Search

Background: Due to its effective osteogenic ability, BMP9 is a promising candidate for bone regeneration medicine. Whereas, BMP9 can also induce adipogenesis simultaneously. LCN2 is a cytokine associated with osteogenesis and adipogenesis. Reducing the adipogenic potential may be a feasible measure to enhance the osteogenic capability of BMP9. Objective: The objective of the study was to explore the role of LCN2 in regulating the BMP9-initialized osteogenic and adipogenic differentiation in mouse embryonic fibroblasts (MEFs), and clarify the possible underlying mechanism. Methods: Histochemical stain, western blot, real-time PCR, laser confocal, immunoprecipitation, cranial defect repair, and fetal limb culture assays were used to evaluate the effects of LCN2 on BMP9-induced osteogenic and adipogenic differentiation, as well as Wnt/β-catenin signaling. Results: LCN2 was down-regulated by BMP9. The BMP9-induced osteogenic markers were inhibited by LCN2 overexpression, but the adipogenic markers were increased; LCN2 knockdown exhibited opposite effects. Similar results were found in bone defect repair and fetal limb culture tests. The level of β-catenin nucleus translocation was found to be reduced by LCN2 overexpression, but increased by LCN2 knockdown. The inhibitory effect of LCN2 overexpression on the osteogenic capability of BMP9 was reversed by β-catenin overexpression; whereas, the effect of LCN2 knockdown on promoting BMP9 osteogenic potential was almost eliminated by β-catenin knockdown. LCN2 could bind with LRP6 specifically, and the inhibitory effect of LCN2 on the osteogenic potential of BMP9 could not be enhanced by LRP6 knockdown. Conclusion: LCN2 inhibits the BMP9-induced osteogenic differentiation but promotes its adipogenic potential in MEFs, which may be partially mediated by reducing Wnt/β-catenin signaling via binding with LRP6.

Background: Feeding and eating disorders related to cognitive and psycho-behavioral symptoms are strongly associated with health status in persons with dementia (PWD). Non-pharmacological interventions have been the priority selection to address this significant issue. However, the direct targets of non-pharmacological interventions are unclear and there is no consistent evidence of recommendations on the intervention of different dementia stages and the settings of intervention practice. Objective: To provide caregivers with a set of self-help non-pharmacological interventions for feeding and eating disorders in PWD. Methods: Based on the process of evidence summary, a systematic literature search was performed on dementia websites and seven databases. Two researchers screened the studies independently and appraise the quality. The evidence was graded by Joanna Briggs Institute Grades of Recommendation. Results: Twenty-eight articles were included. Twenty-three non-pharmacological intervention recommendations were categorized into six themes containing oral nutritional supplementation, assistance with eating and drinking, person-centered mealtime care, environmental modification, education or training, and multi-component intervention. These interventions corresponded to three direct targets including improving engagement, making up for loss ability, and increasing food intake directly. They were applied to different stages of dementia and most interventions were targeted at PWD in long-term care institutions. Conclusion: This article summarized the direct targets and the specific implementation of recommendations at different stages of dementia to provide caregivers with self-help non-pharmacological interventions. The practice of recommendations was more applicable to institutionalized PWD. When applied to PWD at home, caregivers need to identify the specific feeding and eating conditions at different stages and adopted the interventions in conjunction with the wishes of the PWD and professional advice.

Yuan Liu,* Chen Song,* Zhiqiang Tian, Wei Shen Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Shen, Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China, Tel +86 13385110723, Email shenweijs@outlook.comPurpose: This study aims to construct a machine learning model that can recognize preoperative, intraoperative, and postoperative high-risk indicators and predict the onset of venous thromboembolism (VTE) in patients.Patients and Methods: A total of 1239 patients diagnosed with gastric cancer were enrolled in this retrospective study, among whom 107 patients developed VTE after surgery. We collected 42 characteristic variables of gastric cancer patients from the database of Wuxi People’s Hospital and Wuxi Second People’s Hospital between 2010 and 2020, including patients’ demographic characteristics, chronic medical history, laboratory test characteristics, surgical information, and patients’ postoperative conditions. Four machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), support vector machine (SVM), and k-nearest neighbor (KNN), were employed to develop predictive models. We also utilized Shapley additive explanation (SHAP) for model interpretation and evaluated the models using k-fold cross-validation, receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and external validation metrics.Results: The XGBoost algorithm demonstrated superior performance compared to the other three prediction models. The area under the curve (AUC) value for XGBoost was 0.989 in the training set and 0.912 in the validation set, indicating high prediction accuracy. Furthermore, the AUC value of the external validation set was 0.85, signifying good extrapolation of the XGBoost prediction model. The results of SHAP analysis revealed that several factors, including higher body mass index (BMI), history of adjuvant radiotherapy and chemotherapy, T-stage of the tumor, lymph node metastasis, central venous catheter use, high intraoperative bleeding, and long operative time, were significantly associated with postoperative VTE.Conclusion: The machine learning algorithm XGBoost derived from this study enables the development of a predictive model for postoperative VTE in patients after radical gastrectomy, thereby assisting clinicians in making informed clinical decisions.Keywords: gastric neoplasms, gastrectomy, venous thromboembolism, risk factors, machine learning, prediction model

Yuan Liu,* Chen Song,* Zhiqiang Tian, Wei Shen Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Shen, Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, 214000, People’s Republic of China, Tel +86 13385110723, Email shenweijs@outlook.comPurpose: The occurrence of myocardial injury, a grave complication post complete mesocolic excision (CME), profoundly impacts the immediate and long-term prognosis of patients. The aim of this inquiry was to conceive a machine learning model that can recognize preoperative, intraoperative and postoperative high-risk factors and predict the onset of myocardial injury following CME.Patients and Methods: This study included 1198 colon cancer patients, 133 of whom experienced myocardial injury after surgery. Thirty-six distinct variables were gathered, encompassing patient demographics, medical history, preoperative examination characteristics, surgery type, and intraoperative details. Four machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), multilayer perceptron (MLP), and k-nearest neighbor algorithm (KNN), were employed to fabricate the model, and k-fold cross-validation, ROC curve, calibration curve, decision curve analysis (DCA), and external validation were employed to evaluate it.Results: Out of the four predictive models employed, the XGBoost algorithm demonstrated the best performance. The ROC curve findings indicated that the XGBoost model exhibited remarkable predictive accuracy, with an area under the curve (AUC) value of 0.997 in the training set and 0.956 in the validation set. For internal validation, the k-fold cross-validation method was utilized, and the XGBoost model was shown to be steady. Furthermore, the calibration curves demonstrated the XGBoost model’s high predictive capability. The DCA curve revealed higher benefit rates for patients who underwent interventional treatment under the XGBoost model. The AUC value for the external validation set was 0.74, which indicated that the XGBoost prediction model possessed good extrapolative capacity.Conclusion: The myocardial injury prediction model for patients undergoing CME that was developed using the XGBoost machine learning algorithm in this study demonstrates both high predictive accuracy and clinical utility.Keywords: colonic neoplasms, myocardial injury, surgery, prognosis, risk factor, machine learning

Yuan Liu, Wei Shen, Zhiqiang Tian Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of ChinaCorrespondence: Wei Shen, Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China, Tel +86 13385110723, Email shenweijs@outlook.comPurpose: Postoperative delirium (POD) is a common postoperative complication in elderly patients, and it greatly affects the short-term and long-term prognosis of patients. The purpose of this study was to develop a machine learning model to identify preoperative, intraoperative and postoperative high-risk factors and predict the occurrence of delirium after nonbrain surgery in elderly patients.Patients and Methods: A total of 950 elderly patients were included in the study, including 132 patients with POD. We collected 30 characteristic variables, including patient demographic characteristics, basic medical history, preoperative examination characteristics, type of surgery, and intraoperative information. Three machine learning algorithms, multilayer perceptron (MLP), extreme gradient boosting (XGBoost), and k-nearest neighbor algorithm (KNN), were applied to construct the model, and the k-fold cross-validation method, ROC curve, calibration curve, decision curve analysis (DCA) and external validation were used for model evaluation.Results: XGBoost showed the best performance among the three prediction models. The ROC curve results showed that XGBoost had a high area under the curve (AUC) value of 0.982 in the training set; the AUC value in the validation set was 0.924, and the prediction model was highly accurate. The k-fold cross-validation method was used for internal validation, and the XGBoost model was stable The calibration curve showed high predictive power of the XGBoost model. The DCA curve showed a higher benefit rate for patients who received interventional treatment under the XGBoost model. The AUC value for the external validation set was 0.88, indicating that the predictive model was extrapolative.Conclusion: The prediction model of POD derived from the machine learning algorithm in this study has high prediction accuracy and clinical utility, which is beneficial for clinicians to diagnose and treat patients in a timely manner.Keywords: postoperative delirium, prevention, risk factors, machine learning, prediction model

Fungicides play a significant role in the integrated management of plant pathogens. However, the irrational application of the fungicides with similar structures have led to development of cross-resistance. Therefore, the need to seek novel fungicides with new structure is desired.Twenty-eight novel sulfoximine derivatives incorporating nitroguanidine moieties were designed, synthesized, and evaluated as antifungal agents. The bioassay results indicated that most of the synthesized compounds displayed excellent fungicidal activities against Sclerotinia sclerotiorum, Rhizoctonia solani, Fusarium graminearum, and Pyricularia grisea. Among them, compounds 6cNovel sulfoximine derivatives containing nitroguanidine possess the potential antifungal activity, and the unique structure may offer an alternative option for fungicide development in the future. This article is protected by copyright. All rights reserved.

In this study, an antibiotics-free hydrogel with self-regulated nitric oxide release kinetics was developed, which could eliminate bacteria in early stages of wound healing while facilitating wound closure at later stages.

This review focuses on the obstructions faced by aptamers in cancer therapy applications and recent breakthroughs, showing the future trends of aptamer-conjugated nanomedicines.

Purpose of the article: There are at two-folds, i.e. creating a public information management system and driving the City of Riga towards a smart sustainable tourism destination with a value-created tourism digital business model in the post pandemic era.Method: It is grounded by literature review and conceptual framework construction, and the information management system for Riga is established based on the needs of developing Riga into a smart sustainable tourism destination.Scientific aim: The aim is to identify factors of a public information management system which is storing and processing massive data with information and communication technologies (ICTs), and to illustrate factors of smart sustainable tourism destinations.Findings: These include the establishment of a framework of public information management system for Riga city, with supporting information and communication technologies (ICTs), as well as uncovering dimensions and outcomes of smart sustainable tourism destinations. The Riga public information management system will promote the city as a smart sustainable tourism destination. The dimensions of a smart tourism destination are presented, namely, smart economy, smart environment, smart governance, smart living, smart mobility, and smart people. The governance aspects include city governance, environ-urban configuration, socio-institutional structure and techno-economic, while social, environmental and economic issues are stressed.Conclusions: We present a framework of a public information management system containing functions of storing and processing massive data with six ICTs, and revealing three indicators, people, technologies, and governance, for Riga as a data-driven smart sustainable tourism destination.

The high incidence and mortality of cervical cancer (CC) require an urgent need for exploring novel valuable therapeutics. Triptonide (TN) is a small molecule monomer extracted from the Chinese herb Tripterygium wilfordii Hook. Our results showed that TN, at only nanomolar concentrations, strongly inhibited growth, colony formation, proliferation, migration, and invasion of established and primary human cervical cancer cells. TN induced apoptosis and cell cycle arrest in cervical cancer cells. Moreover, cervical cancer cell in vitro migration and invasion were suppressed by TN. It was however noncytotoxic and proapoptotic to normal cervical epithelial cells and human skin fibroblast cells. Gene set enrichment analysis (GSEA) of RNA sequencing data of differentially expressed genes (DEGs) in TN-treated cervical cancer cells implied that DEGs were enriched in the receptor tyrosine kinase (RTK) signaling and PI3K-Akt-mTOR cascade. In cervical cancer cells, RTKs, including EGFR and PDGFRα, were significantly downregulated and Akt-mTOR activation was largely inhibited after TN treatment. In vivo, oral administration of TN significantly inhibited subcutaneous cervical cancer xenograft growth in nude mice. EGFR and PDGFRα downregulation as well as Akt-mTOR inactivation was detected in TN-treated HeLa xenograft tumor tissues. Thus, TN inhibits human cervical cancer cell growth in vitro and in vivo. Its anticervical cancer activity was associated with RTK downregulation and Akt-mTOR inactivation.

There are few nomograms for the prognosis of Chinese patients with triple-negative breast cancer (TNBC).To construct and validate a nomogram for overall survival (OS) of Chinese TNBC patients after surgery.This study used the data of SEER*stat 8.3.5 and selected Chinese patients with TNBC operated on between 2010 and 2015. Univariate and multivariate Cox proportional hazard regression models were used. The identified variables were integrated to form a predictive nomogram and risk stratification model; it was assessed with C-indexes and calibration curves.The median and maximal OS of the 336 patients was 39 and 83 mo, respectively. The multivariate analysis showed that age (The nomogram provided prognostic superiority over the traditional tumor, node and metastasis system. It could help clinicians make individual OS or risk predictions for Chinese TNBC patients after surgery.

This study aimed to determine the association between vessel wall enhancement and progression of arterial stenosis and clinical outcomes in patients with moyamoya (MMD) using high-resolution magnetic resonance (HRMR) vessel wall imaging.Consecutive participants diagnosed with MMD were prospectively recruited and underwent HRMR at baseline and during follow-up, which had an interval period of ≥ 6 months and were clinically followed up for ≤ 24 months to record the occurrence of ischemic stroke. The relationship between vessel wall enhancement and arterial stenosis progression and stroke occurrence was evaluated.HRMR vessel wall imaging was used to identify 309 stenotic lesions at the internal carotid artery (ICA) in 170 participants (mean age: 37.7 ± 11.3 years old, male: 44.1%). The baseline presence (adjusted odds ratio [aOR] = 3.57, 95% CI = 1.97-6.44, p0.001) and progression (aOR = 2.96, 95% CI = 1.29-6.80, p = 0.010) of vessel wall enhancement and middle cerebral artery (MCA) involvement (aOR = 4.98, 95% CI = 1.50-16.52, p = 0.009) were significantly associated with rapid progression of arterial stenosis. Furthermore, vessel wall enhancement (adjusted HR = 3.59, 95% CI = 1.33-9.70, p = 0.011) and rapid progression of arterial stenosis (adjusted HR = 4.52, 95% CI = 1.48-13.81, p = 0.008) were correlated with future stroke occurrence.The baseline presence of vessel wall enhancement was associated with rapid progression of arterial stenosis and increased risk for stroke in MMD patients. Our findings suggest that vessel wall enhancement may serve as a predictor of disease progression and poor outcomes in MMD.• The baseline presence of vessel wall enhancement was significantly associated with the rapid progression of arterial stenosis. • The baseline presence of vessel wall enhancement and rapid progression of arterial stenosis were both correlated with increased risk for future occurrence of stroke. • Our findings suggest that vessel wall enhancement may serve as a predictor of rapid progression of arterial stenosis and poor outcomes in MMD patients.

Ficolins, belonging to the fibrinogen-related protein superfamily, are important pattern recognition receptors in innate immunity. Here, a ficolin gene Ptficolin was characterized from the swimming crab Portunus trituberculatus. The completed cDNA sequence of Ptficolin encoded a signal peptide, a coiled-coil region and a fibrinogen-like domain but without the typical collagen region of vertebrate ficolins. Ptficolin showed higher expression in stomach and hepatopancreas, and presented a time-dependent response after pathogen challenge and injury stimulation. The recombinant Ptficolin (rPtficolin) could bind to various PAMPs and microorganisms, and agglutinate microorganisms and rabbit erythrocytes in a Ca

To investigate the predictors of clinical outcomes in unresponsive patients with acquired brain injuries.Patients with coma or disorders of consciousness were enrolled from August 2019 to March 2021. A retrospective analysis of demographics, etiology, clinical score, diagnosis, electroencephalography (EEG), and event-related potential (ERP) data from 1 week to 2 months after coma onset was conducted. Findings were assessed for predicting favorable outcomes at 6 months post-coma, and functional outcomes were determined using the Glasgow Outcome Scale-Extended (GOS-E).Of 68 patients, 22 patients had a good neurological outcome at 6 months, while 11 died. Univariate analysis showed that motor response (Motor-R; p 0.001), EEG pattern (p = 0.015), sleep spindles (p = 0.018), EEG reactivity (EEG-R; p 0.001), mismatch negativity (MMN) amplitude at electrode Fz (FzMMNA; p = 0.001), P3a latency (p = 0.044), and P3a amplitude at electrode Cz (CzP3aA; p 0.001) were significantly correlated with patient prognosis. Multivariable logistic regression analysis showed that FzMMNA, CzP3aA, EEG-R, and Motor-R were significant independent predictors of a favorable outcome. The sensitivity and specificity of FzMMNA (dichotomized at 1.16 μV) were 86.4% and 58.5%, and of CzP3aA (cut-off value 2.76 μV) were 90.9% and 70.7%, respectively. ERP amplitude (ERP-A), a combination of FzMMNA and CzP3aA, improved prediction accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.884. A model incorporating Motor-R, EEG-R, and ERP-A yielded an outstanding predictive performance (AUC=0.921) for a favorable outcome.ERP-A and the prognostic model resulted in the efficient prediction of a favorable outcome in unresponsive patients.

Legumes in the inverted repeat-lacking clade (IRLC) each produce a unique set of nodule-specific cysteine-rich (NCR) peptides, which act in concert to determine the terminal differentiation of nitrogen-fixing bacteroid. IRLC legumes differ greatly in their numbers of NCR and sequence diversity. This raises the significant question how bacteroid differentiation is collectively controlled by the specific NCR repertoire of an IRLC legume. Astragalus sinicus is an IRLC legume that forms indeterminate nodules with its microsymbiont Mesorhizobium huakuii 7653R. Here, we performed transcriptome analysis of root and nodule samples at 3, 7, 14, 28 days postinoculation with M. huakuii 7653R and its isogenic ∆ bacA mutant. BacA is a broad-specificity peptide transporter required for the host-derived NCRs to target rhizobial cells. A total of 167 NCRs were identified in the RNA transcripts. Comparative sequence and electrochemical analysis revealed that A. sinicus NCRs (AsNCRs) are dominated by a unique cationic group (termed subgroup C), whose mature portion is relatively long (>60 amino acids) and phylogenetically distinct and possessing six highly conserved cysteine residues. Subsequent functional characterization showed that a 7653R variant harboring AsNCR083 (a representative of subgroup C AsNCR) displayed significant growth inhibition in laboratory media and formed ineffective white nodules on A. sinicus with irregular symbiosomes. Finally, bacterial two-hybrid analysis led to the identification of GroEL1 and GroEL3 as the molecular targets of AsNCR067 and AsNCR076. Together, our data contribute to a systematic understanding of the NCR repertoire associated with the A. sinicus and M. huakuii symbiosis. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Blood pressure in patients with traumatic brain injury (TBI) is associated with clinical outcome. However, evidence of blood pressure (BP) range is scarce and the association between BP and clinical outcome is mostly controversial. We aimed to investigate the association between blood pressure and clinical outcome in TBI.This is a retrospective cohort study using the Taipei Tzu Chi Hospital trauma database from January 2009 to June 2019; totally, 13,114 patients were examined. The primary outcome of this investigation was in-hospital mortality and the secondary outcomes were intensive care unit (ICU) admission rate and prolong ICU stay (defined as stay in ICU ≥ 14 days). Subgroups analysis of Glasgow Coma Scale (GCS) and Triage SBP was also conducted.A total of 1782 traumatic adult patients with TBI (AIS score3) were finally included. The cut-off points are 130 mmHg to 149 mmHg in all TBI patients with lower odds ratio of mortality. In different TBI severity, U-shape relationship also presented and we also found that cut-off points of 130 to 149 mmHg in mild TBI and 110 to 129 mmHg in moderate TBI have lower odds ratio of mortality. The mortality is significantly increased in BP below 90 mmHg and above 190 mmHg in TBI patients.Traumatic brain injury population presented a U-shape relationship between triage SBP and in-hospital mortality. Early resuscitation and correct hypotension/hypertension in TBI population with BP below 90 mmHg and above 190 mmHg may prevent from increased mortality.

UCP4, as an uncoupling protein in mitochondrial intima, is closely related to the resistance to oxidative stress and the function of mitochondria. However, whether and how its antioxidant capacity also works in crustaceans has not been reported in detail. This study showed that the expression of PvUCP4 was negatively correlated with the expression of pva-miR-144. The content of reactive oxygen species (ROS), ATP, and apoptosis was significantly increased, while the mitochondrial membrane potential (MMP) was seriously depolarized, Edema, vacuolation, and ambiguity of cristae and membrane were observed clearly in mitochondria after the knockdown of PvUCP4 induced by V. alginolyticus. The sharp drop in THC and severe damage in the hepatopancreas were all due to the knockout of PvUCP4 under the stress of V. alginolyticus. The co-transfection of pva-miR-144 and PvUCP4 could partially recover MMP compared with the abnormal expression of pva-miR-144. Similarly, co-transfection of pva-miR-144 and PvUCP4 could partially eliminate apoptosis compared with the abnormal expression of pva-miR-144. In addition, PvUCP4 3'-UTR has a pva-miR-144 predicted binding site in 1417-1428, which also was confirmed by the dual luciferase reporter assay. By the way, the results of ROS, MMP, and apoptosis showed that PvDJ-1 regulated the expression of PvUCP4 through PvNF-κB. Altogether, these results indicated that PvUCP4 has the antioxidant function of resisting oxidation reaction and weakening oxidative damage, to protect the normal operation of mitochondrial function and maintaining the cell homeostasis in shrimp.

As one of the five great lakes in China, the Chaohu Lake Basin is the main water source for regional economic and ecological development in Hefei city and is considered a source of drinking water. The spatial-temporal distributions and occurrence of soluble trace elements were studied in the surrounding ten rivers in the Chaohu Lake Basin as well as water quality and risk assessment during the normal and wet seasons. Principal component analysis (PCA) showed that the main source of river pollution during the two seasons was the mining industry. High values of most elements were found in the northwestern rivers in the two seasons. The temporal changes in the elements showed that the distributions of As, Mn, Cd, and Cu in the two seasons were very different, but the trends of Ni, Co, and V were basically the same. The sodium adsorption ratio (SAR) showed that almost all river samples needed to be treated before irrigation, and the water quality index (WQI) showed that most samples were of excellent water quality for drinking. The ecological risk assessment results showed that the risks in the two seasons were all slight. The results of the health risk evaluation suggested that no noncarcinogenic risks were found in the normal season and that the carcinogenic risks from Cr and As reached their highest levels in the normal and wet seasons, respectively. This research can provide vital data for rational water control and water quality conservation, offer a scientific basis for ecological environment safety, and offer a reference for carcinogenic and noncarcinogenic health risks to regional residents.

Methylglyoxal (MGO) is a highly reactive metabolite mainly formed as a byproduct of glycolysis. Elevated MGO has been considered as a risk factor for several diseases including diabetes and neurodegeneration. While MGO modifications on proteins were globally profiled, the cross-links between proteins induced by MGO in proteomes are unexplored to date. Here, we reported a quantitative chemoproteomic platform based on mass shifts that enables identification of events of protein cross-links induced by MGO in proteomes. A total of 66 cross-linked targets were identified from the profiling experiments when cells were treated with MGO, among which the components of functional complexes such as spliceosomes and ribosomes were enriched. We found that inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) was homocross-linked by MGO and the active-site Cys331 was critical for mediating the cross-link, which in turn affected IMPDH2's activity. Our study has provided new clues for the functional impact in proteomes by MGO, and the methodology can be, in principle, applied to profile protein cross-links induced by other reactive metabolites.

To summarize the awareness levels of breast cancer (BC) worldwide and investigate factors associated with BC awareness to determine differences in awareness between China and other countries.This systematic review followed the PRISMA guidelines and included 92 articles up to July, 2021. We calculated percentages for BC awareness levels and conducted subgroup analysis and cumulative meta-analysis.A total 84% (95% confidence interval [95%CI]: 78-90%) of women knew about BC; however, only 51% (95%CI: 37-66%) and 40% (95%CI: 24-56%) of women were aware of BC symptoms and BC risk factors, respectively. The most commonly known BC symptom was breast lump (71%, 95%CI: 62-80%), and BC family history was the most well-known BC risk factor (61%, 95%CI: 54-69%). Subgroup analysis showed lower awareness levels among Chinese and Asian women than women from other countries. Cumulative meta-analysis showed no obvious progress in BC awareness levels over time. We investigated 15 awareness-related factors, the most frequent of which were education level (61.8%), occupation (29.4%), and age (26.5%).BC awareness levels remain low. Improving BC awareness is critical, especially in developing countries.Effective education programs are urgently needed to improve women's BC awareness.

Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (met), [Leu]enkephalin (leu), β-endorphin (β-end), α-neodynorphin, dynorphin A (dynA), dynorphin B (dynB), big dynorphin (Big dyn), nociceptin/orphanin FQ (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [124, 101, 92]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered 'opioid-related' rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [304], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone. The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol, in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin, are in clinical use for itch.

Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1 knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1 knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1B knockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1 knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1 knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8(+) T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95 % CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8(+) T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.

Objective Purpose To observe the safety and effect of the C-pupilloplasty for the treatment of iris coloboma and traumatic iris defects. Methods A total of 21 cases (21 eyes) with iris coloboma or traumatic iris defects who underwent C-pupilloplasty (a single-pass three-throw technique) from Feb. 2016 to Mar. 2020 were analyzed retrospectively. Uncorrected visual acuity, refraction, corneal topographic keratometry and endothelial cell density were examined. Results All the patients were successfully treated, and a central and round pupil was restored. The mean follow-up duration was 8.76 ± 3.58 months (ranging from 2 to 14 months). All patients had round or round-like pupils with a diameter less than or equal to 3 mm after the C-pupilloplasty. Very slightly endothelial loss, negligible symptoms such as glare, distortion, dizziness and photophobia were observed. Conclusion We introduced a new technique of pupilloplasty (C-pupilloplasty) which could be a more straight forward and more effective treatment for iris coloboma and traumatic iris defect.

Improvement in acid phosphatase (APase) activity is considered as an important approach to enhance phosphorus (P) utilization in crops. Here, GmPAP14 was significantly induced by low P (LP), and its transcription level in ZH15 (P efficient soybean) was higher than in NMH (P inefficient soybean) under LP conditions. Further analyses demonstrated that there were several variations in gDNA (G-GmPAP14Z and G-GmPAP14N) and the promoters (P-GmPAP14Z and P-GmPAP14N) of GmPAP14, which might bring about differential transcriptional levels of GmPAP14 in ZH15 and NMH. Histochemical staining measurements revealed that a stronger GUS signal was present in transgenic Arabidopsis with P-GmPAP14Z under LP and normal P (NP) conditions compared with the P-GmPAP14N plant. Functional research demonstrated that transgenic Arabidopsis with G-GmPAP14Z had a higher level of GmPAP14 expression than the G-GmPAP14N plant. Meanwhile, higher APase activity was also observed in the G-GmPAP14Z plant, which led to increases in shoot weight and P content. Additionally, validation of variation in 68 soybean accessions showed that varieties with Del36 displayed higher APase activities than the del36 plant. Thus, these results uncovered that allelic variation in GmPAP14 predominantly altered gene expression to influence APase activity, which provided a possible direction for research of this gene in plants.

Breast cancer is a devastating malignancy, among which the luminal A (LumA) breast cancer is the most common subtype. In the present study, we used a comprehensive bioinformatics approach in the hope of identifying novel prognostic biomarkers for LumA breast cancer patients. Transcriptomic profiling of 611 LumA breast cancer patients was downloaded from TCGA database. Differentially expressed genes (DEGs) between tumor samples and controls were first identified by differential expression analysis, before being used for the weighted gene co-expression network analysis. The subsequent univariate Cox regression and LASSO algorithm were used to uncover key prognostic genes for constructing multivariate Cox regression model. Patients were stratified into high-risk and low-risk groups according to the risk score, and subjected to multiple downstream analyses including survival analysis, gene set enrichment analysis (GSEA), inference on immune cell infiltration and analysis of mutation burden. Receiving operator curve analysis was also performed. A total of 7071 DEGs were first identified by edgeR package, pink module was found significantly associated with invasive lobular carcinoma (ILC). 105 prognostic genes and 9 predictors were identified, allowing the identification of a 5-key prognostic genes (LRRC77P, CA3, BAMBI, CABP1, ATP8A2) after intersection. These 5 genes, and the resulting Cox model, displayed good prognostic performance. Furthermore, distinct differences existed between two risk-score stratified groups at various levels. The identified 5-gene prognostic model will help deepen the understanding of the molecular and immunological mechanisms that affect the survival of LumA-ILC patients and guide and proper monitoring of these patients.