Early detection and effective treatment of severe COVID-19 patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control ...individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model was validated using 10 independent patients, 7 of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 COVID-19 patients, leading to 16 correct assignments. We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation, complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.
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•93 proteins show differential expression in severe COVID-19 patient sera•204 metabolites in COVID-19 patient sera correlate with disease severity•A model composed of 29 serum factors shows patient stratification potential•Pathway analysis highlights metabolic and immune dysregulation in COVID-19 patients
Proteomic and metabolomic analysis of COVID-19 sera identifies differentially expressed factors that correlate with disease severity and highlights dysregulation of multiple immune and metabolic components in clinically severe patients.
Traditional anticancer treatments have several limitations, but cancer is still one of the deadliest diseases. As a result, new anticancer drugs are required for the treatment of cancer. The use of ...metal nanoparticles (NPs) as alternative chemotherapeutic drugs is on the rise in cancer research. Metal NPs have the potential for use in a wide range of applications. Natural or surface-induced anticancer effects can be found in metals. The focus of this review is on the therapeutic potential of metal-based NPs. The potential of various types of metal NPs for tumor targeting will be discussed for cancer treatment. The in vivo application of metal NPs for solid tumors will be reviewed. Risk factors involved in the clinical application of metal NPs will also be summarized.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
ObjectiveType 2 diabetes mellitus is increasing in young adults, and greater adiposity is considered a major risk factor. However, whether there is an association between obesity and diabetes and how ...this might be impacted by age is not clear. Therefore, we investigated the association between body mass index (BMI) and diabetes across a wide range of age groups (20–30, 30–40, 40–50, 50–60, 60–70 and ≥70 years old).DesignWe performed a retrospective cohort study using healthy screening programme data.SettingA total of 211 833 adult Chinese persons >20 years old across 32 sites and 11 cities in China (Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, Nantong) were selected for the study; these persons were free of diabetes at baseline.Primary and secondary outcome measuresFasting plasma glucose levels were measured and information regarding the history of diabetes was collected at each visit. Diabetes was diagnosed as fasting plasma glucose ≥7.00 mmol/L and/or self-reported diabetes. Patients were censored at the date of diagnosis or the final visit, whichever came first.ResultsWith a median follow-up of 3.1 years, 4174 of the 211 833 participants developed diabetes, with an age-adjusted incidence rate of 7.35 per 1000 persons. The risk of incident diabetes increased proportionally with increasing baseline BMI values, with a 23% increased risk of incident diabetes with each kg/m2 increase in BMI (95% CI 1.22 to 1.24). Across all age groups, there was a linear association between BMI and the risk of incident diabetes, although there was a stronger association between BMI and incident diabetes in the younger age groups (age×BMI interaction, p<0.0001).ConclusionsAn increased BMI is also independently associated with a higher risk of developing diabetes in young adults and the effects of BMI on incident diabetes were accentuated in younger adults.
Biofilm infections can induce chronic inflammation and stall the normal orchestrated course of wound-healing cascades. Herein, pH-switchable antimicrobial hydrogel with nanofiber networks for biofilm ...eradication and rescuing stalled healing in chronic wounds is reported on the basis of the self-assembly of a designed octapeptide (IKFQFHFD) at neutral pH. This hydrogel is biocompatible and exhibits an acidic pH (pathological environment of infected chronic wounds)-switchable broad-spectrum antimicrobial effect via a mechanism involving cell wall and membrane disruption. The antimicrobial activity of hydrogel is derived from its acidic pH-dependent nanofiber network destabilization and activated release of IKFQFHFD, which is antimicrobial only at acidic pH due to the antimicrobial peptide-like molecular structure. In addition, supramolecular nanofiber networks loaded with drugs of cypate (photothermal agent) and proline (procollagen component) are further developed. In vitro experiments show that loaded drugs exhibit acidic pH (pH ∼ 5.5)-responsive release profiles, and synergistic biofilm eradication and subsequent healing cascade activation of cells proliferation are achieved on the basis of the supramolecular nanofiber networks. Remarkably, the nanofiber networks of hydrogel enable in vivo complete healing of MRSA biofilm infected wound in diabetic mice within 20 days, showing great potential as promising chronic wound dressings. The proposed synergistic strategy for eradicating biofilm and activating subsequent healing cascades may offer a powerful modality for the management of clinical chronic wounds.
Metal-nitrogen-co-doped graphene has great potential for use as a high-efficiency catalyst in energy applications. In this paper, density functional theory (DFT) with the projector-augmented wave and ...generalized gradient approximation (PAW-GGA) method was used to explore the catalytic activity of M@Gra (M = Ni, Pd, Pt, and Ru) on different types of graphene for oxygen reduction reaction (ORR) applications. Both the direct hydrogenation and dissociative mechanism of O2 are used to evaluate the ORR performance, and the binding energy of the intermediates, rate-determining step, overpotential, and activation energy of metal-nitrogen-co-doped graphene are considered. The catalytic properties of 4Ru@Gra and 1Pt@Gra make them the best candidates for ORRs, as 4Ru@Gra and 1Pt@Gra exhibit a stronger interaction (ΔG *OH) with the nanosheets and excellent ORR catalytic performance compared to other compounds. Precious metals have a significant influence on reducing O2 and decreasing the reaction energy, and the strong interaction of *O may lead to a high overpotential for the ORR process. This demonstrates that these compounds can moderately bind with the ORR intermediates by tuning the relative free energy, resulting in the ORR intermediates binding neither too strongly nor too weakly, and this may lead to slow or fast kinetics. The 1Ni@Gra support has a higher activation energy for O2 dissociation of 0.74 eV as well as a small activation energy of 0.13 eV, and the rate-determining step is controlled by the binding of *OH. The ORR reduction pathway occurs via direct hydrogenation with four-electron reduction, and it was determined that the energy barrier was 0.35 eV for the *OOH form, which is lower than the energy barrier (0.74 eV) of the 2O* species produced from the O2 dissociation in 1Ni@Gra. This indicates that the direct hydrogenation pathway is preferred as the most favorable of the ORR mechanisms.
Background and Aims
Hepatic ischemia‐reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ...ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear.
Approach and Results
RNF5 expression was significantly down‐regulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression of cell lines were subjected to hypoxia‐reoxygenation challenge. Results showed that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, whereas RNF5 overexpression had the opposite effect. Furthermore, hepatocyte‐specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48‐linked ubiquitination, thereby inhibiting the activation of apoptosis‐regulating kinase 1 (ASK1) and its downstream c‐Jun N‐terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR.
Conclusions
We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5‐PGAM5 axis may be a promising therapeutic target for HIR.
A patient's infectivity is determined by the presence of the virus in different body fluids, secretions, and excreta. The persistence and clearance of viral RNA from different specimens of patients ...with 2019 novel coronavirus disease (COVID-19) remain unclear. This study analyzed the clearance time and factors influencing 2019 novel coronavirus (2019-nCoV) RNA in different samples from patients with COVID-19, providing further evidence to improve the management of patients during convalescence.
The clinical data and laboratory test results of convalescent patients with COVID-19 who were admitted to from January 20, 2020 to February 10, 2020 were collected retrospectively. The reverse transcription polymerase chain reaction (RT-PCR) results for patients' oropharyngeal swab, stool, urine, and serum samples were collected and analyzed. Convalescent patients refer to recovered non-febrile patients without respiratory symptoms who had two successive (minimum 24 h sampling interval) negative RT-PCR results for viral RNA from oropharyngeal swabs. The effects of cluster of differentiation 4 (CD4)+ T lymphocytes, inflammatory indicators, and glucocorticoid treatment on viral nucleic acid clearance were analyzed.
In the 292 confirmed cases, 66 patients recovered after treatment and were included in our study. In total, 28 (42.4%) women and 38 men (57.6%) with a median age of 44.0 (34.0-62.0) years were analyzed. After in-hospital treatment, patients' inflammatory indicators decreased with improved clinical condition. The median time from the onset of symptoms to first negative RT-PCR results for oropharyngeal swabs in convalescent patients was 9.5 (6.0-11.0) days. By February 10, 2020, 11 convalescent patients (16.7%) still tested positive for viral RNA from stool specimens and the other 55 patients' stool specimens were negative for 2019-nCoV following a median duration of 11.0 (9.0-16.0) days after symptom onset. Among these 55 patients, 43 had a longer duration until stool specimens were negative for viral RNA than for throat swabs, with a median delay of 2.0 (1.0-4.0) days. Results for only four (6.9%) urine samples were positive for viral nucleic acid out of 58 cases; viral RNA was still present in three patients' urine specimens after throat swabs were negative. Using a multiple linear regression model (F = 2.669, P = 0.044, and adjusted R = 0.122), the analysis showed that the CD4+ T lymphocyte count may help predict the duration of viral RNA detection in patients' stools (t = -2.699, P = 0.010). The duration of viral RNA detection from oropharyngeal swabs and fecal samples in the glucocorticoid treatment group was longer than that in the non-glucocorticoid treatment group (15 days vs. 8.0 days, respectively; t = 2.550, P = 0.013) and the duration of viral RNA detection in fecal samples in the glucocorticoid treatment group was longer than that in the non-glucocorticoid treatment group (20 days vs. 11 days, respectively; t = 4.631, P < 0.001). There was no statistically significant difference in inflammatory indicators between patients with positive fecal viral RNA test results and those with negative results (P > 0.05).
In brief, as the clearance of viral RNA in patients' stools was delayed compared to that in oropharyngeal swabs, it is important to identify viral RNA in feces during convalescence. Because of the delayed clearance of viral RNA in the glucocorticoid treatment group, glucocorticoids are not recommended in the treatment of COVID-19, especially for mild disease. The duration of RNA detection may relate to host cell immunity.
Background
Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for ...guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs.
Materials and Methods
By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts (n = 183 and 214).
Results
We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive +), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative −, CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway.
Conclusion
We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.
Implications for Practice
An immunohistochemistry (IHC)‐based classification approach was developed for triple‐negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression‐based classification. This IHC‐based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype‐specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice.
Impacts of sudden stratospheric warming (SSW) on three severe cold events (C1–C3) over Northern Hemisphere in early 2021 were investigated using subseasonal‐to‐seasonal ensemble forecasts. The SSW ...was characterized by successive displacement and split of the stratospheric polar vortex (SPV). Ensemble‐based sensitivity analyses showed that C1 over Siberia and C2 over western Canada were more related to SPV variations at a lead time of 1–2 weeks than C3 over central U.S. Within ensemble forecasts, a more elongated SPV with higher geopotential height over northern Eurasia were conducive to C1, whereas a SPV with the more poleward retreat from displacement contributed to C2. The forecast accuracy of stratospheric heights over the sensitive region at 2 weeks lead was significantly correlated with the forecast skill of the tropospheric circulation pattern preceding C1, implying that prediction of specific cold weather events may be improved by a better forecast of key features in SPV variations.
Plain Language Summary
Unusually extreme cold events have frequently occurred during the boreal winter in recent decades. These cold air outbreaks at the surface can be profoundly influenced by variations in the stratospheric polar vortex (SPV) with a lead time of weeks. The winter of early 2021 was characterized by successive extreme cold events over Asia and North America, leading to huge societal impacts, such as the unprecedented power outages over central U.S. in mid‐February 2021. These cold events were accompanied by a weak SPV that had been successively displaced and then split. Based on real‐time ensemble forecasts, we show that weakening and stretching of the SPV contributed to the cold event over Siberia. By contrast, the return of the SPV from displacement favored the cold event over western Canada. The subsequent cold surge over central U.S. was more related to mid‐latitude tropospheric processes than stratospheric processes. The prediction of some extremely cold weather events may be significantly improved by more accurate forecasts of the key features of the evolution of the SPV with a lead time of about two weeks.
Key Points
Sudden stratospheric warming with a displaced‐to‐split polar vortex in early 2021 had significant influences on surface cold events
Cold event in Siberia (Canada) was related to weakening (poleward retreat between displacement and split) of stratospheric polar vortex
Accurate forecasts of stratospheric variations improved forecast of the tropospheric pattern preceding the cold event over Siberia
The low electrocatalytic activity of pristine graphite felt (GF) electrodes toward V(II)/V(III) and V(IV)/V(V) redox couples is a major concern in vanadium redox flow batteries (VRFBs). For ...overcoming this challenge, herein a novel composite electrode is proposed comprising of two components: multidimensional frame carbon (MFC) derived from edge‐rich carbon and GF that serves as the frame for the in situ growth of MFC. The high electrocatalytic activity, rapid charge migration, and reduced local current emanating from the 0D, 2D, and 3D coexistent structures of the MFC material, respectively, enhance the performance of the GF. Consequently, the battery assembled using the MFC GF electrode achieves a maximum current density of 500 mA cm−2, along with high stability and preeminent energy efficiency at a current density of 200 mA cm−2 for over 400 cycles. For the first time via density functional theory analysis on VRFBs, this study reveals that the edge‐rich carbon atoms possess higher electrocatalytic activity in both positive and negative electrolytes than the plane carbon atoms and heteroatoms. Therefore, this study is of immense significance in guiding and promoting the application of edge‐rich carbon in the battery‐based energy storage industry.
An edge‐rich multidimensional structure frame carbon originates from the in situ recrystallization and annealling of sodium citrate. With the help of density functional theory, this work reveals that the edge carbon atoms possess higher electrocatalytic activity than the plane carbon atom for V(II)/V(III) and V(IV)/V(V) redox couples in vanadium redox flow batteries.
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