Feasibility of Ultrasound-Guided Percutaneous Axillary Artery Cannulation for Veno-Arterial Extracorporeal Membrane Oxygenation and its Effect on the Recovery of Spontaneous Heartbeat in Patients with ECPR.

Objective: The measurement of the right and left axillary arteries and aortic arch and their vessels by multi-row spiral CT angiography provides the basis for clinical catheter selection and depth for axillary artery placement. This study reported the clinical experience of 7 patients who successfully underwent ultrasound-guided percutaneous axillary artery cannulation for veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Methods: Patients who had CT angiography of the thoracic aorta at our institution between January 2020 and March 2022 were assessed for eligibility and included. The diameters of the cephalic trunk (D1), right common carotid artery (D2), right axillary artery (D3), left common carotid artery (D4), left axillary artery opening (D5), right axillary artery cannulation length (L1), and left axillary artery cannulation length (L2) were measured. The tangential angles α, ß, and γ of the cephalic trunk, left common carotid artery and left subclavian and aorta was measured using an automatic angle-forming tool. The decision to use a 15F cannula for ultrasound-guided percutaneous axillary artery cannulation in veno-arterial extracorporeal membrane oxygenation (VA-ECMO) aims to achieve optimal vascular access. This cannula size strikes a balance, providing sufficient blood flow rates for ECMO support while minimizing the risk of complications associated with larger cannulas. Precise measurements of arterial dimensions, including the cephalic trunk, common carotid arteries, and axillary arteries, play a crucial role in guiding catheter selection and determining the depth of axillary artery placement. These measurements allow for tailored approaches based on individual patient characteristics, enhancing the safety and efficacy of the intervention. Additionally, measuring tangential angles (α, ß, and γ) provides insights into arterial alignment, optimizing the cannula trajectory for efficient blood flow. The use of an automatic angle-forming tool enhances measurement precision, contributing to procedural accuracy, minimizing complications, and ensuring the success of ultrasound-guided percutaneous axillary artery cannulation. In summary, the choice of a 15F cannula and precise measurements are essential components of the methodology, emphasizing safety, efficacy, and personalized approaches in VA-ECMO. From March to June 2022, 7 patients (6 males and 1 female) in our intensive care medicine department underwent successful ultrasound-guided percutaneous axillary artery cannulation for VA-ECMO with 15F cannula, including 3 cases with extracorporeal cardiopulmonary resuscitation (ECPR) and 4 cases with circulatory collapse. Results: 292 patients met the study criteria, 215 males and 77 females, with a mean age of 67.2±14.2 years. The measurements showed that D1 was (13.1±2.0) mm, D2 was (8.8±2.5) mm, D3 was (6.1±1.2) mm, D4 was (8.3±3.5) mm, D5 was (6.1±1.1) mm, L1 was (114.1±17.8) mm, and L2 was (128.4±20.2) mm. The tangential angles α of the cephalic trunk left common carotid artery and left subclavian artery to the aorta were (43.8°±17.1°), ß was (50.7°±14.8°), and γ was (62.4°±19.1°). Males had significantly wider D3 and D5, longer L1 and L2, and smaller gamma angles than females (P < .05). Three ECPR cases showed no recovery of the spontaneous heartbeat with femoral artery cannulation for VA-ECMO but recovered spontaneous heartbeat after axillary artery cannulation for VA-ECMO was adopted. The measurements in this study have important implications for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) procedures. They provide crucial information about arterial dimensions, including the cephalic trunk, common carotid arteries, and axillary arteries. This information guides clinicians in selecting catheters and determining the ideal depth for percutaneous axillary artery cannulation during ECMO interventions. Notable gender differences in arterial dimensions highlight the need for personalized approaches in ECMO procedures. Customizing catheter choices and cannulation depth based on individual patient characteristics, informed by these measurements, improves the safety and effectiveness of the intervention. The measured tangential angles (α, ß, and γ) offer insights into arterial alignment, crucial for optimizing cannula trajectory and ensuring proper alignment for efficient blood flow. The use of an automatic angle-forming tool enhances measurement precision, contributing to procedural accuracy and minimizing the risk of complications during ECMO procedures. In summary, these measurements directly enhance the precision and safety of VA-ECMO procedures, underscoring the importance of personalized approaches based on individual anatomical variations and improving overall intervention success and outcomes. Conclusion: Ultrasound-guided percutaneous axillary artery cannulation for VA-ECMO with a 15F cannula is clinically feasible. Axillary artery cannulation for VA-ECMO contributes to the restoration of spontaneous heartbeat in ECPR patients more than femoral artery cannulation, and the possible mechanism is a better improvement of coronary blood flow. However, the study has limitations, including a modest sample size and a single-center, retrospective design, impacting its generalizability. To validate and extend these findings, further research with larger and diverse cohorts, including prospective investigations, is necessary to ensure their applicability across various clinical settings and patient demographics in VA-ECMO.

COVID-19 in patients with myasthenia gravis: a single-center retrospective study in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been a great concern since 2019. Patients with myasthenia gravis (MG) may be at higher risk of COVID-19 and a more severe disease course. We examined the associations between COVID-19 and MG. METHODS: This single-center retrospective cohort study involved 134 patients who were diagnosed with MG from June 2020 to November 2022 and followed up until April 2023. They were divided into a COVID-19 group and non-COVID-19 group. Logistic regression analysis was used to detect factors potentially associating COVID-19 with MG. RESULTS: Of the 134 patients with MG, 108 (80.6%) had COVID-19. A higher number of comorbidities was significantly associated with an increased risk of COVID-19 (p = 0.040). A total of 103 patients (95.4%) had mild/moderate COVID-19 symptoms, and 4 patients (3.7%) were severe/critical symptoms (including 2 deaths). Higher age (p = 0.036), use of rituximab (p = 0.037), tumors other than thymoma (p = 0.031), Hashimoto's thyroiditis (p = 0.011), more comorbidities (p = 0.002), and a higher baseline MG activities of daily living (MG-ADL) score (p = 0.006) were risk factors for severe COVID-19 symptoms. The MG-ADL score increased by ≥ 2 points in 16 (15.7%) patients. Dry cough and/or expectoration (p = 0.011), use of oral corticosteroids (p = 0.033), and use of more than one kind of immunosuppressant (p = 0.017) were associated with the increase of the post-COVID-19 MG-ADL score. CONCLUSION: Most patients with MG have a mild course of COVID-19. However, patients with older age, many comorbidities, a high MG-ADL score, and use of a variety of immunosuppressants during COVID-19 may be more prone to severe symptoms.

Development of smart packaging film incorporated with sodium alginate-chitosan quaternary ammonium salt nanocomplexes encapsulating anthocyanins for monitoring milk freshness.

This study focused on the preparation, functionality, and application of smart food packaging films based on polyvinyl alcohol (PVA) and anthocyanins (ACNs) -loaded sodium alginate-chitosan quaternary ammonium salt (HACC-SA) nanocomplexes. The average encapsulation rate of anthocyanins-loaded nanocomplexes reached 62.51 %, which improved the hydrophobicity and water vapor barrier of the PVA film. FTIR confirmed that the nanocomplexes were immobilized in the PVA film matrix by hydrogen bonding, which improved the mechanical properties of the film. The SEM and XRD results demonstrated that the HACC-SA-ACNs nanocomplexes were uniformly distributed in the film matrix and the crystallinity of PVA was decreased. The P/HACC-SA-ACNs film showed a significant response to buffers of pH 2-13 and high color stability after 21 days of storage compared to the P/ACNs film. Furthermore, the color of the composite film changed from purple to red as the milk freshness decreased during 72 h of milk freshness monitoring, indicating that the P/HACC-SA-ACNs films were suitable and promising for application as smart packaging materials.

Protocol for analysis of intracellular conversion of artezomib molecules into new proteasome inhibitors in Plasmodium falciparum parasites.

Artezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme.1 Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization. For complete details on the use and execution of this protocol, please refer to Zhan et al.1.

Enhanced Antioxidative Capacity Transfer between Sow and Fetus via the Gut-Placenta Axis with Dietary Selenium Yeast and Glycerol Monolaurate Supplementation during Pregnancy.

This study aims to investigate the impact of dietary supplementation with selenium yeast (SeY) and glycerol monolaurate (GML) on the transfer of antioxidative capacity between the mother and fetus during pregnancy and its underlying mechanisms. A total of 160 sows with similar body weight and parity of 3-6 parity sows were randomly and uniformly allocated to four groups (n = 40) as follows: CON group, SeY group, GML group, and SG (SeY + GML) group. Animal feeding started from the 85th day of gestation and continued to the day of delivery. The supplementation of SeY and GML resulted in increased placental weight and reduced lipopolysaccharide (LPS) levels in sow plasma, placental tissues, and piglet plasma. Furthermore, the redox balance and inflammatory markers exhibited significant improvements in the plasma of sows fed with either SeY or GML, as well as in their offspring. Moreover, the addition of SeY and GML activated the Nrf2 signaling pathway, while downregulating the expression of pro-inflammatory genes and proteins associated with inflammatory pathways (MAPK and NF-κB). Vascular angiogenesis and nutrient transportation (amino acids, fatty acids, and glucose) were upregulated, whereas apoptosis signaling pathways within the placenta were downregulated with the supplementation of SeY and GML. The integrity of the intestinal and placental barriers significantly improved, as indicated by the increased expression of ZO-1, occludin, and claudin-1, along with reduced levels of DLA and DAO with dietary treatment. Moreover, supplementation of SeY and GML increased the abundance of Christensenellaceae_R-7_group, Clostridium_sensus_stricto_1, and Bacteroidota, while decreasing levels of gut microbiota metabolites LPS and trimethylamine N-oxide. Correlation analysis demonstrated a significant negative relationship between plasma LPS levels and placental weight, oxidative stress, and inflammation. In summary, dietary supplementation of SeY and GML enhanced the transfer of antioxidative capacity between maternal-fetal during pregnancy via gut-placenta axis through modulating sow microbiota composition.

iSUMO-RsFPN: A predictor for identifying lysine SUMOylation sites based on multi-features and feature pyramid networks.

SUMOylation is a protein post-translational modification that plays an essential role in cellular functions. For predicting SUMO sites, numerous researchers have proposed advanced methods based on ordinary machine learning algorithms. These reported methods have shown excellent predictive performance, but there is room for improvement. In this study, we constructed a novel deep neural network Residual Pyramid Network (RsFPN), and developed an ensemble deep learning predictor called iSUMO-RsFPN. Initially, three feature extraction methods were employed to extract features from samples. Following this, weak classifiers were trained based on RsFPN for each feature type. Ultimately, the weak classifiers were integrated to construct the final classifier. Moreover, the predictor underwent systematically testing on an independent test dataset, where the results demonstrated a significant improvement over the existing state-of-the-art predictors. The code of iSUMO-RsFPN is free and available at https://github.com/454170054/iSUMO-RsFPN.

Structure-based design and synthesis of anti-fibrotic compounds derived from para-positioned 3,4,5-trisubstituted benzene.

Liver fibrosis is an abnormal wound-healing response to liver injuries. It can lead to liver cirrhosis, and even liver cancer and liver failure. There is a lack of treatment for liver fibrosis and it is of great importance to develop anti-fibrotic drugs. A pivotal event in the process of developing liver fibrosis is the activation of hepatic stellate cells (HSCs), in which the nuclear receptor Nur77 plays a crucial role. This study aimed to develop novel anti-fibrotic agents with Nur77 as the drug target by modifying the structure of THPN, a Nur77-binding and anti-melanoma compound. Specifically, a series of para-positioned 3,4,5-trisubstituted benzene ring compounds with long-chain backbone were generated and tested for anti-fibrotic activity. Among these compounds, compound A8 was with the most potent and Nur77-dependent inhibitory activity against TGF-ß1-induced activation of HSCs. In a crystal structure analysis, compound A8 bound Nur77 in a peg-in-hole mode as THPN did but adopted a different conformation that could interfere the Nur77 interaction with AKT, which was previous shown to be important for an anti-fibrotic activity. In a cell-based assay, compound A8 indeed impeded the interaction between Nur77 and AKT leading to the stabilization of Nur77 without the activation of AKT. In a mouse model, compound A8 effectively suppressed the activation of AKT signaling pathway and up-regulated the cellular level of Nur77 to attenuate the HSCs activation and ameliorate liver fibrosis with no significant toxic side effects. Collectively, this work demonstrated that Nur77-targeting compound A8 is a promising anti-fibrotic drug candidate.

ß-Sitosterol Alleviates the Proliferation and Migration of Cystitis Glandularis-Associated Cells by Targeting HMGCR to Induce NLRP3-Dependent Pyroptosis.

BACKGROUND: Cystitis glandularis (CG) is a proliferative lesion of the bladder mucosa, and the incidence rate of CG has increased year by year. Considering the potential function of ß-sitosterol in CG, we aim to fathom its effect and mechanism of CG. METHODS: Primary human cells isolated from CG patients and following transfection as needed, were treated with different concentrations of ß-sitosterol. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and transwell assay was used to test the cell migration. Meanwhile, co-immunoprecipitation was employed to evaluate the interaction between 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and NLR family pyrin domain containing 3 (NLRP3). Additionally, pyroptosis-associated proteins and HMGCR expressions were tested using western blot or quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ß-sitosterol suppressed cell viability and migration, enhanced cell pyroptosis, and upregulated expressions of NLRP3, Cleaved Caspase-1, interleukin-1ß (IL-1ß), gasdermin D-N-terminal domain (GSDMD-N), and HMGCR in CG primary cells (p < 0.05). HMGCR silencing promoted cell viability and migration, inhibited cell pyroptosis, and downregulated expressions of NLRP3, Cleaved Caspase-1, IL-1ß, and GSDMD-N in ß-sitosterol-affected CG primary cells (p < 0.05). HMGCR interacted with NLRP3. CONCLUSIONS: ß-sitosterol alleviates the proliferation and migration of CG-associated cells by targeting HMGCR to induce NLRP3-dependent pyroptosis. These findings confirmed the therapeutic effect of ß-sitosterol on treating CG.

Lung-PNet: An Automated Deep Learning Model for the Diagnosis of Invasive Adenocarcinoma in Pure Ground-Glass Nodules on Chest CT.

BACKGROUND. Pure ground-glass nodules (pGGNs) on chest CT representing invasive adenocarcinoma (IAC) warrant lobectomy with lymph node resection. For pGGNs representing other entities, close follow-up or sublobar resection without node dissection may be appropriate. OBJECTIVE. The purpose of this study was to develop and validate an automated deep learning model for differentiation of pGGNs on chest CT representing IAC from those representing atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). METHODS. This retrospective study included 402 patients (283 women, 119 men; mean age, 53.2 years) with a total of 448 pGGNs on noncontrast chest CT that were resected from January 2019 to June 2022 and were histologically diagnosed as AAH (n = 29), AIS (n = 83), MIA (n = 235), or IAC (n = 101). Lung-PNet, a 3D deep learning model, was developed for automatic segmentation and classification (probability of IAC vs other entities) of pGGNs on CT. Nodules resected from January 2019 to December 2021 were randomly allocated to training (n = 327) and internal test (n = 82) sets. Nodules resected from January 2022 to June 2022 formed a holdout test set (n = 39). Segmentation performance was assessed with Dice coefficients with radiologists' manual segmentations as reference. Classification performance was assessed by ROC AUC and precision-recall AUC (PR AUC) and compared with that of four readers (three radiologists, one surgeon). The code used is publicly available (https://github.com/XiaodongZhang-PKUFH/Lung-PNet.git). RESULTS. In the holdout test set, Dice coefficients for segmentation of IACs and of other lesions were 0.860 and 0.838, and ROC AUC and PR AUC for classification as IAC were 0.911 and 0.842. At threshold probability of 50.0% or greater for prediction of IAC, Lung-PNet had sensitivity, specificity, accuracy, and F1 score of 50.0%, 92.0%, 76.9%, and 60.9% in the holdout test set. In the holdout test set, accuracy and F1 score (p values vs Lung-PNet) for individual readers were as follows: reader 1, 51.3% (p = .02) and 48.6% (p = .008); reader 2, 79.5% (p = .75) and 75.0% (p = .10); reader 3, 66.7% (p = .35) and 68.3% (p < .001); reader 4, 71.8% (p = .48) and 42.1% (p = .18). CONCLUSION. Lung-PNet had robust performance for segmenting and classifying (IAC vs other entities) pGGNs on chest CT. CLINICAL IMPACT. This automated deep learning tool may help guide selection of surgical strategies for pGGN management.

Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway.

AIM: Liver fibrosis remains a great challenge in the world. Spinosin (SPI), a natural flavonoid-C-glycoside, possesses various pharmacological activities including anti-inflammatory and anti-myocardial fibrosis effects. In this study, we investigate whether SPI can be a potential lead for the treatment of liver fibrosis and explore whether the orphan nuclear receptor Nur77, a negative regulator of liver fibrosis development, plays a critical role in SPI's action. METHODS: A dual luciferase reporter system of α-SMA was established to evaluate the effect of SPI on hepatic stellate cell (HSC) activation in LX2 and HSC-T6 cells. A mouse model of CCl4-induced liver fibrosis was used to test the efficacy of SPI against liver fibrosis. The expression levels of Nur77, inflammatory cytokines and collagen were determined by Western blotting and qPCR. Potential kinase pathways involved were also analyzed. The affinity of Nur77 with SPI was documented by fluorescence titration. RESULTS: SPI can strongly suppress TGF-ß1-mediated activation of both LX2 and HSC-T6 cells in a dose-dependent manner. SPI increases the expression of Nur77 and reduces TGF-ß1-mediated phosphorylation levels of ASK1 and p38 MAPK, which can be reversed by knocking out of Nur77. SPI strongly inhibits collagen deposition (COLA1) and reduces inflammatory cytokines (IL-6 and IL-1ß), which is followed by improved liver function in the CCl4-induced mouse model. SPI can directly bind to R515 and R563 in the Nur77-LBD pocket with a Kd of 2.14 µM. CONCLUSION: Spinosin is the major pharmacological active component of Ziziphus jujuba Mill. var. spinosa which has been frequently prescribed in traditional Chinese medicine. We demonstrate here for the first time that spinosin is a new therapeutic lead for treatment of liver fibrosis by targeting Nur77 and blocking the ASK1/p38 MAPK signaling pathway.

The potential mechanism of concentrated mannan-oligosaccharide promoting goldfish's (Carassius auratus Linnaeus) resistance to Ichthyophthirius multifiliis invasion.

Because of the low host specificity, Ichthyophthirius multifiliis (Ich) can widely cause white spot disease in aquatic animals, which is extremely difficult to treat. Prior research has demonstrated a considerable impact of concentrated mannan-oligosaccharide (cMOS) on the prevention of white spot disease in goldfish, but the specific mechanism is still unknown. In this study, transcriptome sequencing, histological analysis, immunofluorescence analysis, phagocytosis activity assay and qRT-PCR assay were used to systematically reveal the potential mechanism of cMOS in supporting the resistance of goldfish (Carrasius auratus) to Ich invasion. According to the transcriptome analysis, the gill tissue of goldfish receiving the cMOS diet showed greater expression of mannose-receptor (MRC) related genes, higher phagocytosis activity, up-regulated expression of phagocytosis-related genes and inflammatory-related genes compared with the control, indicating that cMOS can have an effect on phagocytosis and non-specific immunity of goldfish. After the Ich challenge, transcriptome analysis revealed that cMOS fed goldfish displayed a higher level of phagocytic response, whereas non-cMOS fed goldfish displayed a greater inflammatory reaction. Besides, after Ich infection, cMOS-fed goldfish displayed greater phagocytosis activity, a stronger MRC positive signal, higher expression of genes associated with phagocytosis (ABCB2, C3, MRC), and lower expression of genes associated with inflammation (IL-1ß, IL-17, IL-8, TNF-α, NFKB). In conclusion, our experimental results suggest that cMOS may support phagocytosis by binding to MRC on the macrophage cell membrane and change the non-specific immunity of goldfish by stimulating cytokine expression. The results of this study provide new insights for the mechanism of cMOS on parasitic infection, and also suggest phagocytosis-related pathways may be potential targets for prevention of Ich infection.

Identification of (E)-1-((1H-indol-3-yl)methylene)-4-substitute-thiosemicarbazones as potential anti-hepatic fibrosis agents.

Liver fibrosis remains a global health challenge due to its rapidly rising prevalence and limited treatment options. The orphan nuclear receptor Nur77 has been implicated in regulation of autophagy and liver fibrosis. Targeting Nur77-mediated autophagic flux may thus be a new promising strategy against hepatic fibrosis. In this study, we synthesized four types of Nur77-based thiourea derivatives to determine their anti-hepatic fibrosis activity. Among the synthesized thiourea derivatives, 9e was the most potent inhibitor of hepatic stellate cells (HSCs) proliferation and activation. This compound could directly bind to Nur77 and inhibit TGF-ß1-induced α-SMA and COLA1 expression in a Nur77-dependent manner. In vivo, 9e significantly reduced CCl4-mediated hepatic inflammation response and extracellular matrix (ECM) production, revealing that 9e is capable of blocking the progression of hepatic fibrosis. Mechanistically, 9e induced Nur77 expression and enhanced autophagic flux by inhibiting the mTORC1 signaling pathway in vitro and in vivo. Thus, the Nur77-targeted lead 9e may serve as a promising candidate for treatment of chronic liver fibrosis.

Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.

The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S ß6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone ß2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sß6A117D with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds ß2 and ß5 in wild type Pf20S as well as WLW-vs binds ß2 and ß5 in Pf20Sß6A117D. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.

Treatment Outcomes in COVID-19 Patients with Brucellosis: Case Series in Heilongjiang and Systematic Review of Literature.

Objective: Clinical characteristics and outcome in COVID-19 with brucellosis patients has not been well demonstrated, we tried to analyze clinical outcome in local and literature COVID-19 cases with brucellosis before and after recovery. Methods: We retrospectively collected hospitalization data of comorbid patients and prospectively followed up after discharge in Heilongjiang Infectious Disease Hospital from January 15, 2020 to April 29, 2022. Demographics, epidemiological, clinical symptoms, radiological and laboratory data, treatment medicines and outcomes, and follow up were analyzed, and findings of a systematic review were demonstrated. Results: A total of four COVID-19 with brucellosis patients were included. One patient had active brucellosis before covid and 3 patients had nonactive brucellosis before brucellosis. The median age was 54.5 years, and all were males (100.0%). Two cases (50.0%) were moderate, and one was mild and asymptomatic, respectively. Three cases (75.0%) had at least one comorbidity (brucellosis excluded). All 4 patients were found in COVID-19 nucleic acid screening. Case C and D had only headache and fever on admission, respectively. Four cases were treated with Traditional Chinese medicine, western medicines for three cases, no adverse reaction occurred during hospitalization. All patients were cured and discharged. Moreover, one case (25.0%) had still active brucellosis without re-positive COVID-19, and other three cases (75.0%) have no symptoms of discomfort except one case fell fatigue and anxious during the follow-up period after recovery. Conducting the literature review, two similar cases have been reported in two case reports, and were both recovered, whereas, no data of follow up after recovery. Conclusion: These cases indicate that COVID-19 patients with brucellosis had favorable outcome before and after recovery. More clinical studies should be conducted to confirm our findings.

Interactions between enzyme preparations and trace element sources on growth performance and intestinal health of broiler chicks.

This experiment was conducted to explore the interactions between enzyme preparations and trace element sources on growth performance and intestinal health of broilers chicks. A total of 480 one-day-old healthy male yellow-feather broilers with similar weight were randomly arranged in a 2  ×  2 factorial design with 2 kinds of compound trace element sources (inorganic [I] and organic [O] trace element supplemented with 80, 8, 60, 40, 0.15 mg/kg of Fe, Cu, Mn, Zn, and Se, respectively) and 2 levels of enzyme preparations (0 and 200 mg/kg). The 4 groups named I, O, IE, and OE with 6 replicates and 20 birds per replicate. The trail lasted for 28 days. Results showed that the average weight (ABW), average daily gain (ADG) of broilers in IE and OE groups significantly increased while the F/G significantly decreased as compared with group I and O (P < 0.05). Enzyme preparation supplementation, regardless of the trace element sources, significantly increased the duodenal and jejunal endogenous enzyme (e.g., Try and AACT) activity, and improved the morphology and jejunal barrier function evidenced by the increased villus height and MUC-2 mRNA expression (P < 0.05). Sequencing data manifested that enzyme preparations favorably modulated the cecal microflora by increasing bacterial diversity and abundance of short-chain fatty acid (SCFA)-producing bacteria (e.g., Anaerostipes, Anaerofusis, and Pygmaioactor), while decreasing the abundance of harmful bacteria (e.g., Desulfovibrio). Factorial analysis indicated that there were no interactions between enzyme preparation and trace element sources on growth performance and intestinal health of broiler chicks. In conclusion, dietary supplementation with enzyme preparations, regardless of the trace element sources, could enhance endogenous enzyme activity, improve intestinal morphology and barrier functions, and favorably modulate the cecal microflora, thereby improving the intestinal health and growth performance of broiler chicks.

Met stimulates ARID1A degradation and activation of the PI3K-SREBP1 signaling to promote milk fat synthesis in bovine mammary epithelial cells.

Methionine (Met) can promote milk fat synthesis in bovine mammary epithelial cells (BMECs), but the potential molecular mechanism is largely unknown. In this report, we aim to explore the role and molecular mechanism of AT-rich interaction domain 1A (ARID1A) in milk fat synthesis stimulated by Met. ARID1A knockdown and activation indicated that ARID1A negatively regulated the synthesis of triglycerides, cholesterol and free fatty acids and the formation of lipid droplets in BMECs. ARID1A also negatively regulated the phosphorylation of PI3K and AKT proteins, as well as the expression and maturation of SREBP1. Met stimulated the phosphorylation of PI3K and AKT proteins, as well as the expression and maturation of SREBP1, while ARID1A gene activation blocked the stimulatory effects of Met. We further found that ARID1A was located in the nucleus of BMECs, and Met reduced the nuclear localization and expression of ARID1A. ARID1A gene activation blocked the stimulation of PI3K and SREBP1 mRNA expression by Met. In summary, our data suggests that ARID1A negatively regulates milk fat synthesis stimulated by Met in BMECs through inhibiting the PI3K-SREBP1 signaling pathway, which may provide some new perspectives for improving milk fat synthesis.

Spatial-temporal distribution of global production-living-ecological space during the period 2000-2020.

Global production-living-ecology space closely corresponds with sustainable development's economic, social and ecological elements. The dataset of global production-living-ecological space in this paper was generated by combining the global land cover obtained using GlobeLand30 and the population density supplied by NASA's Socioeconomic Data and Applications Center in 2000, 2010, and 2020. The verification was carried out using the random sampling function of ArcGIS software on the basis of Google Earth sample images. The overall accuracy of the global production-living-ecological space data in 2020 was 83.94% and the Kappa coefficient was 0.81. The overall accuracy of the global production-living-ecological space data in 2010 was 87.00% and the Kappa coefficient was 0.84. The overall accuracy of the spatial data in 2000 was 86.06% and the Kappa coefficient was 0.83. The dataset fills a gap in the global production-living-ecology space database and will be an essential reference for assessing the coordinated development of sustainable development goals.

Change characteristics and influencing factors of grassland degradation in adjacent areas of the Qinghai-Tibet Plateau and suggestions for grassland restoration.

Natural grasslands are being progressively degraded around the world due to climate change and socioeconomic factors. Most of the drivers, processes, and consequences of grassland degradation are studied separately, and it is not yet clear whether the change characteristics and influence factors of adjacent areas of grassland are identical. We analyzed changes in grassland area and quality, and the influences of climate changes and socioeconomic factors from 1980-2018 in Maqu County, Xiahe County and Luqu County on the eastern Qinghai-Tibet Plateau (QTP). We found that areas with high and medium coverage grassland in Maqu County and Luqu County decreased continuously with time, while low coverage grassland areas increased in three counties. In Xiahe County, the medium coverage grassland area reduced with time (except for 2010), while the high and low coverage grassland areas increased. The actual net primary productivity of the three counties showed a downward trend. In Maqu County, the total grassland area had an extremely significant positive correlation with number of livestock going to market, commodity rate, gross domestic product (GDP), primary industry, tertiary industry, household density, and levels of junior middle school education and university education in the area. In Luqu County, the total grassland area high coverage grassland area were significantly negatively correlated with total number of livestock, secondary industry, levels of primary school education, and temperature. Ecological education was positively correlated with high coverage grassland, and negatively correlated with low coverage grassland in all three areas. The results of this study suggest that the best ways to restore the area and quality of grasslands in these areas would be to reduce the local cultivated land area and slow down the development of the primary and tertiary industries in Maqu County, and to control industry development and the total number of livestock in Luqu County. This study also suggests that improving education level and strengthening the level of ecological education are conducive to the restoration of grasslands.

Covalent Macrocyclic Proteasome Inhibitors Mitigate Resistance in Plasmodium falciparum.

The Plasmodium proteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinin and related analogues. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible, macrocyclic inhibitors of the Plasmodium falciparum proteasome. We identified compounds with excellent potency and low cytotoxicity; however, the first generation suffered from poor microsomal stability. Further optimization of an existing macrocyclic scaffold resulted in an irreversible covalent inhibitor carrying a vinyl sulfone electrophile that retained high potency and low cytotoxicity and had acceptable metabolic stability. Importantly, unlike the parent reversible inhibitor that selected for multiple mutations in the proteasome, with one resulting in a 5,000-fold loss of potency, the irreversible analogue only showed a 5-fold loss in potency for any single point mutation. Furthermore, an epoxyketone analogue of the same scaffold retained potency against a panel of known proteasome mutants. These results confirm that macrocycles are optimal scaffolds to target the malarial proteasome and that the use of a covalent electrophile can greatly reduce the ability of the parasite to generate drug resistance mutations.

Mitochondrial metabolism-related signature depicts immunophenotype and predicts therapeutic response in testicular germ cell tumors.

In recent years, there has been growing evidence linking mitochondrial dysfunction to the development and progression of cancer. However, the role of mitochondrial metabolism-related genes (MMRGs) in testicular germ cell tumor (TGCT) remains unclear. We downloaded clinical pathology, transcriptome, and somatic mutation data for TGCT from public databases and conducted univariate Cox regression analysis to investigate prognostic correlations. We also used consensus clustering to identify molecular subtypes, comparing differential expression genes, biological processes, Kyoto Encyclopedia of Genes and Genomes pathways, mutations, prognosis, immune infiltration, drug sensitivity, and immune therapeutic response between these subtypes. We constructed multi-gene risk features and nomograms for TGCT prognosis. Fifteen MMRGs were significantly correlated with progression-free survival in TGCT patients. Based on these genes, we identified 2 molecular subtypes which showed significant differences in somatic mutations, prognosis, and immune cell infiltration. These subtypes could also indicate drug sensitivity and immune therapeutic response; the subtype with poor prognosis showed a higher potential benefit from some drugs and immunotherapy. Abnormalities in immune-related biological processes and extracellular matrix as well as Kyoto Encyclopedia of Genes and Genomes pathways such as PI3K-AKT signaling pathway, pat5hways in cancer, primary immunodeficiency, and neutrophil extracellular trap formation were associated with significant differences in phenotypes among subtypes. Finally, we constructed an 8-gene TGCT risk feature based on differential expression genes between subtypes which performed well in TGCT patient prognostic evaluation. Our study elucidated the prognostic correlation between MMRGs and TGCT and established MMRG-derived molecular subtypes and risk features for personalized treatment of TGCT which have potential clinical application value.