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Abstract The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

A vast amount of knowledge has been acquired through human activities such as farming, hunting, and fishing. Throughout history, humans have utilized living creatures for disease treatment, relying on the natural world's healing powers. The special “healers” may be able to treat patients via the power of nature. However, there was no systematic introduction or summary of these treatments. Therefore, we conducted a literature review based on PubMed, Google Scholar, Web of Science, Scopus, CNKI and WanFang DATA. Here, we defined this unique method as “animal healer” and six common kinds of animal healers were reviewed. These are fish therapy, pet therapy, worm therapy, leech therapy, maggot therapy, and bee therapy. According to the different characteristics of healers, treatment methods mainly included bite, parasitism, contact and communication. With the advantages of green and effectiveness, animal healers have great therapy potential against a variety of refractory diseases. The main purpose of this review is to draw people's attention to animal healer, promote it to become a possible clinical treatment strategy, and make further exploration in species cultivation, mechanism research, animal welfare, standard setting, safety evaluation and other aspects. In the future, animal healers will play an increasingly important role in medicine and hopefully solve more medical problems and dilemmas.

Abstract Cleats are the main channels for fluid transport in coal reservoirs. However, the microscale flow characteristics of both gas and water phases in primary cleats have not been fully studied as yet. Accordingly, the local morphological features of the cleat were determined using image processing technology and a transparent cleat structure model was constructed by microfluidic lithography using the multiphase fluid visualization test system. Besides, the effect of microchannel tortuosity characteristics on two‐phase flow was analyzed in this study. The results are as follows: (1) The local width of the original cleat structure of coal was strongly nonhomogeneous. The cleats showed contraction and expansion in the horizontal direction and undulating characteristics in the vertical direction. (2) The transient flow velocity fluctuated due to the structural characteristics of the primary cleat. The water‐driven gas interface showed concave and convex instability during flow, whereas the gas‐driven water interface presented a relatively stable concave surface. (3) The meniscus advanced in a symmetrical pattern in the flat channel, and the flow stagnated due to the influence of undulation points in a partially curved channel. The flow would continue only when the meniscus surface bypassed the stagnation point and reached a new equilibrium position. (4) Enhanced shearing at the gas–liquid interface increased the gas‐injection pressure, which in turn increased residual liquids in wall grooves and liquid films on the wall surface.

AbstractCurcuminoids are functional food additives, and the effect on gonadal hormone biosynthesis remains unclear. Gonads contain 3β-hydroxysteroid dehydrogenase isoforms, h3β-HSD2 (humans) and r3β-HSD1 (rats), which catalyse pregnenolone into progesterone. The potency and mechanisms of curcuminoids to inhibit 3β-HSD activity were explored. The inhibitory potency was bisdemethoxycurcumin (IC50, 1.68 µM) >demethoxycurcumin (3.27 µM) > curcumin (13.87 µM) > tetrahydrocurcumin (109.0 µM) > dihydrocurcumin and octahydrocurcumin on KGN cell h3β-HSD2, while that was bisdemethoxycurcumin (1.22 µM) >demethoxycurcumin (2.18 µM) > curcumin (4.12 µM) > tetrahydrocurcumin (102.61 µM) > dihydrocurcumin and octahydrocurcumin on testicular r3β-HSD1. All curcuminoids inhibited progesterone secretion by KGN cells under basal and forskolin-stimulated conditions at >10 µM. Docking analysis showed that curcuminoids bind steroid-active site with mixed or competitive mode. In conclusion, curcuminoids inhibit gonadal 3β-HSD activity and de-methoxylation of curcumin increases inhibitory potency and metabolism of curcumin by saturation of carbon chain losses inhibitory potency.

Tendinopathy is a medical condition that includes a spectrum of inflammatory and degenerative tendon changes caused by traumatic or overuse injuries. The pathological mechanism of tendinopathy has not been well defined, and no ideal treatment is currently available. Platelet-rich plasma (PRP) is an autologous whole blood derivative containing a variety of cytokines and other protein components. Various basic studies have found that PRP has the therapeutic potential to promote cell proliferation and differentiation, regulate angiogenesis, increase extracellular matrix synthesis, and modulate inflammation in degenerative tendons. Therefore, PRP has been widely used as a promising therapeutic agent for tendinopathy. However, controversies exist over the optimal treatment regimen and efficacy of PRP for tendinopathy. This review focuses on the specific molecular and cellular mechanisms by which PRP manipulates tendon healing to better understand how PRP affects tendinopathy and explore the reason for the differences in clinical trial outcomes. This article has also pointed out the future direction of basic research and clinical application of PRP in the treatment of tendinopathy, which will play a guiding role in the design of PRP treatment protocols for tendinopathy.

Bisphenols (BPs) as endocrine-disrupting compounds have drawn attention to their health hazards. Whether a BP interferes with glucocorticoid metabolism remains unclear. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) is a key glucocorticoid-metabolizing enzyme that controls fetal glucocorticoid levels across the placental barrier and mineralocorticoid receptor specificity in the kidney. In this study, 11 BPs were tested to inhibit human placental and rat renal 11β-HSD2 and were analyzed for inhibitory potency, mode action, and docking parameters. BPs had inhibitory potency against human 11β-HSD2: BPFL>BPAP>BPZ>BPB>BPC>BPAF>BPA>TDP and the IC10 values were 0.21, 0.55, 1.04, 2.04, 2.43, 2.57, 14.43, and 22.18 μM, respectively. All BPs are mixed inhibitors except BPAP, which is a competitive inhibitor for human 11β-HSD2. Some BPs also inhibited rat renal 11β-HSD2, with BPB (IC50, 27.74 ± 0.95) > BPZ (42.14 ± 0.59) > BPAF (54.87 ± 1.73) > BPA (77.32 ± 1.20) > other BPs (about 100 μM). Docking analysis showed that all BPs bound to the steroid-binding site, interacting with the catalytic residue Tyr232 of both enzymes and the most potent human 11β-HSD2 inhibitor BPFL acts possibly due to its large fluorene ring that has hydrophobic interaction with residues Glu172 and Val270 and π-stacking interaction with catalytic residue Tyr232. The increase in the size of substituted alkanes and halogenated groups in the methane moiety of the bridge of BPs increases its inhibitory potency. Regressions of the lowest binding energy with inhibition constant indicated that there was an inverse regression. These results indicated that BPs significantly inhibited human and rat 11β-HSD2 activity and that there were species-dependent differences.

Introduction: At present, the mu opioid receptor is the most important neuroaesthetics receptor in anesthesiology research, and the damage that it does to the nervous system is unknown.Methods: We investigated the effects of loperamide, an agonist of the mu opioid receptor, on protein expression in HT22 cells using stable isotope labeling of amino acids in cell culture (SILAC), immobilized metal affinity chromatography (IMAC) enrichment, and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 7,823 proteins were identified.Results and Discussion: Bioinformatic analysis revealed that mu opioid receptor agonism can induce distinct changes in the proteome of HT22 cells. These findings improve our understanding of narcotic drugs.

As a broad-spectrum antibiotic, tetracycline (TC) has been continually detected in soil and seawater environments, which poses a great threat to the ecological environment and human health. Herein, a black graphitic carbon nitride (CN-B) photocatalyst was synthesized by the one-step calcination method of urea and phloxine B for the degradation of tetracycline TC in seawater under visible light irradiation. The experimental results showed that the photocatalytic degradation rate of optimal CN-B-0.1 for TC degradation was 92% at room temperature within 2 h, which was 1.3 times that of pure CN (69%). This excellent photocatalytic degradation performance stems from the following factors: (i) ultrathin nanosheet thickness reduces the charge transfer distance; (ii) the cyanogen defect promotes photogenerated carriers’ separation; (iii) and the photothermal effect of CN-B increases the reaction temperature and enhances the photocatalytic activity. This study provides new insight into the design of photocatalysts for the photothermal-assisted photocatalytic degradation of antibiotic pollutants.

Abstract Background The Paracoccus sp. strain isolated from sludge was identified and evaluated for catalytic activity in the degradation of penicillin G. Results High degradation efficiency and synergistic catalytic effects of the whole cell and visible light without additional catalysts were observed. The key factors influencing the degradation and kinetics of penicillin G were investigated. The results showed the phenylacetic acid, which was produced during penicillin G biodegradation, exhibited stronger inhibiting effects on KDSPL-02. However, this effect was reduced by visible light irradiation without any additional photocatalyst; furthermore, the rate of penicillin G biodegradation was accelerated, reaching a 100% rate in 12 h at a penicillin G concentration of 1.2 g/L. Four key intermediates produced during penicillin G degradation were isolated and identified by LC–MS, 1H NMR, and 13C NMR. Enzymes involved in the PAA pathway were proposed from a genomic analysis of KDSPL-02. Conclusions These results provide a new method for bio-degrading of penicillin or other antibiotic pollutants using photoaccelerating biocatalysts with greater efficiency and more environmentally friendly conditions.

Abstract Background Biodegradation of antibiotics is a promising method for the large-scale removal of antibiotic residues in the environment. However, the enzyme that is involved in the biodegradation process is the key information to be revealed. Results In this study, the beta-lactamase from Ochrobactrum tritici that mediates the biodegradation of penicillin V was identified and characterized. When searching the proteins of Ochrobactrum tritici, the β-lactamase (OtLac) was identified. OtLac consists of 347 amino acids, and predicted isoelectric point is 7.0. It is a class C β-lactamase according to BLAST analysis. The coding gene of OtLac was amplified from the genomic DNA of Ochrobactrum tritici. The OtLac was overexpressed in E. coli BL21 (DE3) and purified with Ni2+ column affinity chromatography. The biodegradation ability of penicillin V by OtLac was identified in an in vitro study and analyzed by HPLC. The optimal temperature for OtLac is 32 ℃ and the optimal pH is 7.0. Steady-state kinetics showed that OtLac was highly active against penicillin V with a Km value of 17.86 μM and a kcat value of 25.28 s−1 respectively. Conclusions OtLac demonstrated biodegradation activity towards penicillin V potassium, indicating that OtLac is expected to degrade penicillin V in the future.

As obligate blood-feeding ectoparasites, ticks secrete a great diversity of antithrombin molecules during feeding. In this study, a novel antithrombin gene named Doenitin-1 was characterized from the tick Haemaphysalis doenitzi. It has an open reading frame size of 426 bp; it encodes 141 amino acids and has a predicted molecular weight of 15.8 kDa. The fibrinogen coagulation test showed that the time of coagulation was increased significantly with increase in rDoenitin-1 protein concentration, and the activated partial thromboplastin time (APTT) and prothrombin time (PT) assays showed that rDoenitin-1 significantly prolonged the coagulation time of APTT, indicating that rDoenitin-1 has an anticoagulant activity in vitro. In addition, rDoenitin-1 presents a significant inhibitory activity in thrombin and cathepsin G. The hemolysis rate of rDoenitin-1 in healthy human blood cells was 4.25%, and no obvious hemolysis activity was observed. The comparison with other life stages shows that the higher expression occurs in adults, and tissue comparison indicated a higher expression in the midgut. The RNAi results indicated that interference of Doenitin-1 significantly reduced the engorgement rate and egg hatchability of H. doenitzi, and that the engorged body weight was slightly reduced. In conclusion, the results suggested that the novel gene Doenitin-1 functions in blood-feeding of H. doenitzi and performs various functions during feeding and reproduction of H. doenitzi. Doenitin-1 may be a potential vaccine candidate for tick control and for developing new antithrombotic drugs in the future.

Controlled drug release and synergistic therapies have an important impact on improving therapeutic efficacy in cancer theranostics. Herein, a new near-infrared (NIR) light-controlled multi-functional nanoplatform (GNR@mSiO2-DOX/PFP@PDA) was developed for synergistic chemo-photothermal therapy (PTT) of tumours. In this nano-system, doxorubicin hydrochloride (DOX) and perfluoro-n-pentane (PFP) were loaded into the channels of mesoporous SiO2 simultaneously as a first step. A polydopamine (PDA) layer as the gatekeeper was coated on their surface to reduce premature release of drugs at physiological temperature. Upon 808 nm NIR irradiation, the gold nanorods (GNR) in the core of the nanoplatform show high photothermal conversion efficiency, which not only can provide the heat for PTT, but also can decompose the polymer PDA to allow DOX release from the channels of mesoporous SiO2. Most importantly, the photothermal conversion of GNR can also lead the liquid–gas phase transition of PFP to generate bubbles to accelerate the release of DOX, which can realize the chemotherapy of tumours. The subsequent synergistic chemo-PTT (contributed by the DOX and GNR) shows good anti-cancer activity. This work shows that the NIR-triggered multi-functional nanoplatform is of capital significance for future potential applications in drug delivery and cancer treatment.

In this paper we study the climate change characteristics of rainstorm and risk assessment of rainstorm rainfall in Jinshan of Shanghai in recent 60 years with the daily rain data at Jinshan meteorological station from 1959 to 2016 by the methods of abrupt change test, morlet wavelet and so on. The results are as follows. (1) The rainstorm days had been increasing and rainstorm intensity had been increasing indistinctively in Jinshan in recent 60 years. The mutation of rainstorm days from low to high occurred in 1988. The first date of rainstorm had tended to occur early in the recent 60 years. Jinshan had been into the early occurrence stage of rainstorm since 1990s. The last date of rainstorm had tended to occur lately since the 21st century. (2) The risk probability and disaster intensity were the highest for typhoon rainstorm, followed by low pressure rainstorm. The high risk levels of warm sector rainstorm, stationary front rainstorm, low pressure rainstorm and typhoon rainstorm were 50-75 mm, 50-75 mm, 50-90 mm and 50-100 mm, respectively. The corresponding risk probabilities were 28.4%-100%, 28.9%-100%, 32.3%-100% and 33.6%-100%, respectively.

ABSTRACT Substantial concentrations of penicillin V potassium (PVK) have been found in livestock manure, soil, and wastewater effluents, which may pose potential threats to human health and contribute to the emergence of penicillin-resistant bacterial strains. In this study, bacterial strains capable of degrading PVK were isolated from sludge and characterized. Strain X-2 was selected for biodegradation of PVK. Based on morphological observations and 16S rRNA gene sequencing, strain X-2 was identified as an Ochrobactrum tritici strain. To enhance the PVK degradation ability of PVK, a whole-cell biodegradation process of Ochrobactrum tritici X-2 was established and optimized. In the whole-cell biodegradation process, the optimal temperature and pH were 30°C and 7.0, respectively. Under the optimized conditions, the degradation rate using 0.5 mg/ml PVK reached 100% within 3 h. During biodegradation, two major metabolites were detected: penicilloic acid and phenolic acid. The present study provides a novel method for the biodegradation of PVK using Ochrobactrum tritici strains, which represent promising candidates for the industrial biodegradation of PVK. IMPORTANCE Substantial concentrations of penicillin V potassium (PVK) have been found in the environment, which may pose potential threats to human health and contribute to the emergence of penicillin-resistant bacterial strains. In this study, antibiotic-degrading bacterial strains for PVK were isolated from sludge and characterized. Ochrobactrum tritici was selected for the biodegradation of PVK with high efficiency. To enhance its PVK degradation ability, a whole-cell biodegradation process was established and optimized using Ochrobactrum tritici. The degradation rate with 0.5 mg/ml PVK reached 100% within 3 h. The potential biodegradation pathway was also investigated. To the best of our knowledge, the present study provides new insights into the biodegradation of PVK using an Ochrobactrum tritici strain, a promising candidate strain for the industrial biodegradation of β-lactam antibiotics.

This article discusses kinds of transformational giftedness, or giftedness that makes a positive, meaningful, and possibly enduring difference to the world. We extend previous work by suggesting that there are two kinds of transformation that matter: self-transformation and other-transformation. Combining these two kinds of transformation yields a 2 × 2 grid of four kinds of giftedness: non-transformational giftedness (no transformation), transformational giftedness (self- and other-transformation combined), self-realized giftedness (whereby one transforms oneself but not others), and other-realized giftedness (whereby one transforms others but not oneself). We open with a discussion of some of the history of conceptions of giftedness. Then we discuss transformational giftedness as it has been defined in the recent past. We then introduce our concepts of self- and other-transformation. We also describe two other kinds of giftedness—inert giftedness, which is giftedness in personal attributes that has not been realized in interactions with others and the world; and transactional giftedness, which is a give-and-take form of giftedness whereby one meets certain societal expectations in exchange for being identified as gifted. We finally conclude that the gifted movement needs to focus much more on developing transformational giftedness, or at least the potential for it, in our young people.

The basic properties of the fly ash, recycled brick powder and recycled concrete powder, compared the recycled brick powder and recycled concrete powder instead of fly ash in concrete preparation, influence on the working performance and mechanical properties; and through the modifier to improve the concrete slump loss is too large, analyzes the mechanism of change influence of modifiers on mechanical properties of concrete. The results showed that the recycled brick powder and recycled concrete powder in certain fineness conditions, its performance with fly ash; retarder, activator and some surfactant composition modifier has obvious effect on the working performance and mechanical properties; and hydration calcium silicate aluminum increased the role of large the mechanical properties of concrete.

According to China's criminal law, the production and sale of online game cheating programs are often charged of "providing special programs specially used for intruding into computer information system". And they are also sometimes charged of "deliberately creates or propagates computer virus and other destructive programs". Some types of game cheating programs such as "injection game cheating program" meet the criterion of "intruding into computer information system" in the Criminal Law, while other types of game cheating programs such as "offline game cheating program" do not. The "Destructiveness" of game cheating programs should be analyzed according to specific game cheating program and the legal interests it embodied in computer information systems. It should be determined on the basis of legislator's intention, rather than directly use the criterion of evaluating the "destructiveness" of programs in computer science. [ABSTRACT FROM AUTHOR]

Objective This study aimed to compare the effects of patient-controlled intravenous analgesia (PCIA) with and without low-basal infusion on postoperative hypoxaemia.Design A randomised parallel-group non-inferiority trial.Setting The trial was conducted at a grade-A tertiary hospital from December 2021 to August 2022.Participants 160 adults undergoing gastrointestinal tumour surgery and receiving postoperative PCIA.Interventions Participants randomly received a low-basal (0.1 mg/hour of hydromorphone) or no-basal infusion PCIA for postoperative 48 hours.Primary and secondary outcome measures Primary outcome was area under curve (AUC) per hour for hypoxaemia, defined as pulse oxygen saturation (SpO2)