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To explore the adaptative strategies of single-veined plants along the environmental gradient, we collec-ted leaves of 57 Pinaceae species (including Abies, Larix , Pinus and Picea ) from 48 sites along a latitudinal gradient (26°58'-35°33' N) on the eastern Qinghai-Tibet Plateau. By measuring three traits of leaf vein, including vein length per leaf area, vein diameter, and vein volume per unit leaf volume, we analyzed the trade-off between vein traits and their relationship with environmental changes. The results showed no significant difference in vein length per leaf area among different genera, but significant difference in vein diameter and vein volume per unit leaf volume. There was a positive correlation between vein diameter and vein volume per unit leaf volume for all genera. There was no significant correlation of vein length per leaf area with vein diameter and vein volume per unit leaf volume. With the increases of latitude, vein diameter and vein volume per unit leaf volume significantly decreased. In contrast, vein length per leaf area did not show a latitudinal trend. Mean annual temperature was the main factor driving the variation in vein diameter and vein volume per unit leaf volume. The relationships between vein length per leaf area and environmental factors were relatively weak. These results indicated that the single-veined Pinaceae plants have a special adaptative strategy to environmental changes through adjusting vein diameter and vein volume per unit leaf volume, which is quite different from complex vein structures such as reticular veins.

With the increase in the medical level, the improvement of adverse drug reaction(ADR) monitoring systems, and the enhancement of public awareness of safe medication, drug safety incidents have been frequently reported. Drug-induced liver injury(DILI), especially liver injury attributed to herbal and dietary supplements(HDS), has globally attracted high attention, bringing great threats and severe challenges to the people for drug safety management such as clinical medication and medical supervision. Consensus on drug-induced liver injury had been published by the Council for International Organizations of Medical Sciences(CIOMS) in 2020. In this consensus, liver injury attributed to HDS was included in a special chapter for the first time. The hot topics, including the definition of HDS-induced liver injury, epidemiological history, potential risk factors, collection of related risk signals, causality assessment, risk prevention, control and management were discussed from a global perspective. Based on the previous works, some experts from China were invited by CIOMS to undertake the compilation of this chapter. Meanwhile, a new causality assessment in DILI based on the integrated evidence chain(iEC) method was widely recognized by experts in China and abroad, and was recommended by this consensus. This paper briefly introduced the main contents, background, and characteristics of the Consensus on drug-induced liver injury. Significantly, a brief interpretation was illustrated to analyze the special highlights of Chapter 8, "Liver injury attributed to HDS", so as to provide practical references for the medical staff and the researchers who worked on either Chinese or Western medicine in China.

Currently, Bacille Calmette-Guerin(BCG) is still the only admitted vaccine to prevent tuberculosis around the world. The target population is infants and children, but its protective efficacy is limited. As more and more studies have shown that re-vaccination with BCG protects against tuberculosis in adults, BCG can also induce non-specific immunity against other respiratory diseases and some chronic diseases by training immunity, especially the immune effects against COVID-19. At present, the epidemic of COVID-19 has not been effectively contained, and it is worth considering whether BCG vaccine can be used as an intervention to prevent COVID-19. The WHO and China do not have a policy to support BCG revaccination, and as more and more BCG vaccines are discovered, whether selective revaccination can be carried out in some high-risk populations and whether the vaccine can be used more widely have led to intense discussions. This article reviewed the effects of specific immunity and non-specific immunity of BCG on tuberculosis and non-tuberculous diseases.

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target.

Acute kidney injury (AKI) is one of the most challenging clinical problems in kidney disease due to serious complications and high mortality rate, which can lead to acute lung injury (ALI) through inflammatory reactions and oxidative stress. Adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway has been reported to be involved in the development of renal ischemia-reperfusion through autophagy and it remains unclear whether AMPK/mTOR pathway has an effect on the AKI-induced ALI. In this study, we aimed to investigate the effects of autophagy-related AMPK/mTOR signaling pathway on inflammatory factors and oxidative stress in an AKI-induced ALI model. The 48 male Sprague-Dawley rats were divided into four groups randomly: (i) sham, (ii) ischemia/reperfusion injury (IRI), (iii) IRI + rapamycin (RA), and (iv) IRI + 3-methyladenine (3-MA). Unilateral flank incisions were made and right kidneys were excised. The left kidney was subjected to 60 min of ischemia followed by 12, 24, 48, and 72 h of reperfusion. The levels of Scr, blood urea nitrogen (BUN), Wet/Dry ratio, indexes of inflammation, and oxidative stress were assayed. Histological examinations were performed. The protein expression of AMPK, mTOR, LC3-II/LC3-I ratio, and Beclin-1, ULK1 was evaluated by western blotting and immunohistochemistry. Compared to the rats from the sham group, IRI rats showed significantly pulmonary damage after AKI with increased Scr, BUN, Wet/Dry ratio, indexes of inflammation, and oxidative stress. The expression of AMPK, LC3-II/LC3-I ratio, Beclin-1, and ULK1 and were increased, while p62 and mTOR were decreased. In addition, RA treatment significantly attenuated lung injury by promoting autophagy through the activation of the AMPK/mTOR pathway, and 3-MA treatment exhibited adverse effects inversely. Therefore, the activation of the AMPK/mTOR pathway after renal IRI induction could significantly attenuate kidney injury and following AKI-induced ALI by inducing autophagy, which alienates inflammation, oxidative stress, and apoptosis., Competing Interests: None

Objectives: To explore the difference in CT values between pulmonary thromboembolism and postmortem clot in postmortem CT pulmonary angiography (CTPA) to further improve the application value of virtual autopsy., Methods: Postmortem CTPA data with the definite cause of death from 2016 to 2019 were collected and divided into pulmonary thromboembolism group ( n =4), postmortem clot group ( n =5), and control group ( n =5). CT values of pulmonary trunk and left and right pulmonary artery contents in each group were measured and analyzed statistically., Results: The average CT value in the pulmonary thromboembolism group and postmortem clot group were (168.4±53.8) Hu and (282.7±78.0) Hu, respectively, which were lower than those of the control group (1 193.0±82.9) Hu ( P <0.05). The average CT value of the postmortem clot group was higher than that of the pulmonary thromboembolism group ( P <0.05)., Conclusions: CT value is reliable and feasible as a relatively objective quantitative index to distinguish pulmonary thromboembolism and postmortem clot in postmortem CTPA. At the same time, it can provide a scientific basis to a certain extent for ruling out pulmonary thromboembolism deaths.

Taxus , also known as "gold in plants" because of the famous agents with emphases on Taxol and Docetaxel, is a genus of the family Taxaceae, distributed almost around the world. The plants hold an important place in traditional medicine in China, and its products are used for treating treat dysuria, swelling and pain, diabetes, and irregular menstruation in women. In order to make a further study and better application of Taxus plants for the future, cited references from between 1958 and 2022 were collected from the Web of Science, the China National Knowledge Internet (CNKI), SciFinder, and Google Scholar, and the chemical structures, distribution, and bioactivity of flavonoids identified from Taxus samples were summed up in the research. So far, 59 flavonoids in total with different skeletons were identified from Taxus plants, presenting special characteristics of compound distribution. These compounds have been reported to display significant antibacterial, antiaging, anti-Alzheimer's, antidiabetes, anticancer, antidepressant, antileishmaniasis, anti-inflammatory, antinociceptive and antiallergic, antivirus, antilipase, neuronal protective, and hepatic-protective activities, as well as promotion of melanogenesis. Flavonoids represent a good example of the utilization of the Taxus species. In the future, further pharmacological and clinical experiments for flavonoids could be accomplished to promote the preparation of relative drugs.

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved. However, the mechanism by which the CDC25B C473D mutant weakens its binding to CDK2/CyclinA is unclear. In order to study the effect of CDC25B C473D mutants on CDK2/CyclinA substrates, we constructed and verified the rationality of the CDC25B WT :CDK2/CyclinA system and CDC25B C473D :CDK2/CyclinA system and conducted molecular dynamics (MD) simulation analysis. In the post-analysis, the fluctuations of residues ARG488-SER499, LYS541-TRP550 on CDC25B and residues ASP206-ASP210 on CDK2 were massive in the mutant CDC25B C473D :CDK2/CyclinA system. And the interactions between residue ARG492 and residue GLU208, residue ARG544 and residue GLU42, residue ARG544 and TRP550 were weakened in the mutant CDC25B C473D :CDK2/CyclinA system. The results showed that when CYS473 on CDC25B was mutated into ASP473, the mutant CDC25B C473D :CDK2/CyclinA system was less stable than the wild-type CDC25B WT :CDK2/CyclinA system. Finally, active site CYS473 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25B CYS473 and CDK2 in the CDC25B C473D :CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately provided a useful understanding of the weak interactions between CDC25B CYS473D and CDK2/CyclinA.Communicated by Ramaswamy H. Sarma.

Competing Interests: Conflicts of interest: The authors declare that there are no conflicts of interest.

Chicken manure is a source of antibiotic resistance genes (ARGs) and pathogenic microbes. Mikania micrantha Kunth (MM) is an invasive plant containing phytochemicals as antimicrobial agents. To explore its impacts on ARGs and pathogen-host interactions (PHIs), MM was added to composting mixtures. The findings indicated that compared with control (CK), MM significantly improved the phytochemical abundances, particularly stilbenoids and diarylheptanoids (4.87%), and ubiquinones (2.66%) in the treatment (T) compost. Besides, significant ARGs reduction was noted, where rpoB2, RbpA, FosB1, vatC, and vatB were removed from T compost. PHIs significantly declined in T compost, where the growth of Xanthomonas citri, Streptococcus pneumoniae, Fusarium graminearum, Vibrio cholerae, and Xanthomonas campestris were inhibited. Multiple variable analyses demonstrated that temperature and pH revealed a significant role in ARGs and PHIs decline. Accordingly, this study considerably recommends MM as a promising compost additive in terms of its antimicrobial potential toward pathogenic microbes and ARGs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective. Chronic stress (CS)-induced abnormal metabolism and other subsequent aspects of abnormality are threatening human health. Little is known regarding whether and how protein post-translational-modifications (PTMs) correlate with abnormal metabolism under CS. The aim of this study was to address this issue and also identify novel key protein PTM. Methods. First, we screened which pan-PTM had significant change between control and CS female mice and whether clinical CS females had similar pan-PTM change. Second, we performed quantitative PTM-omics and metabolomics to verify the correlation between abnormal protein PTMs and atypical metabolism. Third, we performed quantitative phospho-omics to identify the key PTM-regulating enzyme and investigate the interaction between PTM protein and PTM-regulating enzyme. Fourth, we attempted to rectify the abnormal metabolism by correcting the activity of the PTM-regulating enzyme. Finally, we examined whether the selected key protein was also correlated with stress scores and atypical metabolism in clinical women. Results. We initially found that multiple tissues of CS female mice have downregulated pan-crotonylation, and verified that the plasma of clinical CS females also had downregulated pan-crotonylation. Then we determined that ATP5O-K51 crotonylation decreased the most and also caused gross ATP5O decrement, whereas the plasma of CS mice had downregulated phospholipids. Next, downregulating ATP5O crotonylation partially recapitulated the downregulated phospholipid metabolism in CS mice. Next, we verified that HDAC2-S424 phosphorylation determined its decrotonylation activity on ATP5O-K51. Furthermore, correcting HDAC2 hyper-phosphorylation recovered the gross ATP5O level and partially rescued the downregulated phospholipid metabolism in CS mice. Finally, the ATP5O level was also significantly lower and correlated with high stress scores and downregulated phospholipid metabolism in clinical female plasma. Conclusion. This study discovered a novel PTM mechanism involving two distinct types of PTM in CS and provided a novel reference for the clinical precautions and treatments of CS., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Liang-Jian Chen et al.)

Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC 0-24 ) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose ( P =  0.045), peak concentration ( P =  0.020), and sdrC ( P =  0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose ( P =  0.009), cardiovascular disease ( P =  0.043), sequence type 5 (ST5; P = 0.017), tst ( P =  0.050), and sec gene ( P =  0.044) associated with bacteriological failure. Although the AUC 0-24 /MIC was higher in the groups with bacterial eradication, the difference was not statistically significant ( P =  0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P =  0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB , tst , and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB , tst , and sec .

Herbivore-induced plant volatiles (HIPVs) have been associated with plant-plant-herbivorous-natural enemies communication and an enhanced response to the subsequent attack. Spodoptera litura is a serious cosmopolitan pest that has developed a high level of resistance to many insecticides. However, the underlying molecular and biochemical mechanism by which HIPV priming reduces S. litura larval sensitivity to insecticides remains largely unknown. This study was conducted to explore the potential of volatile from undamaged, or artificially damaged, or S. litura-damaged tomato plants on the susceptibility of S. litura to the insecticides beta-cypermethrin indoxacarb and chlorpyrifos. We found that larvae exposed to volatile from S. litura-damaged or artificially damaged tomato plants were significantly less susceptible to the three insecticides than those exposed to volatile from undamaged tomato plants. Elevated activities of detoxifying enzymes [cytochrome P450 monooxygenases (P450s), glutathione S-transferases (GSTs), and esterases (ESTs)], were expressed in S. litura larvae exposed to volatile from S. litura-damaged tomato plants than those exposed to volatile from undamaged tomato plants. Similarly, seven detoxification-related genes [GSTs (SlGSTe1, SlGSTo1, and SlGSTe3) and P450s (CYP6B48, CYP9A40, CYP321A7, and CYP321B1)] in the midgut and fat body of larvae were up-regulated under exposure to volatile from S. litura-damaged tomato plants. Increased volatile organic compounds emissions were detected in the headspace of tomato plants damaged by S. litura compared to the undamaged plants. Collectively, these findings suggest that HIPVs can considerably reduce caterpillar susceptibility to insecticides, possibly through induction-enhanced detoxification mechanisms, and provide valuable information for implementing an effective integrated pest management strategy., (Copyright © 2022. Published by Elsevier Inc.)

Aims: To investigate the effect of erythropoietin (EPO) on the differentiation of neural stem cells (NSCs)/neural progenitors (NPs) in the treatment of hypoxic-ischemic injury and its potential mechanisms., Methods: Fetal NSCs/NPs were treated with EPO after oxygen and glucose deprivation/reoxygenation (OGD/R). Cell viability, proliferation, and differentiation of NSCs/NPs were detected by CellTiter-Glo, Edu assay, flow cytometry, and quantitative real-time PCR (qPCR). Immunofluorescence staining, co-immunoprecipitation (Co-IP), and western blotting were used to test the existence of EPO receptor/β common receptor (EPOR/βCR) heterodimer on NSCs/NPs and the possible pathway., Results: EPO treatment at different time points increased cell viability without affecting proliferation. EPO treatment immediately after OGD/R promoted oligodendrocyte and astrocyte differentiation, while decreasing neuronal differentiation of NSCs/NPs. EPOR/βCR heterodimer existed on the cell surface of the fetal cortical NSCs/NPs, EPO treatment significantly increased the mRNA expression of βCR and elevated the correlation between EPOR and βCR levels. In addition, mass spectrometry analysis identified Syne-1 as a downstream signaling molecule of the EPOR/βCR heterodimer. Immunofluorescence staining and western blotting indicated that the βCR/Syne-1/H3K9me3 pathway was possibly involved in the differentiation of fetal neural stem cells into the glial cell effect of EPO., Conclusion: EPO treatment immediately after OGD/R could not facilitate fetal NSCs/NPs neurogenesis but promoted the formation of the EPOR/βCR heterodimer on fetal NSCs/NPs, which mediates its function in glial differentiation., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Purpose: To explore the efficacy of uterine artery embolization (UAE) in the treatment of uterine fibroid and share the experience of transvaginal fibroid expulsion (FE) after UAE., Methods: We retrospectively analyzed the changes in uterine and fibroid volume in 152 patients with symptomatic uterine fibroid after UAE at Fujian Provincial Hospital and Fujian Longyan People Hospital from March 2014 to March 2020. After a 12-month follow-up, the improvement in postoperative clinical symptoms and the incidence of complications were evaluated. We also shared the clinical features and imaging findings of four patients with FE after UAE., Results: All 152 patients successfully underwent UAE. After a 12-month follow-up, the postoperative volumes of the uterus and fibroid at 3, 6, and 12 months were significantly reduced or disappeared compared to those before surgery (P < 0.05). Clinical symptoms, such as menorrhagia, dysmenorrhea, prolonged menstrual period, anemia, increased leucorrhea, pelvic discomfort, and urinary tract compression, were significantly improved after UAE. Among the 152 patients, the incidences of postoperative fever, nausea, vomiting, lower abdominal pain, and increased vaginal secretion were 7.89%, 7.24%, 3.95%, 19.08%, and 4.61%, respectively. Additionally, there were six cases of FE, with an incidence of 3.95%. Three cases of fibroid specimens and pathological images of fibroid biopsy, which were expelled through the vagina, were also provided., Conclusion: UAE is a satisfactory alternative surgical method for symptomatic uterine fibroid with definitive efficacy and high safety. However, it is necessary to guard against the occurrence of postoperative complications such as FE., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Additives are considered a promising approach to accelerate the composting process and alleviate the dissemination of pollutants to the environment. However, nearly all previous articles have focused on the impact of additive amounts on the reduction of HMs, which may not fully represent the main factor shaping HMs bioavailability status during composting. Simultaneously, previous reviews only explored the impacts, speciation, and toxicity mechanism of HMs during composting. Hence, a global-scale meta-analysis was conducted to investigate the response patterns of HMs bioavailability and compost parameters to different additives, composting duration, and composting factors (additive types, feedstock, bulking agents, and composting methods) by measuring the weighted mean values of the response ratio "[ln (RR)]" and size effect (%). The results revealed that additives significantly lessened HMs bioavailability by ≥ 40% in the final compost products than controls. The bioavailability decline rates were -40%, -60%, -57%, -55%, -42%, and -44% for Zn, Pb, Ni, Cu, Cr, and Cd. Simultaneously, additives significantly improved the total nitrogen (TN) (+16%), pH (+5%), and temperature (+5%), and decreased total organic carbon (TOC) (-17%), moisture content (MC) (-18%), and C/N ratio (-19%). Furthermore, we found that the prolongation of composting time significantly promoted the effect of additives on declining HMs bioavailability (p < 0.05). Nevertheless, increasing additive amounts revealed an insignificant impact on decreasing the HMs bioavailability (p > 0.05). Eventually, using zeolite as an additive, chicken manure as feedstock, sawdust as a bulking agent, and a reactor as composting method had the most significant reduction effect on HMs bioavailability (p < 0.05). The findings of this meta-analysis may contribute to the selection, modification, and application of additives and composting factors to manage the level of bioavailable HMs in the compost products., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Many species of devastating insect pests have acquired a high degree of resistance to insecticides in the field during the last few decades. Spodoptera exigua, for example, is the most damaging pests of economic crops with a worldwide spread. In a present study, the comparative growth, reproduction, and detoxification enzyme activity were evaluated along with exposure to three insecticides at low lethal doses of lufenuron, indoxacarb, and spinosad as compared to the control. Results indicate that the larval developmental time was significantly extended on lufenuron (21.5 ± 29 days) followed by indoxacarb (20.28 ± 0.24 days) and spinosad (19.74 ± 0.23 days) as compared to that on the control (18.13 ± 0.13 days). Similarly, the lowest number of eggs of S. exigua females were recorded on lufenuron (328.75 ± 50.81 eggs) followed by spinosad (367 ± 36.4 eggs) and indoxacarb (411.58 ± 42.38 eggs) as compared to that on the control (560.2 ± 13.47). Interestingly, the lowest intrinsic rate of increase (r) (0.121 ± 0.009) and highest mean generation time (T) (36.2 ± 0.35 days) were observed when larvae were treated to a low lethal concentration (LC 20 ) of lufenuron as compared to that of indoxacarb, spinosad, and control. In addition, considerably lower activity of all detoxification enzymes in larvae was recorded on lufenuron after control as compared to that on indoxacarb and spinosad. Our study serves as a reference and basis for the toxicity and low lethal evaluation of lufenuron, indoxacarb, and spinosad on life table parameters and enzymatic properties in S. exigua, which may contribute to identifying targets for effective control of S. exigua., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As a result of the COVID-19 global pandemic, many intellectual property (IP) owners have signed on to the "Open COVID Pledge", an agreement that makes corporate and university IP available free of charge for the purpose of facilitating the development of technologies that will end the pandemic and minimize the impact of disease. Joining this pledge is relatively straightforward for already-disclosed IPs. However, few, if any, has considered how to encourage owners of "non-disclosed patent applications" and "trade secrets" to sign on to this meaningful pledge. In other words, so far there is no proposal to extend the Open COVID Pledge for confidential pending patents and trade secrets., Methods: We propose an innovative and flexible framework to cover both non-disclosed patent applications and trade secrets to mobilize inventors to participate in the Open COVID Pledge., Results: By focusing on immediate publication of the patent-applying technology and extending provisional right to such applications which is subject to the Open Pledge during this pandemic, our recommendations are workable for inventors who would like to pledge their non-disclosed technologies for the detection, prevention and treatment of the COVID-19, in the meantime preserving their IP rights for the post-pledge period., Conclusion: This paper offers a way forward to guide pledgers and implementers who are interested in supporting the effort by addressing some of the issues associated with the free sharing of non-disclosed patent applications and trade secrets in the fight against COVID-19., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Introduction and Importance: In most diverticulitis of Meckel's Diverticulum (MD), perforation, obstruction and hemorrhage causing acute abdomen are seen, however, multiple inflammatory polyps(IPs) are rare, which are seen in our case., Case Presentation: We present the case of 28-year-old female, who was admitted in the clinic for intermittent abdominal pain for 5 years. Histopathology suggested MD chronic diverticulitis and multiple inflammatory polyps., Clinical Discussion: Our patient presented was diagnosed preoperatively with suspected MD, and an laparoscopy was indicated. Intraoperatively, a huge MD with multiple IPs was found and treated by surgical excision and the specimens were sent for histopathological analysis. Histopathology revealed MD's diverticulitis with IPs containing ectopic gastric mucosa. The patient had successful recovery., Conclusion: Meckel's diverticulitis is a rare cause of multiple IPs. This case can remind physicians that IPs caused by Meckel's diverticulum should be considered in differential diagnosis of adults presenting with the isolated symptom of chronic abdominal pain., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gamithromycin is a long-acting azalide antibiotic that has been developed recently for the treatment of swine respiratory diseases. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff, and optimum dosing regimen of gamithromycin were evaluated in piglets against Streptococcus suis in China, including a subset with capsular serotype 2. Short post-antibiotic effects (PAEs) (0.5-2.6 h) and PA-SMEs (2.4-7.7 h) were observed for gamithromycin against S. suis . The serum matrix dramatically facilitated the intracellular uptake of gamithromycin by S. suis strains, thus contributing to the potentiation effect of serum on their susceptibilities, with a Mueller-Hinton broth (MHB)/serum minimum inhibitory concentration (MIC) ratio of 28.86 for S. suis . Dose-response relationship demonstrated the area under the concentration (AUC)/MIC ratio to be the predictive PK/PD index closely linked to activity ( R 2 > 0.93). For S. suis infections, the net stasis, 1-log 10 , and 2-log 10 kill effects were achieved at serum AUC 24h /MIC targets of 17.9, 49.1, and 166 h, respectively. At the current clinical dose of 6.0 mg/kg, gamithromycin PK/PD cutoff value was determined to be 8 mg/L. A PK/PD-based dose assessment demonstrated that the optimum dose regimen of gamithromycin to achieve effective treatments for the observed wild-type MIC distribution of S. suis in China with a probability of target attainment (PTA) ≥ 90% was 2.53 mg/kg in this study. These results will aid in the development of clinical dose-optimization studies and the establishment of clinical breakpoints for gamithromycin in the treatment of swine respiratory infections due to S. suis ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Liu, Chen, Yao, Liao, Liu, Sun and Zhou.)

Microtubule-severing proteins (MTSPs), are a family of proteins which use adenosine triphosphate to sever microtubules. MTSPs have been shown to play an important role in multiple microtubule-involved cellular processes. One member of this family, fidgetin ( FIGN ), is also involved in male fertility; however, no studies have explored its roles in female fertility. In this study, we found mouse fidgetin is rich within oocyte zona pellucida (ZP) and is the only MTSP member to do so. Fidgetin also appears to interact with all three ZP proteins. These findings prompted us to propose that fidgetin might prevent polyspermy. Results from in vitro maturation oocytes analysis showed that fidgetin knockdown did cause polyspermy. We then deleted all three fidgetin isoforms with CRISPR/Cas9 technologies; however, female mice remained healthy and with normal fertility. Of all mouse MTSPs, only the mRNA level of fidgetin-like 1 ( FIGNL1 ) significantly increased. Therefore, we assert that fidgetin-like 1 compensates fidgetin's roles in fidgetin knockout female mice.

Background: An impeccable female meiotic prophase is critical for producing a high-quality oocyte and, ultimately, a healthy newborn. SYCP3 is a key component of the synaptonemal complex regulating meiotic homologous recombination. However, what regulates SYCP3 stability is unknown., Methods: Fertility assays, follicle counting, meiotic prophase stage (leptotene, zygotene, pachytene and diplotene) analysis and live imaging were employed to examine how FBXW24 knockout (KO) affect female fertility, follicle reserve, oocyte quality, meiotic prophase progression of female germ cells, and meiosis of oocytes. Western blot and immunostaining were used to examined the levels & signals (intensity, foci) of SYCP3 and multiple key DSB indicators & repair proteins (γH2AX, RPA2, p-CHK2, RAD51, MLH1, HORMAD1, TRIP13) after FBXW24 KO. Co-IP and immuno-EM were used to examined the interaction between FBXW24 and SYCP3; Mass spec was used to characterize the ubiquitination sites in SYCP3; In vivo & in vitro ubiquitination assays were utilized to determine the key sites in SYCP3 & FBXW24 for ubiquitination., Results: Fbxw24-knockout (KO) female mice were infertile due to massive oocyte death upon meiosis entry. Fbxw24-KO oocytes were defective due to elevated DNA double-strand breaks (DSBs) and inseparable homologous chromosomes. Fbxw24-KO germ cells showed increased SYCP3 levels, delayed prophase progression, increased DSBs, and decreased crossover foci. Next, we found that FBXW24 directly binds and ubiquitinates SYCP3 to regulate its stability. In addition, several key residues important for SYCP3 ubiquitination and FBXW24 ubiquitinating activity were characterized., Conclusions: We proposed that FBXW24 regulates the timely degradation of SYCP3 to ensure normal crossover and DSB repair during pachytene. FBXW24-KO delayed SYCP3 degradation and DSB repair from pachytene until metaphase II (MII), ultimately causing failure in oocyte maturation, oocyte death, and infertility., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Bruck syndrome (BS) is a rare autosomal recessive inherited osteogenesis imperfecta disease characterized by increased bone fragility and joint contracture. The pathogenic gene of type I BS is FKBPl0 , whereas that of type II BS is PLOD2 . No significant difference has been found in the clinical phenotype between the two types of BS. In this study, we performed genetic analysis of a BS pedigree caused by PLOD2 variant and studied the corresponding cellular function., Methods: Serum biochemistry, parathyroid hormone (PTH), 25-hydroxyvitamin D [25-(OH) D], osteocalcin, and 24-h urinary calcium levels of a family member with BS was assessed. The genes of the proband were analyzed by second-generation sequencing and exon capture techniques. Sanger sequencing was also performed for the suspected responsible variant of the family member. Wild- and variant-type lentivirus plasmids were constructed by gene cloning and transfected into HEK293T cells. Cell function was verified by real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence detection., Results: In this pedigree, the proband was found to have a homozygous variant c.1856G > A (p.Arg619His) in exon 17 of PLOD2 (NM&#95;182943.3). His consanguineous parents and sisters were p.Arg619His heterozygous carriers. The mRNA expression of PLOD2 in the constructed p.Arg619His variant cells was significantly upregulated, while the expression of PLOD2 and collagen I protein in the cell lysate was significantly downregulated. Immunofluorescence revealed that the wild-type PLOD2 was mainly located in the cytoplasm, and the expression of the PLOD2 protein after c.1856G > A variant was significantly downregulated, with almost no expression, aligning with the western blot results. The serum sodium, potassium, calcium, phosphorus, magnesium, alkaline phosphatase, PTH, 25-(OH) D, osteocalcin, and 24 h urinary calcium levels of the proband, his parents, and sisters were normal., Conclusion: Through gene and cell function analyses, PLOD2 Arg619His missense variant was preliminarily confirmed to cause BS by reducing protein expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Ruan, Hu, Gan, Lin, Fang, Liao, Tang, He and Luo.)

The thiophene [2,3-d]pyrimidine structure-like small molecules were discovered from structure-based virtual screening of 1 billion compounds. Base on enzyme activity assay results, a SHP2-specific molecule inhibitor Comp#2 with IC 50 of 1.174 μM, 85-fold more selective for SHP2 than the highly related SHP1 (IC 50  > 100 μM). The compound can effectively inhibit SHP2-mediated cell signaling and cancer cell proliferation, including cervix cancer, human pancreatic cancer, large cell lung cancer, and mouse glioma cell. Moreover, the in vivo assay indicated that Comp#2 could inhibit cervix cancer tumors growth in BABL/c mice. This work has shown the specific SHP2 inhibitor can inhibit glioblastoma growth in vivo., (Copyright © 2022. Published by Elsevier Inc.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human pathogen causing coronavirus disease 2019 (COVID-19). Rare cases of COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) after the ChAdOx1 nCoV-19 (AstraZeneca) vaccination have been reported. We performed a test for anti-heparin/ platelet factor 4 (PF4) antibodies and functional assay using flow cytometry., Method: A healthy woman presented to the emergency department with chest pain, headache, and abdominal pain after the first vaccination with AstraZeneca. Polymerase chain reaction (PCR) test for SARS-CoV-2 was negative. Chest computed tomography (CT) showed pulmonary artery embolism and brain magnetic resonance imaging (MRI) revealed cerebral sinus-venous thrombosis. Abdominal CT demonstrated the thrombosis with occlusion in her right hepatic vein. Laboratory studies revealed decreased platelet counts, and high D-dimer level. Finally, laboratory results indicated high PF4 antibodies level high and a positive platelet activation test, confirming the diagnosis of VITT., Results: Treatments including intravenous immunoglobulin, methylprednisolone and direct oral anticoagulant were administered. The results of a follow-up platelet count and D-dimer were normal. In addition, the titer of PF4 antibodies (optical density: 0.425; normal ≤ 0.4, enzyme-linked immunosorbent assay) fell. After a 3-month follow-up, her general condition improved gradually., Conclusions: The use of COVID-19 vaccines to prevent SARS-CoV-2 infections and complications is considered the most practicable policy for controlling the COVID-19 pandemic and is being forcefully pursued in the global area. Appropriate laboratory diagnosis facilitates the accurate and rapid diagnosis. Early recognizing and appropriate strategies for VITT are required and can provide these patients with more favorable patient outcomes. This report also elected to make comparisons of clinical manifestation, laboratory diagnosis, and management in patients with VITT., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Follow-up guidelines for serrated polyps (SPs) are mainly based on factors such as histology and size with limited evidence. The underlying genomic mechanism of SPs in relation to recurrence risks is utterly unknown., Methods: We applied targeted next-generation sequencing (NGS) approach on two groups of SPs [polyp-relapsed SPs (PRSPs) vs. polyp-free SPs (PFSPs)] based on the surveillance outcomes to compare differences of DNA variants in 71 colorectal cancer-associated genes. A multicenter validation cohort was established longitudinally from 2016 to 2019 to confirm the relevant results., Results: Among the 96 NGS samples, at least one mutant after filtration was detected in 90 samples (94%). Molecular profiling presented BRAF , KRAS , and APC as top 3 mutated genes. FBXW7 , MSH2 , and ERBB2 might be recurrence-relevant, while DMD , BRCA1 , and BRCA2 might be negatively correlated with recurrence. Notably, ERBB2 mutants (R678Q and V842I) (n = 5) had higher risks of polyp recurrence than the wild types (n = 85), with a median polyp-free interval of 15 months compared to 26 months [P < 0.001; hazard ratio (HR) = 4.9; 95% confidence interval (CI) = 1.9-12.8]. Furthermore, a multicenter cohort composed by 321 SPs verified that ERBB2 -mutated SPs had increased risks of polyp recurrence (P < 0.001; HR = 3.7; 95% CI = 2.3-6.0) and advanced neoplastic lesion (ANL) recurrence (P < 0.001; HR = 10.0; 95% CI = 2.7-36.9) compared with wild-type SPs, respectively., Conclusions: Our results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Zhang, Chen, Zhou, Tang, Wang, Chen, Chen and Li.)

Environmental DNA (eDNA) integrated with metabarcoding is a promising and powerful tool for species composition and biodiversity assessment in aquatic ecosystems and is increasingly applied to evaluate fish diversity. To date, however, no standardized eDNA-based protocol has been established to monitor fish diversity. In this study, we investigated and compared two filtration methods and three DNA extraction methods using three filtration water volumes to determine a suitable approach for eDNA-based fish diversity monitoring in the Pearl River Estuary (PRE), a highly anthropogenically disturbed estuarine ecosystem. Compared to filtration-based precipitation, direct filtration was a more suitable method for eDNA metabarcoding in the PRE. The combined use of DNeasy Blood and Tissue Kit (BT) and traditional phenol/chloroform (PC) extraction produced higher DNA yields, amplicon sequence variants (ASVs), and Shannon diversity indices, and generated more homogeneous and consistent community composition among replicates. Compared to the other combined protocols, the PC and BT methods obtained better species detection, higher fish diversity, and greater consistency for the filtration water volumes of 1 000 and 2 000 mL, respectively. All eDNA metabarcoding protocols were more sensitive than bottom trawling in the PRE fish surveys and combining two techniques yielded greater taxonomic diversity. Furthermore, combining traditional methods with eDNA analysis enhanced accuracy. These results indicate that methodological decisions related to eDNA metabarcoding should be made with caution for fish community monitoring in estuarine ecosystems.

Background: Bronchial artery aneurysm (BAA) is a rare disease. Rupture of BAA can lead to life-threatening hemoptysis, and once diagnosed, treatment is needed regardless of symptoms. Transcatheter artery embolization is the first choice of treatment because it is minimally invasive and effective. This study aimed to retrospectively compare the embolization treatment of a case of true BAA and that of a pseudobranchial aneurysm and explore the choice of embolization method for BAA with short neck or no neck., Materials and Methods: Embolization treatment and imaging characteristics of one case of true BAA and one case of pseudobronchial aneurysm admitted to our hospital were analyzed retrospectively. Embolization methods and therapeutic effects of two cases of BAAs were compared., Results: Case 1 was that of an intact true BAA inside the mediastinum located at the opening of the bronchial artery. The distal end of the aneurysm was embolized, and tumor cavity was occluded. No recurrence of BAA was found after the operation. Case 2 was that of a ruptured and hemorrhagic pseudobronchial aneurysm of the mediastinum. Coil embolization combined with covered stent graft exclusion of the thoracic aorta were performed, and the left bronchial artery and BAA were almost occluded. Nine months postoperatively, the mediastinal hematoma was almost completely absorbed., Conclusion: Endovascular embolization has become the most commonly used for the treatment of BAA. Different methods should be selected according to the location and nature of the aneurysm., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Ji, Zhang, Tang, Wang, Ruan, Zhou, Wu, Cai, Zhang, Meng, Luo and Fang.)

Background: With long-term pharmacotherapy, Parkinson's disease (PD) is expectedly to incur a significant healthcare burden. However, drug utilization and costing study is limited, so is the cost composition and its impact on resource allocation. This study took a healthcare provider's perspective to quantify medical and drug expenses and the utilization of drugs for managing PD and its complications., Methods: Medical resources use and associated cost of outpatient visits and inpatient admission episodes for PD patients were extracted from electronic medical records at a tertiary hospital in China from 1 January 2016 to 15 August 2018. Total and average direct medical (costs of outpatient visits and inpatient admission episodes) and drug costs were calculated during the study period and each calendar year. Drug cost was quantified by defined daily dose cost (DDDc) and levodopa equivalent dose cost (LEDc) per outpatient visit or inpatient admission episode for PD in Chinese yuan (¥), stratified by medication categories, and presented in descriptive statistics., Results: Overall, 18,158 outpatient visits and 366 inpatient admissions were incurred by 2,640 outpatients and 330 inpatients, with a median age of 71.0 and 73.5 years, respectively. Drug cost accounted for 97.82% and 23.33% of outpatient and inpatient medical expenditure. The average cost of drugs for managing PD accounted for 60.48% (¥952.50) and 2.70% (¥564.90) of cost per outpatient visit and inpatient episode, while drugs for managing PD complications was 11.38% and 0.70%, respectively. The highest DDDc and LEDc of drugs for managing PD per outpatient visit or inpatient episode were incurred by pramipexole (¥56.90-72.70 and ¥227.48-290.67) and entacapone (¥37.70-45.70 and ¥228.64-276.77). The DDDc and LEDc of pramipexole is more than 10 times that of levodopa/benserazide (DDDc: ¥4.90-5.70; LEDc: ¥10.14-11.98) and carbidopa/levodopa (DDDc: ¥4.00-5.00; LEDc: ¥11.02-13.95)., Conclusions: The outpatient direct medical cost for patients with PD was predominantly attributed to drug cost for managing PD, but drug cost weighed less of the inpatient cost. After adjusting the dose and number of patients, drugs with indirect dopamine effects had an excessively higher cost than dopamine precursors. Their long-term cost-effectiveness in real-world settings warrants further studies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1014/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Danofloxacin is a synthetic fluoroquinolone with broad-spectrum activity developed for use in veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff values and the optimum doses of danofloxacin against P. multocida and H. parasuis in piglets. Single dose serum pharmacokinetics was determined in piglets after intravenous and intramuscular administration of 2.5 mg/kg. Danofloxacin was well absorbed and fully bioavailable (95.2%) after intramuscular administration of 2.5 mg/kg. The epidemiological cutoff (ECOFF) values of danofloxacin from 931 P. multocida isolates and 263 H. parasuis isolates were 0.03 and 4 mg/L, respectively. Danofloxacin MICs determined in porcine serum were markedly lower than those measured in artificial broth, with a broth/serum ratio of 4.33 for H. parasuis . Compared to P. multocida , danofloxacin exhibited significantly longer post-antibiotic effects (3.18-6.60 h) and post-antibiotic sub-MIC effects (7.02-9.94 h) against H. parasuis . The mean area under the concentration-time curve/MIC (AUC 24h /MIC) targets of danofloxacin in serum associated with the static and bactericidal effects were 32 and 49.8, respectively, for P. multocida , whereas they were 14.6 and 37.8, respectively, for H. parasuis . Danofloxacin AUC 24h /MIC targets for the same endpoints for P. multocida were higher than those for H. parasuis . At the current dose of 2.5 mg/kg, the PK/PD cutoff (CO PD ) values of danofloxacin against P. multocida and H. parasuis were calculated to be 0.125 and 0.5 mg/L, respectively, based on Monte Carlo simulations. The predicted optimum doses of danofloxacin for a probability of target attainment (PTA) of > 90% to cover the overall MIC population distributions of P. multocida and H. parasuis in this study were 2.38 and 13.36 mg/kg, respectively. These PK/PD-based results have potential relevance for the clinical dose optimization and evaluation of susceptibility breakpoints for danofloxacin in the treatment of swine respiratory tract infections involving these pathogens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Sun, Wang, Li, Niu, Li, Feng, Sun, Liu and Liao.)

Background: Tolerance is more easily induced in liver transplant models than in other organs; CD8 + CD45RC low regulatory T cells (Tregs) have been shown to induce tolerance in heart allografts. Whether CD8 + CD45RC low Tregs could induce tolerance in a liver transplant model and how dendritic cells (DCs) mediate the CD8 + CD45RC low Tregs effect remains to be investigated., Methods: A rat liver transplantation model was established and used to test tolerance and acute rejection compared to control groups. Liver function and histopathological changes of allograft were examined by enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&E) staining, respectively. The distribution and proportion of CD8 + CD45RC low Tregs and plasmacytoid dendritic cells (pDCs) in the allografts and spleen were determined using flow cytometry. Cytokine secretion levels were determined using ELISA and real-time quantitative PCR (qRT-PCR)., Results: The rat liver transplantation model was well established, with a success rate of 93.3% (28/30). The mean survival time of the tolerant and acute-rejection rats were 156 and 14 days, respectively. The proportions of CD8 + CD45RC low Tegs were higher in the allografts of tolerant rats than in those of acute-rejection rats (33.1 ± 4.3 and 12.4 ± 4.6, respectively; P = 0.04). Significant accumulation of pDCs was observed in tolerant liver graft rats compared to that in acute-rejection rats (1.46 ± 0.23 and 0.80 ± 0.20, respectively; P = 0.02). Importantly, CD8 + CD45RC low Tregs were positively associated with the frequency of pDCs (P = 0.001, r 2  = 0.775). The protein and mRNA expression of IL-10 and TGF-β in the allograft group were increased, possibly being responsible for tolerance induction., Conclusion: CD8 + CD45RC low T cells interact with pDCs through the induction of IL-10 and TGF-β expression and are responsible for inducing immune tolerance in rat liver transplantation., (Copyright © 2021. Published by Elsevier B.V.)

Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA., (© 2021. The Author(s).)

Little is known about the shift of lymphocytes under the condition of the model for end-stage liver disease score and the follow-up period. Then, we detected the peripheral blood from liver transplant recipients by flow cytometry and compared the results. The model for end-stage liver disease score affected the percentages of T-cell subsets and B cells during the short-term follow-up period, but failed to influence the lymphocyte subsets during the long-term follow-up period. In contrast, the follow-up period not only affected the absolute counts of T-cell subsets and natural killer (NK) cells in patients with the low model for end-stage liver disease scores, but also influenced the percentages and absolute counts of T-cell subsets in patients with the high model for end-stage liver disease scores. In the two-way ANOVA, we further revealed that the model for end-stage liver disease score was associated with the percentages of T cells and CD4 + T cells and the absolute numbers of T-cell subsets and B cells, while the follow-up period was associated with the percentages of T-cell subsets and the absolute numbers of lymphocyte subsets. Therefore, patients with either the low model for end-stage liver disease scores or the long-term follow-up period are in a relatively activated immune condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pan, Cao, Li, Jia, Wang, He and Zhu.)

Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the SERPINA1 gene, which culminates in the accumulation of misfolded alpha-1 antitrypsin (ZAAT) within the endoplasmic reticulum (ER) of hepatocytes. AATD is associated with liver disease resulting from hepatocyte injury due to ZAAT-mediated toxic gain-of-function and ER stress. There is evidence of mitochondrial damage in AATD-mediated liver disease; however, the mechanism by which hepatocyte retention of aggregated ZAAT leads to mitochondrial injury is unknown. Previous studies have shown that ER stress is associated with both high concentrations of fatty acids and mitochondrial dysfunction in hepatocytes. Using a human AAT transgenic mouse model and hepatocyte cell lines, we show abnormal mitochondrial morphology and function, and dysregulated lipid metabolism, which are associated with hepatic expression and accumulation of ZAAT. We also describe a novel mechanism of ZAAT-mediated mitochondrial dysfunction. We provide evidence that misfolded ZAAT translocates to the mitochondria for degradation. Furthermore, inhibition of ZAAT expression restores the mitochondrial function in ZAAT-expressing hepatocytes. Altogether, our results show that ZAAT aggregation in hepatocytes leads to mitochondrial dysfunction. Our findings suggest a plausible model for AATD liver injury and the possibility of mechanism-based therapeutic interventions for AATD liver disease.

Purpose: To retrospectively compare the efficacy and safety of prostatic artery embolization (PAE) combined with transurethral resection of the prostate (TURP) and simple TURP in treating large (> 100 mL) benign prostatic hyperplasia (BPH)., Methods: We retrospectively analyzed the clinical data of 13 and 17 patients with large BPH who underwent TURP and PAE + TURP, respectively, from January 2016 to January 2020. The changes in various indices before and after surgery were compared between the two groups., Results: In the PAE + TURP group, the operation time (OT), intraoperative blood loss (BL), postoperative bladder flushing time (PBFT), and postoperative catheter retention time (PCRT) were lower, and the speed of the excised lesion (SEL) was higher than that in the TURP group (P < 0.05). Following-up for 12 months, the prostatic volume (PV), maximum urinary flow rate (Qmax), postvoid residual volume (PVR), International Prostate Symptom Score (IPSS), quality of life (QoL) score, total prostate-specific antigen (T-PSA), and free prostate-specific antigen (F-PSA) in each group improved as compared to before the surgery (P < 0.05), and the above improved indicators, IPSS ratio, and obstructive symptoms in the PAE + TURP group were higher than those in the TURP group (P < 0.05). The incidence of postoperative complications in the PAE + TURP group was lower than that in the TURP group. We obtained the pathological picture of a prostate biopsy after PAE for the first time., Conclusion: Compared to TURP alone, PAE + TURP should be promoted, because of its greater efficacy and safety in treating large BPH and fewer post-surgical complications., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recurrence of nasopharyngeal carcinoma (NPC) after chemoradiotherapy is common, but submucosal recurrence of NPC is rare. The final pathological results determine the optimal therapeutic schedule for treatment of NPC recurrence, but tissue retrieval from submucosal lesions is usually difficult. The present study aimed to assess the safety and efficacy of a novel approach of endonasopharyngeal ultrasound-guided transnasopharyngeal needle aspiration (ENUS-TNNA) for submucosal neoplasms in patients with suspected NPC recurrence., Methods: Between March 2017 and June 2021, 11 post-chemoradiotherapy patients with suspected magnetic resonance imaging (MRI) findings of submucosal recurrence of NPC underwent ENUS-TNNA. The safety and effectiveness of using ENUS-TNNA to sample submucosal neoplasms were evaluated., Results: Needle aspiration biopsies were performed without any incidences in all cases. Out of the 11 patients, nine were diagnosed with submucosal recurrence of NPC via histopathological or cytological evaluations. Of the two puncture-negative cases, one patient had atypical imaging findings and clinical manifestations and was therefore followed-up using MRI. After follow-up for 3 years, this patient was still considered to be cancer-free due to the shrinking diameters of the submucosal lesions. For the other puncture-negative patient, submucosal biopsy samples were obtained using a surgical method. Pathological examination of these biopsies revealed that an angiosarcoma had developed after radiotherapy. There were no severe complications that occurred during the ENUS-TNNA procedure., Conclusion: ENUS-TNNA is a safe, effective, and minimally invasive approach to obtain tissue samples from the submucosal region of the nasopharynx for patients with suspected NPC recurrence., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cell division cycle 25B (CDC25B) was responsible for regulating the various stages of cell division in the cell cycle. R492L was one of the common types of CDC25B mutants. Researches showed that compared to CDC25B WT , CDC25B R492L mutant had a ∼100-fold reduction in the rate constant for forming phosphatase intermediate (k 2 ). However, the molecular basis of how the CDC25B R492L mutant influenced the process of binding between CDC25B and CDK2/CyclinA was not yet known. Therefore, the optimizations of three-dimensional structure of the CDC25B WT -CDK2/CyclinA system and the CDC25B R492L -CDK2/CyclinA system were constructed by ZDOCK and RDOCK, and five methods were employed to verify the reasonability of the docking structure. Then the molecular dynamics simulations on the two systems were performed to explore the reason why CDC25B R492L mutant caused the weak interactions between CDC25B R492L and CDK2/CyclinA, respectively. The remote docking site (Arg488-Tyr497) and the second active site (Lys538-Arg544) of CDC25B were observed to have high fluctuations in the CDC25B R492L -CDK2/CyclinA system with post-analysis, where the high fluctuation of these two regions resulted in weak interactions between CD25B and CDK2. In addition, Asp38-Glu42 and Asp206-Asp210 of CDK2 showed the slightly descending fluctuation, and CDK2 revealed an enhanced the self-interaction, which made CDK2 keep a relatively stable state in the CDC25B R492L -CDK2/CyclinA system. Finally, Leu492 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25B R492L and CDK2 in the CDC25B R492L -CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately offered a helpful understanding of the weak interactions between CDC25B R492L and CDK2., (Copyright © 2021. Published by Elsevier Inc.)

Granzyme B-producing B cells have been reportedly reported to be an important regulatory B cell subset in the pathogenesis of many diseases. However, its role in liver transplant recipients with acute rejection has never been well elucidated. Seventeen liver transplant recipients with acute rejection and 25 controls with stable liver function were enrolled in this study to determine the function of granzyme B-producing B cells via flow cytometry. Liver transplant recipients with acute rejection had higher expression of granzyme B in CD19 + B cells when compared with controls. Following rejection, the granzyme B production was even elevated although comparison failed to reach significance. The percentages of CD27 + granzyme B + CD19 + B cells and CD138 + granzyme B + CD19 + B cells were lower than those of CD27 - granzyme B + CD19 + B cells and CD138 - granzyme B + CD19 + B cells in patients with acute rejection, respectively. While the production of CD27 and CD138 was not different between liver transplant recipients with and without acute rejection but increased expression of the two surface markers was observed following rejection. Furthermore, the frequency of granzyme B + CD19 + B cells correlated with the level of alanine aminotransferase instead of tacrolimus. CD19 + B cells could produce granzyme B when stimulated with IgG + IgM and CpG in the presence of the supernatant of activated CD4 + CD25 - T cells. In return, granzyme B + CD19 + B cells could suppress the proliferation of CD4 + CD25 - T cells in a granzyme B- and contact-dependent manner. The increased expression of granzyme B in CD19 + B cells from liver transplant recipients with acute rejection might function as a feedback loop for the activation of the CD4 + CD25 - T cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal lung disease characterized by progressive and non-reversible abnormal matrix deposition in lung parenchyma. Myofibroblasts originating mainly from resident fibroblasts via fibroblast-to-myofibroblast transition (FMT) are the dominant collagen-producing cells in pulmonary fibrosis. N 6 -methyladenosine (m 6 A) modification has been implicated in various biological processes. However, the role of m 6 A modification in pulmonary fibrosis remains elusive. In this study, we reveal that m 6 A modification is upregulated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model, FMT-derived myofibroblasts, and IPF patient lung samples. Lowering m 6 A levels through silencing methyltransferase-like 3 (METTL3) inhibits the FMT process in vitro and in vivo. Mechanistically, KCNH6 is involved in the m 6 A-regulated FMT process. m 6 A modification regulates the expression of KCNH6 by modulating its translation in a YTH-domain family 1 (YTHDF1)-dependent manner. Together, our study highlights the critical role of m 6 A modification in pulmonary fibrosis. Manipulation of m 6 A modification through targeting METTL3 may become a promising strategy for the treatment of pulmonary fibrosis., Competing Interests: Declaration interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies have suggested a link between Helicobacter pylori (H. pylori) infection and nonalcoholic fatty liver disease (NAFLD), yet long-term follow-up studies to elucidate this association are lacking. We aimed to identify the relationship between NAFLD and H. pylori in these people., Methods: A total of 2,934 adults between June 2013 and October 2017 were collected; among them, 675 people met the requirements. People were assessed for H. pylori infection diagnosis as detected by the carbon-13 urea breath test; they were also assessed for NAFLD diagnosis by ultrasound., Results: H. pylori infection was present in 206 patients (30.5%), and 469 (69.5%) participants were classified as controls. Participants with H. pylori infection had a higher rate of incident NAFLD than those who were uninfected (37/206; 18% versus 73/469; 15.6%) ( p < 0.001). Compared with the control group, the recovery rate of NAFLD in the H. pylori+ve group was low (6/206, 2.9% versus 33/469, 7.0%) ( p < 0.001). Besides, the incidence of uric acid, postprandial blood glucose, TG, LDL-C, HDL-C, and fasting plasma glucose was significantly different between the two groups ( p < 0.001), but no difference was found in alanine aminotransferase (ALT), liver-total protein, urea nitrogen, and cholesterol ( p > 0.05)., Conclusion: H. pylori infection was a risk factor for NAFLD and affected the occurrence or reversal of NAFLD, indicating that H. pylori infection eradication might play a role in reducing the risk of NAFLD., Competing Interests: The authors have no conflicts of interest related to the manuscript., (Copyright © 2021 Xia-Xia Zhao et al.)

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC 50  = 2.07 μM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Female ovaries degenerate about 20 years earlier than testes leading to reduced primordial follicle reserve and a reduction in oocyte quality. Here we found that bridge integrator 2 (BIN2) is enriched in mouse ovaries and oocytes and that global knockout of this protein improves both female fertility and oocyte quality. Quantitative ovarian proteomics and phosphoproteomics showed that Bin2 knockout led to a decrease in phosphorylated ribosomal protein S6 (p-RPS6), a component of the mammalian target of rapamycin pathway and greatly increased nicotinamide nucleotide transhydrogenase (NNT), the free-radical detoxifier. Mechanistically, we find that phosphorylation of BIN2 at Thr423 and Ser424 leads to its translocation from the membrane to the cytoplasm, subsequent phosphorylation of RPS6 and inhibition of Nnt translation. We synthesized a BIN2-penetrating peptide (BPP) designed to inhibit BIN2 phosphorylation and found that a 3-week BPP treatment improved primordial follicle reserve and oocyte quality in aging and after chemotherapy-induced premature ovarian failure without discernible side effects., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Highly enantioselective formal [3 + 2] cycloaddition of N -2,2,2-trifluoroethylisatin ketimines with aurone derivatives of low reactivity using chiral dinuclear zinc catalysts has been developed via a Brønsted base and Lewis acid cooperative activation model. These transformations involving a domino Michael/Mannich reaction sequence led to efficient construction of a range of chiral spiro[benzofuran-pyrrolidine] scaffolds bearing three biologically relevant heterocyclic moieties and two adjacent spiro quaternary stereocenters in high yields (up to 95%) and with good enantioselectivities (up to 99% ee).

Backgrounds: Dehydroevodiamine (DHE) is a quinazoline alkaloid isolated from a Chinese herbal medicine, named Euodiae Fructus (Wu-Zhu-Yu in Chinese). This study aimed to investigate the therapeutic effects and potential mechanism of DHE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) based on integrated approaches., Methods: Therapeutic effects of DHE on serum biochemical indices and histopathology of gastric tissue in MNNG-induced CAG rats were analyzed. MNNG-induced GES-1 human gastric epithelial cell injury model was established. Cell viability and proliferation was quantified by a cell counting kit-8 assay. Cell morphology and mitochondrial membrane potential (MMP) were detected by a high content screening (HCS) assay. Cell migration and invasion were detected by a Transwell chamber. Moreover, UHPLC-Q-TOF/MS was performed to investigate the potential metabolites and signaling pathway affecting the protective effects of DHE on MNNG-induced cell migration and invasion of GES-1. Furthermore, in view of the key role of angiogenesis in the transformation of inflammation and cancer, this study explored relative mRNA and protein expression levels of HIF-1α-mediated VEGF pathway in vivo and in vitro by RT-PCR and Western Blotting, respectively., Results: The results showed that the therapeutic effects of DHE on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. Besides, DHE has an effect on increasing cell proliferation of GES-1 cells, ameliorating MNNG-induced gastric epithelial cell damage and mitochondrial dysfunction. In addition, DHE could inhibit MNNG induced migration and invasion of GES-1 cells. Cell metabolomics analyses showed that the protective effect of DHE on GES-1 cells is mainly associated with the regulation of inflammation metabolites and energy metabolism related pathways. It was found that DHE has a regulating effect on tumor angiogenesis and can inhibit the relative gene and protein expression of HIF-1α-mediated VEGF signaling pathway., Conclusions: The present work highlighted the role of DHE ameliorated gastric injury in MNNG-induced CAG rats in vivo and GES-1 cell migration in vitro by inhibiting HIF-1α/VEGF angiogenesis pathway. These results suggest that DHE may be the effective components of Euodiae Fructus, which provides a new agent for the treatment of CAG., (Copyright © 2021. Published by Elsevier GmbH.)

Spodoptera litura (Fabricius) is a widely distributed, highly polyphagous pest that can cause severe damage to a variety of economically important crops. Various populations have developed resistance to different classes of insecticides. In this study, we report on two indoxacarb-resistant S. litura populations, namely Ind-R (resistance ratio = 18.37-fold) derived from an indoxacarb-susceptible (Ind-S) population and a population caught from a field (resistance ratio = 46.72-fold). A synergist experiment showed that piperonyl butoxide (PBO) combined with indoxacarb produced higher synergistic effects (synergist ratio = 5.29) in the Ind-R population as compared to Ind-S (synergist ratio = 3.08). Elevated enzyme activity of cytochrome P450 monooxygenases (P450s) was observed for Ind-R (2.15-fold) and the Field-caught population (4.03-fold) as compared to Ind-S, while only minor differences were noticed in the activities of esterases and glutathione S-transferases. Furthermore, expression levels of P450 genes of S. litura were determined by quantitative reverse transcription PCR to explore differences among the three populations. The results showed that the mRNA levels of CYP6AE68, a novel P450 gene belonging to the CYP6 family, were constitutively overexpressed in Ind-R (32.79-fold) and in the Field-caught population (68.11-fold). CYP6AE68 expression in S. litura was further analyzed for different developmental stages and in different tissues. Finally, we report that RNA interference-mediated silencing of CYP6AE68 increased the mortality of fourth-instar larvae exposed to indoxacarb at the LC 50 dose level (increase by 33.89%, 29.44% and 22.78% for Ind-S, Ind-R and the Field-caught population, respectively). In conclusion, the findings of this study indicate that expression levels of CYP6AE68 in S. litura larvae are associated with indoxacarb resistance and that CYP6AE68 may play a significant role in detoxification of indoxacarb., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Lymphocytes play an important role in antitumor immunity following organ transplantation. However, the function of granzyme B + CD19 + B cells on the hepatocellular carcinoma cells from liver transplant recipients remains largely unknown; we aimed to analyze the function and elucidate the mechanisms behind it. Blood samples and clinical data from liver transplant recipients and healthy controls at Beijing Chaoyang Hospital as well as from a validation cohort were collected and analyzed. In this study, we found decreased granzyme B + CD19 + B cells were correlated with early hepatocellular carcinoma recurrence and could further identify liver transplant recipients with poor tumor differentiation, microvascular invasion, increased total tumor diameter, and tumor beyond Milan criteria. Notably, granzyme B + CD19 + B cells directly inhibited the proliferation, migration, and invasion of hepatocellular carcinoma cells. Upon activation regulatory B cells from liver transplant recipients with hepatocellular carcinoma recurrence displayed a CD5 + CD38 + CD27 + CD138 + CD19 + granzyme B + phenotype, but the increased expression of CD5, CD38, and CD138, and the decreased protein level and transcriptional level requiring JAK/STAT signaling. In an independent validation cohort, liver transplant recipients with decreased granzyme B + CD19 + B cells had not only early hepatocellular carcinoma cell recurrence but also shorter survival. Our study provides comprehensive data from liver transplant recipients with hepatocellular carcinoma, indicating a critical role of granzyme B + CD19 + B cells in preventing cancer progression. Our findings warrant further investigations for the design of future immunotherapies leading to immune responses and improved patient survival., Competing Interests: None., (AJCR Copyright © 2021.)

Continuous rain disaster is a kind of complex disaster with high frequency in the Basin area of Sichuan Province. Continuous rainy weather may appear in every growing stage of rice, with consequences on the yield and quality. Based on the meteorological data of 105 meteorological stations between 1981 and 2019, combining the observation data of rise production, agricultural statistics and the basic geographic information, we quantitatively evaluated and compared the continuous-rain disasters in the whole growth period and the four growth stages (sowing-jointing, jointing-booting, booting-early filling, mid-late filling-maturity) between transplanted rice and direct-seeded rice in the basin area of Sichuan Province. The results showed that the disaster index of continuous-rain for rice was higher in the sowing-jointing stage and the mid-late filling-maturity stage, higher in the northern and southwest edges of the basin, and lower in the middle, western and southern basin. The area with high-risk was relatively limited, which concentrated in the northern edge of the basin and scattered in the southern region of the basin. The low-risk area was the most widely distributed, which concentrated in the western and central parts of the basin. The total area of high-disaster areas for transplanted rice was 2.4 times as large as that for direct-seeded rice.