Fracture Behavior and Mechanism of Nb-Si-Based Alloys with Heterogeneous Layered Structure.

Novel Nb-Si-based alloys with heterogeneous layers that have the same composition (Nb-16 at.%Si) but different phase morphologies were designed in this work. Heterogeneous layered structure (HLS) was successfully fabricated in Nb-16Si alloys by layering composite powders after various degrees of mechanical alloying (6 h, 12 h, 18 h, and 24 h) alternately and subsequent spark plasma sintering (SPS). The influence of HLS on the fracture behavior at both room and elevated temperature was investigated via single-edge notched bending (SENB) and high-temperature compression, respectively. The results show that the diversified HLS is obtained by combining hard layers containing fine equiaxed crystals and/or soft ones with coarse lamellar niobium solid solution (Nbss). By affecting the crack propagation in SENB, HLS is favorable for improving the fracture toughness and exhibits a significant increase compared with the corresponding homogenous microstructure. Moreover, for the same HLS, a more excellent performance is achieved when the initial crack is located in the soft layer and extended across the interface to the hard one through crack bridging, crack deflection, crack branching, and shielding effect. Fracture starts in the soft layer (from powders of ball-milled for 12 h) of a 12-24 alloy, and a maximum KQ value (14.89 MPa·mm1/2) is consequently obtained, which is 33.8% higher than that of the homogeneous Nb-16Si alloy. Furthermore, the heterogeneous layered alloys display superior high-temperature compression strength, which is attributable to the dislocation multiplication and fine-grained structure. The proposed strategy in this study offers a promising route for fabricating Nb-Si-based alloys with optimized and improved mechanical properties to meet practical applications.

Investigating the mechanism of rough phenotype in a naturally attenuated Brucella strain: insights from whole genome sequencing.

Objective: Brucellosis, a significant zoonotic disease, not only impacts animal health but also profoundly influences the host immune responses through gut microbiome. Our research focuses on whole genome sequencing and comparative genomic analysis of these Brucella strains to understand the mechanisms of their virulence changes that may deepen our comprehension of the host immune dysregulation. Methods: The Brucella melitensis strain CMCC55210 and its naturally attenuated variant CMCC55210a were used as models. Biochemical identification tests and in vivo experiments in mice verified the characteristics of the strain. To understand the mechanism of attenuation, we then performed de novo sequencing of these two strains. Results: We discovered notable genomic differences between the two strains, with a key single nucleotide polymorphism (SNP) mutation in the manB gene potentially altering lipopolysaccharide (LPS) structure and influencing host immunity to the pathogen. This mutation might contribute to the attenuated strain's altered impact on the host's macrophage immune response, overing insights into the mechanisms of immune dysregulation linked to intracellular survival. Furthermore, we explore that manipulating the Type I restriction-modification system in Brucella can significantly impact its genome stability with the DNA damage response, consequently affecting the host's immune system. Conclusion: This study not only contributes to understanding the complex relationship between pathogens, and the immune system but also opens avenues for innovative therapeutic interventions in inflammatory diseases driven by microbial and immune dysregulation.

Tumor-Agnostic Approvals: Insights and Practical Considerations.

Since the first approval of a tumor-agnostic indication in 2017, a total of seven tumor-agnostic indications involving six drugs have received approval from the FDA. In this paper, the master protocol subteam of the Statistical Methods in Oncology Scientific Working Group, Biopharmaceutical Session, American Statistical Association, provides a comprehensive summary of these seven tumor-agnostic approvals, describing their mechanisms of action; biomarker prevalence; study design; companion diagnostics; regulatory aspects, including comparisons of global regulatory requirements; and health technology assessment approval. Also discussed are practical considerations relating to the regulatory approval of tumor-agnostic indications, specifically (i) recommendations for the design stage to mitigate the risk that exceptions may occur if a treatment is initially hypothesized to be effective for all tumor types and (ii) because drug development continues after approval of a tumor-agnostic indication, recommendations for further development of tumor-specific indications in first-line patients in the setting of a randomized confirmatory basket trial, acknowledging the challenges in this area. These recommendations and practical considerations may provide insights for the future development of drugs for tumor-agnostic indications.

Effect of Ultrasonic Vibration on Microstructure and Fluidity of Aluminum Alloy.

The effect of ultrasonic vibration on the fluidity and microstructure of cast aluminum alloys (AlSi9 and AlSi18 alloys) with different solidification characteristics was investigated. The results show that ultrasonic vibration can affect the fluidity of alloys in both solidification and hydrodynamics aspects. For AlSi18 alloy without dendrite growing solidification characteristics, the microstructure is almost not influenced by ultrasonic vibration, and the influence of ultrasonic vibration on its fluidity is mainly in hydrodynamics aspects. That is, appropriate ultrasonic vibration can improve fluidity by reducing the flow resistance of the melt, but when the vibration intensity is high enough to induce turbulence in the melt, the turbulence will increase the flow resistance greatly and decrease fluidity. However, for AlSi9 alloy, which obviously has dendrite growing solidification characteristics, ultrasonic vibration can influence solidification by breaking the growing α (Al) dendrite, consequently refining the solidification microstructure. Ultrasonic vibration could then improve the fluidity of AlSi9 alloy not only from the hydrodynamics aspect but also by breaking the dendrite network in the mushy zone to decrease flow resistance.

Effect of Cr on Microstructure and Properties of WVTaTiCrx Refractory High-Entropy Alloy Laser Cladding.

WVTaTiCrx (x = 0, 0.25, 0.5, 0.75, 1) refractory high-entropy alloy coatings were prepared on a 42-CrMo steel plate using laser cladding. The purpose of this work is to investigate the effect of the Cr content on the microstructure and properties of the WVTaTiCrx coating. The morphologies and phase compositions of five coatings with different Cr contents were comparatively observed. In addition, the hardness and high-temperature oxidation resistance of the coatings were also analyzed. As a result, with the increase in Cr, the coating grains were more refined. All the coating is mainly composed of the BCC solid-solution phase, which promotes the precipitation of the Laves phase with the increase in Cr. The addition of Cr greatly improves the hardness, high-temperature oxidation resistance and corrosion resistance of the coating. The WVTaTiCr (Cr1) exhibited superior mechanical properties, especially in terms of its exceptional hardness, high-temperature oxidation resistance and outstanding corrosion resistance. The average hardness of the WVTaTiCr alloy coating reaches 627.36 HV. After 50 h of high-temperature oxidation, the oxide weight of WVTaTiCr increases by 5.12 mg/cm2, and the oxidation rate is 0.1 mg/(cm2·h). In 3.5 wt% NaCl solution, the corrosion potential of WVTaTiCr is -0.3198 V, and the corrosion rate is 0.161 mm/a.

Effects of oral immunonutritional supplement on 3-year disease-free survival in gastric cancer patients with pathological stage III after total gastrectomy (CRUCIAL): study protocol of a multicentre, randomised clinical trial.

INTRODUCTION: The nutritional status of patients with gastric cancer (GC) after total gastrectomy continues to deteriorate and lasts a long time after discharge, which is an independent risk factor for mortality. Recent guidelines have recommended appropriate nutritional support after discharge for cancer surgery patients with malnutrition or nutritional risk. The evidence on the efficacy of oral immunonutritional supplement (INS) and its effect on long-term disease-free survival (DFS) in patients with GC is limited. This study was designed to test the hypothesis that oral INS compared to diet alone may improve 3-year DFS of GC patients with pathological stage III after total gastrectomy (Nutrition Risk Screening 2002 score ≥3 at discharge). METHODS AND ANALYSIS: This is a pragmatic, open-label, multicentre, randomised controlled study. 696 eligible GC patients with pathological stage III after total gastrectomy will be randomised in a 1:1 ratio to oral INS group or normal diet group for 6 months. The primary endpoint is 3-year DFS after discharge. The following secondary endpoints will be evaluated: 3-year overall survival; unplanned readmission rate at 3 and 6 months after discharge; quality of life, body mass index and haematological index at 3, 6 and 12 months after discharge; incidence of sarcopenia at 6 and 12 months after discharge; and the tolerance to chemotherapy. The adverse events of oral INS will also be evaluated during the intervention. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of Jinling Hospital, Nanjing University (number 2021NZKY-069-01). The present study may validate the effectiveness of oral immunonutritional therapy in improving 3-year DFS for GC patients with pathological stage III after total gastrectomy for the first time. The results of this trial will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05253716.

Survival of SARS-CoV-2 in artificial seawater and on the surface of inanimate materials.

There is a potential risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread through human contact with seafood and the inanimate materials contaminated by the virus. In this study, we examined the stability of the virus in artificial seawater (ASW) and on the surface of selected materials. SARS-CoV-2 (3.75 log10 TCID50 ) in ASW at 22℃ maintained infectious about 3 days and at 4℃ the virus survived more than 7 days. It should be noticed that viable virus at high titer (5.50 log10 TCID50 ) may survive more than 20 days in ASW at 4℃ and for 7 days at 22℃. SARS-CoV-2 on stainless steel and plastic bag maintained infectious for 3 days, and on nonwoven fabric for 1 day at 22℃. In addition, the virus remained infectious for 9 days on stainless steel and non-woven fabric, and on plastic bag for 12 days at 4℃. It is important to highlight the role of inanimate material surfaces as a source of infection and the necessity for surface decontamination and disinfection.

Ultrasmall Au nanoparticles modified 2D metalloporphyrinic metal-organic framework nanosheets with high peroxidase-like activity for colorimetric detection of organophosphorus pesticides.

Ultrasmall Au nanoparticles (UsAuNPs) in the size range of 4.0-7.0 nm was successfully immobilized on the surface of 2D metalloporphyrinic metal-organic framework nanosheets (2D MOF). Firstly, The obtained hybrid nanomaterial, UsAuNPs/2D MOF, was fully characterized by TEM, HRTEM, element mapping images and XPS. Then, the peroxidase-like activity of UsAuNPs/2D MOF was comparatively studied with other hybrid nanozyme to explore the influence of AuNPs size on peroxidase-like activity. Further, UsAuNPs/2D MOF with outstanding peroxidase-like activity was selected to form ternary cascade enzyme reaction with acetylcholinesterase (AChE) and choline oxidase (ChOx). Based on the inhibitory effect of organophosphorus pesticides on AChE, a fast and sensitive colorimetric method was established for trichlorfon detection with the advantages of simple operation, low detection limit (1.7 µM), good linear range (1.7-42.4 µM) and high accuracy (recovery rate of 96.6-105.3%). Finally, this method was applied to visual analysis of trichlorfon concentration in tomatoes, cucumbers and eggplants.

A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry.

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.

Protoporphyrin IX and verteporfin potently inhibit SARS-CoV-2 infection in vitro and in a mouse model expressing human ACE2.

The SARS-CoV-2 infection is spreading rapidly worldwide. Efficacious antiviral therapeutics against SARS-CoV-2 is urgently needed. Here, we discovered that protoporphyrin IX (PpIX) and verteporfin, two Food and Drug Administration (FDA)-approved drugs, completely inhibited the cytopathic effect produced by SARS-CoV-2 infection at 1.25 µmol/L and 0.31 µmol/L, respectively, and their EC50 values of reduction of viral RNA were at nanomolar concentrations. The selectivity indices of PpIX and verteporfin were 952.74 and 368.93, respectively, suggesting a broad margin of safety. Importantly, PpIX and verteporfin prevented SARS-CoV-2 infection in mice adenovirally transduced with human angiotensin-converting enzyme 2 (ACE2). The compounds, sharing a porphyrin ring structure, were shown to bind viral receptor ACE2 and interfere with the interaction between ACE2 and the receptor-binding domain of viral S protein. Our study suggests that PpIX and verteporfin are potent antiviral agents against SARS-CoV-2 infection and sheds new light on developing novel chemoprophylaxis and chemotherapy against SARS-CoV-2.

Independent drug action and its statistical implications for development of combination therapies.

Researchers have long sought to find combinations of cancer drugs that might achieve synergy. However, while observed in some preclinical tumor models, synergistic effects are rarely seen in clinical trials. In fact, growing evidence in clinical trial data shows that the treatment effect of most approved combination therapies can be largely explained by the independent drug action model at the patient level. Previous statistical research on drug combinations mainly centered on experimental designs for dose-finding followed by measure of combination efficacy. In this paper, we introduce the independent drug action model to those working in late stage clinical development, propose a new approach to predict the progression-free survival of combination therapies, and discuss its statistical implications for trial design and monitoring. The discussion is enriched with real data examples.

Retraction Note to: SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity.

Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)-biomimetic liposomes encapsulating 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine-induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP-adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP-mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

Treating Foot Injuries by Grafting Pedicled Distal Peroneal Artery Perforator Flaps.

Treating mid- and forefoot wounds is challenging. We share our clinical experience and describe the treatment of foreand midfoot wounds by grafting pedicled distal peroneal artery perforator (PNAP) flaps. The study enrolled 21 patients with fore- and midfoot injuries, who underwent grafting with a pedicled distal PNAP flap between August 2013 and May 2016. All of the flaps survived and were followed for 2 to 11 months. The appearance and texture of these flaps were good. The range of motion of the injured ankle was similar to the unaffected side. There were no complications, such as scar contracture, ulcer, or tenderness. The pedicled distal PNAP flaps can effectively extend the length of the flap pedicles and are better for repairing fore- and midfoot wounds than the traditional distally pedicled sural neuro-fasciocutaneous flaps.

Intranasal Administration of Chitosan Against Influenza A (H7N9) Virus Infection in a Mouse Model.

Influenza virus evolves constantly in an unpredictable fashion, making it necessary to vaccinate people annually for effective prevention and control of influenza. In general, however, during the first wave of an influenza outbreak caused by a newly emerging virus strain, influenza morbidity and mortality have been observed to rise sharply due to the lack of a matching vaccine. This necessitates the exploration of novel intervention approaches, particularly those prophylactic or therapeutic agents that have a broad range of antiviral activities and are also proven to be non-toxic. Here, we reported that stimulation of the innate immune system by intranasal administration of chitosan as a single agent was sufficient to completely protect BALB/c mice from lethal infection by H7N9 virus, a newly emerged viral strain that is highly pathogenic to humans. Remarkably, animals could still be protected against lethal challenge by H7N9 (10×LD50), even ten days after the intranasal chitosan administration. The significantly enhanced infiltration of leukocytes in the bronchoalveolar lavage and elevated levels of proinflammatory cytokines in the bronchia/lung tissues revealed the potent activation of mucosal immune responses by intranasally delivered chitosan. We also observed that chitosan can protect mice from three other virus strains. The marked breadth and magnitude of protection against diverse viral strains makes chitosan an attractive candidate as a universal anti-influenza agent.

[Continuous renal replacement therapy and negative fluid balance improves renal function and prognosis of patients with acute kidney injury in sepsis].

OBJECTIVE: To investigate the influence of fluid balance and model of renal replacement therapy (RRT) on renal function and prognosis of patients suffering from septic acute kidney injury (AKI). METHODS: A retrospective cohort analysis of 117 septic AKI patients who had undergone RRT between January 2009 and December 2014 was performed in the Second Affiliated Hospital of Nanjing Medical University. The patients were divided into positive fluid balance group (n = 52) and negative fluid balance group (n = 65) according to the total amount of fluid calculated from the difference between fluid administered and fluid lost during the first 1 week of RRT. The incidence of renal recovery and death of the patients by 60 days as the endpoint events were taken to judge the prognosis of two groups. RRT strategies included continuous renal replacement therapy (CRRT) and intermittent renal replacement therapy (IRRT). Multiple factors including estimated glomerular filtration rate (eGFR), sequential organ failure assessment (SOFA) score, RRT model, the accumulation of fluid before initiation of RRT, and negative fluid balance during RRT were analyzed for outcome predictors by Cox proportional hazards model. RESULTS: There were no differences between two groups regarding clinical characteristics. The percentage of receiving CRRT in the negative fluid balance group was slightly higher than that of the positive fluid balance group (52.31% vs. 36.54%, χ² = 2.899, P = 0.089). With Kaplan-Meier survival curves, it was shown that the patients of negative fluid balance group had a higher rate of recovery of renal function (χ² = 4.803, P = 0.028) and significantly lower mortality rate (χ² = 9.505, P = 0.002). The rate of recovery of renal function by 60 days was higher in the negative fluid balance group than that in the positive fluid balance group (47.69% vs. 28.85%, χ² = 3.991, P = 0.046), while the mortality rate was significantly lowered in the negative fluid balance group compared with that of the positive fluid balance group (40.00% vs. 67.31%, χ² = 4.378, P = 0.036). Cox multivariate regression was used for excluding confounding factors. After adjusting for the clinically relevant variables, RRT negative fluid balance was significantly associated with recovery of renal function [ hazard ratios (HR) = 2.440, 95% confidence intervals (95%CI) = 1.089-5.464, P = 0.030] and mortality (HR = 0.443, 95%CI = 0.238-0.822, P = 0.010]. Higher eGFR before RRT and CRRT were independent favorable factors for recovery of renal function (HR = 1.014, 95%CI = 1.003-1.026, P = 0.012; HR = 3.138, 95%CI = 1.765-7.461, P = 0.002), and higher SOFA score was associated with a significantly higher risk of death (HR = 1.115, 95%CI = 1.057-1.177, P < 0.001). CONCLUSIONS: Once the patients with septic AKI showed the signs of fluid overload, timely RRT and effective removal of excessive liquid may reverse the adverse prognosis. RRT with negative fluid balance is beneficial for the recovery of renal function, and reduce the mortality in patients with septic AKI, and CRRT model is a good choice.