Cooperative Rh/Achiral Phosphoric Acid-Enabled [3+3] Cycloannulation of Carbonyl Ylides with Quinone Monoimines: Synthesis of Benzofused Dioxabicyclo[3.2.1]octane Scaffolds.

A cooperative Rh/achiral phosphoric acid-enabled [3+3] cycloaddition of in situ-generated carbonyl ylides with quinone monoimines has been developed. With the ability to build up the molecular complexity rapidly and efficiently, this method furnishes highly functionalized oxa-bridged benzofused dioxabicyclo[3.2.1]octane scaffolds bearing two quaternary centers in good to excellent yields under mild conditions. Moreover, the utility of the current method was demonstrated by gram-scale synthesis and elaboration of the products into various functionalized oxa-bridged heterocycles.

Biomedical application of materials for external auditory canal: History, challenges, and clinical prospects.

Biomaterials play an integral role in treatment of external auditory canal (EAC) diseases. Regarding the special anatomic structure and physiological characteristics of EAC, careful selection of applicable biomaterials was essential step towards effective management of EAC conditions. The bioactive materials can provide reasonable biocompatibility, reduce risk of host pro-inflammatory response and immune rejection, and promote the healing process. In therapeutic procedure, biomaterials were employed for covering or packing the wound, protection of the damaged tissue, and maintaining of normal structures and functions of the EAC. Therefore, understanding and application of biomaterials was key to obtaining great rehabilitation in therapy of EAC diseases. In clinical practice, biomaterials were recognized as an important part in the treatment of different EAC diseases. The choice of biomaterials was distinct according to the requirements of various diseases. As a result, awareness of property regarding different biomaterials was fundamental for appropriate selection of therapeutic substances in different EAC diseases. In this review, we firstly introduced the characteristics of EAC structures and physiology, and EAC pathologies were summarized secondarily. From the viewpoint of biomaterials, the different materials applied to individual diseases were outlined in categories. Besides, the underlying future of therapeutic EAC biomaterials was discussed.

Synthetic microbial communities: Sandbox and blueprint for soil health enhancement.

We summarize here the use of SynComs in improving various dimensions of soil health, including fertility, pollutant removal, soil-borne disease suppression, and soil resilience; as well as a set of useful guidelines to assess and understand the principles for designing SynComs to enhance soil health. Finally, we discuss the next stages of SynComs applications, including highly diverse and multikingdom SynComs targeting several functions simultaneously.

Probing structural superlubricity of two-dimensional water transport with atomic resolution.

Low-dimensional water transport can be drastically enhanced under atomic-scale confinement. However, its microscopic origin is still under debate. In this work, we directly imaged the atomic structure and transport of two-dimensional water islands on graphene and hexagonal boron nitride surfaces using qPlus-based atomic force microscopy. The lattice of the water island was incommensurate with the graphene surface but commensurate with the boron nitride surface owing to different surface electrostatics. The area-normalized static friction on the graphene diminished as the island area was increased by a power of ~-0.58, suggesting superlubricity behavior. By contrast, the friction on the boron nitride appeared insensitive to the area. Molecular dynamic simulations further showed that the friction coefficient of the water islands on the graphene could reduce to <0.01.

Evaluation of the application potential of Bdellovibrio sp. YBD-1 isolated from Yak faeces.

Studies on Bdellovibrio and like organisms (BALOs), obligate predatory bacteria, have highlighted the possibility of regulating bacteria and biofilms; however, yak-derived BALOs are yet to be reported. We aimed to characterize the BALOs isolated and identified from yak (Bos grunniens) feces and examine application potential. BALOs were isolated from healthy yak fecal samples, with Escherichia coli (ATCC 25922) as prey using the double-layer agar method, identified by transmission electron microscopy (TEM), and the specific 16S rDNA sequencing analysis. Sequencing of the 16S rDNA gene indicated that this isolate was 91% similar to the Bdellovibrio sp. NC01 reference strain and was named YBD-1. Proportion of YBD-1 lysed bacteria is 12/13. The YBD-1 showed best growth at 25-40°C, 0-0.25% (w/v) NaCl, and pH 6.5-7.5. YBD-1 significantly reduced the planktonic cells and biofilms of E.coli in co-culture compared to the E.coli group. Additionally, SEM analysis indicated that YBD-1 significantly reduced biofilm formation in E. coli. Furthermore, quantitative Real Time-polymerase chain reaction (qRT-PCR) showed that the expression of the virulence genes fim and iroN and the genes pgaABC involved in biofilm formation went down significantly. We concluded that YBD-1 may have the potential to control bacterial growth and biofilm-associated bacterial illnesses.

Quantitative prediction of postpartum hemorrhage in cesarean section on machine learning.

BACKGROUND: Cesarean section-induced postpartum hemorrhage (PPH) potentially causes anemia and hypovolemic shock in pregnant women. Hence, it is helpful for obstetricians and anesthesiologists to prepare pre-emptive prevention when predicting PPH occurrence in advance. However, current works on PPH prediction focus on whether PPH occurs rather than assessing PPH amount. To this end, this work studies quantitative PPH prediction with machine learning (ML). METHODS: The study cohort in this paper was selected from individuals with PPH who were hospitalized at Shijiazhuang Obstetrics and Gynecology Hospital from 2020 to 2022. In this study cohort, we built a dataset with 6,144 subjects covering clinical parameters, anesthesia operation records, laboratory examination results, and other information in the electronic medical record system. Based on our built dataset, we exploit six different ML models, including logistic regression, linear regression, gradient boosting, XGBoost, multilayer perceptron, and random forest, to automatically predict the amount of bleeding during cesarean section. Eighty percent of the dataset was used as model training, and 20 % was used for verification. Those ML models are constantly verified and improved by root mean squared error(RMSE) and mean absolute error(MAE). Moreover, we also leverage the importance of permutation and partial dependence plot (PDP) to discuss their feasibility. RESULT: The experiment results show that random forest obtains the highest accuracy for PPH amount prediction compared to other ML methods. Random forest reaches the mean absolute error of 21.7, less than 5.4 % prediction error. It also gains the root mean squared error of 33.75, less than 9.3 % prediction error. On the other hand, the experimental results also disclose indicators that contributed most to PPH prediction, including Ca, hemoglobin, white blood cells, platelets, Na, and K. CONCLUSION: It effectively predicts the amount of PPH during a cesarean section by ML methods, especially random forest. With the above insight, ML predicting PPH amounts provides early warning for clinicians, thus reducing complications and improving cesarean sections' safety. Furthermore, the importance of ML and permutation, complemented by incorporating PDP, promises to provide clinicians with a transparent indication of individual risk prediction.

TNFAIP1 promotes macrophage lipid accumulation and accelerates the development of atherosclerosis through the LEENE/FoxO1/ABCA1 pathway.

Macrophage lipid accumulation is a critical contributor to foam cell formation and atherosclerosis. Tumor necrosis factor-α-induced protein 1 (TNFAIP1) is closely associated with cardiovascular disease. However, its role and molecular mechanisms in atherogenesis remain unclear. TNFAIP1 was knocked down in THP-1 macrophage-derived foam cells and apolipoprotein-deficient (apoE-/-) mice using lentiviral vector. The expression of lncRNA enhancing endothelial nitric oxide synthase expression (LEENE), Forkhead box O1 (FoxO1) and ATP binding cassette transporter A1 (ABCA1) was evaluated by qRT-PCR and/or western blot. Lipid accumulation in macrophage was assessed by high-performance liquid chromatography and Oil red O staining. RNA immunoprecipitation and RNA pull-down assay were performed to verify the interaction between LEENE and FoxO1 protein. Atherosclerotic lesions were analyzed using HE, Oil red O and Masson staining. Our results showed that TNFAIP1 was significantly increased in THP-1 macrophages loaded with oxidized low-density lipoprotein. Knockdown of TNFAIP1 enhanced LEENE expression, promoted the direct interaction of LEENE with FoxO1 protein, stimulated FoxO1 protein degradation through the proteasome pathway, induced ABCA1 transcription, and finally suppressed lipid accumulation in THP-1 macrophage-derived foam cells. TNFAIP1 knockdown also up-regulated ABCA1 expression, improved plasma lipid profiles, enhanced the efficiency of reverse cholesterol transport and attenuated lesion area in apoE-/- mice. Taken together, these results provide the first direct evidence that TNFAIP1 aggravates atherosclerosis by promoting macrophage lipid accumulation via the LEENE/FoxO1/ABCA1 signaling pathway. TNFAIP1 may represent a promising therapeutic target for atherosclerotic cardiovascular disease.

Prospective Evaluation of Artificial Intelligence Triage of Incidental Pulmonary Emboli on Contrast-Enhanced CT Examinations of the Chest or Abdomen.

Background: Artificial intelligence (AI) algorithms improved detection of incidental pulmonary embolism (IPE) on contrast-enhanced CT (CECT) examinations in retrospective studies; however, prospective validation studies are lacking. Objective: To assess the effect on radiologists' real-world diagnostic performance and report turnaround times of a radiology department's clinical implementation of an AI triage system for detecting IPE on CECT examinations of the chest or abdomen. Methods: This prospective single-center study included consecutive adult patients who underwent CECT of the chest or abdomen for reasons other than PE detection from May 12, 2021 to June 30, 2021 (phase 1) or from July 1, 2021 to September 29, 2021 (phase 2). Before phase 1, the radiology department installed a commercially available AI triage algorithm for IPE detection that automatically processed CT examinations and notified radiologists of positive results through an interactive floating widget. In phase 1, the widget was inactive, and radiologists interpreted examinations without AI assistance. In phase 2, the widget was activated, and radiologists interpreted examinations with AI assistance. A review process involving a panel of radiologists was implemented to establish the reference standard for the presence of IPE. Diagnostic performance and report turnaround times were compared using Pearson Chi-square test and Wilcoxon rank-sum test, respectively. Results: Phase 1 included 1467 examinations in 1434 patients (mean age, 53.8±18.5 years; 753 male, 681 female); phase 2 included 3182 examinations in 2886 patients (mean age, 55.4±18.2 years; 1520 male, 1366 female). The frequency of IPE was 1.4% (20/1467) in phase 1 and 1.6% (52/3182) in phase 2. Radiologists without AI, in comparison with radiologists with AI, showed significantly lower sensitivity (80.0% vs 96.2%, P=.03), without a significant difference in specificity (99.1% vs 99.9%, P=.58), for detection of IPE. The mean report turnaround time for IPE-positive examinations was not significantly different between radiologists without AI and radiologists with AI (78.3 vs 64.6 min, P=.26). Conclusion: An AI triage system improved radiologists' sensitivity for IPE detection on CECT examinations of the chest or abdomen without significant change in report turnaround times. Clinical Impact: This prospective real-world study supports the use of AI assistance for maximizing IPE detection.

A portent of catastrophic carbon dioxide embolism in laparoscopic hepatectomy: A case report.

INTRODUCTION: Laparoscopic hepatectomy (LH) poses a high risk of carbon dioxide embolism due to extensive hepatic transection, long surgery duration, and dissection of the large hepatic veins or vena cava. PATIENT CONCERNS: A 65-year-old man was scheduled to undergo LH. Following intraperitoneal carbon dioxide (CO2) insufflation and hepatic portal occlusion, the patient developed severe hemodynamic collapse accompanied by a decrease in the pulse oxygen saturation (SpO2). DIAGNOSIS: Although a decrease in end-tidal carbon dioxide (ETCO2) was not observed, CO2 embolism was still suspected because of the symptoms. INTERVENTIONS AND OUTCOMES: The patient was successfully resuscitated after the immediate discontinuation of CO2 insufflation and inotrope administration. CO2 embolism must always be suspected during laparoscopic surgery whenever sudden hemodynamic collapse associated with decreased pulse oxygen saturation occurs, regardless of whether ETCO2 changes. Instant arterial blood gas analysis is imperative, and a significant difference between PaCO2 and ETCO2 is indicative of carbon dioxide embolism. CONCLUSION: Instant arterial blood gas analysis is imperative, and a significant difference between PaCO2 and ETCO2 is indicative of carbon dioxide embolism.

DUSP22 inhibits lung tumorigenesis by suppression of EGFR/c-Met signaling.

DUSP22, an atypical dual-specificity phosphatase enzyme, plays a significant role in regulating multiple kinase signaling pathways by dephosphorylation. Our study demonstrated that decreased DUSP22 expression is associated with shorter disease-free survival, advanced TNM (tumor, lymph nodes, and metastasis), cancer stage, and higher tumor grade in lung adenocarcinoma (LUAD) patients. Exogenous DUSP22 expression reduces the colony-forming capacity of lung cancer cells and inhibits xenograft tumor growth primarily by targeting EGFR and suppressing its activity through dephosphorylation. Knockdown of DUSP22 using shRNA enhances EGFR dependency in HCC827 lung cancer cells and increases sensitivity to gefitinib, an EGFR inhibitor. Consistently, genetic deletion of DUSP22 enhances EGFRdel (exon 19 deletion)-driven lung tumorigenesis and elevates EGFR activity. Pharmacological inhibition of DUSP22 activates EGFR, ERK1/2, and upregulates downstream PD-L1 expression. Additionally, lentiviral deletion of DUSP22 by shRNA enhances lung cancer cell migration through EGFR/c-Met and PD-L1-dependent pathways. Gefitinib, an EGFR inhibitor, mechanistically suppresses migration induced by DUSP22 deletion and inhibits c-Met activity. Furthermore, cabozantinib, a c-Met inhibitor, reduces migration and attenuates EGFR activation caused by DUSP22 deletion. Collectively, our findings support the hypothesis that loss of DUSP22 function in lung cancer cells confers a survival advantage by augmenting EGFR signaling, leading to increased activation of downstream c-Met, ERK1/2, and PD-L1 axis, ultimately contributing to the progression of advanced lung cancer.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay.

BACKGROUND: Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. METHODS AND RESULTS: The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion. CONCLUSIONS: In conclusion, anti-PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

Establishment of orthotopic osteosarcoma animal models in immunocompetent rats through muti-rounds of in-vivo selection.

Immunodeficient murine models are usually used as the preclinical models of osteosarcoma. Such models do not effectively simulate the process of tumorigenesis and metastasis. Establishing a suitable animal model for understanding the mechanism of osteosarcoma and the clinical translation is indispensable. The UMR-106 cell suspension was injected into the marrow cavity of Balb/C nude mice. Tumor masses were harvested from nude mice and sectioned. The tumor fragments were transplanted into the marrow cavities of SD rats immunosuppressed with cyclosporine A. Through muti-rounds selection in SD rats, we constructed orthotopic osteosarcoma animal models using rats with intact immune systems. The primary tumor cells were cultured in-vitro to obtain the immune-tolerant cell line. VX2 tumor fragments were transplanted into the distal femur and parosteal radius of New Zealand white rabbit to construct orthotopic osteosarcoma animal models in rabbits. The rate of tumor formation in SD rats (P1 generation) was 30%. After four rounds of selection and six rounds of acclimatization in SD rats with intact immune systems, we obtained immune-tolerant cell lines and established the orthotopic osteosarcoma model of the distal femur in SD rats. Micro-CT images confirmed tumor-driven osteolysis and the bone destruction process. Moreover, the orthotopic model was also established in New Zealand white rabbits by implanting VX2 tumor fragments into rabbit radii and femurs. We constructed orthotopic osteosarcoma animal models in rats with intact immune systems through muti-rounds in-vivo selection and the rabbit osteosarcoma model.

Investigation of Rapid Emergence of Colistin Resistance in a Newborn Infected with KPC2-Producing Hypervirulent Carbapenem-Resistant Klebsiella pneumoniae.

OBJECTIVES: Hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKp) poses a significant threat to public health. This study reports an infection related to hv-CRKp in a premature infant and reveals its colistin resistance and evolutionary mechanisms within the host. METHODS: Three KPC-producing CRKp strains were isolated from a patient with sepsis and CRKp osteoarthritis who had been receiving colistin antimicrobial therapy. The minimum inhibitory concentrations (MICs) of Ceftazidime,Ceftazidime-Avibactam(CAZ-AVI),Meropenem,Imipenem,Tigecycline,Amikacin,Minocycline,Sulfamethoxazole/Trimethoprim,Ciprofloxacin,Levofloxacin,Aztreonam,Cefepime,Cefoperazone/Sulbactam,Piperacillin/Tazobactam and colistin were determined using the microbroth dilution method.The whole-genome sequencing analysis was conducted to determine the STs, virulence genes, and antibiotic resistance genes of three CRKp strains. RESULTS: Whole-genome sequencing revealed that all three CRKp strains belonged to the sequence type (ST) 11 clone and carried a plasmid encoding blaKPC-2. The three strains all possessed the iucABCDiutA virulence cluster, peg-344 gene, and rmpA/rmpA2 genes, defining them as hv-CRKp. Further experiments and whole-genome analysis revealed that a strain of Kp has developed resistance to colistin. The mechanism found to be responsible for the colistin resistance was a deletion mutation of approximately 9000 bp including mgrB gene. CONCLUSION: This study characterizes the colistin resistance of ST11 clone hv-CRKp during colistin treatment and its rapid evolution within the host.

Redefining intestinal stemness: The emergence of a new ISC population.

In tissue homeostasis, intestinal stem cells (ISCs) undergo continuous self-renewal to sustain rapid cellular turnover. In this issue of Cell, Capdevila et al.1 and Malagola, Vasciaveo, et al.2 identify a new ISC population in the upper crypt that can generate Lgr5+ stem cells during homeostasis.

Effect of heat-reinforcing needling on hypoxia-inducible factor 1α and glycolysis activity in rabbits with cold syndrome of rheumatoid arthritis. / çƒ­è¡¥é’ˆæ³•å¯¹ç±»é£Žæ¹¿å ³èŠ‚ç‚Žå¯’è¯å®¶å ”è†å ³èŠ‚æ»‘è†œç»„ç»‡ç¼ºæ°§è¯±å¯¼å› å­1αå’Œç³–é µè§£æ´»æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of heat-reinforcing needling (HRN) on synovial inflammation, hypoxia-inducible factor-1α (HIF-1α) and glycolytic activity in serum and synovial tissue in rabbits with cold syndrome of rheumatoid arthritis (RA), so as to explore its mechanisms underlying improvement of RA. METHODS: A total of 32 rabbits were randomly divided into normal, model, inhibitor and HRN groups, with 8 rabbits in each group. The RA with cold syndrome model was induced by injecting ovalbumin dry powder and Freund's complete adjuvant combined with cold freezing. Rabbits in the inhibitor group were intraperitoneally injected with 2-methoxyestradiol (2.5 mg/kg), rabbits in the HRN group were received HRN at bilateral "Zusanli" (ST36) for 30 min. The treatments were conducted once daily for 14 consecutive days. After the interventions, the knee circumference and pain threshold were measured. The contents of nicotinamide adenine dinucleotide phosphoric (NADPH), Hexokinase II (HK2) and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) in serum of rabbits were detected by ELISA. The pathological morphology of synovial tissue of the knee joints were observed by HE staining. The positive expressions of tumor necrosis factor (TNF-α), interleukin (IL)-1ß, IL-6 and IL-17 in synovial tissue of knee joint were detected by immunohistochemistry. The content of lactic acid in synovial tissue of rabbit knee joint was detected by spectrophotometry. The expression levels of HIF-1α, pyruvate kinase 2 (PKM2) and lactate dehydrogenase (LDHA) in synovial tissue of knee joint were detected by Western blot. RESULTS: After intervention, compared with the normal group, the knee circumference was significantly enlarged (P<0.05), the pain threshold was significantly decreased (P<0.05)；the synovial tissue of knee joints showed significant cell proliferation and inflammatory infiltration, the pathological score was significantly increased (P<0.05)；positive expressions of TNF-α, IL-1ß, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all P<0.05) in the model group. Compared with model group, the circumference of knee joint was significantly decreased (P<0.05), the pain threshold was significantly increased (P<0.05)；in synovial tissue, the pathological score was decreased (P<0.05)；the positive expressions of TNF-α, IL-1ß, IL-6 and IL-17 in synovial tissue were decreased (P<0.05), the lactic acid content in synovial tissue was decreased (P<0.05)；the contents of NADPH, HK2 and PFKFB3 in serum and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were decreased (P<0.05) in inhibitor group and HRN group. Compared with the inhibitor group, the synovial pathological score was significantly increased (P<0.05), positive expressions of TNF-α, IL-1ß, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all P<0.05) in HRN group. CONCLUSIONS: HRN can increase the pain threshold, reduce the knee circumference and inhibit the inflammatory response in rabbits with cold syndrome of RA. The possible mechanism is related to the down-regulation of HIF-1α and glycolysis activity.

Detection of calcitonin gene-related peptide based on increased antigen-driven interaction with antibody variable regions.

Introduction: Calcitonin gene-related peptide (CGRP) is involved in trigeminal neuralgia and migraine, and measuring the CGRP concentration in the serum is crucial for the early prediction of these conditions. Current methods for CGRP detection are primarily radioimmunoassay, which needs radioactive substances and enzyme-linked immunosorbent assays (ELISAs) which need long detection time and some have a narrow detection range. Methods: The genes of anti-CGRP antibody variable regions were cloned into pDong1 vector to obtain pDong1/Fab-CGRP, with which phage-Fab was prepared, and the concentration of CGRP was detected by competitive ELISA. The pDong1/Fab-CGRP was modified to obtain pDong1/OS-CGRP, with which the co-expression solution containing phage-displayed heavy chain variable fragments (phage-VH) and light chain was obtained. CGRP was detected by OS-ELISA based on phage-VH, antibody light chain, and anti-light chain antibody. The VL gene was cloned into the pMAL vector to obtain pMAL-VL (CGRP), with which maltose binding protein fused with VL (MBP-VL) was prepared. CGRP was detected by OS-ELISA employing MBP-VL and phage-VH. Results: OS-ELISAs that measure the CGRP concentration by quantifying the interaction between variable regions were investigated. OS-ELISA using phage-VH and secreted light chains in the same culture system exhibited a limit of detection (LOD) of 0.05 nM, offering higher sensitivity than competitive assay with an LOD of 0.75 nM, whereas using phage-VH and separately prepared MBP-VL exhibited an LOD of 0.15 nM and a broader detection range of 0.15-500 nM than competitive ELISA, whose detection range was 0.75-10 nM. Discussion: The combination of the two OS assays achieved high sensitivity and a broad detection range for CGRP, which may have significance in clinical applications.

Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma.

Carnosine dipeptidase 1 (CNDP1), an enzyme integral to the hydrolysis of dipeptides containing histidine, plays an indispensable role in myriad physiological processes, including hydrolysis of proteins, maturation of specific biochemical functionalities within proteins, tissue regeneration, and regulation of cell cycle. However, the implications of CNDP1 in oncogenesis and its prognostic value are not yet fully elucidated. Initially, we procured the GSE40367 dataset from the Gene Expression Omnibus and established a protein-protein interaction network. Thereafter, we conducted functional and pathway enrichment analyses utilizing GO, KEGG, and GSEA. Moreover, we undertook an association analysis concerning the expression of CNDP1 with immune infiltration, along with survival analysis across various cancers and specifically in hepatocellular carcinoma (HCC). Our study uncovered a total of 2,248 differentially expressed genes, with a down-regulation of CNDP1 in HCC and other cancers. Our explorations into the relationship between CNDP1 and immune infiltration disclosed a negative correlation between CNDP1 expression and the presence of immune cells in HCC. Survival analyses revealed that diminished expression of CNDP1 correlates with an adverse prognosis in HCC and several other types of cancer. These observations intimate that CNDP1 holds promise as a novel prognostic biomarker for both pan-cancer and HCC.

Evaluating the quality of home care in community health service centres: A machine learning approach.

AIMS: The aim of the study is to develop a model using a machine learning approach that can effectively identify the quality of home care in communities. DESIGN: A cross-sectional design. METHODS: In this study, we evaluated the quality of home care in 170 community health service centres between October 2022 and February 2023. The Home Care Service Quality Questionnaire was used to collect information on home care structure, process and outcome quality. Then, an intelligent and comprehensive evaluation model was developed using a convolutional neural network, and its performance was compared with random forest and logistic regression models through various performance indicators. RESULTS: The convolutional neural network model was built upon seven variables, which encompassed the qualification of home nursing staff, developing and practicing emergency plan to cope with different emergency rescues in home environment, being equipped with medication and supplies for first aid according to specific situations, assessing nutrition condition of home patients, allocation of the number of home nursing staff, cases of new pressure ulcers and patient satisfaction rate. Remarkably, the convolutional neural network model demonstrated superior performance, outperforming both the random forest and regression models. CONCLUSION: The successful development and application of the convolutional neural network model highlight its ability to leverage data from community health service centres for rapid and accurate grading of home care quality. This research points the way to home care quality improvement. IMPACT: The model proposed in this study, coupled with the aforementioned factors, is expected to enhance the accuracy and efficiency of a comprehensive evaluation of home care quality. It will also help managers to take purposeful measures to improve the quality of home care. REPORTING METHOD: The reporting of this study (Observational, cross-sectional study) conforms to the STROBE statement. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The application of this model has the potential to contribute to the advancement of high-quality home care, particularly in lower-middle-income communities.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) activates p38 to affect pulmonary fibrosis.

Objective: We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors. Methods: The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA. Results: In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-ß1 (TGF-ß1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1ß (IL-1ß) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells. Conclusion: Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.

Phage therapy combats pandrug-resistant Acinetobacter baumannii infection safely and efficiently.

Phage therapy offers a promising approach to combat the growing threat of antimicrobial resistance. Yet, key questions remain regarding dosage, administration routes, combination therapy, and the causes of therapeutic failure. In this study, we focused on a novel lytic phage, ФAb4B, which specifically targeted the A. baumannii strains with KL160 CPS, including the pan-drug resistant A. baumannii YQ4. ФAb4B exhibited the ability to effectively inhibit biofilm formation and eradicate mature biofilms independently of dosage. Additionally, it demonstrated a wide spectrum of antibiotic-phage synergy and did not show any cytotoxic or hemolytic effects. Continuous phage injections, both intraperitoneally and intravenously over 7 days, showed no acute toxicity in vivo. Importantly, phage therapy significantly improved neutrophil counts, outperforming ciprofloxacin (CIP). However, excessive phage injections suppressed neutrophil levels. The combinatorial treatment of phage-CIP rescued 91% of the mice, a superior outcome compared to phage alone (67%). The efficacy of the combinatorial treatment was independent of phage dosage. Notably, prophylactic administration of the combinatorial regimen provided no protection, but even when combined with a delayed therapeutic regimen, it saved all the mice. Bacterial resistance to the phage was not a contributing factor to treatment failure. Our preclinical study systematically describes the lytic phage's effectiveness in both in vitro and in vivo settings, filling in crucial details about phage treatment against bacteriemia caused by A. baumannii, which will provide a robust foundation for the future of phage therapy.