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Climate change has had large impacts on marine animals, including neon flying squid Ommastrephes bartramii (O. bartramii) in the North Pacific Ocean. O. bartramii statoliths from 2012, 2015, and 2016 were used to evaluate the variations in life cycle events. The relationship between mantle length and body weight showed significant differences between years and gender. The oldest squid was collected in 2016 at 271 days old, further proving that O. bartramii has nearly a 1-year life span. The hatching season ranged from December to May and the peak hatching time in 2015 was one-half month later than in 2012 and 2016. Growth rates varied with environmental factors such as sea surface temperature (SST) and chlorophyll a concentration (chl. a), indicating that higher SST and chl. a concentrations led to faster growth. An extreme El Niño event with lower SST in 2015 also led to younger age class and slower growth rates. The occurrence of differences in body size and growth rates between years, caused by the interannual variations of environmental factors, makes it necessary to use separate growth curves for different years when analyzing North Pacific O. Bartramii populations.

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related areas. The inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue integration. It is of great importance to modulate this inflammatory-fibrous response, which is mainly mediated by the multidirectional interaction between fibroblasts and macrophages. In this study, macrophages are induced to generate M1 and M2 macrophage immune microenvironments. Their cytokine profiles have been proven to have potentially multi-regulatory effects on fibroblasts. The multi-reparative effects of soft tissue cells (human gingival fibroblasts) cultured on metal material (titanium alloy disks) in M1 and M2 immune microenvironments are then dissected. Fibroblasts in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop, while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration, including soft tissue regeneration, cell adhesion on materials, and contraction to immobilize soft tissue. Enlighted by the close interaction between macrophages and fibroblasts, we propose the concept of an “inflammatory-fibrous complex” to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses, thus advancing the development of metal soft tissue materials.

Objective The aim of the present study was to detect the association between platelet glycoprotein-specific autoantibodies and the patient response to short-term high-dose dexamethasone (HD-DXM) + prednisone maintenance treatment. Methods The data from 112 adult patients newly diagnosed with ITP who were administered first-line HD-DXM + prednisone maintenance therapy between January 2016 and January 2021 were retrospectively analyzed. Results A total of 72 patients positive for platelet glycoprotein-specific antibodies were enrolled in the antibody-positive group, and 40 patients not positive for platelet glycoprotein-specific antibodies were enrolled in the antibody-negative group. In the antibody-positive group, six platelet glycoprotein-specific antibody types were found: 41.67% of the patients were anti-GP IIb/IIIa-positive only, 5.56% were anti-GP Ib/IX-positive only, 5.56% were anti-P-selectin-positive only, 19.44% were anti-GP IIb/IIIa- and anti-GP Ib/IX-positive, 16.67% were anti-GP Ib/IX- and P-selectin-positive and 11.11% were positive for all three antibodies. There was no significant difference in the overall response rate between the antibody-positive group and the antibody-negative group (94.44 versus 80.00%, p = .221). However, the CR rate was significantly higher in the antibody-positive group than in the antibody-negative group (69.44% versus 40.00%, p = .032). The logistic regression analysis revealed that platelet glycoprotein-specific antibody positivity and age were two factors that could affect patient response. Conclusions The present study discovered that adult patients newly diagnosed with ITP who had positive platelet glycoprotein-specific antibody test results were likely to achieve a better response after treatment with HD-DXM + prednisone maintenance.

Context Acacetin is a natural source of flavonoids with anti-inflammatory and antioxidant effects.Objective This study determines acacetin’s protective effect and mechanism on myocardial ischaemia/reperfusion (I/R) injury.Materials and methods Sprague-Dawley rats were divided into sham and I/R injury and treatment with acacetin. Acacetin (10 mg/kg) was subcutaneously injected for 7 days. ECG and echocardiography were conducted to determine arrhythmia and heart function. The pathological characters of the heart were determined with triphenyl tetrazolium chloride staining, Haematoxylin & Eosin staining, and Masson staining. Expression of proteins in infarct tissues was examined with western blots.Results Administrated with acacetin in I/R rats significantly reduced the arrhythmia score from 4.90 to 2.50 and the reperfusion arrhythmia score from 3.79 to 1.82 in the vehicle or the acacetin group, respectively. LVEF was improved from 33.5% in the I/R group to 43.7% in the acacetin group, LVFS was increased from 16.4% to 24.5%, LVIDs was decreased from 6.5 to 5.3 mm. The inflammatory cell infiltration, myocardial fibrosis, and collagen 1 and 3 were reduced by acacetin. Acacetin promoted SOD and decreased MDA. In myocardial tissues, the expression level of TLR4 and IL-6 were restrained, and IL-10 was promoted. Apoptotic protein Bax was suppressed, and anti-apoptotic protein Bcl-2 was promoted in the acacetin group. Interestingly, the transcription factor Nrf-2/HO-1 pathway was also reversed by acacetin.Discussion and conclusion Our findings indicated that acacetin has a potential therapeutic effect in clinical application on treating I/R-induced heart injury.

Objectives To determine the trends in anemia prevalence, treatment rates, and their associated demographic and socioeconomic status factors in the U.S. nationally representative population.Methods We extracted data from individuals ≥20-year-old from the NHANES from 2005 to 2018. The trends of anemia prevalence and treatment were assessed by Cochran–Armitage test. The association between two dependent variables (anemia status and treatment) and demographic were examined by multiple logistic regression.Results The general anemia prevalence has a significant increasing trend from 5.71% to 6.86% (P trend

Zea mays (maize) is an important agricultural crop that produces a variety of valuable terpenoids, including several triterpenoids. However, no oxidosqualene cyclase (OSC) enzymes, which catalyze the first step in triterpenoid biosynthesis, have been identified in maize. Here, we identified a novel OSC (ZmOSC1) in maize using a combination of genomic mining and phylogenetic analyses. To functionally characterize the candidate OSC, we constructed a yeast strain that produced high levels of 2,3-oxidosqualene. When ZmOSC1 was expressed in this strain, three compounds were detected and identified as hop-17(21)-en-3-ol, hopenol B and simiarenol, respectively. For their biosynthesis, we proposed a potential cyclization mechanism catalyzed by ZmOSC1 via the generation of a dammarenyl cation, followed by sequential cationic ring expansion, cyclization, cationic migration and further proton elimination. This study discovered and characterized an OSC from maize for the first time, and laid a foundation to produce three bioactive pentacyclic triterpenes, hop-17(21)-en-3-ol, hopenol B and simiarenol, using synthetic biology approaches.

Introduction: High mobility group box 1 protein participates in the pathogenesis of allergic rhinitis. Activation of the inflammasome can mediate the release of high mobility group box 1. The role of the absent in melanoma 2 inflammasome in allergic rhinitis remains unclear. Objective: This study aimed to investigate the function of absent in melanoma 2 inflammasome in murine allergic rhinitis and the interaction between high mobility group box 1 and the absent in melanoma 2 inflammasome. Methods: A murine allergic rhinitis model was established using twenty Balb/c mice. Expression of the components of the absent in melanoma 2 inflammasome: absent in melanoma 2, apoptosis-associated speck-like protein containing a CARD (Asc), caspase-1 p20, and additional nod-like receptor family pyrin domain containing 3 (Nlrp3) were detected by western blotting during allergic rhinitis. Alterations of absent in melanoma 2, caspase-1, and high mobility group box 1 after ovalbumin challenge were demonstrated by immunohistochemistry. TdT-mediated dUTP Nick end labeling, TUNEL assay, and cleavage of caspase-3 and PARP-1 were used for the observation of pyroptosis. Results: Eosinophilia and goblet cell infiltration were observed in the nasal mucosa of mice in the allergic rhinitis group. Absent in melanoma 2, Asc, and caspase-1 p20 increased after ovalbumin exposure while Nlrp3 did not. High mobility group box 1 was released in the nasal mucosa of allergic rhinitis mice. TUNEL-positive cells increased in the epithelium and laminae propria, whereas cleavage of caspase-3 and PARP-1 was not observed. Conclusions: The absent in melanoma 2 inflammasome was activated and pyroptosis may occur in the nasal mucosa after ovalbumin treatment. These may contribute to the translocation of high mobility group box 1 and the development of allergic rhinitis.

Abstract Background This article discusses the management of an adolescent woman with a delayed diagnosis of adnexal torsion (AT) whose ovaries were successfully preserved. Case presentation The patient was a 14-year-old female teen admitted with the chief complaint of lower abdominal pain for 3 days and worsening pain for 2 days. Magnetic resonance imaging suggested a high possibility of torsion in the anterosuperior uterine mass and was accompanied by severe ovarian edema, bleeding, and enlargement. Intraoperatively, the left fallopian tube was characterized by thickening and torsion and appeared blackish purple. The left fallopian tube paraovarian cyst was about 20 cm in size, and the left adnexa was twisted 1080° along the left infundibulopelvic ligament (suspensory ligament of the left ovary). The left ovary appeared blackish purple, with an enlarged diameter of about 10 cm. At the request and with the informed consent of the patient’s parents, we preserved the left ovary and removed the left fallopian tube. The results of the endocrine, ultrasound, and tumor marker tests were normal 1 month after surgery. Follicles and blood flow signals seen in ultrasound examinations indirectly proved the successful preservation of the left ovary in the follow-up. Conclusions Our attempt to preserve the ovaries in an adolescent with a delayed diagnosis of AT was successful.

Abstract Background Lipid and glucose metabolism abnormalities are associated with nonalcoholic fatty liver disease (NAFLD). The triglyceride–glucose (TyG) index is a recently developed indicator that can identify individuals at risk for NAFLD. However, the applicability of the TyG index for identifying NAFLD in patients with type 2 diabetes mellitus (T2DM) is unclear. The aim of this study was to investigate the ability of the TyG index to identify individuals at risk for NAFLD in the T2DM population. Methods A total of 2280 participants with T2DM were recruited in this cross-sectional study. The TyG index was calculated, and NAFLD was diagnosed by ultrasonography. Binary logistic regression models were used to evaluate the association of the TyG index, glycemic parameters and lipid parameters with NAFLD. Results Logistic regression analysis showed that the TyG index was significantly associated with NAFLD in subjects with T2DM, the odds ratio (OR) were 3.27 (95% confidence interval [CI], 2.03–5.27; P

Abstract Repair of spinal cord injury (SCI) depends on microenvironment improvement and the reconnection between injured axons and regenerated neurons. Here, we fabricate a GelMA-MXene hydrogel nerve conduit with electrical conductivity and internal-facing longitudinal grooves and explore its function in SCI repair. It is found that the resultant grooved GelMA-MXene hydrogel could effectively promote the neural stem cells (NSCs) adhesion, directed proliferation and differentiation in vitro. Additionally, when the GelMA-MXene conduit loaded with NSCs (GMN) is implanted into the injured spinal cord site, effective repair capability for the complete transection of SCI was demonstrated. The GMN group shows remarkable nerve recovery and significantly higher BBB scores in comparison to the other groups. Therefore, GMN with the microgroove structure and loaded with NSCs is a promising strategy in treating SCI.

Abstract Background An over-expression of the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer and is associated with aggressive disease and poor prognosis. SCT200 is a newly developed recombinant, fully humanized, anti-EGFR monoclonal antibody. This study aimed to evaluate its safety, tolerability, pharmacokinetics (PK), and efficacy in patients with wild-type KRAS/NRAS/BRAF metastatic colorectal cancer (mCRC). Methods This phase I study comprising dose-escalation phase and dose-expansion phase. SCT200 was administrated intravenously to groups of three to six patients. An every 3-week dosing cycle (0.5–15.0 mg/kg) and multiple dosing schedule were evaluated. Blood samples were collected at preset intervals for PK assessment, radiological imaging was used for efficacy assessment, and continuous safety monitoring was performed in each group during the study. Results From December 16, 2014 to December 31, 2018, fifty-six patients with wild-type K RAS/NRAS/BRAF mCRC receiving ≥ 1 dose of SCT200 were evaluated. Among them, 44.6% (25/56) of the patients failed at least two prior lines of chemotherapy. No dose-limiting toxicities occurred in any group. All of the patients experienced treatment-emergent adverse events (TEAEs). 96.4% (54/56) of patients experienced treatment-related adverse events (TRAEs), and 26.8% (15/56) of patients with Grade ≥ 3 TRAEs. No serious TRAEs were observed. The most common TRAEs were dermotoxicity and hypomagnesemia. PK analysis showed non-linear PK in the range of 0.5 - 8.0 mg/kg of single dose SCT200, the clearance decreased, and the elimination half-life (T1/2) prolonged following dose increase. In the multiple-dose period, the clearance decreased, peak concentration increased, and T1/2 prolonged during prolonged drug administration, and a steady state was reached after five consecutive dose of 6.0 mg/kg quaque week (QW). The objective response rate (ORR) was 30.4% (17/56, 95% confidence interval [CI], 18.8%–44.1%). The ORR in the dose-expansion group (6.0 mg/kg QW) was 48.0% (12/25, 95% CI, 27.8%–68.7%), the median progression-free survival was 5.2 months (95%CI, 3.6–5.5), and the median overall survival was 20.2 months (95%CI, 12.1-not reached). Conclusions SCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC. Trial registration This study was registered with ClinicalTrials.gov ( NCT02211443 ).

Abstract Due to the strong coupling among the conductors of 10 kV three‐core armored cables and the difficulty in identifying its defects and fault types, a method is proposed based on the input impedance spectrum. Firstly, the phase mode transformation matrix of a three‐core cable is obtained by combining the multi‐conductor transmission line theory with the loop analysis method to realize decoupling between conductors. Secondly, the input impedance matrices of a cable under different situations are derived. Based on this, a method is proposed to identify the local defects and fault types. The capacitive defects and inductive defects are identified according to the left or right offset of the amplitude spectrum; the short circuit and break faults of the cable can be identified according to the number of resonant points in the amplitude spectrum and the initial phase angle of the phase spectrum. Finally, to verify the correctness of the proposed method, a 10 kV three‐core cable is taken as an example to carry out PSCAD circuit simulation and practical test. The results show that the proposed method can effectively identify the local defects and fault types of the three‐core cable.

This study identifies the evolutionarily conserved Exportin 4 as an essential regulator in the nuclear export of circRNAs. Defective circRNA export results in R-loop formation and DNA damage in cells, as well as testis and neurological defects in mice.

Scutellarin related drugs have superior therapeutic effects on cerebrovascular and cardiovascular diseases. Here, an optimal biosynthetic pathway for scutellarin was constructed in Yarrowia lipolytica platform due to its excellent metabolic potential. By integrating multi-copies of core genes from different species, the production of scutellarin was increased from 15.11 mg/L to 94.79 mg/L and the ratio of scutellarin to the main by-product was improved about 110-fold in flask condition. Finally, the production of scutellarin was improved 23-fold and reached to 346 mg/L in fed-batch bioreactor, which was the highest reported titer for de novo production of scutellarin in microbes. Our results represent a solid basis for further production of natural products on unconventional yeasts and have a potential of industrial implementation.

Exosomes are membrane bound extracellular vesicles that play an important role in many biological processes. While they have great application value, exosome isolation is still considered a major scientific challenge. In the present study, a novel separation strategy for exosomes is proposed based on the specific interaction between immobilized peptide ligands and phosphatidylserine moieties which are highly abundant on the surface of exosomes. With the new affinity method, intact model exosomes can be recovered with a high yield in a short processing time. The purity of exosome samples enriched from serum by the affinity method is far higher than that isolated by ultrafiltration, and similar to that obtained by density gradient centrifugation and ultracentrifugation. Moreover, the variety of contaminants co-isolated by the affinity method is relatively low due to its specific separation principle. Proteomics analysis of exosomes isolated by the affinity method from the serum of healthy, hepatocellular carcinoma patients, and intrahepatic cholangiocarcinoma patients was performed to prove the applicability of this method. In conclusion, our novel strategy shows characteristics of easy preparation, high specificity, and cost-effectiveness, and provides a promising approach for exosome isolation which should have wide applications.

Abstract Background Citrate Synthase (Cs) gene mutation (locus ahL4) has been found to play an important role in progressive hearing loss of A/J mice. HEI-OC1 cells have been widely used as an in vitro system to study cellular and molecular mechanisms related to hearing lose. We previously reported the increased apoptosis and the accumulation of reactive oxygen species in shRNACs-1429 cells, a Cs low-expressed cell model from HEI-OCI. The details of the mechanism of ROS production and apoptosis mediated by the abnormal expression of Cs needed to research furtherly. Methods iTRAQ proteomics was utilized to detect the differentially expressed proteins (DEPs) caused by low expression of Cs. The GO and KEGG pathways analysis were performed for annotation of the differentially expressed proteins. Protein–protein interaction network was constructed by STRING online database. Immunoblotting was utilized to confirm the protein levels of the the differentially expressed proteins. Results The differentially expressed proteins were significantly enriched in various signaling pathways mainly related to mitochondrial dysfunction diseases including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, et al. Most noteworthy, the oxidative phosphorylation pathway was most significantly suppressed in the shRNACs-1429 cells,, in which a total of 10 differentially expressed proteins were enriched and were all downregulated by the abnormal expression of Cs. The downregulations of Ndufb5, Ndufv1 and Uqcrb were confirmed by immunoblotting. Meanwhile, the ATP levels of shRNACs-1429 cells were also reduced. Conclusions These results suggest that low level expression of Cs induces the inhibition of oxidative phosphorylation pathway, which is responsible for the high level production of reactive oxygen species and low level of ATP, leading to the apoptosis of cochlear cells. This study may provide new theories for understanding and therapy of progressive hearing loss.

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8+ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8+ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.

Abstract Background High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown. Method We performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers). Results Exploring the transcriptomes of 19,008 cells, predominantly from BRCA1 + samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1 + samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1 + carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1 + patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions. Conclusion These results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

Abstract Current evidence has suggested that diabetes increases the risk of implanting failure, and therefore, appropriate surface modification of dental implants in patients with diabetes is crucial. TiO2 nanotube (TNT) has an osteogenic nanotopography, and its osteogenic properties can be further improved by loading appropriate drugs. Cinnamaldehyde (CIN) has been proven to have osteogenic, anti-inflammatory, and anti-bacterial effects. We fabricated a pH-responsive cinnamaldehyde-TiO2 nanotube coating (TNT-CIN) and hypothesized that this coating will exert osteogenic, anti-inflammatory, and anti-bacterial functions in a simulated diabetes condition. TNT-CIN was constructed by anodic oxidation, hydroxylation, silylation, and Schiff base reaction to bind CIN, and its surface characteristics were determined. Conditions of diabetes and diabetes with a concurrent infection were simulated using 22-mM glucose without and with 1-μg/mL lipopolysaccharide, respectively. The viability and osteogenic differentiation of bone marrow mesenchymal stem cells, polarization and secretion of macrophages, and resistance to Porphyromonas gingivalis and Streptococcus mutans were evaluated. CIN was bound to the TNT surface successfully and released better in low pH condition. TNT-CIN showed better osteogenic and anti-inflammatory effects and superior bacterial resistance than TNT in a simulated diabetes condition. These findings indicated that TNT-CIN is a promising, multifunctional surface coating for patients with diabetes needing dental implants. Graphical abstract

This study determined the effects of seed structures on seed dormancy and tested methods to break dormancy in seeds of Urochloa hybrid cultivar ‘Mulato II’. Seeds stored for 10 months in indoor ambient conditions were studied to determine effects of seed structures on seed germination and their water permeability. Results showed that seed structures presented a barrier to water permeability. Removal of lemmas, puncturing the seed coat, seed structure removal and sulfuric acid immersion all reduced seed dormancy. Water and alcohol extracts from different parts of seeds inhibited seed germination of Brassica pekinensis seeds. There were 3 mechanisms responsible for seed dormancy; first, the mechanical barrier of seed structures, which excluded water and reduced gas exchange as well as restricting growth of the embryo; second, an endogenous germination inhibitor mainly found in lemmas; and third, water permeability of the seed coat (including pericarp and testa). The mechanical removal of lemmas and immersion in concentrated sulfuric acid reduced seed dormancy, although mechanical removal of the lemma alone was effective, convenient and safer.

Objectives: Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. Methods: In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). Results: For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. Conclusion: A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation.

Abstract Background Chemoresistance is a major factor contributing to the poor prognosis of patients with pancreatic cancer, and cancer stemness is one of the most crucial factors associated with chemoresistance and a very promising direction for cancer treatment. However, the exact molecular mechanisms of cancer stemness have not been completely elucidated. Methods m6A-RNA immunoprecipitation and sequencing were used to screen m6A-related mRNAs and lncRNAs. qRT-PCR and FISH were utilized to analyse DDIT4-AS1 expression. Spheroid formation, colony formation, Western blot and flow cytometry assays were performed to analyse the cancer stemness and chemosensitivity of PDAC cells. Xenograft experiments were conducted to analyse the tumour formation ratio and growth in vivo. RNA sequencing, Western blot and bioinformatics analyses were used to identify the downstream pathway of DDIT4-AS1. IP, RIP and RNA pulldown assays were performed to test the interaction between DDIT4-AS1, DDIT4 and UPF1. Patient-derived xenograft (PDX) mouse models were generated to evaluate chemosensitivities to GEM. Results DDIT4-AS1 was identified as one of the downstream targets of ALKBH5, and recruitment of HuR onto m6A-modified sites is essential for DDIT4-AS1 stabilization. DDIT4-AS1 was upregulated in PDAC and positively correlated with a poor prognosis. DDIT4-AS1 silencing inhibited stemness and enhanced chemosensitivity to GEM (Gemcitabine). Mechanistically, DDIT4-AS1 promoted the phosphorylation of UPF1 by preventing the binding of SMG5 and PP2A to UPF1, which decreased the stability of the DDIT4 mRNA and activated the mTOR pathway. Furthermore, suppression of DDIT4-AS1 in a PDX-derived model enhanced the antitumour effects of GEM on PDAC. Conclusions The ALKBH5-mediated m6A modification led to DDIT4-AS1 overexpression in PDAC, and DDIT-AS1 increased cancer stemness and suppressed chemosensitivity to GEM by destabilizing DDIT4 and activating the mTOR pathway. Approaches targeting DDIT4-AS1 and its pathway may be an effective strategy for the treatment of chemoresistance in PDAC.

Abstract This paper is dedicated to the challenging issue of the cooperative attitude tracking control of a multi-spacecraft system under communication delays. A state estimator using the attitude information of the neighbors is designed for each follower spacecraft to estimate the time-varying attitude information of the leader spacecraft in the case that the leader spacecraft cannot directly communicate with all following spacecraft. By constructing auxiliary variables based on estimated values and proposing a fixed-time control law to ensure that the auxiliary variables of the spacecraft can reach zero in fixed time, which is independent of the initial state, the effects of time-varying reference attitudes on the system can be reduced. The attitude error and the estimation error are proven to converge to the region containing the origin by input-to-state stability theory combined with the Lyapunov–Krasovskii approach. To further illustrate the effectiveness of the proposed control algorithm, numerical simulation results are presented.

Abstract Background For sigmoid colon or rectal cancer, a definite consensus regarding the optimal level ligating the inferior mesenteric artery (IMA) has not been reached. We performed this study to determine whether the ligation level significantly affected short-term and long-term outcomes of patients with sigmoid colon or rectal cancer after curative laparoscopic surgery. Methods Medical records of patients with sigmoid colon or rectal cancer who had undergone curative laparoscopic surgery between January 2008 and December 2014 at the Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine were reviewed. Then, the high tie group (HTG) was compared with the low tie group (LTG) in terms of short-term and long-term outcomes. Results Five-hundred ninety patients were included. No significant differences between two groups regarding baseline characteristics existed. HTG had a significantly higher risk of anastomotic fistula than LTG (21/283 vs 11/307, P = 0.040). Additionally, high ligation was proven by multivariate logistic regression analysis to be an independent factor for anastomotic fistula (P = 0.038, OR = 2.232, 95% CI: 1.047–4.758). Furthermore, LT resulted in better preserved urinary function. However, LTG was not significantly different from HTG regarding operative time (P = 0.075), blood transfusion (P = 1.000), estimated blood loss (P = 0.239), 30-day mortality (P = 1.000), ICU stay (P = 0.674), postoperative hospital stay (days) (P = 0.636), bowel obstruction (P = 0.659), ileus (P = 0.637), surgical site infection (SSI) (P = 0.121), number of retrieved lymph nodes (P = 0.501), and number of metastatic lymph nodes (P = 0.131). Subsequently, it was revealed that level of IMA ligation did not significantly influence overall survival (OS) (P = 0.474) and relapse-free survival (RFS) (P = 0.722). Additionally, it was revealed that ligation level did not significantly affect OS (P = 0.460) and RFS (P = 0.979) of patients with stage 1 cancer, which was also observed among patients with stage 2 or stage 3 cancer. Ultimately, ligation level was not an independent predictive factor for either OS or RFS. Conclusions HT resulted in a significantly higher incidence of anastomotic fistula and worse preservation of urinary function. Level of IMA ligation did not significantly affect long-term outcomes of patients with sigmoid colon or rectal cancer after curative laparoscopic surgery.

Eutectic high-entropy alloys (EHEAs) feature attractive strength–ductility balance at both ambient and cryogenic temperatures. Nevertheless, microstructural origins underpinning these balanced mechanical properties remain elusive. Here the deformation mechanisms of a recently-reported Al19Co20Fe20Ni41 EHEA were comparatively investigated at 298 and 77 K, which revealed a high frequency and density of dislocation multi-slip scenario in the soft eutectic lamellae and the corresponding compatible co-deformation in the adjacent hard lamellae that collectively endowed strong hetero-deformation-induced (HDI) hardening and excellent forest-dislocation hardening. Therefore, better ductility and tensile strength, in comparison to the other widely-studied EHEA system, could be sustained even at liquid-nitrogen temperatures.

Abstract Background Elucidation of the post‐transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin‐proteasome system (UPS) mediates a reversible, stringent and stepwise post‐translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. Methods We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain‐containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno‐associated virus (rAAV) were used to endogenously overexpress full‐length HUWE1 in vitro and in glioma orthotopic xenografts. Results Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N‐Myc mediated by HUWE1, leading to the inactivation of downstream Delta‐like 1 (DLL1)‐NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual‐vector system for packaging and delivery of dCas9‐VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. Conclusions The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual‐vector delivering dCas9‐HUWE1 system uncovers a promising therapeutic strategy for GBM.

Abstract Background Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small cell lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions and the efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in the KRAS gene resistant to ICIs and elucidate resistance mechanism. Methods The association between KRAS variant status and the efficacy of ICIs was explored with a clinical cohort (n = 74), and confirmed with a mouse model. In addition, the tumor immune microenvironment (TIME) of KRAS‐mutant NSCLC, such as CD8+ tumor‐infiltrating lymphocytes (TILs) and PD‐L1 level, was investigated. Cell lines expressing classic KRAS substitutions were used to explore signaling pathway activation involved in the formation of TIME. Furthermore, interventions that improved TIME were developed to increase responsiveness to ICIs. Results We observed the inferior efficacy of ICIs in KRAS‐G12D‐mutant NSCLC. Based upon transcriptome data and immunostaining results from KRAS‐mutant NSCLC, KRAS‐G12D point mutation negatively correlated with PD‐L1 level and secretion of chemokines CXCL10/CXCL11 that led to a decrease in CD8+ TILs, which in turn yielded an immunosuppressive TIME. The analysis of cell lines overexpressing classic KRAS substitutions further revealed that KRAS‐G12D mutation suppressed PD‐L1 level via the P70S6K/PI3K/AKT axis and reduced CXCL10/CXCL11 levels by down‐regulating high mobility group protein A2 (HMGA2) level. Notably, paclitaxel, a chemotherapeutic agent, upregulated HMGA2 level, and in turn, stimulated the secretion of CXCL10/CXCL11. Moreover, PD‐L1 blockade combined with paclitaxel significantly suppressed tumor growth compared with PD‐L1 inhibitor monotherapy in a mouse model with KRAS‐G12D‐mutant lung adenocarcinoma. Further analyses revealed that the combined treatment significantly enhanced the recruitment of CD8+ TILs via the up‐regulation of CXCL10/CXCL11 levels. Results of clinical study also revealed the superior efficacy of chemo‐immunotherapy in patients with KRAS‐G12D‐mutant NSCLC compared with ICI monotherapy. Conclusions Our study elucidated the molecular mechanism by which KRAS‐G12D mutation drives immunosuppression and enhances resistance of ICIs in NSCLC. Importantly, our findings demonstrate that ICIs in combination with chemotherapy may be more effective in patients with KRAS‐G12D‐mutant NSCLC.

Objectives Recently the effects of coronal malalignment (CM) in degenerative lumbar scoliosis (DLS) have been reported, however, there was few studies on the correlated parameters of coronal alignments at pre‐operation. The aims of this current study were to investigate the associations of coronal parameters with scoliosis and coronal alignment, and to explore the relationships between the coronal pelvic tilt and coronal alignment in DLS. Methods One hundred and sixty‐one DLS patients in our hospital from May 2016 to December 2020 were reviewed and documented. The coronal balance distance (CBD, the offset between the center of C7 and the plumb line drawn from the center of S1), major Cobb (MC), fractional Cobb (FC), L4 coronal tilt, L5 coronal tilt, coronal pelvic tilt, apical rotation, and the vertebras in major curve were measured and documented. CM was considered if the CBD ≥ 30mm. All of those participants were assigned into group A (CBD ≥ 30 mm) and group B (CBD

Abstract Background Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated. Results CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors. Conclusions This study indicates that N6-methyladenosine-mediated CELF2 promotes AS of CD44, affecting the ERAD pathway and regulating the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development.

Abstract The incidence of chronic obstructive pulmonary disease (COPD) is related to the interaction between environmental exposure and genetic factors. Far more than 15% of smokers eventually develop COPD. In addition to smoking, genetic susceptibility may be another factor in the development of COPD. IL‐22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Here, we conducted a case–control study to evaluate the association between IL‐22 tag‐single nucleotide polymorphisms (SNPs) and COPD risk. Four tag‐SNPs (rs2227478, rs2227481, rs2227484 and rs2227485) were identified according to linkage disequilibrium (LD) analysis in 30 healthy controls. A total of 513 COPD cases and 504 controls were recruited to perform an association study between these four tag‐SNPs and COPD risk. We found that the “C” allele of rs2227478T>C and the “T” allele of rs2227481C>T were obviously related to decreased COPD susceptibility. Genetic model analysis showed that rs2227478T>C and rs2227481C>T were significantly associated with a decreased risk of COPD under dominant models after adjusting for the above factors. In the recessive model, rs2227485T>C was obviously associated with decreased COPD risk. Our data showed that only rs2227485T>C was associated with a decreased COPD risk after Bonferroni correction. The eQTL analysis showed that rs2227485T>C was significantly associated with IL‐22 expression. The pGL4‐rs2227485‐C gene reporter had a higher promoter activity than pGL4‐rs2227485‐T. In our study, rs2227485T>C, located in the promoter region of IL‐22, was associated with a decreased risk of COPD and increased IL‐22 promoter activity, suggesting that this variant might modulate COPD susceptibility.

Graphene-based nanomaterials (GBNMs) has been thoroughly investigated and extensively used in many biomedical fields, especially cancer therapy and bacteria-induced infectious diseases treatment, which have attracted more and more attentions due to the improved therapeutic efficacy and reduced reverse effect. GBNMs, as classic two-dimensional (2D) nanomaterials, have unique structure and excellent physicochemical properties, exhibiting tremendous potential in cancer therapy and bacteria-induced infectious diseases treatment. In this review, we first introduced the recent advances in development of GBNMs and GBNMs-based treatment strategies for cancer, including photothermal therapy (PTT), photodynamic therapy (PDT) and multiple combination therapies. Then, we surveyed the research progress of applications of GBNMs in anti-infection such as antimicrobial resistance, wound healing and removal of biofilm. The mechanism of GBNMs was also expounded. Finally, we concluded and discussed the advantages, challenges/limitations and perspective about the development of GBNMs and GBNMs-based therapies. Collectively, we think that GBNMs could be potential in clinic to promote the improvement of cancer therapy and infections treatment.

Abstract To evaluate the cardiac safety of anti-HER2-targeted therapy for early breast cancer; to investigate whether trastuzumab combined with pertuzumab increases cardiac toxicity compared with trastuzumab; to evaluate the predictive value of high-sensitivity Troponin (hs-TnI) and QTc for the cardiotoxicity associated with anti-HER2 targeted therapy in early breast cancer. A total of 420 patients with early-stage HER2-positive breast cancer who received trastuzumab or trastuzumab combined with pertuzumab for more than half a year in Tianjin Medical University Cancer Hospital from January 2018 to February 2021 were included. Left ventricle ejection fraction (LVEF), hs-TnI values, and QTc were measured at baseline and 3, 6, 9, 12 months. Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Cardiotoxicity developed in 67 of the 420 patients (15.9%) and all patients had LVEF above 50% before and after treatment. The incidence of cardiotoxicity in trastuzumab and trastuzumab combined with pertuzumab was 14.3% and 17.9%, respectively (P > 0.05). Logistic regression analysis showed that age, coronary heart disease, left chest wall radiotherapy, and anthracyclines sequential therapy were independent risk factors for cardiotoxicity (P

Abstract Breast cancer causes morbidity and mortality among women worldwide, despite much research illuminating the genetic basis of this disease. Anti-angiogenesis therapies have been widely studied, although the association between angiopoietin-2 (ANGPT2) single nucleotide polymorphisms (SNPs) and breast cancer subtypes remains unclear. This case–control study included 464 patients with malignant breast neoplasms and 539 cancer-free females. We explored the effects of ANGPT2 SNPs on the susceptibility for a malignant breast neoplasm in a Chinese Han population. Five ANGPT2 SNPs (rs2442598, rs734701, rs1823375, 11,137,037, and rs12674822) were analyzed using TaqMan SNP genotyping. Carriers of the variant GG allele of rs1823375 were less likely than wild-type carriers to be diagnosed with clinically staged breast cancer, while females with human epidermal growth factor receptor 2 (HER2)-enriched disease carrying the CG or the CG+GG genotype at rs1823375 were significantly less likely than CC genotype carriers to be of lymph node status N1–N3. We also found that the T-T-C-A-T ANGPT2 haplotype significantly increased the risk for developing a malignant breast neoplasm by 1.385-fold (95% CI: 1.025–1.871; p

Abstract Background Saccharomyces cerevisiae is often used as a cell factory for the production of S-adenosyl-l-methionine (SAM) for diverse pharmaceutical applications. However, SAM production by S. cerevisiae is negatively influenced by glucose repression, which is regulated by a serine/threonine kinase SNF1 complex. Here, a strategy of alleviating glucose repression by deleting REG1 (encodes the regulatory subunit of protein phosphatase 1) and overexpressing SNF1 (encodes the catalytic subunit of the SNF1 complex) was applied to improve SAM production in S. cerevisiae. SAM production, growth conditions, glucose consumption, ethanol accumulation, lifespan, glycolysis and amino acid metabolism were analyzed in the mutant strains. Results The results showed that the multiple effects of REG1 deletion and/or SNF1 overexpression exhibited a great potential for improving the SAM production in yeast. Enhanced the expression levels of genes involved in glucose transport and glycolysis, which improved the glucose utilization and then elevated the levels of glycolytic intermediates. The expression levels of ACS1 (encoding acetyl-CoA synthase I) and ALD6 (encoding aldehyde dehydrogenase), and the activity of alcohol dehydrogenase II (ADH2) were enhanced especially in the presence of excessive glucose levels, which probably promoted the conversion of ethanol in fermentation broth into acetyl-CoA. The gene expressions involved in sulfur-containing amino acids were also enhanced for the precursor amino acid biosynthesis. In addition, the lifespan of yeast was extended by REG1 deletion and/or SNF1 overexpression. As expected, the final SAM yield of the mutant YREG1ΔPSNF1 reached 8.28 g/L in a 10-L fermenter, which was 51.6% higher than the yield of the parent strain S. cerevisiae CGMCC 2842. Conclusion This study showed that the multiple effects of REG1 deletion and SNF1 overexpression improved SAM production in S. cerevisiae, providing new insight into the application of the SNF1 complex to abolish glucose repression and redirect carbon flux to nonethanol products in S. cerevisiae.

In order to promote the efficient utilization of clean energy, in this paper, a fast charging demand prediction model based on the intelligent sensing system of dynamic electric vehicles (EVs) under EVs-Traffic-Distribution coupling is proposed. The established model consists of two parts: electric vehicle dynamic driving model and fast charging demand prediction model based on state transition intelligent sensing. The dynamic driving model of electric vehicle reflects the impact of traffic conditions on driving speed and power consumption, as well as the impact of vehicle driving on the road network under various states such as driving, parking and charging. In the fast charging demand prediction model based on state transition intelligent sensing, the intelligent sensing system can recommend the optimal path to users according to real-time road conditions and vehicle driving conditions. Taking a planning area as an example, the Monte Carlo simulation method is used for fast charging load forecasting. The simulation results verify the correctness and effectiveness of the proposed model.

Abstract Background Although targeted agents have been gradually applied in the treatment of HER2-mutated non-small cell lung cancer (NSCLC) in recent years, patients’ therapeutic demands are far from being met. PATHER2 was the first phase 2 trial to explore the efficacy and safety of the HER2-targeted tyrosine kinase inhibitor (TKI) pyrotinib plus the antiangiogenic agent apatinib in previously treated HER2-altered metastatic NSCLC patients. Methods HER2-mutated or HER2-amplified metastatic NSCLC patients who had failed at least first-line chemotherapy or HER2-targeted TKIs received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression, intolerable toxicity, or death. The primary endpoint was the investigator-assessed objective response rate (ORR). Results Between March 2019 and December 2020, 33 patients were enrolled; 13 (39.4%) presented brain metastases, and 16 (48.5%) had received at least two lines of prior chemotherapy or HER2-targeted TKIs. As of September 20, 2021, the median follow-up duration was 11.3 (range, 3.5–26.0) months. The investigator-assessed ORR was 51.5% (17/33; 95% CI, 33.5 to 69.2%), and the disease control rate was 93.9% (31/33; 95% CI, 79.8 to 99.3%). The median duration of response, progression-free survival, and overall survival were 6.0 (95% CI, 4.4 to 8.6) months, 6.9 (95% CI, 5.8 to 8.5) months, and 14.8 (95% CI, 10.4 to 23.8) months, respectively. The most frequent grade ≥ 3 treatment-related adverse events included diarrhea (3.0%) and hypertension (9.1%). No treatment-related deaths were reported. Conclusions Pyrotinib plus apatinib demonstrated promising antitumor activity and a manageable safety profile in HER2-mutated or HER2-amplified metastatic NSCLC patients. Trial registration Chinese Clinical Trial Registry Identifier: ChiCTR1900021684 .

Objective: We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib, and the Bloom syndrome protein (BLM) helicase inhibitor, ML216, in non-small cell lung cancer (NSCLC) cells. Methods: Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays. Mechanistically, the effects of ML216, olaparib, and radiation on cell and tumor proliferation, DNA damage, cell cycle, apoptosis, homologous recombination (HR) repair, and non-homologous end joining (NHEJ) repair activity were determined. Results: Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells, which was seen as decreased surviving fractions and Rad51 foci, increased total DNA damage, and γH2AX and 53BP1 foci (P < 0.05). The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation (P < 0.05), while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells. In addition to increases of double strand break (DSB) damage and decreases of Rad51 foci, olaparib combined with ML216 also increased pDNA-PKcs (S2056) foci, abrogated G2 cell cycle arrest, and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo (P < 0.05). Moreover, Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair, promoted NHEJ repair, and inactivated cell cycle checkpoint signals both in vitro and in vivo (P < 0.05). Conclusions: Taken together, these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells, and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization, as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy.

Abstract Aims The prognosis of heart failure (HF) depends on genetic predisposition, and recent studies have shown that impaired autophagy is involved in HF. This study was aimed to construct a prognostic model combining polygenetic background based on the autophagy pathway and other traditional risk factors (TRF) of HF prognosis. Methods and results Via re‐analysing the transcriptomic data of 50 failing and 14 non‐failing donors, differentially expressed autophagy‐related genes (ARGs) were chosen for further comparison and analysis with whole exome sequencing and follow‐up data of 1000 HF patients. By searching from reported articles, prognosis‐related polymorphisms were identified. ARGs and prognosis‐related polymorphisms were used to develop genetic risk score (GRS) and genetic risk factor (GRF), respectively. We compared the predictive power of five models [Model 1, GRS; Model 2, composite of TRF and N‐terminal B‐type natriuretic peptide (NT‐proBNP); Model 3, composite of TRF, NT‐proBNP, and GRS; Model 4, composite of TRF, NT‐proBNP, and GRF; and Model 5, composite of TRF, NT‐proBNP, GRF, and GRS] by applying receiver operating characteristic curves. Twenty‐four prognosis‐related polymorphisms were used to construct GRF and 11 variants among 48 differentially expressed ARGs associated with clinical outcomes of HF patients were applied for GRS. GRS was strongly associated with cardiac mortality of HF patients, independent of TRF and GRF (95% confidence interval 1.273–1.739, P = 5.78 × 10−7). Comparing with patients with lowest GRS tertile, those with highest tertile had higher risks of developing worse clinical outcomes (hazard ratio = 1.866; 95% confidence interval 1.352–2.575, P = 1.47 × 10−4). The discrimination power of the model including GRS, TRF, GRF, and NT‐proBNP is most considerable (area under curve = 0.777), especially in men, patients over 60, patients with hypertension, patients without diabetes or hyperlipidaemia. Conclusions The model combining autophagy‐related GRS, TRF, GRF, and NT‐proBNP performs well in distinguishing between worse‐prognosis and better‐prognosis HF patients, leading a promising strategy for HF treatment and HF prevention.

In this paper, we research semi-discrete multipoint flux mixed finite element (MFMFE) method for parabolic optimal control problem (OCP). The state and co-state variables are approximated by the lowest order Brezzi-Douglas-Marini (BDM) mixed finite element (MFE) spaces and the control is approximated by piecewise constant. The advantage of this type of mixed element method is that it can decouple the state and adjoint state variables as cell-centered difference schemes rather than to solve saddle point algebraic equations. Error estimates and convergence orders are derived rigorously for state and control variables. Finally, a numerical example is given to confirm our theoretical analysis.

Some H5 viruses isolated in poultry or wild birds between 2020 and 2021 were found to be antigenically different from the vaccine strains (H5-Re11 and H5-Re12) used in China. In this study, we generated three new recombinant vaccine seed viruses by using reverse genetics and used them for vaccine production. The vaccine strain H5-Re13 contains the hemagglutinin (HA) and neuraminidase (NA) genes of an H5N6 virus that bears the clade 2.3.4.4h HA gene, H5-Re14 contains the HA and NA genes of an H5N8 virus that bears the clade 2.3.4.4b HA gene, and H7-Re4 contains the HA and NA genes of H7N9 virus detected in 2021. We evaluated the protective efficacy of the novel H5/H7 trivalent inactivated vaccine in chickens, ducks, and geese. The inactivated vaccine was immunogenic and induced substantial antibody responses in the birds tested. Three weeks after vaccination, chickens were challenged with five different viruses detected in 2020 and 2021: three viruses (an H5N1 virus, an H5N6 virus, and an H5N8 virus) bearing the clade 2.3.4.4b HA gene, an H5N6 virus bearing the clade 2.3.4.4h HA gene, and an H7N9 virus. All of the control birds shed high titers of virus and died within 4 days post-challenge, whereas the vaccinated chickens were completely protected from these viruses. Similar protective efficacy against H5 viruses bearing the clade 2.3.4.4h or 2.3.4.4b HA gene was observed in ducks and geese. Our study indicates that the newly updated H5/H7 vaccine can provide solid protection against the H5 and H7N9 viruses that are currently circulating in nature.

Abstract Stratospheric airships are long‐endurance flight platforms that utilize renewable energy systems. The solar array in these systems cannot generate electricity at night; only an energy storage battery pack can be used to power the entire system. Therefore, accurate modeling and estimation of the output characteristics and operating conditions of battery packs have become the focus of current research. During the actual flight of an airship, uneven temperature distribution causes changes in the output characteristics and differences in the cell voltage of the battery packs. To address this problem, this study establishes an output characteristic model, series–parallel structure coupled with a temperature field model (SPTM), for a battery pack based on the series–parallel structure of a single cell. In addition, the influence of temperature distribution was considered in the model. Then, a flight verification test was conducted, and the test data and simulation data were compared. The average absolute error of the SPTM was maintained at approximately 0.61 V, which accurately reflected the output characteristics of the battery pack. The simulation model was then used to study the cell voltage difference under changes in the temperature distribution and demonstrate the relationship between the cell voltage difference and temperature difference.

Due to the limited wear resistance, AISI 1045 steel has limited applications in harsh environments, and the friction effect leads to premature scrapping. In order to improve the mechanical properties of AISI1045 steel, in this study, WC-Co particles reinforced AISI 1045 steel composites were produced by selective laser melting (SLM), and mainly focused on the influence of laser line energy density (LED) on the microstructure and mechanical properties in detail. The Vickers hardness test and rotational friction test were conducted to determine the Vickers hardness and friction resistance properties of composites. Results demonstrated that the SLM 500 J/m WC-Co/AISI 1045 steel composites possesses higher Vickers hardness and wear resistance compared to that of other samples owing to the finer grains and higher relative density. Herein, the wear mechanism and the binding interface of the SLM composites was also deeply discussed in this paper.

Amphotericin B (AmB) is an amphiphilic drug commonly formulated in liposomes and administered intravenously to treat systemic fungal infections. Recent studies on the liposomal drug product have shed light on the AmB aggregation status in the bilayer, which heat treatment (curing) modifies. Although toxicity was found related to aggregation status - loose aggregates significantly more toxic than tight aggregates - the precise mechanism linking aggregation and toxicity was not well understood. This study directly measured drug release rate from various AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state, drug release, and in vitro toxicity. UV–Vis spectroscopy of these products detected unique curing-induced changes in the UV spectral features: a ∼25 nm blue-shift of the main absorption peak (λmax) in aqueous buffer and a decrease in the OD346/OD322 ratio upon thermal curing, reflecting tighter aggregation. In vitro release testing (IVRT) data showed, by applying and fitting first-order release kinetic models for one or two pools, that curing impacts two significant changes: a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated, more thermodynamically stable drug pool. The kinetic data thus corroborated the trend independently deduced from the UV–Vis spectral data. The in vitro toxicity assay indicated a decreased toxicity with curing, as shown by the significantly increased concentration, causing half-maximal potassium release (TC50). The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation. This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release (directly measured rate constants), providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.

Abstract. Background:. Although existing mycological tests (bronchoalveolar lavage [BAL] galactomannan [GM], serum GM, serum (1,3)-β-D-glucan [BDG], and fungal culture) are widely used for diagnosing invasive pulmonary aspergillosis (IPA) in non-hematological patients with respiratory diseases, their clinical utility in this large population is actually unclear. We aimed to resolve this clinical uncertainty by evaluating the diagnostic accuracy and utility of existing tests and explore the efficacy of novel sputum-based Aspergillus assays. Methods:. Existing tests were assessed in a prospective and consecutive cohort of patients with respiratory diseases in West China Hospital between 2016 and 2019 while novel sputum assays (especially sputum GM and Aspergillus-specific lateral-flow device [LFD]) in a case-controlled subcohort. IPA was defined according to the modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Sensitivity and specificity were computed for each test and receiver operating characteristic (ROC) curve analysis was performed. Results:. The entire cohort included 3530 admissions (proven/probable IPA = 66, no IPA = 3464) and the subcohort included 127 admissions (proven/probable IPA = 38, no IPA = 89). Sensitivity of BAL GM (≥1.0 optical density index [ODI]: 86% [24/28]) was substantially higher than that of serum GM (≥0.5 ODI: 38% [39/102]) (χ2 = 19.83, P

Series of unequal quantity Nd/Ce co-doped ceramic nuclear waste forms, (Gd, Nd)2(Zr, Ce)2O7, were prepared to tailor its ordered pyrochlore or disordered fluorite structure. The phase transition, microtopography, and elemental composition of the ceramic samples were systematically investigated, especially the effect of order-disorder structure on the chemical stability. It was confirmed that unequal quantity of Nd/Ce could synchronously replace the Gd/Zr-sites of Gd2Zr2O7. And the phase transition of order-disorder structure could be successfully tailored by regulating the average cationic radius ratio of (Gd, Nd)2(Zr, Ce)2O7 series. The elements of Gd, Nd, Zr, and Ce are uniformly distributed in the ordered or disordered structures. The MCC-1 leaching results showed that (Gd, Nd)2(Zr, Ce)2O7 pyrochlore ceramic nuclear waste forms had excellent chemical stability, whose elements' normalized leaching rates were as low as 10−4 -10−7 g‧m−2‧d−1 after 7 days. In particular, the chemical stability of disordered structure was superior to that of ordered structure. It was proposed that the force constant and the closest packing were changed with the structure transformation resulting the chemical stability difference.

Abstract Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.

Abstract Trimethylamine-N-oxide (TMAO) derived from the gut microbiota is an atherogenic metabolite. This study investigates whether or not berberine (BBR) could reduce TMAO production in the gut microbiota and treat atherosclerosis. Effects of BBR on TMAO production in the gut microbiota, as well as on plaque development in atherosclerosis were investigated in the culture of animal intestinal bacterial, HFD-fed animals and atherosclerotic patients, respectively. We found that oral BBR in animals lowers TMAO biosynthesis in intestine through interacting with the enzyme/co-enzyme of choline-trimethylamine lyase (CutC) and flavin-containing monooxygenase (FMO) in the gut microbiota. This action was performed by BBR’s metabolite dihydroberberine (a reductive BBR by nitroreductase in the gut microbiota), via a vitamine-like effect down-regulating Choline-TMA-TMAO production pathway. Oral BBR decreased TMAO production in animal intestine, lowered blood TMAO and interrupted plaque formation in blood vessels in the HFD-fed hamsters. Moreover, 21 patients with atherosclerosis exhibited the average decrease of plaque score by 3.2% after oral BBR (0.5 g, bid) for 4 months (*P

Abstract Background In recent years, alkaline phosphatase (ALP) has been considered as one of the independent risk factors of acute ischemic stroke (AIS) and leads to worse clinical outcomes in patients with renal failure. In this study, we aim to investigate whether serum ALP level is associated with poor early-term prognosis in relationship of AIS patients with preserved renal function. Methods A prospectively collected database of AIS patients hospitalized in the Xi’an district of China from January to December, 2015 was analyzed. The demographics, serum ALP levels and stroke outcomes of all patients at 3 months were reviewed. Patients were routinely followed-up for 3 months. Serum ALP level was analyzed as a continuous variable and quintiles (Q1-Q5). Multivariate logistic regression model and a two-piecewise linear regression model were used to investigate the relationship and to determine the threshold effect regarding serum ALP levels and poor 3-month prognosis of AIS patients with preserved renal function. Results Overall, 1922 AIS patients were enrolled with 62.3% of them being men. The risk of having a poor 3-month prognosis was significantly increased in Q1, Q2, Q3 and Q5, when compared to that in Q4 being as the reference. The highest risk was noted in Q5 (odds ratio 2.21, 95% confidence interval: 1.32–3.73, P = 0.003) after being adjusted for confounders. Further analysis revealed a J-shaped curvilinear relationship between ALP levels and a poor 3-month prognosis of strokes (optimal threshold ALP level = 90 U/L). The relationship between both parameters was not significantly affected by age, sex, drinking, hypertension and leukocyte count (stratified by 10 × 109/L) (P for interaction > 0.05). Conclusions Serum ALP was noted as an independent risk factor for a poor 3-month prognosis of AIS patients with preserved renal function. ALP levels higher than 90 U/L could cause an increased risk of a poor 3-month prognosis.

Abstract Background The clinical features and factors affecting the prognostic survival of hepatic hydrothorax (HH) are currently unknown. Methods We conducted a retrospective cohort study of 131 patients with HH using the Kaplan–Meier method and Cox proportional hazards regression analysis to assess factors influencing the prognosis of HH. Results A total of 131 patients were enrolled: the male to female ratio was 80:51 (1.59:1), and the mean age was 52.76 ± 11.88 years. Hepatitis B cirrhosis was the main cause of HH, and abdominal distention and dyspnea were the most common clinical signs. Ascites was present in varying amounts in all patients and was the most common decompensated complication, with pleural effusions mostly seen on the right side (107/131; 82%), followed by the left side (16/131; 12%) and bilateral effusions (8/131; 6%). For overall survival without transplantation, the estimated median survival time was 21 (95% confidence interval [CI]:18–25) months, and survival rates at 6 months, 1 year, and 2 years were 77.2%, 62.4%, and 29.7%, respectively. After controlling for covariates that were associated with liver-related mortality in the univariate analysis, males (hazard ratio [HR]: 1.721, 95% CI: 1.114–2.658, P = 0.005) and combined hepatic encephalopathy (HR: 2.016, 95% CI: 1.101–3.693, P = 0.001) were found to be associated with an increase in liver-related mortality. Conclusions In this cohort of HH patients without liver transplantation, male sex and hepatic encephalopathy were associated with a higher risk of liver-related death.

We observe the error rate threshold of quantum fault-tolerant computation by using optical spatial modes of two entangled photons to encode logical qubits.