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Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Inositol-requiring enzyme 1 (IRE1), a mediator of the unfolded protein response, shows the highest degree of evolutionary conservation. Vertebrates express two IRE1 paralogs: IRE1α, which is universally expressed and IRE1β, which shows specific expression within mucus secreted cells in respiratory and gastrointestinal tracts. The biological properties and regulation of the two IRE1 duplicates show evolutionary differences. As recently suggested, IRE1β-deficient mice display impairment in secreted protein expression and mucosal homeostasis. Abnormal changes in IRE1β caused by external and internal factors can disrupt mucosal homeostasis and further lead to respiratory and gastrointestinal diseases. Here, we highlight the physiological functions of IRE1β in the respiratory and gastrointestinal tracts in response to environmental microbes, viruses, toxins, and food components., Competing Interests: 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., (© 2024 Published by Elsevier Ltd.)

This study aimed to investigate the effects of wild Cordyceps sinensis on chronic obstructive pulmonary disease (COPD) rats through metabolomics approach, combined with biochemical parameters evaluations. Consequently, C. sinensis exhibited regulatory effects on the lung's metabolic profiles in COPD rats. Treatment with C. sinensis potentially modulated glycerophospholipid metabolism, glutathione metabolism, and tryptophan metabolism, thereby alleviating oxidative stress (by decreasing MDA and GSSG, while increasing SOD and GSH) and inflammatory response (by inhibiting TNF-α, IL-8, and MMP-9) in COPD rats while improving lung tissue damage.

In order to control the increasing ozone （O 3 ） pollution in Hebi, Henan Province, clarifying the pollution characteristics of ozone and its precursors is vital. Therefore, we conducted a comprehensive analysis of O 3 pollution utilizing the OFP-PMF-EKMA method combined with online hourly resolution monitoring data of conventional pollutants and volatile organic compounds （VOCs） in the summer of 2022 （June-September）. Ozone formation potential （OFP） was used to identify the key VOCs species, and the PMF model was used to identify the VOCs emission sources, whereas EKMA curves and scenario analysis were used to identify the main ozone control area in Hebi and to determine the reduction ratio of VOCs and NO x in a scientifically refined way. In 2022, Hebi had persistent O 3 pollution, with the highest concentration in June. Conditions of high temperature, low humidity, and low atmospheric pressure contributed to the O 3 accumulation. Aromatic and oxygenated volatile organic compounds （OVOCs） contributed significantly to the OFP and VOCs fraction, which were the dominant active substance and concentration dominant species. The results of the VOCs source analysis indicated that vehicle exhaust sources （25.3%） were the main source of atmospheric VOCs, followed by process sources （17.7%） and biomass combustion sources （17.6%）. Thus, emission sources associated with the combustion of fossil fuels and industrial production emissions were the most urgent sources of atmospheric VOCs to be controlled in Hebi. The O 3 generation in Hebi occurred in the VOCs-sensitive zones, and the emission reduction results showed that a synergistic emission reduction of VOCs and nitrogen oxide （NO x ） could effectively control O 3 pollution with a 75% reduction in VOCs and a 10% reduction in NO x .

Background: Percutaneous endoscopic transforaminal discectomy (PETD) is an effective method for treating lumbar disc herniation, and is typically performed under local anesthesia. However, inadequate analgesia during the procedure remains a concern, prompting the search for a medication that can provide optimal pain control with minimal impact on the respiratory and circulatory systems., Objectives: The aim of this study was to observe the effects of different doses of esketamine combined with dexmedetomidine on reducing visual analog scale (VAS) scores during surgical interventions., Methods: One hundred two patients who underwent PETD were randomly divided into a control group (group C: normal saline + dexmedetomidine), an E1 group (0.1 mg kg -1 esketamine + dexmedetomidine), and an E2 group (0.2 mg kg -1 esketamine + dexmedetomidine). The primary outcome was the maximum visual analogue scale (VAS) (score: 0 = no pain and 10 = worst pain) at six time points. The secondary outcomes included the Assessment of Alertness/Sedation Scale (OAA/S) score and mean arterial pressure (BP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO 2 ) at 11 time points. The incidence of adverse reactions during and 24 h after the operation and patient satisfaction with the anesthesia were also recorded., Results: Compared with those in group C, the VAS scores of patients in groups E1 and E2 were lower at T 6 , T 7 , and T 9 (P < 0.05). From T 4 to T 10 , the OAA/S scores of the E1 and E2 groups were both lower than those of group C (P < 0.05), and at the T 4 -T 6 time points, the OAA/S score of the E2 group was lower than that of group E1 (P < 0.05). At T 4 and T 5 , the HR and BP of patients in groups E1 and E2 were greater than those in group C (P < 0.05). Compared with those in group C, the incidences of intraoperative illusion, floating sensation, postoperative dizziness, and hyperalgesia in groups E1 and E2 were significantly greater (P < 0.01). There was no significant difference in patient RR, SpO 2 , or postoperative satisfaction with anesthesia among the three groups (P > 0.05)., Conclusion: The combination of esketamine and dexmedetomidine can reduce VAS scores during certain stages of this type of surgery; it has minimal impact on respiration and circulation. However, this approach is associated with increased incidences of postoperative dizziness and psychiatric side effects, which may also affect patients' compliance with surgical instructions from medical staff. Patient satisfaction was not greater with dexmedetomidine combined with esketamine than with dexmedetomidine alone., Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR2300068206. Date of registration: 10 February 2023., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Circular RNAs (circRNAs) are newly identified endogenous non-coding RNAs that function as crucial gene modulators in the development of several diseases. By assessing the expression levels of circRNAs in peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD), this study attempted to find new biomarkers for COPD screening., Patients and Methods: We confirmed altered circRNA expression in PBMCs of COPD (n=41) vs controls (n=29). Further analysis focused on the highest and lowest circRNA expression levels. The T -test is used to assess the statistical variances in circRNAs among COPD patients in the smoking and non-smoking cohorts. Additionally, among smokers, the Spearman correlation test assesses the association between circRNAs and clinical indicators., Results: Two circRNAs, hsa&#95;circ&#95;0042590 and hsa&#95;circ&#95;0049875, that were highly upregulated and downregulated in PBMCs from COPD patients were identified and verified. Smokers with COPD had lower hsa&#95;circ&#95;0042590 and higher hsa&#95;circ&#95;0049875, in comparison to non-smokers. There was a significant correlation (r=0.52, P<0.01) between the number of acute exacerbations (AEs) that smokers with COPD experienced in the previous year and the following year (r=0.67, P<0.001). Moreover, hsa&#95;circ&#95;0049875 was connected to the quantity of AEs in the year prior (r=0.68, P<0.0001) as well as the year after (r=0.72, P<0.0001). AUC: 0.79, 95% CI: 0.1210-0.3209, P<0.0001) for hsa&#95;circ&#95;0049875 showed a strong diagnostic value for COPD, according to ROC curve analysis. Hsa&#95;circ&#95;0042590 showed a close second with an AUC of 0.83 and 95% CI: -0.1972--0.0739 (P <0.0001)., Conclusion: This research identified a strong correlation between smoking and hsa&#95;circ&#95;0049875 and hsa&#95;circ&#95;0042590 in COPD PBMCs. The number of AEs in the preceding and succeeding years was substantially linked with the existence of hsa&#95;circ&#95;0042590 and hsa&#95;circ&#95;0049875 in COPD patients who smoke. Additionally, according to our research, hsa&#95;circ&#95;0049875 and hsa&#95;circ&#95;0042590 may be valuable biomarkers for COPD diagnosis., Competing Interests: The authors had no conflicts of interest., (© 2024 Shen et al.)

Phosphorus (P) is a crucial macronutrient for plant growth, development, and reproduction. The effects of low P (LP) stress on leaf senescence and the role of PHR1 in LP-induced leaf senescence are still unknown. Here, we report that PHR1 plays a crucial role in LP-induced leaf senescence, showing delayed leaf senescence in phr1 mutant and accelerated leaf senescence in 35S:PHR1 transgenic Arabidopsis under LP stress. The transcriptional profiles indicate that 763 differentially expressed SAGs (DE-SAGs) were upregulated and 134 DE-SAGs were downregulated by LP stress. Of the 405 DE-SAGs regulated by PHR1, 27 DE-SAGs were involved in P metabolism and transport. PHR1 could bind to the promoters of six DE-SAGs (RNS1, PAP17, SAG113, NPC5, PLDζ2, and Pht1;5), and modulate them in LP-induced senescing leaves. The analysis of RNA content, phospholipase activity, acid phosphatase activity, total P and phosphate content also revealed that PHR1 promotes P liberation from senescing leaves and transport to young tissues under LP stress. Our results indicated that PHR1 is one of the crucial modulators for P recycling and redistribution under LP stress, and the drastic decline of P level is at least one of the causes of early senescence in P-deficient leaves., (© 2023 John Wiley & Sons Ltd.)

Objective: The authors aimed to assess the relationship between elevated renal-resistive index (RRI) and acute kidney injury (AKI) related to extracorporeal membrane oxygenation (ECMO) in neonatal patients., Design: This was a retrospective study., Setting: The study was conducted at a teaching hospital., Participants: Sixteen neonates treated with ECMO at the authors' hospital between June 2021 and December 2022 were included in this study., Interventions: Demographic and clinical data of patients were collected from the computer database. The RRI of patients before and during ECMO treatment was measured by bedside ultrasound. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of elevation of RRI as evidence of neonatal ECMO-related AKI. Logistic regression analysis was utilized to calculate the odds ratio (OR) with a 95% CI., Measurements and Main Results: A total of 16 patients met the inclusion criteria. For the primary outcome, the authors observed that the RRI during ECMO therapy was significantly elevated in patients with AKI compared to those without AKI. As for the secondary outcome, ROC curve analysis revealed an optimal RRI cutoff of 0.797, with an area under the curve of 0.855 (95% CI, 0.664-1, p = 0.027). The sensitivity and specificity of RRI values >0.797 for diagnosing AKI were 72.7% and 80%, respectively. Univariate logistic regression analysis indicated an OR of 1.433 (95% CI 1.192-1.873, p < 0.05) for RRI values above 0.797. This association remained statistically significant even after adjusting for serum cystatin C and Sequential Organ Failure Assessment score, with an adjusted OR of 1.352 (95% CI 1.108-1.612, p < 0.05)., Conclusion: The elevation of the RRI demonstrated a strong correlation with the onset of neonatal ECMO-related AKI, which may offer valuable support for diagnosing neonatal ECMO-related AKI., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Timely and accurate pathogen diagnosis can be challenging in children who contract a respiratory virus following congenital heart surgery (CHS). This often results in suboptimal drug use and treatment delays. Metagenomics next-generation sequencing (mNGS) is a swift, efficient, and unbiased method for obtaining microbial nucleic acid sequences. This technology holds promise as a comprehensive diagnostic tool, especially for pathogens undetectable by traditional methods. However, the efficacy of mNGS in the context of congenital heart disease infections remains uncertain. This study aimed to explore the diagnostic value of mNGS for respiratory virus infections post-CHS., Methods: We conducted a retrospective analysis of patients who developed respiratory tract infections post-CHS and were admitted to our cardiac center between July 2021 and December 2022. The patients were categorized into the following two groups based on the diagnostic method used: (I) the mNGS group (comprising 62 patients); and (II) the conventional microbiological test (CMT) group (comprising 70 patients). Bronchoalveolar lavage fluid (BALF) samples from these patients were tested to identify pathogens., Results: The mNGS group had significantly higher detection rates for both viral infections and mixed viral infections than the CMT group (56.45% vs . 17.14%, P<0.001, and 80.00% vs . 16.67%, P<0.001, respectively). In the mNGS group, 19.35% of the patients received antiviral therapy, and 61.29% received an anti-infective regimen adjustment. Conversely, in the CMT group, only 4.29% received antiviral therapy, and 28.57% received an anti-infective regimen adjustment. A higher percentage of patients showed improved respiratory symptoms in the mNGS group than the CMT group (74.19% vs . 44.29%, P=0.001). Additionally, the mNGS group had a shorter duration of mechanical ventilation and a reduced length of stay in the cardiac intensive care unit than the CMT group (P=0.012)., Conclusions: Using mNGS for BALF enhances the detection of respiratory viral infections and coexisting viral infections post-CHS. This facilitates more precise treatment strategies and could potentially lead to improved patient outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-341/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Objective: To evaluate the efficacy of high-flow nasal cannula oxygenation (HFNC) versus non-invasive ventilation (NIV) in pediatric patients post-congenital heart surgery (CHS) through a meta-analysis., Methods: A comprehensive literature search was conducted across the Chinese biomedical literature database, Vip database, CNKI, Wanfang, PubMed, Embase, Cochrane Library, and Web of Science until December 20, 2022. We selected RCTs or cohort studies that met inclusion criteria for a meta-analysis using RevMan 5.4 software., Results: Our search yielded five publications, comprised of one randomized controlled trial and four cohort studies. Meta-analysis revealed a significant reduction in reintubation rates in children post-CHS treated with HFNC as compared to NIV [RR = 0.36, 95%CI(0.25 ~ 0.53), P < 0.00001]. There was also a notable reduction in the duration of ICU stay [MD = -4.75, 95%CI (-9.38 ~ -0.12), P = 0.04]. No statistically significant differences were observed between HFNC and NIV in terms of duration of mechanical ventilation, 24 h PaO 2 , and PaCO 2 post-treatment (P > 0.05). Furthermore, both groups showed no significant difference in the duration of extracorporeal circulation [MD = -8.27, 95%CI(-17.16 ~ 0.62), P = 0.07]., Conclusions: For pediatric patients post-CHS, HFNC appears to be more effective than NIV in reducing reintubation rates and shortening the CICU stay., (© 2024. The Author(s).)

Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti-inflammatory macrophages, there are few researches on targeting pro-inflammatory macrophages, which is partially attributed to their non-s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro-inflammatory macrophages via antigen recognition, which is named AnCar-Exo LaIMTS . The data indicate that the phagocytosis efficiencies of pro-inflammatory macrophages for different AnCar-Exo LaIMTS show obvious differences. The AnCar-Exo LaIMTS3 has the best targeting ability for pro-inflammatory macrophages in vitro and in vivo. Mechanically, AnCar-Exo LaIMTS3 can specifically recognize the leucine-rich repeat domain of the TLR4 receptor, and then enter into pro-inflammatory macrophages via the TLR4-mediated receptor endocytosis pathway. Moreover, AnCar-Exo LaIMTS3 can efficiently deliver therapeutic cargo to pro-inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF-1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro-inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Fluoride has strong electronegativity and exposes diversely in nature. Water fluoridation is the most pervasive form of occurrence, representing a significant threat to human health. In this study, we investigate the morphometric and physiological alterations triggered by fluoride stimulation during the embryogenesis of zebrafish and reveal its putative effects of stage- and/or dose-dependent. Fluoride exhibits potent biological activity and can be extensively absorbed by the yolk sac, exerting significant effects on the development of multiple organs. This is primarily manifested as restricted nutrient utilization and elevated levels of lipid peroxidation, further leading to the accumulation of superoxide in the yolk sac, liver, and intestines. Moreover, pericardial edema exerts pressure on the brain and eye development, resulting in spinal curvature and reduced body length. Besides, acute fluoride exposure with varying concentrations has led to diverse teratogenic outcomes. A low dose of water fluoridation tends to induce abnormal development of the embryonic yolk sac, while vascular malformation is widely observed in all fluoride-treated groups. The effect of fluoride exposure on blood circulation is universally present, even in zebrafish larvae that do not exhibit obvious deformities. Their swimming behavior is also affected by water fluoridation, resulting in reduced activity and delayed reactions. In conclusion, this study provides valuable insights into the monitoring of environmental quality related to water fluoridation and disease prevention., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ships are important sources of carbon dioxide (CO 2 ) emissions in Guangdong Province. The study of historical evolutions, drivers, and projected pathways of CO 2 emissions can provide scientific support for the development of carbon peaking and carbon neutral strategies in Guangdong Province. The emission factor method, log-average index (LMDI) method, and scenario analysis method were adopted to estimate CO 2 emissions, identify the drivers, and explore the mitigation potential from ships in Guangdong Province, separately. The results showed that:① CO 2 emissions from ships in Guangdong Province increased from 3.319 4 million tons to 6.392 9 million tons from 2006 to 2020, with dry bulk carriers and container ships being the main ship types causing the increase in emissions. ② The positive drivers of CO 2 emissions from ships in Guangdong Province from 2006 to 2020 were transport intensity (51%) and economic factors (49%), and the negative drivers were energy intensity (93%) and cargo class structure (7%). ③ Carbon peaking would not be reached by 2030 if Guangdong Province maintains the current policy (baseline scenario) for ship transportation. ④ Simultaneous optimization of the energy structure and promotion of the energy intensity (energy-efficient and low-carbon scenario) had a 56.51% potential to reduce CO 2 emissions from ships compared to the baseline scenario. This can provide scientific support for Guangdong Province to develop a carbon peaking and carbon neutral control strategy for the shipping industry.

As a high energy consumption organ, kidney relies on a large number of mitochondria to ensure normal physiological activities. Under specific stimulation, mitophagy and mitochondrial dynamics (fission, fusion) cooperatively regulate mitochondrial quality and participate in many life activities such as energy metabolism, inflammatory response, oxidative stress, cell senescence and death. Mitophagy plays a key role in the progression of acute kidney injury and chronic kidney disease. The early induction of oxidative stress in renal parenchyma, the activation of pro-inflammatory cytokines and TGF-β signal pathway are closely related to renal interstitial fibrosis. Macrophage reprogramming is also considered to be an important participant in the progression of kidney fibrosis. This review summarizes the molecular mechanism of mitochondrial autophagy and its relationship with the pathway of promoting fibrosis, and discusses the possibility of restoring mitophagy balance as a pharmacological target for the treatment of renal interstitial fibrosis, so as to provide new ideas for more efficient anti-fibrosis and delay the progress of chronic kidney disease., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The members of PHOSPHATE 1 (PHO1) family play important roles in plant phosphate (Pi) transport and adaptation to Pi deficiency. The functions of PHO1 family proteins have been reported in several plant species, with the exception of Brassica species. Here, we identified 23, 23, and 44 putative PHO1 family genes in Brassica rapa, Brassica oleracea, and Brassica napus by whole genome analysis, respectively. The phylogenetic analysis divided PHO1 family proteins into eight groups, which represented the orthologous relationships among PHO1 members. The gene structure and the conserved motif analysis indicated that the most PHO1 family genes had similar gene structures and the PHO1 proteins shared mutual conserved motifs. The chromosome distribution analysis showed that the majority of BnPHO1 family genes distributed analogously at chromosomes with BrPHO1 and BoPHO1 family genes. The data showed that PHO1 family genes were highly conserved during evolution from diploid to tetraploid. Furthermore, the expression analysis showed that PHO1 family genes had different expression patterns in plant tissues, suggesting the diversity of gene functions in Brassica species. Meanwhile, the expression analysis also revealed that some PHO1 family genes were significantly responsive to Pi deficiency, suggesting that PHO1 family genes play critical roles in Pi uptake and homeostasis under low Pi stress. Altogether, the characteristics of PHO1 family genes provide a reliable groundwork for further dissecting their functions in Brassica species., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis., (© 2023 Federation of American Societies for Experimental Biology.)

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.

A catalyst-free photosensitized strategy has been developed for regioselective imino functionalizations of alkenes via the formation of an EDA complex. This photo-induced protocol facilitates the construction of structurally diverse β-imino sulfones and vinyl sulfones in moderate to high yields. Mechanistic studies reveal that the reaction is initiated with an intermolecular charge transfer between oximes and sulfinates, followed by fragmentation to generate a persistent iminyl radical and transient sulfonyl radical. This catalyst-free protocol also features excellent regioselectivity, broad functional group tolerance and mild reaction conditions. The late stage functionalization of natural product derived compounds and total synthesis of some bioactive molecules have been demonstrated to highlight the utility of this protocol. Meanwhile, the compatibility of different donors has proved the generality of this strategy., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Ketamine is a racemic mixture of equal amounts of R-ketamine and S-ketamine and is well known to anesthesiologists for its unique dissociative anesthetic properties. The pharmacological properties of ketamine, namely, its sympathetic excitation, mild respiratory depression, and potent analgesia, are still highly valued in its use as an anesthetic for some patients. In particular, since its advent, S-ketamine has been widely used as an anesthetic in many countries due to its increased affinity for NMDA receptors and its enhanced anesthetic and analgesic effects. However, the anesthetic and analgesic mechanisms of S-ketamine are not fully understood. In addition to antagonizing NMDA receptors, a variety of other receptors or channels may be involved, but there are no relevant mechanistic summaries in the literature. Therefore, the purpose of this paper is to review the mechanisms of action of S-ketamine on relevant receptors and systems in the body that result in its pharmacological properties, such as anesthesia and analgesia, with the aim of providing a reference for its clinical applications and research., 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 © 2023 Zhou, Peng, Liang, Chen, Liu, Wang, Guo, Deng, Ye, Zhong and Wang.)

In this paper, we study the effect of microbial fermentation on the nutrient composition and flavor of sweet potato slurry, different strains of Aspergillus niger, Saccharomyces cerevisiae, Lactobacillus plantarum, Bacillus coagulans, Bacillus subtilis, Lactobacillus acidophilus , and Bifidobacterium brevis were employed to ferment sweet potato slurry. After 48 h of fermentation with different strains (10% inoculation amount), we compared the effects of several strains on the nutritional and functional constituents (protein, soluble dietary fiber, organic acid, soluble sugar, total polyphenol, free amino acid, and sensory characteristics). The results demonstrated that the total sugar level of sweet potato slurry fell significantly after fermentation by various strains, indicating that these strains can utilize the nutritious components of sweet potato slurry for fermentation. The slurry's total protein and phenol concentrations increased significantly, and many strains demonstrated excellent fermentation performance. The pH of the slurry dropped from 6.78 to 3.28 to 5.95 after fermentation. The fermentation broth contained 17 free amino acids, and the change in free amino acid content is closely correlated with the flavor of the sweet potato fermentation slurry. The gas chromatography-mass spectrometry results reveal that microbial fermentation can effectively increase the kinds and concentration of flavor components in sweet potato slurry, enhancing its flavor and flavor profile. The results demonstrated that Aspergillus niger fermentation of sweet potato slurry might greatly enhance protein and total phenolic content, which is crucial in enhancing nutrition. However, Bacillus coagulans fermentation can enhance the concentration of free amino acids in sweet potato slurry by 64.83%, with a significant rise in fresh and sweet amino acids. After fermentation by Bacillus coagulans , the concentration of lactic acid and volatile flavor substances also achieved its highest level, which can considerably enhance its flavor. The above results showed that Aspergillus niger and Bacillus coagulans could be the ideal strains for sweet potato slurry fermentation., 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 © 2023 Pan, Zhang, Bai, Liu, Zhang, Tian, Zhou, Zhou, Liao, Hou, Yu, Hui and Huang.)

Background: The F-box protein 43 (FBXO43), also referred to as endogenous meiotic inhibitor 2 (EMI2), has been linked to the advancement of various types of cancer, such as hepatocellular carcinoma, breast cancer, cholangiocarcinoma, and gastric cancer. Nevertheless, the precise function of FBXO43 in colorectal cancer (CRC) remains unclear. This study employed data from The Cancer Genome Atlas (TCGA) and clinical specimens to analyze the expression, prognostic value, and chemotherapeutic advantages of FBXO43 in CRC., Methods: Level 3 RNA sequencing data pertaining to 631 cases of colon and rectal adenocarcinomas (COAD-READ) were downloaded from TCGA. The data were utilized to analyze the expression, prognosis, and related signal pathways of FBXO43. The expression of FBXO43 in clinical samples was subsequently confirmed through the use of real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Lastly, a tissue microarray (TMA) consisting of 120 cases of CRC and corresponding normal tissues was established to investigate the relationship between FBXO43 and survival outcomes., Results: Results from both the TCGA analysis and clinical samples indicated that FBXO43 was significantly upregulated in CRC tissues in comparison to normal tissues. Moreover, high level of FBXO43 was found to be relevant to malignant clinical features, such as differentiation, lymph node metastasis, and pathological stage, as well as unfavorable prognosis in CRC patients. Subgroup analysis further demonstrated that FBXO43 could be an effective parameter for stratifying low-risk CRC patients. Notably, survival analysis showed that patients with high level of FBXO43 had worse overall survival (OS) and disease-free survival (DFS) following adjuvant chemotherapy, and FBXO43 was distinctly upregulated in chemotherapy-resistant patients' primary CRC tissues., Conclusions: FBXO43 was upregulated and associated with poor prognosis of CRC; patients with high expression of FBXO43 may not be benefit from adjuvant chemotherapy., Competing Interests: No potential conflicts of interest were disclosed., (Copyright 2023, Liu et al.)

Background: Conventional approach to myocardial strain analysis relies on a software designed for the left ventricle (LV) which is complex and time-consuming and is not specific for right ventricular (RV) and left atrial (LA) assessment. This study compared this conventional manual approach to strain evaluation with a novel semi-automatic analysis of myocardial strain, which is also chamber-specific., Methods: Two experienced observers used the AutoStrain software and manual QLab analysis to measure the LV, RV and LA strains in 152 healthy volunteers. Fifty cases were randomly selected for timing evaluation., Results: No significant differences in LV global longitudinal strain (LVGLS) were observed between the two methods (-21.0% ± 2.5% vs. -20.8% ± 2.4%, p = 0.230). Conversely, RV longitudinal free wall strain (RVFWS) and LA longitudinal strain during the reservoir phase (LASr) measured by the semi-automatic software differed from the manual analysis (RVFWS: -26.4% ± 4.8% vs. -31.3% ± 5.8%, p < 0.001; LAS: 48.0% ± 10.0% vs. 37.6% ± 9.9%, p < 0.001). Bland-Altman analysis showed a mean error of 0.1%, 4.9%, and 10.5% for LVGLS, RVFWS, and LASr, respectively, with limits of agreement of -2.9,2.6%, -8.1,17.9%, and -12.3,33.3%, respectively. The semi-automatic method had a significantly shorter strain analysis time compared with the manual method., Conclusions: The novel semi-automatic strain analysis has the potential to improve efficiency in measurement of longitudinal myocardial strain. It shows good agreement with manual analysis for LV strain measurement., (© 2023. The Author(s).)

Objective: To investigate the feasibility and clinical outcomes of early enteral nutrition (EN) in critically ill neonates supported by extracorporeal membrane oxygenation (ECMO)., Methods: We retrospectively analyzed the clinical data of 16 critically ill neonates who received ECMO support for respiratory and circulatory failure from July 2021 to December 2022 at our center. The patients were divided into two groups: the early EN group (< 24 h) and the late EN group (> 24 h). The related clinical and nutrition-related indicators between the groups were compared., Results: There was a significant difference in the time from ECMO treatment to the start of EN between the early EN group (9 patients, 56.2%) and the late EN group (7 patients, 43.8%) (P < 0.05). However, there were no significant differences in ECMO duration, hospitalization time, vasoactive-inotropic score (VIS), intestinal oxygen saturation, or routine stool occult blood (OB) test between the two groups (all P > 0.05). The incidence of complications such as intestinal obstruction, abdominal distension, diarrhea, and necrotizing enterocolitis (NEC) was slightly lower in the early EN group, but the differences were not statistically significant (all P > 0.05). The early EN group had a shorter time [3.6 (3.5, 5) vs. 7.5 (5.9, 8.5) d] to reach full gastrointestinal nutrition compared to the late EN group (P < 0.05)., Conclusion: Providing early nutritional support through enteral feeding to critically ill neonates receiving ECMO treatment is both safe and practical, but close monitoring of clinical and nutritional indicators is essential., (© 2023. The Author(s).)

Introduction: The pre-Bötzinger complex (pre-BötC), a kernel of inspiratory rhythmogenesis, is a heterogeneous network with excitatory glutamatergic and inhibitory GABAergic and glycinergic neurons. Inspiratory rhythm generation relies on synchronous activation of glutamatergic neuron, whilst inhibitory neurons play a critical role in shaping the breathing pattern, endowing the rhythm with flexibility in adapting to environmental, metabolic, and behavioral needs. Here we report ultrastructural alterations in excitatory, asymmetric synapses (AS) and inhibitory, symmetric synapses (SS), especially perforated synapses with discontinuous postsynaptic densities (PSDs) in the pre-BötC in rats exposed to daily acute intermittent hypoxia (dAIH) or chronic (C) IH., Methods: We utilized for the first time a combination of somatostatin (SST) and neurokinin 1 receptor (NK1R) double immunocytochemistry with cytochrome oxidase histochemistry, to reveal synaptic characteristics and mitochondrial dynamic in the pre-BötC., Results: We found perforated synapses with synaptic vesicles accumulated in distinct pools in apposition to each discrete PSD segments. dAIH induced significant increases in the PSD size of macular AS, and the proportion of perforated synapses. AS were predominant in the dAIH group, whereas SS were in a high proportion in the CIH group. dAIH significantly increased SST and NK1R expressions, whereas CIH led to a decrease. Desmosome-like contacts (DLC) were characterized for the first time in the pre-BötC. They were distributed alongside of synapses, especially SS. Mitochondria appeared in more proximity to DLC than synapses, suggestive of a higher energy demand of the DLC. Findings of single spines with dual AS and SS innervation provide morphological evidence of excitation-inhibition interplay within a single spine in the pre-BötC. In particular, we characterized spine-shaft microdomains of concentrated synapses coupled with mitochondrial positioning that could serve as a structural basis for synchrony of spine-shaft communication. Mitochondria were found within spines and ultrastructural features of mitochondrial fusion and fission were depicted for the first time in the pre-BötC., Conclusion: We provide ultrastructural evidence of excitation-inhibition synapses in shafts and spines, and DLC in association with synapses that coincide with mitochondrial dynamic in their contribution to respiratory plasticity in the pre-BötC., 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 © 2023 Kang, Lu, Yang, Guo, Zhu, Wu, Huang, Wong-Riley and Liu.)

A kind of organosilicon intermediate was prepared using isophorone diisocyanate (IPDI), hydroxyl silicone oil (HSO), and hydroxyethyl acrylate (HEA). The organosilicon modification of epoxy resin was realized by introducing a -Si-O- group into the side chain of epoxy resin by chemical grafting. The effects of organosilicon modification of epoxy resin on the mechanical properties systematically discuss its heat resistance and micromorphology. The results indicate that the curing shrinkage of the resin was decreased and the printing accuracy was improved. At the same time, the mechanical properties of the material are enhanced; the IS and elongation at break (EAB) are enhanced by 32.8 and 8.65%, respectively. The brittle fracture is changed to a ductile fracture, and the tensile strength (TS) of the material is decreased. The glass transition temperature (GTT) of the modified epoxy resin increased by 8.46 °C, and T 50% and T max increased by 1.9 and 6 °C, respectively, indicating that the heat resistance of the modified epoxy resin was improved., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Objective: By using ultrasound strain rate (SR) imaging to evaluate the left atrial (LA) reservoir and pump function after catheter ablation (CA) with persistent atrial fibrillation (PAF)., Methods: A total of 45 patients with PAF underwent echocardiography examination before and after ablation as well as during 6 months of follow-up. Peak SR was measured at each LA segment (septal, lateral, anterior, inferior and posterior) during systole (LAs) and late diastole (LAa)., Results: During 6 months after CA, 30 patients were free of atrial fibrillation recurrence (AFR). left atrial area index (LAAI), left atrial maximum volume index (LAVImax), and E/Ea were obviously higher in patients with before CA, left atrial ejection fraction (LAEF), SR-LAs were lower than in normal cases, the SR-LAa was disappeared. Shortly after ablation, SR-LAa was recovered, and SR-LAs was reduced compared to those at baseline. At midterm follow-up, LAEF and SR-LAs were still lower than the control group, and LAAI and LAVImax were higher. SR-LAa was recovered slowly over time, but still lower., Conclusion: LA reservoir function was seriously damaged and LA pump function disappeared in patients with PAF. LA reservoir function impairment appeared shortly after ablation, it showed improvement at midterm follow-up, but some degree of damage to the LA reservoir and pump function was still present. Speckle tracking imaging is a feasible technique for the assessment of LA function in patients with PAF, which is a potentially valuable clinical tool to assist in the early detection of atrial remodelling and reverse remodelling.

The phytohormone abscisic acid (ABA) plays an important role in the ability of plants to cope with drought stress. As core members of the ABA signaling pathway, protein phosphatase type 2Cs (PP2Cs) have been reported in many species. However, the functions of MdPP2Cs in apple ( Malus domestica ) are unclear. In this study, we identified two PP2C-encoding genes, MdPP2C24/37 , with conserved PP2C catalytic domains, using sequence alignment. The nucleus-located MdPP2C24/37 genes were induced by ABA or mannitol in apple. Genetic analysis revealed that overexpression of MdPP2C24/37 in Arabidopsis thaliana led to plant insensitivity to ABA or mannitol treatment, in terms of inhibiting seed germination and overall seedling establishment. The expression of stress marker genes was upregulated in MdPP2C24/37 transgenic lines. At the same time, MdPP2C24/37 transgenic lines displayed inhibited ABA-mediated stomatal closure, which led to higher water loss rates. Moreover, when exposed to drought stress, chlorophyll levels decreased and MDA and H 2 O 2 levels accumulated in the MdPP2C24/37 transgenic lines. Further, MdPP2C24/37 interacted with MdPYL2/12 in vitro and vivo. The results indicate that MdPP2C24/37 act as negative regulators in response to ABA-mediated drought resistance.

Background: Hypoxic pulmonary hypertension (HPH) is a common complication of chronic lung disease, which severely affects the survival and prognosis of patients. Several recent reports have shown that DNA damage and repair plays a crucial role in pathogenesis of pulmonary arterial hypertension. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a part of DNA-PK is a molecular sensor for DNA damage that enhances DSB repair. This study aimed to demonstrate the expression and potential mechanism of DNA-PKcs on the pathogenesis of HPH., Methods: Levels of DNA-PKcs and other proteins in explants of human and rats pulmonary artery from lung tissues and pulmonary artery smooth muscle cells (PASMC) were measured by immunohistochemistry and western blot analysis. The mRNA expression levels of DNA-PKcs and NOR1 in PASMCs were quantified with qRT-PCR. Meanwhile, the interaction among proteins were detected by Co-immunoprecipitation (Co-IP) assays. Cell proliferation and apoptosis was assessed by cell counting kit-8 assay(CCK-8), EdU incorporation and flow cytometry. Rat models of HPH were constructed to verify the role of DNA-PKcs in pulmonary vascular remodeling in vivo., Results: DNA-PKcs protein levels were both significantly up-regulated in explants of pulmonary artery from HPH models and lung tissues of patients with hypoxemia. In human PASMCs, hypoxia up-regulated DNA-PKcs in a time-dependent manner. Downregulation of DNA-PKcs by targeted siRNA or small-molecule inhibitor NU7026 both induced cell proliferation inhibition and cell cycle arrest. DNA-PKcs affected proliferation by regulating NOR1 protein synthesis followed by the expression of cyclin D1. Co-immunoprecipitation of NOR1 with DNA-PKcs was severely increased in hypoxia. Meanwhile, hypoxia promoted G 2  + S phase, whereas the down-regulation of DNA-PKcs and NOR1 attenuated the effects of hypoxia. In vivo, inhibition of DNA-PKcs reverses hypoxic pulmonary vascular remodeling and prevented HPH., Conclusions: Our study indicated the potential mechanism of DNA-PKcs in the development of HPH. It might provide insights into new therapeutic targets for pulmonary vascular remodeling and pulmonary hypertension., (© 2022. The Author(s).)

To characterize IncI1 and IncF18:A-:B1 multidrug-resistance plasmids from an avian Escherichia coli isolate, antibiotic susceptibility testing, conjugation assays, transformation assays, S1-PFGE, and WGS analysis were performed. The 119,457-bp plasmid pEC014-1 with a multidrug-resistance region (MRR) containing four different segments interspersed with six IS26 elements, belonged to incompatibility group I1 and sequence type 71. The 154,516-bp plasmid pEC014-2 with two replicons, typed as FII-18 and FIB-1, carried 14 resistance determinants including bla TEM-1b , bla OXA-1 , oqxAB, dfrA17, aac(6')-Ib-cr, sul1, sul2, tet(A), floR, catB3, hph(aph(4)-Ia), aacC4(aac(3)-IV), aadA5, arr-3, and a merEDACPTR loci in MRR, and additionally encoded three virulence loci: iroNEDCB, sitABCD, and iucABCD-iutA. Plasmid stability assays showed that pEC014-1 and pEC014-2 were stable in recipient E. coli C600 for at least 15 days of passage. Competition assays were carried out to evaluate the fitness impact of pEC014-2 carriage in vitro, revealing a decrease in host fitness. Growth kinetics showed that the growth rate for pEC014-1 or/and pEC014-2 bearing cells was significantly slower than that of the E. coli C600 host strain in the exponential stage (p < 0.01), with only cells carrying pEC014-1 sustaining rapid growth after 6 h of exponential growth. Our findings highlight the mosaic structures of epidemic plasmid IncI1/ST71 and F18:A-:B1 lineages and contribute to a better understanding of the evolution and dissemination of these multidrug resistance and virulence plasmids., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Members of the genus Marinomonas are known for their environmental adaptation and metabolically versatility, with abundant proteins associated with antifreeze, osmotic pressure resistance, carbohydrase and multiple secondary metabolites. Comparative genomic analysis focusing on secondary metabolites and orthologue proteins was conducted with 30 reference genome sequences in the genus Marinomonas. In this study, a Gram-stain-negative, rod-shaped, non-flagellated and strictly aerobic bacterium, designated as strain E8 T , was isolated from the red algae (Gelidium amansii) in the coastal of Weihai, China. Optimal growth of the strain E8 T was observed at temperatures 25-30 °C, pH 6.5-8.0 and 1-3% (w/v) NaCl. The DNA G + C content was 42.8 mol%. The predominant isoprenoid quinone was Q-8 and the major fatty acids were C 16:0 , summed feature 3 and summed feature 8. The major polar lipids were phosphatidylglycerol (PG) and phosphatidylethanolamine (PE). Based on data obtained from this polyphasic taxonomic study, strain E8 T should be considered as a novel species of the genus Marinomonas, for which the name Marinomonas algarum is proposed. The type strain is E8 T (= KCTC 92201 T  = MCCC 1K07070 T )., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: N-acetyltransferase 10 (NAT10), an abundant nucleolar protein with both lysine and RNA cytidine acetyltransferase activities, has been implicated in Hutchinson-Gilford progeria syndrome and human cancer. We and others recently demonstrated that NAT10 is translocated from the nucleolus to the nucleoplasm after DNA damage, but the underlying mechanism remains unexplored., Methods: The NAT10 and PARP1 knockout (KO) cell lines were generated using CRISPR-Cas9 technology. Knockdown of PARP1 was performed using specific small interfering RNAs targeting PARP1. Cells were irradiated with γ-rays using a 137 Cs Gammacell-40 irradiator and subjected to clonogenic survival assays. Co-localization and interaction between NAT10 and MORC2 were examined by immunofluorescent staining and immunoprecipitation assays, respectively. PARylation of NAT10 and translocation of NAT10 were determined by in vitro PARylation assays and immunofluorescent staining, respectively., Results: Here, we provide the first evidence that NAT10 underwent covalent PARylation modification following DNA damage, and poly (ADP-ribose) polymerase 1 (PARP1) catalyzed PARylation of NAT10 on three conserved lysine (K) residues (K1016, K1017, and K1020) within its C-terminal nucleolar localization signal motif (residues 983-1025). Notably, mutation of those three PARylation residues on NAT10, pharmacological inhibition of PARP1 activity, or depletion of PARP1 impaired NAT10 nucleoplasmic translocation after DNA damage. Knockdown or inhibition of PARP1 or expression of a PARylation-deficient mutant NAT10 (K3A) attenuated the co-localization and interaction of NAT10 with MORC family CW-type zinc finger 2 (MORC2), a newly identified chromatin-remodeling enzyme involved in DNA damage response, resulting in a decrease in DNA damage-induced MORC2 acetylation at lysine 767. Consequently, expression of a PARylation-defective mutant NAT10 resulted in enhanced cellular sensitivity to DNA damage agents., Conclusion: Collectively, these findings indicate that PARP1-mediated PARylation of NAT10 is key for controlling its nucleoplasmic translocation and function in response to DNA damage. Moreover, our findings provide novel mechanistic insights into the sophisticated paradigm of the posttranslational modification-driven cellular response to DNA damage. Video Abstract., (© 2022. The Author(s).)

In nature, prenylation and geranylation are two important metabolic processes for the creation of hemiterpenoids and monoterpenoids under enzyme catalysis. Herein, we have demonstrated bioinspired unnatural prenylation and geranylation of oxindoles using the basic industrial feedstock isoprene through ligand regulation under Pd catalysis. Pentenylated oxindoles (with C 5 added) were attained with high selectivity when using a bisphosphine ligand, whereas upon switching to a monophosphine ligand, selectivity toward geranylated oxindoles (with C 10 added) was achieved. Moreover, the head-to-head product could be further isomerized to an internal skipped diene under Pd-H catalysis. No stoichiometric by-product was formed in the process., (© 2022 Wiley-VCH GmbH.)

Aims: MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented., Methods and Results: We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition., Conclusion: We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Distal ischemic necrosisis a common complication of orthopedic random skin flaps surgery. Paeoniflorin, a natural compound extracted from Paeonia lactiflora, can enhances angiogenesis and alleviates excessive inflammatory response. We investigated the changes of ischemic extra-long flaps with paeoniflorin and its possible mechanism., Methods: We raised dorsal McFarlane flaps in 54 Sprague-Dawley rats. We designed three groups of rats: high-paeoniflorin group (HP, 50 mg/kg/d), low-paeoniflorin group (LP, 20 mg/kg/d), and control group. The flap survival rate was calculated, seven days after flap construction.Blood perfusion was detected by laser Doppler flow imaging, and angiogenesis wasdetected by Lead oxide/gelatin angiography.Oxidative stress levels of flaps were determined by detecting superoxide dismutase (SOD) and malondialdehyde (MDA). The histopathological status of flap was evaluated by hematoxylin and eosin (H&E) staining.Immunohistochemistry was used to determine the expression of high mobility group protein B1 (HMGB1), nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, IL-18, vascular endothelial growth factor (VEGF), cysteine protease-1 (caspase-1) and NLPR3., Results: The flap survival rates and SOD activity in the experimental groups were significantly higher, while MDA activity was lower. Experimental groups showed significantly improved microcirculatory blood flow to the flap and increased angiogenesis. Immunohistochemistry revealed that paeoniflorin was associated with significantly increased VEGF expression, and decreased level of HMGB1, TLR4, TNF-α, NF-κB, IL-6, IL-1β, caspase-1, NLPR3, and IL-18., Conclusions: Paeoniflorin effectively enhanced the survival of rat random skin flaps by promoting vascular hyperplasia, inhibiting pyroptosis, and down-regulating inflammation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Noninvasive myocardial work (MW) is a new technology which is based on strain after considering the load influence on myocardial deformation. We aimed to investigate the feasibility of quantitatively assessing left ventricular myocardial work (LVMW) in patients with systemic lupus erythematosus (SLE) using a left ventricular pressure-strain loop (LVPSL)., Methods: 76 patients with SLE were included in the study (A), further divided into two subgroups according to the presence of lupus nephritis (LN). Global longitudinal strain (GLS), peak strain dispersion (PSD), global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were obtained., Results: 1: Patients with SLE demonstrated a significantly reduced GWE and GLS compared with control group, GWW and PSD were increased, above changes were more pronounced in patients with LN. There was no significant difference in GWI and GCW. 2: Receiver operating characteristic (ROC) analysis demonstrated that GWE was the most powerful tool for detecting myocardial insufficiency early in SLE patients, and the area under the curve (AUC) was 0.804, and was superior to GLS (AUC = 0.707). GWE remains the best indicator of subclinical myocardial injury in patients with LN. The AUC was 0.910, and the best cutoff point was 96.5% (sensitivity 83.3%, specificity 73.3%)., Conclusions: LVPSL can be used to noninvasively assess changes in MW in patients with SLE. Noninvasive GWE is a more sensitive index than GLS to detect subclinical myocardial injury early in SLE patients. This is a potential valuable clinical tool to assist in the early-find myocardial damage.

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-β1 (TGF-β1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-β1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-β1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation., (© 2021. The Author(s).)

Objective: To explore the value of uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7)-161 single nucleotide polymorphism in predicting the occurrence of cardiotoxicity in Chinese human epidermal growth factor 2 (HER-2) positive breast cancer patients who underwent pertuzumab combined with trastuzumab Therapy., Methods: Fifty patients with HER-2 positive breast cancer who planned to receive trastuzumab and pertuzumab therapy for more than four cycles were enrolled in this study, and blood samples were collected. Thirty healthy volunteers of matching ages were selected as the control group. Myocardial parameters such as global work index, global effective work, and global wasted work were measured before treatment (M0) and at the end of four cycles of treatment month three (M3). Blood samples were collected from patients at the M0 stage, and polymorphisms of the UGT2B7-161 gene were detected to evaluate the predictive ability of different gene phenotypes on the myocardial drug toxicity injury., Results: There were 35 myocardial work decreased events among 50 patients. There were 24 (47.3%), 15 (40.8%), and 11 (11.8%) patients carrying UGT2B7-161 CC, CT, and TT genotypes, respectively. The occurrence of myocardial work decreased was decreased in UGT2B7-161 TT and CT genotypes (12.5%) compared with CC genotype (41.7%) with statistical significance (P < 0.001). Multivariate logistic regression model analysis exhibited that UGT2B7-161 genotypes, body mass index, and cardiac troponin I were independent factors influencing the risk of cardiotoxicity., Conclusion: UGT2B7-161 single nucleotide polymorphism is a potential predictive factor for cardiotoxicity in HER-2 positive breast cancer patients receiving trastuzumab and pertuzumab dual-targeted drug therapy., Competing Interests: The authors declare that they have no competing interests., (© 2022 Li et al.)

Two novel, designated strains 29W222 T and 2943 T , were isolated from the marine sediment from Aoshan Bay, Jimo, PR China. Growth was observed at pH 6.0-8.5 (optimum, pH 7.5) for strain 29W222 T , and pH 5.5-8.5 (pH 7.0) for strain 2943 T . Both strains displayed growth in 0.5-6 % NaCl with an optimum at 1 % for 29W222 T ; 0.5 % for 2943 T . Both strains grew optimally at 33 °C. The results of phylogenetic analyses based on 16S rRNA gene sequences indicated that 29W222 T and 2943 T represented members of the genus Fulvivirga and strain 29W222 T was most closely related to Fulvivirga kasyanovii KMM 6220 T (97.9 % sequence similarity) and Fulvivirga imtechensis AK7 T (95.0 %), and 2943 T to Fulvivirga imtechensis AK7 T (95.7 %) and Fulvivirga kasyanovii KMM 6220 T (94.8 %). The genomic DNA G+C contents of 29W222 T and 2943 T were 39.9 and 37.7 mol%, respectively. The results of chemotaxonomic analysis indicated that the sole respiratory quinone was menaquinone 7 (MK-7), and the major fatty acid was iso-C 15 : 0 for both strains. Average nucleotide identity and average amino acid identity values between strain 29W222 T and Fulvivirga kasyanovii KMM 6220 T were 78.9 and 83.6 %, respectively; the corresponding values between 2943 T and Fulvivirga imtechensis AK7 T were 69.8 and 63.6 %, respectively. Therefore, strains 29W222 T and 2943 T represent to two novel species of the genus Fulvivirga , for which the names Fulvivirga marina sp. nov. (29W222 T =KCTC 62848 T =MCCC 1K05194 T ) and Fulvivirga sediminis sp. nov. (2943 T =KCTC 62847 T = MCCC 1K05144 T ) are proposed, respectively.

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca 2+ influx via PreNMDARs. Small conductance Ca 2+ -activated K + (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization., (© 2022. The Author(s).)

Anaerobic ammonium-oxidizing (anammox) bacteria are iron abundant and depend heavily on iron-binding proteins. The iron demand of anammox bacteria is relatively large. However, it still remains some doubts where these large quantities of available iron come from and how they are regulated in anammox bacteria. Herein, iron-rich nanoparticles in anammoxosomes were detected by synchrotron soft X-ray tomography coupled with scanning transmission X-ray microscopy (STXM). The iron-rich nanoparticles were identified as ferric oxide (α-Fe 2 O 3 ) mineral cores, and the local atomic structure of iron-rich nanoparticles was obtained by X-ray absorption fine-structure (XAFS) spectra. The bacterioferritin of Q1Q315 and Q1Q5F8 were detected by proteomics analysis. On this basis, the metabolic pathway centered on iron-rich nanoparticles was proposed., 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 © 2021 Elsevier B.V. All rights reserved.)

Background: Appropriate allocation of nursing staff is key to ensuring efficient nursing in hospitals, and is significantly correlated with patient safety, nursing quality, and nurse job satisfaction. However, there are few studies on nursing workforce allocation in the isolation wards of COVID-19 designated hospitals globally. This study aims to better understand the nursing workforce allocation in the isolation wards of COVID-19 designated hospitals in China, and provide a theoretical basis for efficiently deploying first-line nurses in China and across the world in the future., Methods: An online survey was conducted among the head nurses (n = 229) and nurses (n = 1378) in the isolation wards of 117 hospitals (selected by stratified sampling), using a self-reported human resource allocation questionnaire., Results: The average bed-to-nurse ratios of different isolation wards were different (Z = 36.742, P = 0.000). The bed-to-nurse ratios of the ICU, suspected COVID-19 cases ward, and confirmed COVID-19 cases ward, were 1:1.88, 1:0.56, and 1:0.45, respectively. The nurse work hours per shift in different isolation wards were also different (Z = 8.468, P = 0.014), with the specific values of the ICU, suspected COVID-19 cases ward, and confirmed COVID-19 cases ward, being 5, 6, and 6 h, respectively. A correlation analysis showed that the average work hours per shift was proportional to the overtime work of nurses (r s  = 0.146), the proportion of nurse practitioners was proportional to the overall utilization rate of nursing human resources in the wards (r s  = 0.136), and the proportion of nurses with college degrees was proportional to teamwork (r s  = 0.142). The proportion of nurses above grade 10 was inversely proportional to teamwork and psychological problems (r s  = 0.135, r s  = 0.203). The results of multiple stepwise regression analyses showed that the work hours of nurses per shift was the main factor affecting nurse satisfaction and that the proportion of nurses and the work hours of nurses per shift were both independent factors affecting the length of stay (LOS) of patients., Conclusion: Hospitals in China have made good nursing workforce allocations during the COVID-19 pandemic, but there are certain shortcomings. Therefore, scientific and efficient nursing workforce allocation practice plans should be established to improve the ability of hospitals to deal with public health emergencies and are urgent problems that need to be addressed soon., (© 2022. The Author(s).)

Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future., Competing Interests: Declaration of competing interest Authors declare that all authors listed in the manuscript have involved in this study and authors are ranked according to their contributions. All authors read and approved the current manuscript., (Copyright © 2021. Published by Elsevier Inc.)

Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo . Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease., (©2021 American Association for Cancer Research.)

Bama minipig is a unique miniature swine bred from China. Their favorable characteristics include delicious meat, strong adaptability, tolerance to rough feed, and high levels of stress tolerance. Unfavorable characteristics are their low lean meat percentage, high fat content, slow growth rate, and low feed conversion ratio. Genome-editing technology using CRISPR/Cas9 efficiently knocked out the myostatin gene (MSTN) that has a negative regulatory effect on muscle production, effectively promoting pig muscle growth and increasing lean meat percentage of the pigs. However, CRISPR/Cas9 genome editing technology is based on random mutations implemented by DNA double-strand breaks, which may trigger genomic off-target effects and chromosomal rearrangements. The application of CRISPR/Cas9 to improve economic traits in pigs has raised biosafety concerns. Base editor (BE) developed based on CRISPR/Cas9 such as cytosine base editor (CBE) effectively achieve targeted modification of a single base without relying on DNA double-strand breaks. Hence, the method has greater safety in the genetic improvement of pigs. The aim of the present study is to utilize a modified CBE to generate MSTN-knockout cells of Bama minipigs. Our results showed that the constructed "all-in-one"-modified CBE plasmid achieved directional conversion of a single C·G base pair to a T·A base pair of the MSTN target in Bama miniature pig fibroblast cells. We successfully constructed multiple single-cell colonies of Bama minipigs fibroblast cells carrying the MSTN premature termination and verified that there were no genomic off-target effects detected. This study provides a foundation for further application of somatic cell cloning to construct MSTN-edited Bama minipigs that carry only a single-base mutation and avoids biosafety risks to a large extent, thereby providing experience and a reference for the base editing of other genetic loci in Bama minipigs., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

An emerging view regarding cancer metabolism is that it is heterogeneous and context-specific, but it remains to be elucidated in breast cancers. In this study, we characterized the energy-related metabolic features of breast cancers through integrative analyses of multiple datasets with genomics, transcriptomics, metabolomics, and single-cell transcriptome profiling. Energy-related metabolic signatures were used to stratify breast tumors into two prognostic clusters: cluster 1 exhibits high glycolytic activity and decreased survival rate, and the signatures of cluster 2 are enriched in fatty acid oxidation and glutaminolysis. The intertumoral metabolic heterogeneity was reflected by the clustering among three independent large cohorts, and the complexity was further verified at the metabolite level. In addition, we found that the metabolic status of malignant cells rather than that of nonmalignant cells is the major contributor at the single-cell resolution, and its interactions with factors derived from the tumor microenvironment are unanticipated. Notably, among various immune cells and their clusters with distinguishable metabolic features, those with immunosuppressive function presented higher metabolic activities. Collectively, we uncovered the heterogeneity in energy metabolism using a classifier with prognostic and therapeutic value. Single-cell transcriptome profiling provided novel metabolic insights that could ultimately tailor therapeutic strategies based on patient- or cell type-specific cancer metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

To characterize the formation mechanism and characteristics of two cointegrate plasmids in Salmonella enterica serotype Enteritidis strain S13, plasmids from strain S13 and three corresponding transconjugants were subjected to whole genome sequencing and analyzed using bioinformatics tools. The traits of two fusion plasmids in transconjugants were characterized by stability and conjugation experiments. Sequence analysis indicated that strain S13 contained four plasmids, including mcr-1 -bearing pS13-1, bla CTX-M-55 -carrying pS13-2, tet (M)-bearing pS13-3, and floR -carrying pS13-4. IncN1-F33:A-:B- plasmid pS13-2, respectively, fused with IncFI:A-:B- plasmid pS13-3 and IncX1 plasmid pS13-4, which generated two cointegrate plasmids, designated pS13D and pS13F, which involved in two intermolecular replicative mechanisms mediated by IS 26 and the novel transposon Tn 6952 ( Δ Tn AS3 -IS 26 - Δ IS Ecp1 - ramA - Δ IS 26 - Δ Tn AS1 ), respectively. This is the first report of the fusion of the IncN1-F33:A-:B- plasmid and IncFI:A-:B- plasmid mediated by IS 26 , and with IncX1 plasmid mediated by Tn 6952. The formation and evolution of cointegrate plasmids could expand the resistance and host spectrum of fusion plasmids., 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 © 2021 Liu, He, Zhang, Pan, Wu, Yuan, Liu and Hu.)

Herein, in the presence of three structure-directing agents (SDAs), a family of imidazole-functionalized resorcin[4]arene-based coordination polymers (CPs), [Zn(TIC4R)(HCOO)]·HCOO·0.5DMF·1.5H 2 O ( 1 ), [Zn(TIC4R)(CN)]·HCOO·DMF·2.5H 2 O ( 2 ), and [Zn(TIC4R)(H 2 O)]·2HCOO·2H 2 O ( 3 ), were assembled under solvothermal conditions [TIC4R = tetra(imidazole) resorcin[4]arene]. 1 exhibits a double-layer structure with rectangle windows, and 2 and 3 display monolayer structures. The layers of CPs 2 and 3 are slides with different offsets along the a -axis. In addition, three CPs were used as catalysts to catalyze Knoevenagel condensations. Strikingly, all CPs exhibit remarkable catalytic performance for several substrates. To the best of our knowledge, this is the first time that a small organic acid as SDA was used in the syntheses of resorcin[4]arene-based supramolecular isomers.

The excessive proliferation and migration of smooth muscle cells (SMCs) play an important role in restenosis following percutaneous coronary interventions. MicroRNAs are able to target various genes and involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how MicroRNAs regulated vascular SMC proliferation and vascular remodeling following carotid artery injury in mice. We showed that carotid artery injury-induced neointimal formation was remarkably ameliorated in microRNA (miR)-302 heterozygous mice and SMC-specific miR-302 knockout mice. In contrast, delivery of miR-302a adenovirus to the injured carotid artery enhanced neointimal formation. Upregulation of miR-302a enhanced the proliferation and migration of mouse aorta SMC (MASMC) in vitro by promoting cell cycle transition, whereas miR-302a inhibition caused the opposite results. Moreover, miR-302a promoted Akt activation by corporately decreasing Akt expression and increasing Akt phosphorylation in MASMCs. Application of the Akt inhibitor GSK690693 (5 μmol/L) counteracted the functions of miR-302a in promoting MASMC proliferation and migration. We further revealed that miR-302a directly targeted at the 3' untranslated region of PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and negatively regulated PHLPP2 expression. Restoration of PHLPP2 abrogated the effects of miR-302a on Akt activation and MASMC motility. Furthermore, knockdown of PHLPP2 largely abolished the inhibition of neointimal formation that was observed in miR-302 heterozygous mice. Our data demonstrate that miR-302a exacerbates SMC proliferation and restenosis through increasing Akt signaling by targeting PHLPP2.