioma progression. Results A novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated in glioblastoma tissues and correlated with patients’ poor prognosis. Through integrated analysis of the circRNA-proteins interaction datasets and sequencing results, we reveal ZBTB48 as a transcriptional factor binding with circRNF10, notably promoting upregulation of HSPB1 and IGF2BP3 expression to remodel iron metabolism and facilitates the launch of a circRNF10/ZBTB48/IGF2BP3 positive feedback loop in GSCs. Additionally, circRNF10 can competitively bind to MKRN3 and block E3 ubiquitin ligase activity to enhance ZBTB48 expression. Consequently, circRNF10-overexpressed glioma stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors for ferroptosis evading. Conclusion Our research presents abnormal circRNAs expression causing a molecular and metabolic change of glioma, which we leverage to discover a therapeutically exploitable vulnerability to target ferroptosis.

Patulin contamination has become a bottleneck problem in the safe production of fruit products, although biodegradation technology shows potential application value in patulin control. In the present study, the patulin biodegradation mechanism in a probiotic yeast, Pichia guilliermondii S15-8, was investigated. Firstly, the short-chain dehydrogenase PgSDR encoded by gene A5D9S1 was identified as a patulin degradation enzyme, through RNA sequencing and verification by qRT-PCR. Subsequently, the exogenous expression system of the degradation protein PgSDR-A5D9S1 in E. coli was successfully constructed and demonstrated a more significant patulin tolerance and degradation ability. Furthermore, the structure of PgSDR-A5D9S1 and its active binding sites with patulin were predicted via molecular docking analysis. In addition, the heat-excited protein HSF1 was predicted as the transcription factor regulating the patulin degradation protein PgSDR-A5D9S1, which may provide clues for the further analysis of the molecular regulation mechanism of patulin degradation. This study provides a theoretical basis and technical support for the industrial application of biodegradable functional strains.

Microwave hyperspectral instruments represent one of the main atmospheric sounders of China’s next-generation Fengyun meteorological satellites. In order to better apply microwave hyperspectral observations in the fields of atmospheric parameter retrieval and data assimilation, this paper analyzes the sensitivity of trace gases to five selected bandwidth channels using a radiative transfer model based on the simulated data of microwave hyperspectral radiances at 50–60 GHz. This method uses information entropy and a weighting function to select channels and analyze the impact of this on the retrieval accuracy of atmospheric profiles before and after channel selection. The experimental results show that channel selection can reduce the number of channels by approximately 74.05% while maintaining a large amount of information content, and this retrieval effect is significantly better than that of MWTS-III. After channel selection, the 10 MHz, 30 MHz, and 50 MHz bandwidths have the best retrieval results in the stratosphere, whole atmosphere, and troposphere, respectively. When considering the number of channels, computational scale, and retrieval results comprehensively, the channel selection method is effective.

Bisphenol A (BPA) is a chemical used in the production of certain plastics and resins. Recent research has found that BPA can inhibit the activity of 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3β-HSDs). Whether benzene ring BPA substitutes can inhibit human, rat, and mouse gonadal 3β-HSDs, the structure-activity relationship and the underlying mechanism remain unclear. In this study, we compared 6 benzene ring BPA substitutes to BPA in the inhibition of human, rat, and mouse gonadal 3β-HSDs and conducted structure-activity relationship and in silico docking analysis. The inhibitory activity (IC50) of human 3β-HSD2 in KGN cells ranged from about 0.02 μM for bisphenol H to 8.75 μM for BPA, that of rat 3β-HSD1 in testicular microsomes ranged from 0.099 μM for bisphenol H to 31.32 μM for BPA, and that of mouse 3β-HSD6 ranged from 0.021 μM for BPH to ineffectiveness for 100 μM BPA. These compounds acted as mixed inhibitors with LogP inversely correlated with IC50 and ΔG positively correlated with IC50 value. Docking analysis showed that these compounds bind to the steroid active site of the 3β-HSD enzymes. In conclusion, some benzene ring BPA substitutes potently inhibit gonadal 3β-HSD in various species, and lipophilicity and binding affinity determine their inhibitory strength.

Abstract Organelles are functional areas where eukaryotic cells perform processes necessary for life. Each organelle performs specific functions; however, highly coordinated crosstalk occurs between them. Disorder of organelle networks often occur in various diseases. The endoplasmic reticulum (ER) and mitochondria are crucial organelles in eukaryotic cells as they are the material synthesis and oxidative metabolism centers, respectively. Homeostasis and orchestrated interactions are essential for maintaining the normal activities of cells. However, the mode and mechanism of organelle crosstalk is still a research challenge. Furthermore, the intricate association between organelle dyshomeostasis and the progression of many human diseases remains unclear. This paper systematically summarized the latest research advances in the synergistic mechanism between the endoplasmic reticulum and mitochondria and their crosstalk with other organelles based on recent literature. It also highlights the application potential of organelle homeostasis maintenance as a preventative and treatment strategy for diseases.

Millimeter-wave (mmWave) communication systems leverage the directional beamforming capabilities of antenna arrays equipped at the base stations (BS) to counteract the inherent high propagation path loss characteristic of mmWave channels. In downlink mmWave transmissions, i.e., from the BS to users, distinguishing users within the same beam direction poses a significant challenge. Additionally, digital baseband precoding techniques are limited in their ability to mitigate inter-user interference within identical beam directions, representing a fundamental constraint in mmWave downlink transmissions. This study introduces an innovative analog beamforming-based interference mitigation strategy for downlink transmissions in reconfigurable intelligent surface (RIS)-assisted hybrid analog–digital (HAD) mmWave systems. This is achieved through the joint design of analog beamformers and the corresponding coefficients at both the RIS and the BS. We first present derived closed-form approximation expressions for the achievable rate performance in the proposed scenario and establish a stringent upper bound on this performance in a large number of RIS elements regimes. The exclusive use of analog beamforming in the downlink phase allows our proposed transmission algorithm to function efficiently when equipped with low-resolution analog-to-digital/digital-to-analog converters (A/Ds) at the BS. The energy efficiency of the downlink transmission is evaluated through the deployment of six-bit A/Ds and six-bit pulse-amplitude modulation (PAM) signals across varying numbers of activated RIS elements. Numerical simulation results validate the effectiveness of our proposed algorithms in comparison to various benchmark schemes.

Hypersonic vehicles suffer from extreme aerodynamic heating during flights, especially around the area of leading edge due to its small curvature. Therefore, flush air data sensing (FADS) system has been developed to perform accurate measurement of the air data parameters. In the present study, the method to develop the FADS algorithms with fail-operational capability for a sharp-nosed hypersonic vehicle is provided. To be specific, the FADS system implemented with 16 airframe-integrated pressure ports is used as a case study. Numerical simulations of different freestream conditions have been conducted to generate the database for the FADS targeting in 2≤Ma≤5 and 0km≤H≤30km. Four groups of neural network algorithms have been developed based on four different pressure port configurations, and the accuracy has been validated by 280 groups of simulations. Particularly, the algorithms based on the 16-port configuration show an excellent ability to serve as the main solver of the FADS, where 99.5% of the angle-of-attack estimations are within the error band ±0.2∘. The accuracy of the algorithms is discussed in terms of port configuration. Furthermore, diagnosis of the system health is present in the paper. A fault-tolerant FADS system architecture has been designed, which is capable of continuously sensing the air data in the case that multi-port failure occurs, with a reduction in the system accuracy.

Primary liver cancer is characterized by closely related with chronic liver inflammation, thereby reversing hypoxic immunosuppressive microenvironment of tumor cell growth by immunotherapy drug is a potentially effective strategy. Camrelizumab is an anti-PD-1 antibody being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. We reported a case of an adult critical Chinese patient with primary hepatocellular carcinoma and lung metastasis completely responding to Camrelizumab, most of the lesions were stable and no new lesions occurred after 1-year treatment, which provides us to reconsider the therapeutic effect of Camrelizumab on such patients. Camrelizumab had a safety profile for the patient in our case report, except for the occurrence of RCCEP. This case provides the evidence of the effective antitumor activity and manageable toxicities of Camrelizumab for patients with advanced hepatocellular carcinoma, which was the first application as far as we know.

BackgroundPrediabetes is associated with increased cardiovascular risk and all-cause mortality, while its regression will decrease the risks. This study investigated the associations of six obesity-related indices (waist-to-height ratio (WHtR), body roundness index (BRI), conicity index (CI), body shape index (ABSI), Chinese visceral adiposity index (CVAI), and triglyceride glucose (TyG) index) with prediabetes regression based on the China Health and Retirement Longitudinal Study (CHARLS), enrolling middle-aged and older adults.MethodsWe included 2,601 participants with prediabetes from CHARLS, who were followed up from 2011–2012 to 2015–2016, with blood samples collected for measuring fasting plasma glucose and hemoglobin A1c. All the obesity-related indices at baseline and their dynamic changes were calculated and categorized into tertiles. Logistic regression analysis was applied to obtain the odds ratio (OR) and 95% confidence intervals (CIs). Attributable fractions (AFs) and 95% CIs of these indices and the dynamic changes were calculated with the AF package in R software, and the cutoff values of initial obesity-related indices were obtained by the receiver operating characteristic (ROC) analysis.ResultsDuring the 4-year follow-up period, 562 (21.61%) participants regressed from prediabetes to normoglycemia. They had lower initial BRI, WHtR, CI, ABSI, CVAI, and TyG than those who did not (P < 0.05). After multivariable adjustment, participants in the first tertile of initial BRI (OR, 1.45, 95%CIs, 1.09–1.93), WHtR (OR, 1.46, 95%CIs, 1.10–1.95), and CVAI (OR, 1.47, 95%CIs, 1.11–1.93) had increased odds of prediabetes regression compared with those in the highest tertile. Participants with decreased TyG (OR, 2.08; 95%CIs, 1.61–2.70) also had increased odds of prediabetes regression compared with those with increased TyG. The cutoff values of initial obesity-related indices were 4.374 for BRI, 0.568 for WHtR, 8.621 for TyG, 1.320 for CI, 0.083 for ABSI, and 106.152 for CVAI, respectively. The AFs were 21.10% for BRI < 4.374, 20.85% for WHtR < 0.568, 17.48% for CVAI < 107.794, and 17.55% for ΔTyG < 0, respectively.ConclusionLow initial BRI, WHtR, and CVAI, as well as TyG reduction, were significantly related to prediabetes regression to normoglycemia, and the AFs were around 20%. Less abdominal fat and insulin resistance reduction would benefit future health outcomes among people with prediabetes.

ObjectivesCongenital ventricular aneurysms or diverticulum (VA/VD) are rare cardiac anomalies with lack prenatal evaluation data. The present study aimed to provide the prenatal characteristics and outcomes from a tertiary center and the use of new techniques to evaluate the shape and contractility of these fetuses.MethodsTen fetuses were diagnosed with VA or VD, and 30 control fetuses were enrolled. Fetal echocardiography was performed to make the diagnosis. The prenatal echo characteristics and follow-up data were carefully reviewed. The shape and contractility measurements of the four-chamber view (4CV) and both ventricles were measured and computed using fetal fetal heart quantification (HQ).ResultsA total of 10 fetuses were enrolled, including 4 cases of left ventricular diverticulum, 5 cases of left ventricular aneurysm, and 1 case of right ventricular aneurysm (RVA). Four cases chose to terminate the pregnancy. The RVA was associated with a perimembranous ventricular septal defect. Two cases had fetal arrhythmia, and one case had pericardial effusion. After birth, one case underwent surgical resection at five years old. The 4CV global sphericity index (SI) of free-wall located ventricular outpouching (VO) was significantly lower than the apical ones and the control group (p 95th centile) SI in base segments, and three of four left VOs in the free-wall had significant lower (< 5th centile) SI in the majority of 24 segments. Compared to the control group, the left ventricle (LV) global longitudinal strain, ejection fraction, and fractional area change were significantly decreased (p

The study of business process analysis and optimisation has attracted significant scholarly interest in the recent past, due to its integral role in boosting organisational performance. A specific area of focus within this broader research field is process mining (PM). Its purpose is to extract knowledge and insights from event logs maintained by information systems, thereby discovering process models and identifying process-related issues. On the other hand, statistical model checking (SMC) is a verification technique used to analyse and validate properties of stochastic systems that employs statistical methods and random sampling to estimate the likelihood of a property being satisfied. In a seamless business setting, it is essential to validate and verify process models. The objective of this paper is to apply the SMC technique in process mining for the verification and validation of process models with stochastic behaviour and large state space, where probabilistic model checking is not feasible. We propose a novel methodology in this research direction that integrates SMC and PM by formally modelling discovered and replayed process models and apply statistical methods to estimate the results. The methodology facilitates an automated and proficient evaluation of the extent to which a process model aligns with user requirements and assists in selecting the optimal model. We demonstrate the effectiveness of our methodology with a case study of a loan application process performed in a financial institution that deals with loan applications submitted by customers. The case study highlights our methodology’s capability to identify the performance constraints of various process models and aid enhancement efforts.

Devonian magmatism is one of the most important tectonothermal events in the Central Asian Orogenic Belt (CAOB). However, little is known regarding the petrogenesis and geodynamic setting of the widely distributed Devonian granitoids in the eastern Southern Beishan Orogenic Belt (SBOB). Early-Devonian granitic magmatism has been recognized from the Luotuoquan area, and the granites were emplaced between 404.9 Ma and 399.4 Ma according to LA-ICPMS zircon U–Pb dating. Geochemically, the granites exhibit high SiO2 and Al2O3 contents and are enriched in light rare earth elements as well as Rb, Th, Nd, Zr, and Hf, while being depleted in heavy rare earth elements and Ba, U, Sr, and Ti, with distinct rare earth element fractionation and pronounced negative Eu anomalies. According to the comprehensive analysis, they closely resemble the features typically associated with A-type granites. The zircons εHf(t) values are within the range of +0.90–+5.19 (averaged 3.23) for the monzogranite and syenogranite, whereas their TDM2 values fall between 1.05 and 1.34 Ga, suggesting that the magma source of the monzogranite–syenogranite originated from the partial melting of the Mesoproterozoic crust dominated by metagreywackes. Furthermore, the monzogranite and syenogranite exhibit high temperatures (average 782 °C), thin crustal thickness (average 30 km), and A-type characteristics, suggesting their formation in post-collision extensional settings. We propose the closure of the Beishan Ocean occurred before the early Devonian, followed by a transition in the Southern Beishan Orogenic Belt from a compressional to an extensional setting.

Abstract Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. The pathogenesis of AKI has not been fully elucidated, with a lack of effective treatment. Renal tubular epithelial cells (TECs) play an important role in AKI, and their damage and repair largely determine the progression and prognosis of AKI. In recent decades, it has been found that the mitochondria, endoplasmic reticulum (ER), lysosomes, and other organelles in TECs are damaged to varying degrees in AKI, and that they can influence each other through various signaling mechanisms that affect the recovery of TECs. However, the association between these multifaceted signaling platforms, particularly between mitochondria and lysosomes during AKI remains unclear. This review summarizes the specific pathophysiological mechanisms of the main TECs organelles in the context of AKI, particularly the potential interactions among them, in order to provide insights into possible novel treatment strategies.

ObjectivesInterstitial lung disease (ILD) is frequent in patients with rheumatoid arthritis (RA) and is a potentially life-threatening complication with significant morbidity and mortality. This meta-analysis aims to systematically determine the factors associated with the development of rheumatoid arthritis-related interstitial lung disease (RA-ILD).Materials and methodsAll primary studies which reported the factors associated with of RA-ILD were eligible for the review except case reports. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), and WANFANG electronic databases were searched through to December 30, 2022, for studies investigating the factors associated with RA-ILD. The methodological quality assessment of the eligible studies was performed using the Newcastle-Ottawa Scale (NOS). 2 reviewers extracted relevant data independently. Then, weighed mean differences (WMDs) or pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were obtained for the relationships between the factors and RA-ILD. The statistical meta-analysis, subgroup and sensitivity analyses were performed using the Review Manager 5.3, and publication bias with Egger's test were performed using the Stata12.0 software.ResultsA total of 22 articles were screened for a meta-analysis which involved 1887 RA-ILD patients and 8066 RA without ILD patients. Some identified factors that were associated with an increased risk of RA-ILD included male sex (OR = 1.92, 95% CI: 1.54-2.39; P < 0.00001), older age (WMD = 5.77 years, 95% CI: 3.50-8.04; P < 0.00001), longer duration of RA (WMD = 0.80 years, 95% CI 0.12-1.47; P = 0.02), older age at onset of RA (WMD = 6.41 years, 95% CI: 3.17-9.64; P = 0.0001), smoking (OR = 1.69, 95% CI: 1.30-2.18; P < 0.0001). Five factors of laboratory items associated with the development of RA-ILD were evaluated in the meta-analysis. Compared with RA without ILD patients, positive rheumatoid factor (RF) (OR = 1.72, 95% CI: 1.47-2.01; P < 0.00001) and positive anti-citrullinated protein antibodies (ACPA) (OR = 1.58, 95% CI: 1.31-1.90; P < 0.00001) increased the risk of RA-ILD. Meanwhile, RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94-300.30; P = 0.002) and ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89-272.47; P < 0.00001) were significantly associated with increased risk of RA-ILD. Elevated erythrocyte sedimentation rate (ESR) (WMD = 7.41 (mm/h), 95% CI: 2.21-12.61; P = 0.005) and C-reactive protein (CRP) (WMD = 4.98 (mg/L), 95% CI: 0.76-9.20; P = 0.02) were also significantly associated with the development of the RA-ILD, whereas antinuclear antibody (ANA) positive status was not significantly associated with increased risk of RA-ILD (OR = 1.27, 95% CI: 1.00-1.60; P = 0.05).ConclusionsThis meta-analysis showed that male gender, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were associated with RA-ILD.

Abstract Background Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792 . Registered November 20th, 2017.

Determination of RNA 3D structures in vivo is a challenging problem. Here, the authors describe a chemical crosslinking method (SHARC) that they use in combination with RNA sequencing to measure distances between nucleotides in RNA 3D structures.

Fine spectral detection can basically solve the problem of low vertical resolution at the 183 GHz water-vapor absorption line, and it is expected to become one of the main methods for next-generation geostationary and polar-orbiting satellites. Here, using data from Microwave Humidity Sounder II (MWHS-II) onboard the Chinese Fengyun 3D (FY-3D) satellite in the Global/Regional Assimilation and Prediction System (GRAPES) Four-Dimensional Variational (4D-Var) system of the China Meteorological Administration (CMA), we explore the assimilation application of the water-vapor absorption line at 183.31 ± 1 GHz, 183.31 ± 3 GHz and 183.31 ± 7 GHz, as well as 183.31 ± 1.8 GHz and 183.31 ± 4.5 GHz, two added channels, to assess the impact of adding the 183.31 ± 1.8 GHz and 183.31 ± 4.5 GHz sampling channels on data assimilation and numerical weather prediction. Our findings reveal a significant increase in the specific-humidity increment, which in the middle–upper troposphere is numerically much larger than in the lower troposphere. Specifically, the assimilation of 183.31 ± 1.8 GHz observations, positioned near the center of the water-vapor absorption line, results in a pronounced adjustment compared with the 183.31 ± 4.5 GHz observations. And under the strong constraint of the numerical model, the Root Mean Square Error (RMSE) of the wind field diminishes more significantly (by an average of 2–4%) after assimilating the water-vapor observations at greater heights.

Abstract Lysosomes are organelles involved in cell metabolism, waste degradation, and cellular material circulation. They play a key role in the maintenance of cellular physiological homeostasis. Compared with the lysosomal content of other organs, that of the kidney is abundant, and lysosomal abnormalities are associated with the occurrence and development of certain renal diseases. Lysosomal structure and function in intrinsic renal cells are impaired in diabetic kidney disease (DKD). Promoting lysosomal biosynthesis and/or restoring lysosomal function can repair damaged podocytes and proximal tubular epithelial cells, and delay the progression of DKD. Lysosomal homeostasis maintenance may be advantageous in alleviating DKD. Here, we systematically reviewed the latest advances in the relationship between lysosomal dyshomeostasis and progression of DKD based on recent literature to further elucidate the mechanism of renal injury in diabetes mellitus and to highlight the application potential of lysosomal homeostasis maintenance as a new prevention and treatment strategy for DKD. However, research on screening effective interventions for lysosomal dyshomeostasis is still in its infancy, and thus should be the focus of future research studies. The screening out of cell-specific lysosomal function regulation targets according to the different stages of DKD, so as to realize the controllable targeted regulation of cell lysosomal function during DKD, is the key to the successful clinical development of this therapeutic strategy.

Osthole is a natural coumarin compound which isolated from Cnidium monnieri (L.) Cusson, has extensive pharmacological activities and could be used as a leading compound for drug research and development. In a continuous effort to develop new acetylcholinesterase inhibitors from natural products, eighteen osthole esters were designed, synthesized, and confirmed by 1H NMR, 13C NMR and HRMS. The anti-AChE activity of These derivatives was measured at a concentration of 1.0 mol/mL in vitro by Ellman's method, and the result showed that 4m and 4o had moderate inhibitory activities with 68.8% and 62.6%, respectively. Molecular docking study results further revealed AChE interacted optimally with docking poses 4m and 4o. Network pharmacology also predicted that compound 4m could be involved in Ras signaling pathway, which made it a potential therapeutic target of AD.

This paper deals with an analytical method to effectively calculate the inductance of an exterior-rotor switched reluctance motor (SRM), which evaluates the winding inductance of both the active section and the end section, accounting for the influence of core saturation. According to the inductance calculated by the analytical model, the flux linkage table and torque table can be established, and the steady state performance such as phase current, flux linkage, copper loss and core loss can be predicted. Effectiveness of this method is verified by the finite element method as well as by experimental results of a 12/8 SRM prototype.

Abstract Real time path planning from image information is of vital importance in the fields of robots as it has various applications in real time navigation, autonomous driving, robot arm manipulation and human robot cooperation and so on. To achieve this task, a two stage approach is proposed. At the first stage, a novel change point detection approach is proposed to process the image to extract the shape of the obstacles. At the second stage, several novel approximations are adopted to make the path planning problem tractable. Firstly, the irregular shapes of the obstacles in the environment are approximated as lines and circles, which simplify the distance constraint significantly. Secondly, the non‐convex path planning problem is iteratively decomposed as a sequence of subproblems and alternating minimisation method is proposed to efficiently solve the subproblem. To improve the quality of the solution, good initial points obtained by A* algorithm is provided. Both numerical experiments and real experiments are conducted to demonstrate the effectiveness of the proposed algorithm.

It is very important to monitor pH values. In this paper, we fabricated an all-solid-state AlGaN/GaN-based ion-sensitive heterostructure field effect transistor (ISHFET) pH sensor microprobe. The microprobe could facilitate measurement of pH values. The microprobe was fabricated by packaging the pH sensor microprobe chip into a 21 G medical needle. The performance of the integrated pH sensor microprobe was evaluated in pH range of 4–9.18. A sensitivity of 143.57 µA/pH can be achieved using the pH sensor microprobe with a width to length ratio of 4.2 at a drain–source voltage of 0.5 V. The pH sensor microprobe keeps a similar current when the pH values of solutions are the same. A response time of 1 s can be achieved when no neutralization reaction occurs. The pH sensor microprobe can accurately measure pH of solutions under 0.1M interfering ions. This probe-type AlGaN/GaN-based ISHFET pH sensor may be used in medicine or biology, especially in the detection of pH of biological fluid, blood, and some precious biological samples.

Observational studies have indicated the associations between obesity with bone mineral density (BMD) and fracture but yield inconsistent results. The impact of childhood obesity on bone health in adulthood is even less clear. The present study adopted the Mendelian randomization methods to determine whether the genetically predicted childhood obesity was causally associated with BMD and the risk of fracture. Genetic variants were extracted from genome-wide association studies (GWAS) to identify childhood obesity loci [IEU open GWAS project: childhood obesity (ID: ieu-a-1096)] and single nucleotide polymorphisms (SNPs) as instrumental variables to investigate causality. We used two-sample univariable Mendelian randomization (MR) to estimate causal relationships between childhood obesity on BMD and fracture subtypes based on SNPs from European samples. To avoid bias, Cochran's Q test and leave-one-out variant analysis were performed. The MR analysis shows strong evidence that childhood obesity is causally associated with eBMD (OR 1.068, 95% CI 1.043–1.095, P < 0.001) and a weak decreased risk of leg fracture (OR 0.9990, 95% CI 0.9981–0.9999, P =0.033) based on the inverse variance weighting (IVW) method. After adjusting for diabetes and adult obesity, the results of eBMD remained the same. The MR analysis revealed sufficient evidence to indicate childhood obesity was causally associated with increased BMD and decreased risk of leg fracture in adults. Childhood obesity could be taken into consideration when assessing eBMD.

Environmental factors are believed to influence the evolution of primary Sjögren’s syndrome (pSS). The aims of this study were to investigate the association of pSS with a high-fat diet (HFD) and to relate HFD-induced gut dysbiosis to pSS exacerbation. Male Wild Type (WT) and IL-14α transgenic mice (IL-14α TG) were fed a standard diet (SD) and HFD for 11 months. We found an increase in the autoantibody level, more severe dry eye, severe dry mouth symptoms, and an earlier presence of systemic features in the IL-14α TG mice treated with HFD. These data suggest that HFD can promote the process of pSS in the IL-14α TG mice. In addition, an HFD leads to a decrease in the richness of gut microbiota of IL-14α TG mice treated with HFD. The abundance of Deferribacterota was significantly enriched in the IL-14α TG mice treated with HFD compared with other groups. Through the mental test between gut microbiota and clinical parameters, we found that HFD-induced dysbiosis gut microbiota were associated with pSS clinical parameters. In conclusion, HFD results in the aggravation of pSS progression, likely due to the increase of potentially pathogenic microorganisms.

Background: The global prevalence of inflammatory bowel disease (IBD) is increasing, and mucosal healing is the preferred treatment target of IBD. Sodium (aS,9 R)− 3-hydroxy-16,17-dimethoxy-15-oxidotricyclo[12.3.1.12,6]nonadeca-1(18),2,4,6(19),14,16-hexene-9-yl sulfate hydrate (SDH) is a novel diarylheptane compound, which is designed to treat IBD. Hence, we investigated the potent therapeutic activity of SDH against IBD and explored the underlying mechanisms, and determined if SDH is a safe and well-tolerated oral therapeutic for IBD treatment. Methods: We characterized its therapeutic properties in vitro and in vivo using Caco-2 cell monolayer and dextran sodium sulfate (DSS)- or 2,4,6-trinitro-benzene sulfonic acid (TNBS)-induced colitis models. We conducted nonclinical toxicology and safety pharmacology research, including general toxicity, toxicokinetics, pharmacokinetics, metabolism and plasma protein binding, cardiovascular safety pharmacology, central nervous system safety pharmacology, respiratory safety pharmacology, fertility and early embryonic development toxicity, reverse mutation assay, chromosomal aberration assay and micronucleus test. Results: The results showed that SDH promoted expression of tight junction proteins, and protected the integrity and permeability of the epithelial barrier in both cell and animal models. Moreover, lower doses of SDH showed the similar or better efficacy than cyclosporine A (CsA) and mesalazine in DSS- or TNBS-induced colitis animals. Furthermore, our results identified that SDH has satisfactory safety in these studies we tested. In summary, SDH restored the epithelial barrier through tight junction proteins and was expected to be a novel therapeutic agent for the treatment of IBD.

A simple and efficient hydroxide-mediated SNAr rearrangement was reported to synthesize new depside derivatives containing the diaryl ether skeleton from the natural product barbatic acid. The prepared compounds were determined using 1H NMR, 13C NMR, HRMS, and X-ray crystallographic analysis and were also screened in vitro for cytotoxicity against three cancer cell lines and one normal cell line. The evaluation results showed that compound 3b possessed the best antiproliferative activity against liver cancer HepG2 cell line and low toxicity, which made it worth further study.

RNA crosslinking and proximity ligation methods are used to identify transcriptome-wide base pairing interactions. Here, the authors report PARIS2 (psoralen analysis of RNA interactions and structures 2), a method for RNA duplex determination in vivo with higher efficiency than the previous PARIS method.

A Y842D mutation within the activation loop of fms-like tyrosine kinase 3 (FLT3) has been shown to confer strong resistance to sorafenib in vitro . Whether this type of mutation exerts clinically significant effects in patients with acute myeloid leukaemia (AML) remains unclear. Here, a novel Y842D activating mutation within the kinase domain of FLT3, in a pregnant patient with de novo hyperleucocyte acute myeloid leukaemia, is described. Following induction failure with standard dose idarubicin and cytarabine (IA), the patient received re-induction combined with midostaurin, a promising agent targeting mutant-FLT3, and IA regimen. Fortunately, morphological remission was achieved. During the period of midostaurin treatment, the patient exhibited a symptom that was characteristic of differentiation syndrome, which disappeared following treatment with methylprednisolone. The present case revealed that Y842D, an uncommon activating mutation in the activation loop of FLT3, may be a midostaurin-sensitive mutation type in patients with acute myeloid leukaemia.

ABSTRACTCOVID-19 is caused by SARS-CoV-2 infection and was initially discovered in Wuhan. This outbreak quickly spread all over China and then to more than 20 other countries. SARS-CoV-2 fluorescent microsphere immunochromatographic test strips were prepared by the combination of time-resolved fluorescence immunoassay with a lateral flow assay. The analytical performance and clinical evaluation of this testing method was done and the clinical significance of the testing method was verified. The LLOD of SARS-CoV-2 antibody IgG and IgM was 0.121U/L and 0.366U/L. The specificity of IgM and IgG strips in healthy people and in patients with non-COVID-19 disease was 94%, 96.72% and 95.50%, 99.49%, respectively; and sensitivity of IgM and IgG strips for patients during treatment and follow-up was 63.02%, 37.61% and 87.28%, 90.17%, respectively. The SARS-CoV-2 antibody test strip can provide rapid, flexible and accurate testing, and is able to meet the clinical requirement for rapid on-site testing of virus. The ability to detect IgM and IgG provided a significant benefit for the detection and prediction of clinical course with COVID-19 patients.

Pancreatic cancer is one of the most lethal cancers and its prognosis is extremely poor. Clarification of molecular mechanisms and identification of prognostic biomarkers are urgently needed. Though we previously found that LGMN was involved in pancreatic carcinoma progression, the upstream regulation of LGMN remains unknown. We used reliable software to search for the potential transcription factors that may be related with LGMN transcription, we found that ELK1 could be a new regulator of LGMN transcription that binded directly to the LGMN promoter. Moreover, knocking down of ELK1 reduced pancreatic cancer cells proliferation, invasion and survival, while LGMN restored the malignancy of pancreatic cancer in vitro and in vivo. Overexpression of ELK1 further increased cancer cells proliferation, invasion and survival. Clinically, ELK1 and LGMN were positively correlated with clinical stage, degree of differentiation and Lymph node infiltration. ELK1 and LGMN were identified as independent prognostic factors for overall survival. The patients with low expression of ELK1/LGMN survived an average of 29.65 months, whereas those with high expression of ELK1/LGMN survived an average of 16.67 months. In conclusive, our results revealed a new mechanism by which ELK1 promoted the progression of pancreatic cancer via LGMN and conferred poor prognosis.

Ectodysplasin A (EDA), a ligand of the TNF family, plays an important role in maintaining the homeostasis of the ocular surface. EDA is necessary for the development of the meibomian gland, the lacrimal gland, as well as the proliferation and barrier function of the corneal epithelium. The mutation of EDA can induce the destruction of the ocular surface resulting in keratopathy, abnormality of the meibomian gland and maturation of the lacrimal gland. Experimental animal studies showed that a prenatal ultrasound-guided intra-amniotic injection or postnatal intravenous administration of soluble recombinant EDA protein can efficiently prevent the development of ocular surface abnormalities in EDA mutant animals. Furthermore, local application of EDA could restore the damaged ocular surface to some extent. Hence, a recombinant EDA-based therapy may serve as a novel paradigm to treat ocular surface disorders, such as meibomian gland dysfunction and corneal epithelium abnormalities.

At present, most studies focus on Cu-W composites with high W content (W content > 50 wt%), while there are only sporadic reports on Cu-W composites with low W content (W content < 50 wt%). In this work, Cu-W composites with different W contents (0, 10 wt%, 20 wt% and 30 wt%) were prepared, and the effects of W content on microstructure, density, hardness, electrical conductivity, strength and electrical contact properties were systematically studied, with the expectation of providing an experimental basis and theoretical support for expanding the application range of Cu-W composites with low W content. The results showed that, with the increase in W content, the Cu matrices divided into finer and more uniform grains; the density and electrical conductivity of Cu-W composites decreased; and the compressive yield strength and hardness gradually increased. As the content of W increased, the arc burning time of the Cu-W composite contacts began to fluctuate. There was a loss of both the cathode and the anode contacts of the pure Cu, but the mass transfer of the Cu-W composite contacts occurred as follows: the anode weight increases, while the cathode weight decreases. The addition of W particles changed the non-uniform ablation of the pure Cu, and the surface ablation of the Cu-W composite contacts remained uniform.

Immunotherapy has played a significant role in the treatment of a variety of hematological and solid tumors, but its application in ovarian cancer (OC) remains unclear. This study aimed to identify immune subtypes of OC and delineate an immune landscape for selecting suitable patients for immunotherapy, thereby providing potent therapeutic targets for immunotherapy drug development. Three immune subtypes (IS1–IS3) with distinctive molecular, cellular, and clinical characteristics were identified from the TCGA and GSE32062 cohorts. Compared to IS1, IS3 has a better prognosis and exhibits an immunological “hot”. IS3, in contrast, exhibits an immunological “cold” and has a worse prognosis in OC patients. Moreover, gene mutations, immune modulators, CA125, CA199, and HE4 expression, along with sensitivity either to immunotherapy or chemotherapy, were significantly different among the three immune subtypes. The OC immune landscape was highly heterogeneous between individual patients. Poor prognosis was correlated with low expression of the hub genes CD2, CD3D, and CD3E, which could act not only as biomarkers for predicting prognosis, but also as potential immunotherapy targets. Our study elucidates the immunotyping and molecular characteristics of the immune microenvironment in OC, which could provide an effective immunotherapy stratification method for optimally selecting patients, and also has clinical significance for the development of new immunotherapy as well as rational combination strategies for the treatment of OC patients.

Compression sutures are primarily used to treat atonic postpartum hemorrhage. We herein describe three cases of selective arterial ligation combined with B-Lynch or modified B-Lynch suture for the treatment of intractable postpartum hemorrhage unresponsive to available conservative interventions. Three pregnant women underwent a cesarean section for a macrosomic fetus, fetal distress, and oligohydramnios, respectively. All three women developed intractable postpartum hemorrhage due to uterine atony with no chance of embolization therapy. B-Lynch or modified B-Lynch suture and additional selective arterial ligation were performed using braided absorbable suture. The first woman developed postoperative hematometra and infection without response to drainage and antibiotic therapy. Although laparoscopic exploration was performed to loosen the suture line and drain the hematometra and pyometra, the necrosis and infection could not be controlled. Subtotal hysterectomy was therefore conducted, and the necrotic uterine adnexa was removed. The other two women developed subinvolution of the uterus resulting in prolonged menstruation and amenorrhea, although the uterus was preserved and the bleeding was controlled. Modified B-Lynch suture combined with vascular ligation is an invaluable technique for women with severe intractable postpartum hemorrhage. However, it can lead to serious complications such as uterine necrosis, infection, and subinvolution.