Herein, we report a ruthenium‐catalyzed redox‐neutral α‐alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone ...addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone‐type “carbanions” and active protons in a one‐pot reaction, and at the same time achieves the first Grignard‐type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.
A redox‐neutral α‐alkylation of olefinic alcohols is enabled by a synergistic process combining the isomerization of these alcohols with the nucleophilic addition of hydrazone compounds to the resulting carbonyl groups. A broad scope of substrates, including steroids and protected sugar derivatives, were successfully employed in this process.
Hepatocytic ballooning is a key histological feature in the diagnosis of non‐alcoholic steatohepatitis (NASH) and is an essential component of the two most widely used histological scoring systems ...for diagnosing and staging non‐alcoholic fatty liver disease (NAFLD) namely, the NAFLD activity score (NAS), and the steatosis, activity and fibrosis (SAF) scoring system. As a result of the increasing incidence of NASH globally, the diagnostic challenges of hepatocytic ballooning are unprecedented. Despite the clear pathological concept of hepatocytic ballooning, there are still challenges in assessing hepatocytic ballooning in ‘real life’ situations. Hepatocytic ballooning can be confused with cellular oedema and microvesicular steatosis. Significant inter‐observer variability does exist in assessing the presence and severity of hepatocytic ballooning. In this review article, we describe the underlying mechanisms associated with hepatocytic ballooning. Specifically, we discuss the increased endoplasmic reticulum stress and the unfolded protein response, as well as the rearrangement of the intermediate filament cytoskeleton, the appearance of Mallory‐Denk bodies and activation of the sonic Hedgehog pathway. We also discuss the use of artificial intelligence in the detection and interpretation of hepatocytic ballooning, which may provide new possibilities for future diagnosis and treatment.
Abstract
Photocatalytic formation of hydrocarbons using solar energy via artificial photosynthesis is a highly desirable renewable-energy source for replacing conventional fossil fuels. Using an
l
...-cysteine-based hydrothermal process, here we synthesize a carbon-doped SnS
2
(SnS
2
-C) metal dichalcogenide nanostructure, which exhibits a highly active and selective photocatalytic conversion of CO
2
to hydrocarbons under visible-light. The interstitial carbon doping induced microstrain in the SnS
2
lattice, resulting in different photophysical properties as compared with undoped SnS
2
. This SnS
2
-C photocatalyst significantly enhances the CO
2
reduction activity under visible light, attaining a photochemical quantum efficiency of above 0.7%. The SnS
2
-C photocatalyst represents an important contribution towards high quantum efficiency artificial photosynthesis based on gas phase photocatalytic CO
2
reduction under visible light, where the in situ carbon-doped SnS
2
nanostructure improves the stability and the light harvesting and charge separation efficiency, and significantly enhances the photocatalytic activity.
Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled ...prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.
Persistent luminescent nanoparticles (PLNPs) with intrinsic stimuli‐responsive properties are desirable because of no autofluorescence background and natural responsive luminescence. However, the ...stimuli‐responsive features of pure PLNPs have been unexplored. Here we show a facile one‐pot hydrothermal synthesis of green‐emitting Zn2GeO4:Mn2+,Pr3+ nanoparticles (ZGMP) with regular shape, uniform size and good afterglow luminescent performance. We also report the pH stimuli‐responsive luminescent behavior of ZGMP and its possible mechanism. Taking the intriguing feature of pH responsive persistent luminescence, we explore ZGMP as autofluorescence‐free probes to achieve stimuli‐activated signal switch for biosensing by integrating enzyme catalysis reaction mediated pH modulation. The pH‐responsive persistent luminescence also makes ZGMP promising for high‐level information encryption.
Uniformly torpedo‐shaped green‐emitting Zn2GeO4: Mn2+, Pr3+ nanoparticles with good persistent luminescence performance were synthesized by a simple hydrothermal method. The pH‐responsive persistent luminescence of ZGMP was found and explored for autofluorescence‐free biosensing and high‐level information encryption.
•Vibration of fluid-conveying pipes is isolated by quasi-zero stiffness systems.•Nonlinear solution is obtained via Galerkin method and the finite difference.•The fluid flow can deteriorate the ...performance of vibration isolation.
Fluid-conveying pipes are always subjected to various excitations to cause unwanted vibrations. A quasi-zero stiffness system consisting of three linear springs is adopted as the nonlinear isolator to attenuate the transverse vibrations of fluid-conveying pipes induced by foundation excitations. A dynamic model of nonlinear forced vibration of the fluid-conveying pipe coupled with two nonlinear isolators is established for the nonlinear continuous system and validated by using two methods, Galerkin method and the finite difference method. The influence of the quasi-zero stiffness isolators on the vibration characteristics and vibration transmission of the pipe is investigated by analyzing the natural frequency, vibration mode, and nonlinear vibration response. The effects of flow speed of the fluid and the system parameters of the isolator are studied to evaluate the isolation performance. It is found that the quasi-zero stiffness isolator and fluid flow can shift several natural frequencies of vibration of the pipeline to the low-frequency region. When the linear stiffness of the vibration isolation is zero in the vertical direction, the first two modes of the bending vibration of the fluid-conveying pipe tend to become rigid mode. While achieving high-efficiency vibration isolation in the high-frequency region, the vibration in the low-frequency region is complicated. The flow speed of the fluid can deteriorate the performance of vibration isolation.
Hybrid flow shop scheduling problems are encountered in many real-world manufacturing operations such as computer assembly, TFT-LCD module assembly, and solar cell manufacturing. Most research ...considers the scheduling problem in regard to time requirements and the steps needed to improve production efficiency. However, the increasing amount of carbon emissions worldwide is contributing to the worsening global warming problem. Many countries and international organizations have started to pay attention to this problem, even creating mechanisms to reduce carbon emissions. Furthermore, manufacturing enterprises are showing growing interest in realizing energy savings. Thus, the present research study focuses on reducing energy costs and completion time at the manufacturing-system level. This paper proposed a multi-objective mixed-integer programming for energy-efficient hybrid flow shop scheduling with lot streaming in order to minimize both the production makespan and electric power consumption. Due to a trade-off between these objectives and the computational complexity of the proposed multi-objective mixed-integer program, this study adopts the genetic algorithm (GA) to obtain approximate Pareto solutions more efficiently. In addition, a multi-objective energy efficiency scheduling algorithm is also developed to calculate the fitness values of each chromosome in GA.
Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading ...cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κβ ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.
The additive or synergistic sustained antitumour effect of immune checkpoint inhibitors in combination with oxaliplatin-based chemotherapy has previously been reported. We investigated the efficacy ...of nivolumab plus oxaliplatin-based chemotherapy versus placebo plus oxaliplatin-based chemotherapy as first-line therapy for patients with HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer.
We did a randomised, multicentre, double-blind, placebo-controlled, phase 2–3 trial (ATTRACTION-4) at 130 centres (hospitals, cancer centres, and medical centres) across Japan, South Korea, and Taiwan. We enrolled patients aged 20 years and older with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastro-oesophageal junction cancer (regardless of PD-L1 expression), at least one measurable lesion per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1), and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned (1:1) to chemotherapy every 3 weeks (intravenous oxaliplatin 130 mg/m2 on day 1 plus either oral S-1 40 mg/m2 SOX or oral capecitabine 1000 mg/m2 CAPOX, twice daily on days 1–14), in addition to either 360 mg nivolumab intravenously every 3 weeks (nivolumab plus chemotherapy group) or placebo (placebo plus chemotherapy group). Randomisation was done using an interactive web response system with block sizes of four and stratified by intensity of PD-L1 expression, ECOG performance status score, disease status, and geographical region. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population, which included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02746796. Trial recruitment is complete and follow-up is ongoing.
Between March 23, 2017, and May 10, 2018, 724 patients were randomly assigned to treatment: 362 patients to the nivolumab plus chemotherapy group and 362 to the placebo plus chemotherapy group. At the time of data cutoff on Oct 31, 2018, with a median follow-up of 11·6 months (IQR 8·7–14·1), median progression-free survival at a prespecified interim analysis was 10·45 months (95% CI 8·44–14·75) in the nivolumab plus chemotherapy group and 8·34 months (6·97–9·40) in the placebo plus chemotherapy group (hazard ratio HR 0·68; 98·51% CI 0·51–0·90; p=0·0007). At the time of data cutoff on Jan 31, 2020, with a median follow-up of 26·6 months (IQR 24·1–29·0), median overall survival at the final analysis was 17·45 months (95% CI 15·67–20·83) in the nivolumab plus chemotherapy group and 17·15 months (15·18–19·65) in the placebo plus chemotherapy group (HR 0·90; 95% CI 0·75–1·08; p=0·26). The most common treatment-related grade 3–4 adverse events were neutrophil count decreased (71 20% of 359 patients in the nivolumab plus chemotherapy group vs 57 16% of 358 patients in the placebo plus chemotherapy group) and platelet count decreased (34 9% vs 33 9%). Treatment-related serious adverse events of any grade were observed in 88 (25%) patients in the nivolumab plus chemotherapy group and in 51 (14%) in the placebo plus chemotherapy group, of which the most common was decreased appetite (18 5% vs ten 3%). Six treatment-related deaths occurred: three in the nivolumab plus chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo plus chemotherapy group (one each of sepsis, haemolytic anaemia, and interstitial lung disease).
Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer, and could potentially be a new first-line treatment option for these patients.
Ono Pharmaceutical and Bristol-Myers Squibb.
Functional active wound dressings are expected to provide a moist wound environment, offer protection from secondary infections, remove wound exudate and accelerate tissue regeneration, as well as to ...improve the efficiency of wound healing. Chitosan-based hydrogels are considered as ideal materials for enhancing wound healing owing to their biodegradable, biocompatible, non-toxic, antimicrobial, biologically adhesive, biological activity and hemostatic effects. Chitosan-based hydrogels have been demonstrated to promote wound healing at different wound healing stages, and also can alleviate the factors against wound healing (such as excessive inflammatory and chronic wound infection). The unique biological properties of a chitosan-based hydrogel enable it to serve as both a wound dressing and as a drug delivery system (DDS) to deliver antibacterial agents, growth factors, stem cells and so on, which could further accelerate wound healing. For various kinds of wounds, chitosan-based hydrogels are able to promote the effectiveness of wound healing by modifying or combining with other polymers, and carrying different types of active substances. In this review, we will take a close look at the application of chitosan-based hydrogels in wound dressings and DDS to enhance wound healing.
Functional active wound dressings are expected to provide a moist wound environment, offer protection from secondary infections, remove wound exudate and accelerate tissue regeneration, as well as to improve the efficiency of wound healing.
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