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Abstract Ischemia/reperfusion (I/R) is an important inducer of acute kidney injury (AKI), and triggers the generation of reactive oxygen species (ROS) and the expression of matrix metalloproteinase 2 (MMP2), exacerbating kidney damage. Given the immense potential of vitamin E (VitE) as a natural fat-soluble antioxidant in kidney protection, we designed the nanoparticles (NPs) that could dual respond to ROS and MMP2, aiming to accurately deliver VitE to renal injury cells. The NPs utilized Gel-SH as a sensitive receptor for MMP2 and diselenide as a sensitive receptor for ROS, while PEG2k modification enhanced biocompatibility and prevented phagocytosis mediated by the mononuclear phagocyte system. The amphiphilic Gel-SH and diselenide encapsulate the liposoluble VitE and self-assemble into the NPs with a hydrodynamic size of 69.92 nm. Both in vivo and in vitro experiments based on these NPs show good biocompatibility and the ability of target renal injury cells. In vivo kidney I/R injury models and in vitro cell hypoxia/reoxygenation models, the NPs have demonstrated effects in reducing oxidative stress and alleviating AKI. Notably, VitE can preferentially react with peroxyl radical (LOO•) than polyunsaturated fatty acid (PUFA), inhibiting the formation of carbon centered radical (L•), thereby blocking the chain reaction between PUFA and LOO• in ferroptosis. The NPs also inhibit the transition from AKI to chronic kidney disease, with few side effects. Thus, the NPs with dual-responsiveness to MMP2 and ROS for targeted delivery of VitE to renal injury cells exhibit remarkable effects in inhibiting ROS and the chain reactions of ferroptosis, making it a promising therapeutic agent against AKI caused by I/R. Graphical abstract

Abstract Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.

Abstract Background Immune thrombocytopenia (ITP) is a common cause of severe thrombocytopenia in dogs. The pathogenesis of nonassociative, primary ITP (pITP) appears complex, with ill‐defined thrombopoietic response. Objectives Develop an immunoassay to measure plasma canine thrombopoietin (TPO) concentration and characterize TPO concentrations in dogs with pITP. Animals Forty‐one healthy dogs, 8 dogs in an induced ITP model (3 control, 5 ITP), and 58 pITP dogs. Methods Recombinant canine TPO (rcTPO) was purchased and its identity confirmed by mass spectrometry. Monoclonal antibodies were raised to rcTPO and used to configure a sandwich ELISA using streptavidin‐biotin detection. Assay performance, coefficients of variability, and healthy dog plasma TPO reference interval (RI) were determined, followed by assay of ITP samples. Results Assay dynamic range was 15 pg/mL (lower limit of detection) to 1000 pg/mL TPO, with limit of quantitation of 62 pg/mL. Plasma TPO RI was 0 to 158 pg/mL, with plasma TPO 6000 pg/mL. In contrast, only 2/58 pITP dogs had TPO values above RI. Conclusions and Clinical Importance Plasma TPO concentration is paradoxically low at diagnosis for most dogs with pITP. This finding suggests that ineffective thrombopoiesis contributes to thrombocytopenia in pITP dogs and supports evaluating TPO receptor agonist treatment as used for pITP in humans. The TPO assay provides a new tool to study thrombopoiesis in pITP and other thrombocytopenic syndromes in dogs.

Abstract Astrocytes, the predominant glial cells in the central nervous system, play essential roles in maintaining brain function. Reprogramming induced pluripotent stem cells (iPSCs) to become astrocytes through overexpression of the transcription factors, NFIB and SOX9, is a rapid and efficient approach for studying human neurological diseases and identifying therapeutic targets. However, the precise differentiation path and molecular signatures of induced astrocytes remain incompletely understood. Accordingly, we performed single-cell RNA sequencing analysis on 64,736 cells to establish a comprehensive atlas of NFIB/SOX9-directed astrocyte differentiation from human iPSCs. Our dataset provides detailed information about the path of astrocyte differentiation, highlighting the stepwise molecular changes that occur throughout the differentiation process. This dataset serves as a valuable reference for dissecting uncharacterized transcriptomic features of NFIB/SOX9-induced astrocytes and investigating lineage progression during astrocyte differentiation. Moreover, these findings pave the way for future studies on neurological diseases using the NFIB/SOX9-induced astrocyte model.

Abstract Energy efficiency and physical-layer security are crucial considerations in the advancement of mobile edge computing systems. This paper addresses the trade-off between secure-reliability and energy consumption in finite blocklength (FBL) communications. Specifically, we examine a three-node scenario involving a user, a legitimate edge computing server, and an eavesdropper, where the user offloads sensitive data to the edge server while facing potential eavesdropping threats. We propose an optimization framework aimed at minimizing energy consumption while ensuring secure-reliability by decomposing the problem into manageable subproblems. By demonstrating the convexity of the objective function concerning the variables, we establish the existence of an optimal parameter selection for the problem. This implies that practical optimization of parameters can significantly enhance system performance. Our numerical results demonstrate that the application of FBL regime and retransmission mechanism can effectively reduce the energy consumption of the system while ensuring secure-reliability. For the quantitative analyses, the retransmission mechanism is 33.1% better than no retransmission, and the FBL regime is 13.1% better than infinite blocklength (IBL) coding.

Abstract Peripheral intravenous central catheter (PICC) is a common tool for intravenous infusion for children who need central venous access. Although it is safe for physicians and nurses to place, complications like infection, occlusion, phlebitis, and bleeding can occur. We report a 5-month-old infant who suffered respiratory failure caused by catheter malposition resulting in massive fluid infusion into the thoracic cavity. Point-of-care ultrasound (POCUS) was utilized to identify a massive pleural effusion that prompted urgent drainage. Complications related to PICC in pediatric patients are not common but difficult to immediately identify sometimes. Therefore, careful attention should be paid by physicians to identify and reduce the risk of complications associated with PICC. Thus, visual tools are strongly advised to enhance the safety of invasive procedures.

A case of herpetiform pemphigus is reported. A 76-year-old man suffered from erythema, blisters and pruritus on the trunk and extremities for 10 months. Dermatological examination revealed a large number of erythemas, papules, hyperpigmented spots and isolated pinpoint-to-green bean-sized blisters over the erythemas on the trunk and limbs. The blisters appeared hemispheric, with thick walls and clear fluid. Nikolsky's sign was negative. Some blisters were ruptured, with erosive surface. Skin histopathology showed epidermal blisters containing eosinophils and neutrophils, and perivascular infiltrates of lymphohistiocytes and eosinophils in the superficial dermis. Direct immunofluorescence showed reticular deposition of IgG and C3 in the epidermis. Diagnosis was herpetiform pemphigus. The patient was treated with methylprednisolone, cyclophosphamide, rupatadine, ketotifen, and topical compound clobetasol propionate ointment. Nine days later, most of the blisters dried up, and the patient was discharged, without recurrence during 6-month telephone follow-up.

Abstract Background The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. Methods CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming’s two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. Discussion The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. Trial registration The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.

Abstract Background Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times. Method Clinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups. Results Compared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P

ABSTRACTPertussis is a vaccine-preventable infectious disease; however, data on pertussis antibody levels in a nationwide population are still limited in China. We aimed to pool the seropositivity rates of IgG antibodies against pertussis toxin (PT-IgG) across the country. We systematically searched PubMed, Web of Science, Embase, and the China National Knowledge Infrastructure Database for studies published between January 1, 2010, and June 30, 2023. Studies reporting the seroprevalence of PT-IgG among a healthy Chinese population were included. Pooled estimates were obtained using random-effects meta-analyzes. The meta-analysis included 39 studies (47,778 participants) reporting anti-PT IgG seropositivity rates. The pooled rate for all ages was 7.06% (95% CI, 5.50%-9.07%). Subgroup analyzes showed rates ranging from 6.36% to 12.50% across different age groups. This meta-analysis indicated a low anti-PT IgG seropositivity rate in the Chinese population, particularly among school-aged children and young adults. This finding underscores the urgent need to refine immunization strategies.

BackgroundCircadian rhythms impact metabolism and the therapeutic effects of drugs. The purpose of this study was to determine the association between PER and CRY polymorphisms and caffeine citrate treatment response in infants with apnea of prematurity.MethodsA total of 221 preterm infants of gestational age 0.05). Infants in the non-response groups had a higher incidence of moderate and severe bronchopulmonary dysplasia (BPD) (P = 0.043), retinopathy of prematurity (ROP) (P = 0.035), and invasive ventilation (P = 0.027), and their duration of oxygen use (P = 0.041) was longer. When corrected for false discovery rate, the PER3 rs228669 recessive model (PFDR = 0.045) and the over-dominant model (PFDR = 0.045) were both associated with caffeine citrate treatment response. Preterm infants with the rs228669 CC genotype had a significantly lower rate of caffeine citrate non-response in the recessive model (OR = 0.28, 95% CI = 0.12–0.66), which was significantly higher in preterm infants with the CT genotype in the over-dominant model (OR = 4.18, 95% CI = 1.64–10.66). GMDR analysis revealed an interaction between the PER and CRY genes (P

Using glass fibre-reinforced polymer (GFRP) bars to reinforce seawater sea-sand concrete (SWSSC) is a feasible way to replace traditional concrete structures. Thus, this paper aims to understand the shear response of GFRP bar-reinforced SWSSC (GFRP-SWSSC) deep beams. Experimental and numerical programs were carried out on four-point shear tests of GFRP-SWSSC deep beams without stirrups. Seventy specimens were tested to investigate the effects of key parameters on shear responses, including concrete categories, seashell content, section heights, and GFRP bar diameter. The test results indicated that the cracking strength of GFRP-SWSSC deep beams was slightly higher than ordinary concrete deep beams. The increased section height of GFRP-SWSSC deep beams and the decreased shell content remarkably enhanced the stiffness and shear ultimate strength. The corresponding finite element model (FEM) of GFRP-SWSSC specimens was established and validated by comparison with test results. Further, three guidelines predictions for the shear strength of GFRP-SWSSC beams were too conservative. The new design formulae derived from modified tension-compression theory were put forward to evaluate the shear strength of GFRP-SWSSC deep beams, and the comparisons demonstrated that the proposed design formulae achieved sufficient accurate predictions for practical engineering. Based on research on shear performance, the hybrid GFRP-SWSSC structure is a feasible solution to resource shortages, which provides a promising application prospect in marine engineering.

To investigate the influence of aspect ratio and width-to-thickness ratio on the axial compression behavior of square pultruded glass fiber-reinforced polymer (GFRP) tubular stub columns, axial compression tests were conducted on 12 GFRP tubular columns. The mechanical properties of the GFRP tubular columns, including load-bearing capacity, initial stiffness, compressive toughness, and ductility coefficient, were analyzed. The test results reveal that all GFRP tubular columns exhibit crushing failure, with specific failure modes, including mid-section fracture and longitudinal tearing along the corners of the columns. The load-bearing capacity is negatively correlated with the aspect ratio and width-to-thickness ratio. The initial stiffness negatively correlates with the aspect ratio, and the compressive toughness negatively correlates with the width-to-thickness ratio. The Hashin damage criteria for the C3D8R solid element was developed by utilizing the explicit finite element subroutine ABAQUS-VUMAT to analyze the axial compression behavior of GFRP tubular columns. Through parameter analysis, the relationship between the load-bearing capacity and fiber orientation was obtained, and an empirical equation for predicting the load-bearing capacity of the GFRP tubular column was proposed.

Background and objectivesHeart failure (HF) is a disease with numerous genetic and environmental factors that affect it. The results of previous studies indicated that immune phenotypes are associated with HF, but there have been inconclusive studies regarding a causal relationship. Therefore, Mendelian randomization (MR) analyses were undertaken to confirm the causal connections between immune phenotypes and HF, providing genetic evidence supporting the association of immune cell factors with HF risk.MethodsWe selected instrumental variables that met the criteria based on data from the results of genome-wide association studies (GWAS) of immune phenotype and all-cause HF. An evaluation of the causal association between 731 immune cell factors and HF risk was carried out using the inverse variance weighted (IVW), MR-Egger regression (MR-Egger), and weighted median (WM) analysis methods. To determine the horizontal pleiotropy, heterogeneity, and stability of the genetic variants, the MR-Egger intercept test, Cochran's Q test, MR-PRESSO, and leave-one-out sensitivity analysis were performed.ResultsMR principal method (IVW) analysis showed that a total of 38 immune cell-related factors were significantly causally associated with HF. Further analyses combining three methods (IVW, MR-Egger and WME) showed that six exposure factors significantly associated with heart failure, as shown below. The effect of Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell on heart failure was positive. Whereas, a reverse effect was observed for CD14+ CD16+ monocyte% monocyte.ConclusionWe investigated the causal relationship between immune phenotypes and all-cause HF. According to the results, Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell Absolute Count, CD62l- CD86+ myeloid Dendritic cell% Dendritic cell, CD39+ CD8+ T cell% CD8+ T cell, CD3 on Central Memory CD4+ T cell aggravate HF, and the risk of HF is decreased by CD14+ CD16+ monocyte% monocyte. These phenotypes may serve as new biomarkers, providing new therapeutic insights for the prevention and treatment of all-cause HF.

Abstract Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single‐cell RNA sequencing, spatial transcriptomics, and bulk ATAC‐sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9highARlow expression is identified, which is markedly enriched after neoadjuvant androgen‐deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell‐cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage‐specific PCa microenvironment at single‐cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.

Ultra-high reliability and ultra-low latency communication (URLLC) are critical challenges for upcoming 6G applications. Cloud computing and mobile edge computing (MEC) offer potential solutions but incur high deployment and maintenance costs due to reliance on central or edge servers. Moreover, the surge in users and data exacerbates latency concerns. Therefore, with more flexible servers deployment, fog computing is more capable of URLLC requirements. In this work, we propose a fog computing model utilizing mobile devices’ computing capabilities to mitigate latency delays. We characterise the problem as an optimisation problem in quadratic variables. And we reduce the problem to a mixed integer convex optimisation problem in two dimensions using decomposition subproblems. Based on this, we introduce a partial offloading algorithm based on the finite blocklength (FBL) mechanism, which improves the energy efficiency. Simulations demonstrate the efficiency of our algorithm in URLLC, with a 49% reduction in energy consumption compared to no retransmission and a 36% reduction in energy consumption compared to infinite blocklength (IBL) coding.

Existing secure two-party comparison protocols usually allowed one party (e.g., Alice) to obtain a comparison result first, and then Alice informed the other one (e.g., Bob) of the comparison result.Obviously, if Alice refused or failed to send the comparison result to Bob, Bob learned nothing about the comparison result, which broke the fairness of the two-party comparison protocol.Based on this, a rational-security and fair two-party comparison protocol TEAM was proposed by seamlessly combining the threshold Paillier cryptosystem and game theory.Specifically, a novel secure two-party comparison protocol based on the threshold Paillier cryptosystem was designed and then searched for equilibrium points at which two parties could obtain comparison results.Strict theoretical analysis demonstrate that TEAM guarantees rational two-party to always obtain the comparison result without sacrificing any of their inputs.In other words, TEAM was correct, secure, and fair.In addition, the experimental results show that TEAM improves up to 50 times in terms of efficiency compared with previous methods under the same experimental settings.

ABSTRACTThe role of adhesion receptor integrin αvβ3 in T-ALL was unclear. Firstly, we performed quantitative real-time PCR to assess medullary expression of integrin β3(ITGB3) in T-ALL patients and high ITGB3 expression was relevant with the central nervous system leukemia(CNSL) incidence. Decreasing of cell invasion was observed in Jurkat and Molt4 treated with integrin αvβ3 specific antibody and inhibitor as well as cells with ITGB3 interference. Further, phosphorylation of FAK, cRAF, MEK and ERK decreased in cells with integrin αvβ3 inhibition or interference. Invasion decreased in T-ALL cells treated with FAK and ERK inhibitors. In conclusion, inhibition of integrin αvβ3 signals significantly limits the cell invasion of T-ALL cells.

The sugC gene of Streptococcus suis (S. suis) is a coding gene for the ATP-binding transporter-associated protein with strong pathogenicity. In order to reveal the effect of the sugC gene on the virulence of S. suis serotype 2, a wild-type strain of TJS75, isolated from fattening pigs’ brain tissue samples, was used as a parent strain, and a knockout sugC gene (ΔsugC) and complementary strain (CΔsugC) were successfully constructed via homologous recombination technology. The biological characteristics of TJS75, ΔsugC and CΔsugC were compared and analyzed through growth curves, biochemical characteristics, hemolysis characteristics, cell infection tests and pathogenicity tests on BALB/c mice. The results of the growth characteristic experiments in vitro showed that the plateau stage growth period of ΔsugC was delayed compared to the TJS75 strain, but there was no difference in the total number of bacteria. The biochemical characteristics and hemolysis ability of ΔsugC in sheep blood had no difference compared with TJS75, but its adhesion and invasion abilities in PK-15 cells were decreased. Knockout of the sugC gene had no impact on the expression levels of adhesion-related genes in TJS75 in real-time PCR analysis. In addition, the LD50 of ΔsugC in BALB/c mice was 1.47 × 108 CFU, seven times higher than that of TJS75 (LD50 = 2.15 × 107 CFU). These results illustrate that the deletion of sugC reduced the virulence of TJS75 to BALB/c mice, but its role in the adhesion and invasion of PK-15 cells in this strain needs to be further explored. In summary, this study provides evidence that the sugC gene is a virulence-related gene in the S. suis serotype 2 strain and plays a crucial role in the adhesion and invasion of S. suis. This study lays a foundation for the further exploration of the potential virulence factors and pathogenesis of S. suis.

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed.

Over the last few decades, the construction industry has witnessed a growing utilization of aluminum alloys, primarily due to their beneficial characteristics. This trend has sparked numerous research endeavors seeking a more comprehensive understanding of the structural behavior of these alloys, as well as the development of accurate and dependable design principles. This paper aims to provide an all-encompassing review of the existing body of research in this field, delving into the experimental, numerical, and analytical investigations conducted on structural aluminum alloys. The scope of this review encompasses studies that focus on the mechanical properties of aluminum alloys when subjected to monotonic, cyclic, and thermal loading conditions. Additionally, a significant amount of attention is dedicated to examining the structural performance and design considerations pertaining to aluminum columns, beams, and plates, incorporating both experimental and numerical approaches. Furthermore, the performance of connections and composite aluminum-concrete members is thoroughly discussed. The assessment of the applicability of international design specifications to structural aluminum alloys is also addressed in this paper. Throughout the review process, various gaps in our current knowledge are identified, and recommendations for future research endeavors aimed at bridging these gaps are proposed.

Energetic plasticizers are an essential component of propellants and have a significant impact on their performance, such as energy, combustion, and mechanics. Therefore, there is significant practical value in understanding how plasticizers affect the performance of propellants. In this work, the glass transition temperatures of several energetic plasticizers were compared. By adding energetic plasticizers with good compatibility with the propellant and a low glass transition temperature to the propellant, nitramine gun propellants containing different energetic plasticizers were prepared through a semi-solvent method. The compatibility, thermal behavior, phase structure, composition, mechanical properties, energy, and combustion performance of the nitramine gun propellants were characterized. The influence of plasticizers on the phase structure of the propellant and its mechanism on the combustion performance of the propellant were discussed. Energetic plasticizers GAPE, DNPH, and BuNENA have good compatibility and chemical stability with NC-RDX and display good plasticization. GAPE–NC–RDX, DNPH–NC–RDX, and BuNENA–NC–RDX propellants exhibit stable combustion performance at −40 °C, 20 °C, and 50 °C. Compared with the nitramine gun propellant plasticized with NG, the impact strength of the propellant plasticized with DNPH and BuNENA increased by 108.1 % and 17.2 % at −40 °C, respectively. This work offers a solution to improve the phase structure, mechanical properties, and combustion stability of heterogeneous gun propellants and provides a way to suppress the excessive burning rate and flame temperature of propellants.

A mixed nitrate ester propellant composed of nitrocellulose, nitroglycerin, triethylene glycol dinitrate, and dendrimer DP-2 was studied to explore the effects of DP-2 on the rheological properties of the propellant during the solventless extrusion process. The results showed that the apparent shear viscosity of the propellant decreased gradually with the increased mass fraction of the DP-2 from 0 wt% to 2 wt%. Additionally, it was evident that the inclusion of 0.5 wt% DP-2 leads to a notable decrease in both the apparent shear viscosity of the propellant and the torque of screw by over 50%. However, in contrast to the change in fluidity observed from 0 wt% to 0.5 wt%, the enhancement trend of propellant fluidity becomes less significant as the DP-2 content continues to increase. The effects of DP-2 on thermal properties, chemical stability, mechanical sensitivity, mechanical property, and combustion behavior of the propellant were comprehensively assessed. The results demonstrated that DP-2 exhibited promising potential as a flow modification additive for the manufacture of the propellant by solventless extrusion process.

Drying is a complicated physical process which involves simultaneous heat and mass transfer in the removal of solvents inside propellants. Inappropriate drying techniques may result in the formation of a hard skin layer near the surface to block the free access of most solvent through for long stick propellants with large web thickness, which lead to lower drying efficiency and worse drying quality. This study aims to gain a comprehensive understanding of drying process and clarify the mechanism of the blocked layer near the propellant surface. A new three-dimensional coupled heat and mass transfer (3D-CHMT) model was successfully developed under transient conditions. The drying experiment results show that the 3D-CHMT model could be applied to describe the drying process well since the relative error of the content of solvent between simulation and experiment values is only 5.5%. The solvent behavior simulation demonstrates that the mass transfer process can be divided into super-fast (SF) and subsequent minor-fast (MF) stages, and the SF stage is vital to the prevention of the blocked layer against the free access for solvent molecules inside propellant grains. The effective solvent diffusion coefficient (Deff) of the propellant surface initially increases from 3.4 × 10−6 to 5.3 × 10−6 m2/s as the temperature increases, and then decreases to 4.1 × 10−8 m2/s at 60–100 min. The value of Deff of surface between 0–1.4 mm has a unique trend of change compared with other regions, and it is much lower than that of the internal at 100 min under simulation conditions. Meanwhile, the temperature of the propellant surface increases rapidly at the SF stage (0–100 min) and then very slowly thereafter. Both the evolution of Deff and temperature distribution demonstrate that the blocked layer near the propellant surface has been formed in the time period of approximately 0–100 min and its thickness is about 1.4 mm. To mitigate the formation of blocked layer and improve its drying quality of finial propellant products effectively, it should be initially dried at lower drying temperature (30–40 °C) in 0–100 min and then dried at higher drying temperature (50–60 °C) to reduce drying time for later drying process in double base gun propellants. The present results can provide theoretical guidance for drying process and optimization of drying parameters for long stick propellants with large web thickness.

Although there is a well‐known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinicogenomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients. Genomic data retrieved from The Cancer Genome Atlas (TCGA; locoregional PC), Memorial Sloan Kettering Cancer Center [MSKCC; metastatic castration‐sensitive PC (mCSPC)], and Stand Up To Cancer [SU2C; metastatic castration‐resistant PC (mCRPC)] cohorts were used as comparators representing Western men. Genomic mutations were analyzed using an integrated bioinformatic strategy. A comparison of the disease stages revealed that mutations in tumor protein 53 (TP53), androgen receptor (AR), forkhead box A1 (FOXA1), and genes involved in the cell cycle pathway were enriched in mCRPC. Mutations in adenomatous polyposis coli (APC) gene were found to be more prevalent in patients with visceral metastasis. Genomic differences between Western and Chinese men were mainly observed in castration‐sensitive PC, with tumors from Chinese men having more FOXA1 (11.4% vs. 4.2%) but fewer TP53 (4.8% vs. 13%) mutations in locoregional PC and harboring fewer TP53 (11% vs. 29.2%), phosphatase and tensin homolog (PTEN; 2.5% vs. 10.3%), and APC (1.7% vs. 7.4%) mutations in the mCSPC stage than those of Western men. Patients of both ethnicities with mCRPC had similar mutational spectra. Furthermore, FOXA1 class‐2 was less common than FOXA1 class‐1 and showed no enrichment in metastasis, contrary to the findings in the Western cohort. Our study provides a valuable resource for a better understanding of PC in China and reveals the genomic alterations associated with PC disparity across races.

Background: Measles and rubella are vaccine-preventable diseases targeted for elimination in most World Health Organization regions, and China is considered to have momentum towards measles elimination. Therefore, this study aimed to assess the population immunity levels against measles and rubella in Zhejiang Province in China in order to provide valuable insights for informing future public health measures and contributing to the ongoing global campaign against these diseases. Materials and methods: A cross-sectional serological survey was conducted in 2022. A total of 2740 blood samples were collected from healthy individuals spanning the age range of 0–59 years, representing diverse demographic strata across 11 prefectures in Zhejiang Province in China. The sera were tested for measles and rubella IgG antibodies to determine positivity rates and geometric mean concentrations (GMCs). Results: The overall positivity rate for the measles IgG antibody was 85.3%, with a GMC of 588.30 mIU/mL. The positivity rate for the rubella IgG antibody was 70.9%, and the GMC was 35.30 IU/mL. Measles IgG antibody positivity rates across the 0–11 months, 12–23 months, 24–35 months, 3–5 years, 6–9 years, 10–14 years, 15–19 years, 20–29 years, and 30–59 years age groups were 63.1%, 92.5%, 97.0%, 94.0%, 85.8%, 77.3%, 86.9%, 84.9%, and 88.7%, respectively (trend χ2 = 118.34, p < 0.001). Correspondingly, rubella antibody positivity rates for these same age brackets were 55.9%, 87.9%, 94.7%, 88.2%, 69.9%, 54.2%, 72.6%, 67.5%, and 74.3% (trend χ2 = 199.18, p < 0.001). Both univariate and multivariate analyses consistently demonstrated that age, immunization history, and differing economic levels were significant factors contributing to variations in antibody levels. Conclusions: The seroprevalence of measles and rubella was lower than that required for herd immunity. Periodic vaccination campaigns should be launched to increase immunity.

The glucose metabolism of poultry draws wide attention as they have nearly twice the fasting blood glucose than that of mammals. To define the relationship between glucose metabolism and breed of chicken, the outcomes from different growth rate chickens showed that Arbor Acres (AA) broilers, a well-known fast-growing breed, had a lower fasting blood glucose concentration and glucose clearance rate when compared to Silky chickens, a Chinese traditional medicinal chicken with black skin and a slow growth rate. Moreover, AA broilers had a relatively slow rise in blood glucose in response to oral glucose solution than the Silky chickens on 21 and 42 d (P

The hardness and adhesion of protective hard coatings to the substrate are the most important parameters that influence the performance of the tool. Herein, we propose an effective strategy, by in-situ hot press sintering, to fabricate a novel niobium carbide coating with high hardness and excellent interfacial bond strength on GCr15. The coating is composed of Nb2C, NbC, and α-Fe phases. The volume fraction of niobium carbide (Nb2C and NbC) phases reaches 93%. Along the direction of coating thickness, the grain morphology of niobium carbide changes from equiaxed (Nb2C) to columnar (NbC), and then to equiaxed (NbC), presenting a gradient microstructure. The coating/substrate interface displays an excellent macro/micro interface. The formation of the gradient microstructure is attributed to the nucleation-growth process controlled by the carbon concentration gradient diffusion. The novel gradient coating can simultaneously achieve superhardness (20.2 ± 0.3 GPa) and excellent bond strength (>210 ± 20 MPa). The excellent bond strength is mainly attributed to the in-situ formation of the coating and the gradient microstructures. The tensile test results show that the fracture mechanism of the niobium carbide coating on GCr15 is mainly a brittle fracture of niobium carbide coating and a small amount of coating debonding.

Background: PSMA-negative but FDG-positive (PSMA−/FDG+) lesion in dual-tracer ( 68 Ga-PSMA and 18 F-FDG) positron emission tomography/computed tomography (PET/CT) is associated with an unfavorable response to Lutetium-177 ( 177 Lu)-PSMA-617. This study sought to develop both radiomics and clinical models for the precise prediction of the presence of PSMA−/FDG+ lesions in patients with castration-resistant prostate cancer (CPRC). Methods: A cohort of 298 patients who underwent dual-tracer PET/CT with a less than 5-day interval was included. The evaluation of the prognostic performance of the radiomics model drew upon the survival data derived from 40 patients with CRPC treated with 177 Lu-PSMA-617 in an external cohort. Two endpoints were evaluated: (a) prostate-specific antigen (PSA) response rate, defined as a reduction exceeding 50% from baseline and (b) overall survival (OS), measured from the initiation of 177 Lu-PSMA-617 to death from any cause. Results: PSMA−/FDG+ lesions were identified in 56 (18.8%) CRPC patients. Both radiomics (area under the curve [AUC], 0.83) and clinical models (AUC, 0.78) demonstrated robust performance in PSMA−/FDG+ lesion prediction. Decision curve analysis revealed that the radiomics model yielded a net benefit over the ‘screen all’ strategy at a threshold probability of ⩾4%. At a 5% probability threshold, the radiomics model facilitated a 21% reduction in 18 F-FDG PET/CT scans while only missing 2% of PSMA−/FDG+ cases. Patients with a low estimated score exhibited significantly prolonged OS (hazard ratio = 0.49, p = 0.029) and a higher PSA response rate (75% versus 35%, p = 0.011) compared to those with a high estimated score. Conclusion: This study successfully developed two models with accurate estimations of the risk associated with PSMA−/FDG+ lesions in CRPC patients. These models held potential utility in aiding the selection of candidates for 177 Lu-PSMA-617 treatment and guiding 68 Ga-PSMA PET/CT-directed radiotherapy.

Antibiotic resistance in Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus remains a major public health concern worldwide. Furthermore, these microbes frequently co-exist in biofilm-associated infections, largely nullifying antibiotic-based therapy. Therefore, it is imperative to develop an efficient therapeutic strategy for combating infections caused by polymicrobial biofilms. In this study, we investigated the antibacterial and antibiofilm activity of the bacteriophage endolysin Ply113 in vitro. Ply113 exhibited high and rapid lytic activity against E. faecium, E. faecalis, and S. aureus, including vancomycin-resistant Enterococcus and methicillin-resistant S. aureus isolates. Transmission electron microscopy revealed that Ply113 treatment led to the detachment of bacterial cell walls and considerable cell lysis. Ply113 maintained stable lytic activity over a temperature range of 4–45°C, over a pH range of 5.0–8.0, and in the presence of 0–400 mM NaCl. Ply113 treatment effectively eliminated the mono-species biofilms formed by E. faecium, E. faecalis, and S. aureus in a dose-dependent manner. Ply113 was also able to eliminate the dual-species biofilms of E. faecium–S. aureus and E. faecalis–S. aureus. Additionally, Ply113 exerted potent antibacterial efficacy in vivo, distinctly decreasing the bacterial loads in a murine peritoneal septicemia model. Our findings suggest that the bacteriophage endolysin Ply113 is a promising antimicrobial agent for the treatment of polymicrobial infections.

IntroductionPrevious studies have shown disrupted effective connectivity in the large-scale brain networks of individuals with major depressive disorder (MDD). However, it is unclear whether these changes differ between first-episode drug-naive MDD (FEDN-MDD) and recurrent MDD (R-MDD).MethodsThis study utilized resting-state fMRI data from 17 sites in the Chinese REST-meta-MDD project, consisting of 839 patients with MDD and 788 normal controls (NCs). All data was preprocessed using a standardized protocol. Then, we performed a granger causality analysis to calculate the effectivity connectivity (EC) within and between brain networks for each participant, and compared the differences between the groups.ResultsOur findings revealed that R-MDD exhibited increased EC in the fronto-parietal network (FPN) and decreased EC in the cerebellum network, while FEDN-MDD demonstrated increased EC from the sensorimotor network (SMN) to the FPN compared with the NCs. Importantly, the two MDD subgroups displayed significant differences in EC within the FPN and between the SMN and visual network. Moreover, the EC from the cingulo-opercular network to the SMN showed a significant negative correlation with the Hamilton Rating Scale for Depression (HAMD) score in the FEDN-MDD group.ConclusionThese findings suggest that first-episode and recurrent MDD have distinct effects on the effective connectivity in large-scale brain networks, which could be potential neural mechanisms underlying their different clinical manifestations.

Acute myeloid leukemia (AML) is a hematological malignancy that commonly occurs in children. The prognosis of pediatric AML is relatively poor, thus threatening the patient’s survival. The aberrant expression of the axon guidance factor, netrin-1, is observed in various types of malignancies, and it participates in the proliferation and apoptosis of tumor cells. Herein, we aimed to explore the role of netrin-1 in AML cells. Netrin-1 is highly expressed in AML patients. Proliferation and anti-apoptosis were observed in AML cells treated with netrin-1. The interaction between netrin-1 and Unc-5 netrin receptor B (UNC5B) was detected through coimmunoprecipitation, and UNC5B ribonucleic acid interference restrained the influence of netrin-1 on the AML cells. The phosphorylation of focal adhesion kinase-protein kinase B (FAK-Akt) was upregulated in AML cells treated with netrin-1. Both FAK and Akt inhibitors abrogated the effects of netrin-1 on the proliferation and apoptosis of AML cells. In conclusion, netrin-1 could promote the growth and reduce the apoptosis of AML cells in a concentration-dependent manner, and that these effects were mediated by activating the FAK-Akt signaling pathway via the UNC5B.

AbstractWoody plants are important sources of edible oil, and the tea plant (Camellia sinensis) is a new option. In this study, the contents and composition of fatty acids in seed kernels of 10 conventional cultivars and 4 albino cultivars were analyzed and compared by GC-MS. A total of 22 fatty acids were identified. The main fatty acids were oleic acid (C18:1Δ9) (9.1051–15.0670%), linoleic acid (C18:2Δ9,12) (3.6386–7.7231%), and palmitic acid (C16:0) (2.3660–3.9445%), respectively. The ratio of saturated fatty acids, monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids of albino cultivar “Zhonghuang 2” (ZH No.2) was 1.00:2.67:1.85, of which the proportion of MUFAs was significantly lower than those of most conventional cultivars and albino cultivar “Suyuhuang”. Therefore, it is necessary to determine the chemical constituents before the development and utilization of tea seeds, especially for albino cultivars. Furthermore, ZH No.2 could be chosen as parent for improving the fatty acid composition of tea seeds in the breeding project.

ABSTRACTObjective Most previous studies on abusive supervision (AS) and employee wellbeing have used cross-sectional designs and explored long-term effects. However, AS has been reported to vary on a daily basis and this variance exceeds inter-person variance. Therefore, the current study examined the short-term (within 1 day) effects of leaders’ daily AS on employee sleep and wellbeing. Based on the spillover effect theory, we posited that daily AS is a negative experience that can lead to insomnia, thereby affecting next-day wellbeing. In addition, we hypothesized that these effects could be moderated by individuals’ tendencies to engage in rumination (low or high).Method A daily diary design was used to examine the relationship between daily AS and next-day wellbeing. Our analysis of data from 128 full-time employees across 10 consecutive working days using multi-level model.Results Our results showed that insomnia mediated the relationship between daily AS and next-day employee wellbeing, and further showed that this relationship was moderated by rumination.Conclusions These data demonstrate a spillover effect from AS at work to quality of sleep at home, and that use of rumination as a coping strategy can exacerbate the effects of AS on insomnia and next-day employee wellbeing.

Nitroguanidine (NQ) in solvent-based triple-base propellants (STP) has a propensity to peel off and detach from the matrix, leading to significant defects, such as interface debonding within the propellant’s microstructure. This ultimately results in reduced and unstable mechanical properties. To address this critical issue, an efficient and eco-friendly manufacturing process was employed to successfully produce solventless triple-base propellants (SLTPs) as a comparison to conventional STPs. SLTP samples exhibit a mutually supportive three-dimensional spatial structure, with NQ crystals within the propellant matrix more securely bonded to the interface. They also demonstrate higher relative density (1.68 g·cm−3), more stable molding dimensions (no contraction), and enhanced tensile strength (41.92 MPa). Quasi-static structural failure tests reveal that the standard deviation of compressive strength for SLTP samples in three axes is smaller, registering at 1.10. The dynamic structural damage performance analysis indicates that the failure of energetic composite materials is attributable to separation fracture damage after the appearance of cracks on the tensile surface at −40 and 25 °C. Furthermore, the structural failure of these materials occurs due to significant collapse failure after the compression surface bends inward at 50 °C. Consequently, the present study offers a reliable theoretical foundation and procedural strategy for enhancing the structural strength of triple-base propellants.

Abstract Antibiotic resistance and the ability to form biofilms of Enterococcus faecalis have compromised the choice of therapeutic options, which triggered the search for new therapeutic strategies, such as the use of phage endolysins and antimicrobial peptides. However, few studies have addressed the synergistic relationship between these two promising options. Here, we investigated the combination of the phage endolysin Ply2660 and the antimicrobial peptide LL-37 to target drug-resistant biofilm-producing E. faecalis. In vitro bactericidal assays were used to demonstrate the efficacy of the Ply2660–LL-37 combination against E. faecalis. Larger reductions in viable cell counts were observed when Ply2660 and LL-37 were applied together than after individual treatment with either substance. Transmission electron microscopy revealed that the Ply2660–LL-37 combination could lead to severe cell lysis of E. faecalis. The mode of action of the Ply2660–LL-37 combination against E. faecalis was that Ply2660 degrades cell wall peptidoglycan, and subsequently, LL-37 destroys the cytoplasmic membrane. Furthermore, Ply2660 and LL-37 act synergistically to inhibit the biofilm formation of E. faecalis. The Ply2660–LL-37 combination also showed a synergistic effect for the treatment of established biofilm, as biofilm killing with this combination was superior to each substance alone. In a murine peritoneal septicemia model, the Ply2660–LL-37 combination distinctly suppressed the dissemination of E. faecalis isolates and attenuated organ injury, being more effective than each treatment alone. Altogether, our findings indicate that the combination of a phage endolysin and an antimicrobial peptide may be a potential antimicrobial strategy for combating E. faecalis.

Ferroelectric hafnia-based thin films are promising for applications in memories and neuromorphic devices due to their robust ferroelectricity at reduced dimensions. Here, the authors demonstrate stabilization of the metastable orthorhombic phase in Hf0.5 Zr0.5O2 films by interface engineering with a hole doping mechanism.

ObjectiveTo date, no national-scale drug usage survey for adolescents with depression has been conducted in China, and the purpose of this study was to examine the national trends in prescriptions in Chinese adolescent depression patients from 2017 to 2021.MethodsPrescribing data were extracted from the Hospital Prescription Analysis Cooperative Project. The average number of patients per year, the cost of treatment, and the prescription patterns (monotherapy vs. combination therapy) were analyzed, and subgroup analyses were conducted depending on age, sex, and drug class.ResultsThe study included 674,099 patients from 136 hospitals located in nine major areas of China. Of all patients, the proportion of adolescents increased from 1.63% in 2017 to 6.75% in 2021. Visits by adolescent depression patients increased from 1,973 in 2017 to 9,751 in 2021, and the corresponding cost increased from 607,598 Chinese Yuan in 2017 to 2,228,884 Chinese Yuan in 2021. The incidence of adolescent depression among female individuals was far beyond that among male individuals. Combination therapy was more frequent than monotherapy, and the most commonly prescribed drugs were antidepressants, antipsychotics, antiepileptics, and antianxietics. Despite the use of sertraline decreasing from 47.90 to 43.39%, it was the most frequently used drug.ConclusionIn summary, the prescriptions and cost of treatment for adolescent depression patients both increased rapidly. The widespread use of those drugs with weak clinical evidence reflects the current state of China, which should arouse our attention. The study can provide references for clinical treatment decisions and a basis for more efficient allocation of healthcare resources by the government.

This study aimed to determine the level of viral hepatitis knowledge as well as the self-awareness of hepatitis B virus surface antigen (HBsAg) positive individuals, to provide data support for the next steps in viral hepatitis prevention and control. We conducted a cross-sectional survey to assess the knowledge of viral hepatitis among the general population aged 15–69 years in Zhejiang Province, China. A total of 3,626 individuals were surveyed with 10 questions. The knowledge level of the participants is reflected by the scores from the survey. Adequate knowledge was defined as a score of ≥ 6. The knowledge rate was defined as the ratio of the number of individuals with adequate knowledge to the total number of individuals. The knowledge rate of viral hepatitis among the general population aged 15–69 years in Zhejiang Province was 52.34% (mean score, 5.23). The majority of participants (52.51%) had adequate knowledge of viral hepatitis. Multiple logistic regression analysis showed that medical staff had the best knowledge of viral hepatitis, followed by individuals with university or higher education, those aged 40–49 years, and those with a history of hepatitis B vaccination. 34.16% of HBsAg positive participants were aware of their infection status before. The mean score of knowledge of viral hepatitis was significantly lower among HBsAg-positive than HBsAg-negative individuals. Knowledge of viral hepatitis in Zhejiang Province was still low, especially among HBsAg-positive individuals with no awareness of their infection status. More effort should be needed to improve public awareness of viral hepatitis.

Abstract Background Infants with rule-out infections are responsible for the majority of empirical antibiotics treatment (EAT) in neonatal intensive care units (NICUs), particularly very preterm infants (VPIs). Antibiotic overuse has been linked to adverse outcomes. There is a paucity of data on the association between EAT and clinical outcomes (containing the nutritional outcomes) of VPIs without infection-related morbidities. Methods Clinical data of VPIs admitted in 28 hospitals in 20 provinces of China from September 2019 to December 2020 were collected. EAT of VPIs was calculated as the number of days with initial usage in the first week after birth, and then categorized into 3 groups (antibiotic exposure: none, 1-4 days, and > 4 days). Clinical characteristics, nutritional status , and the short-term clinical outcomes among 3 groups were compared and analyzed. Results In total, 1834 VPIs without infection-related morbidities in the first postnatal week were enrolled, including 152 cases (8.3%) without antibiotics, 374 cases (20.4%) with EAT ≤4 days and 1308 cases (71.3%) with EAT > 4 days. After adjusting for the confounding variables, longer duration of EAT was associated with decreased weight growth velocity and increased duration of reach of full enteral feeding in EAT > 4 days group (aβ: -4.83, 95% CI: − 6.12 ~ − 3.53; aβ: 2.77, 95% CI: 0.25 ~ 5.87, respectively) than those receiving no antibiotics. In addition, the risk of feeding intolerance (FI) in EAT > 4 days group was 4 times higher than that in non-antibiotic group (aOR: 4.14, 95%CI: 1.49 ~ 13.56) and 1.8 times higher than that in EAT ≤4 days group (aOR: 1.82, 95%CI: 1.08 ~ 3.17). EAT > 4 days was also a risk factor for greater than or equal to stage 2 necrotizing enterocolitis (NEC) than those who did not receive antibiotics (aOR: 7.68, 95%CI: 1.14 ~ 54.75) and those who received EAT ≤4 days antibiotics (aOR: 5.42, 95%CI: 1.94 ~ 14.80). Conclusions The EAT rate among uninfected VPIs was high in Chinese NICUs. Prolonged antibiotic exposure was associated with decreased weight growth velocity, longer duration of reach of full enteral feeding, increased risk of feeding intolerance and NEC ≥ stage 2. Future stewardship interventions to reduce EAT use should be designed and implemented.

Abstract Background and aims Hereditary spherocytosis (HS) is one of the most common hereditary haemolytic disorders. Here, two unrelated families with the probands displaying typical manifestations of HS were enrolled. Our study aimed to characterize the effect of two novel variants in HS patients on gene splicing to help minimize the rate of misdiagnosis of HS and enhance clinicians’ understanding of the disease. Participants and methods A retrospective review was conducted. Peripheral blood samples were collected from all the family members, and genomic DNA was extracted for genetic diagnostics. First, high-throughput sequencing technology was used for the preliminary screening of candidate causative variants. Thereafter, the variants were verified via Sanger sequencing. Furthermore, a pathogenicity analysis of the detected variants was performed including in silico prediction and in vitro experiments. We constructed matched wild-type and mutant-type minigene plasmid of ANK1 based on HEK293T cells to address the effects of variants on mRNA splicing. Results The c.1305 + 2 T > A (family1) and c.1305 + 2del (family2) variants were detected in the ANK1 gene. These two de novo mutations described by us which have not been reported prior to this study. Moreover, the validation results of splicing reporter systems revealed that the intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the minigene plasmid expressing the c.1305 + 2 T > A variant transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 229 and r.1305_1306ins1305 + 1_1305 + 552. The minigene plasmid expressing c.1305 + 2del transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 228 and r.1305_1306ins1305 + 1_1305 + 551. Conclusion The two de novo variants identified in the ANK1 gene were the genetic etiology of the probands with HS in our study. Our findings further enrich the HS genotype database and provide a basis for genetic counselling and molecular diagnosis.

The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)‐guided precision treatment in metastatic castration‐resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual‐tracer [68Ga‐prostate‐specific membrane antigen (PSMA) and 18F‐fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu‐PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA−/FDG+ disease on dual‐tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression‐free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty‐three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy‐four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs.

The emerging cell membrane (CM)-camouflaged poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) (CM@PLGA NPs) have witnessed tremendous developments since coming to the limelight. Donning a novel membrane coat on traditional PLGA carriers enables combining the strengths of PLGA with cell-like behavior, including inherently interacting with the surrounding environment. Thereby, the in vivo defects of PLGA (such as drug leakage and poor specific distribution) can be overcome, its therapeutic potential can be amplified, and additional novel functions beyond drug delivery can be conferred. To elucidate the development and promote the clinical transformation of CM@PLGA NPs, the commonly used anucleate and eukaryotic CMs have been described first. Then, CM engineering strategies, such as genetic and nongenetic engineering methods and hybrid membrane technology, have been discussed. The reviewed CM engineering technologies are expected to enrich the functions of CM@PLGA for diverse therapeutic purposes. Third, this article highlights the therapeutic and diagnostic applications and action mechanisms of PLGA biomimetic systems for cancer, cardiovascular diseases, virus infection, and eye diseases. Finally, future expectations and challenges are spotlighted in the concept of translational medicine.

Chemical-exfoliated borophene and its application in multi-imaging guided photothermal therapy.

Objective: Primary urethral carcinoma (PUC) is a rare malignant carcinoma but with limited therapeutic options. This review aims to provide an overview of the current strategies on this patient settings. Methods: Recent literature ranging from January 1987 and December 2021 was assessed through PubMed search to assess the diagnostic and therapeutic principles of PUC. Results: A complete of examination including cystoscopy, imaging, and biopsy should be conducted for these patients. Once diagnosed, the clinical decision of PUC should be made according to the tumor location, pathological pattern, and extent of the tumor. For patients with superficial and distal urethral lesions, organ sparing approaches or radical reconstructive procedures can be utilized. While for more advanced disease or nodal involvement, an optimal multimodal treatment strategy consisted of surgery and radiochemotherapy should be adopted. For patients with urothelial carcinoma of the prostate, the management including transurethral resection of the prostate followed by bacille Calmette-Guerin or radical cystoprostatectomy should depend on the infiltration depth of PUC. Conclusion: A complete of examination is important for the diagnosis of PUC. The management of PUC should be determined by the location, pathological pattern, and extent of the tumor. More multi-institutional collaborations should be held to investigate better treatment modalities for PUC.

Background: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been approved for use in breast cancer susceptibility gene (BRCA)-mutated metastatic castration-resistant prostate cancer (mCPRC) patients. Our aim was to evaluate the adverse events (AEs) and efficacy of Olaparib in the treatment of mCRPC patients from the Chinese mainland. Methods: We retrospectively included mCPRC patients treated with Olaparib more than for 28 days. Patients with alterations in 15 homologous recombination repair (HRR) genes were defined as the HRRmt group, and the rest were defined as the HRRwt group. The efficacy was analyzed by prostate-specific antigen (PSA) decreased rate and PSA progression-free survival (PFS). The partial response, good response, and high response of PSA were defined as a reduction of between 0% and 50%, greater than 50%, and greater than 90% from baseline. Results: A total of 43 patients were enrolled in this study, including 26 HRRmt group patients and 17 HRRwt group patients. Two HRRwt patients received additional abiraterone therapy. A partial response, good response, and high response were achieved in 89% (23/26), 59% (15/26), and 15% (4/26) of HRRmt group patients, respectively. In HRRwt group, 59% (10/17), 35% (6/17), and 12% (2/17) of patients met the criteria of partial response, good response, and high response, respectively. Median PFS was 8.0 months in the HRRmt group and 3.0s months in the HRRwt group (HR, 0.61; 95% CI, 0.24–1.14; p = 0.148), respectively. All the 20 patients had AEs during Olaparib treatment. Ten episodes of grade 3 or 4 AEs were observed in four patients. The most common all-grade AEs were fatigue or asthenia (70%), anemia (65%), and decreased appetite (55%). Conclusions: Most of the AEs were tolerated, and Olaparib was effective in mCRPC patients with HRR deficiency. In addition, the underlying mechanism of the efficacy of Olaparib observed in HRRwt group patients remained explored.