Publications by authors named "J Y Wang"

134,348 Publications

Narrative review of the influence of diabetes mellitus and hyperglycemia on colorectal cancer risk and oncological outcomes.

Transl Oncol 2021 Apr 7;14(7):101089. Epub 2021 Apr 7.

Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100 Tzyou 1st Road, Kaohsiung City 807, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Taiwan; Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan; Center for Liquid Biopsy and Cohort Research, Taiwan. Electronic address:

Diabetes mellitus (DM) and hyperglycemia have been shown to have significant effects on the incidence, chemoresistance, and prognosis of colorectal cancer (CRC), as well as the outcomes of localized and metastatic CRC. Inflammation and endocrine effects may act as central mechanisms of DM and cancer and stimulate the insulin-like growth factor 1-phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (IGF-1-PI3K-AKT-mTOR) pathway. Dysregulation of the AMP-activated protein kinase (AMPK) pathway leads to metabolic imbalance and indicates cancer risk. The use of metformin for chemoprevention has been shown to reduce CRC and adenoma incidence through the upregulation of AMPK, which causes cell cycle arrest in the Gap 1-S (G1-S) phase and inhibits the mTOR pathway, even potentially reversing the epithelial-mesenchymal transition. However, evidence of the effects of metformin remain controversial in cancer prognosis. Several genes, such as transcription factor 7-like 2(TCF7L2), tumor protein P53 inducible nuclear protein 1(TP53INP1), gremlin 1 (GREM1), and potassium voltage-gated channel subfamily Q member 1(KCNQ1), are pleiotropically related to DM as well as cancer risk and prognosis. Epigenetic modification of members of the Let-7 family such as miR-497, miR-486, and miR-223 is strongly associated with impaired glucose tolerance and CRC risk. Herein we review the pathophysiological and epidemiological evidence as well as potential underlying molecular mechanisms by which DM and hyperglycemia affect CRC risk. We also suggest potential roles of glucose modulation in CRC therapy and propose an agenda for future research and clinical practice.
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http://dx.doi.org/10.1016/j.tranon.2021.101089DOI Listing
April 2021

Study on the Hg removal characteristics and synergistic mechanism of iron-based modified biochar doped with multiple metals.

Bioresour Technol 2021 Apr 2;332:125086. Epub 2021 Apr 2.

College of Electrical and Power Engineering, Taiyuan University of Technology, Taiyuan 030024, PR China. Electronic address:

An iron-based composite adsorbent with biochar as the support was prepared by coprecipitation and the sol-gel method. Both single-iron-based modified biochar without doping with other metals and iron-based modified biochar doped with multiple metals (Ce, Cu, Co, Mn) were synthesised. The adsorption kinetics were analysed, and temperature-programmed desorption measurements were performed to reveal the inherent difference in mechanism between the oxidation and adsorption of Hg by the modified biochar and to elucidate the key mechanism of Hg removal. The results show that the removal of Hg by the modified biochar mainly includes adsorption and oxidation processes. The adsorption process is divided into two stages, external and internal mass transfer, both of which occur via multilayer adsorption. HgO and Hg-OM are the main forms of Hg present on the modified biochar surface. Doped metal oxides can play a synergistic role in enhancing the mercury removal performance of the modified biochar.
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http://dx.doi.org/10.1016/j.biortech.2021.125086DOI Listing
April 2021

Efficient catalytic ozonation of bisphenol A by three-dimensional mesoporous CeO-loaded SBA-16.

Chemosphere 2021 Mar 29;278:130412. Epub 2021 Mar 29.

School of Environment, South China Normal University, Guangzhou, 510006, China; MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou, 510006, China; Guangdong Provincial Engineering Technology Research Center for Drinking Water Safety, South China Normal University, Guangzhou, 510006, China. Electronic address:

Herein, we demonstrated the construction of three-dimensional (3D) cerium oxide (CeO)/SBA-16 nanocomposites for efficient removal of bisphenol A (BPA) via a catalytic ozonation, with a high BPA mineralization up to 60.9% in 90 min. On one hand, the CeO/SBA-16 mesoporous structured materials presented large surface area and uniform pore distribution, which was conducive to the adsorption of transformation by-products (TBPs) and then, the mass transfer. On the other hand, CeO/SBA-16 could enhance the ozone utilization efficiency and meanwhile facilitate the formation of OH, the main reactive oxygen species. Through the exploration of dissoluble organic matters and the identification of the reaction intermediates, two BPA degradation pathways were proposed. This approach reported here will benefit the design and construction of mesoporous structured materials for catalytic elimination of hazards to remediate the environment.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130412DOI Listing
March 2021

Adsorptive removal of Sr(II) from aqueous solution by polyvinyl alcohol/graphene oxide aerogel.

Chemosphere 2021 Apr 5;278:130492. Epub 2021 Apr 5.

Laboratory of Environmental Technology, INET, Tsinghua University, Beijing, 100084, China; Collaborative Innovation Center for Advanced Nuclear Energy Technology, INET, Tsinghua University, Beijing, 100084, China. Electronic address:

In this study, a new adsorbent, polyvinyl alcohol (PVA) and graphene oxide (GO), was prepared, characterized and used for the removal of Sr from aqueous solution. In PVA/GO composite, the inter-lamellar spacing of adjacent GO layers was dramatically enlarged due to the intercalation of PVA molecules, such a unique architecture significantly mitigated the aggregation of GO layers, which facilitated the accessible exposure of active sites and the mass transfer of strontium ions (Sr), thus enhancing the adsorption capacity toward Sr. The adsorption of Sr by PVA/GO composite conformed to the pseudo second-order kinetic model (R = 0.9994), the Langmuir model (R = 0.9042), and the Freundlich model (R = 0.9598). The complexation interaction between Sr and oxygen atoms/π-electron domain of PVA/GO composite was primarily responsible for the adsorption mechanism, based on the characterization results of X-ray photoelectron spectroscopy (XPS), scanning electron microscope equipped with energy dispersion spectroscopy (SEM-EDS) and powder X-ray diffraction (PXRD).
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http://dx.doi.org/10.1016/j.chemosphere.2021.130492DOI Listing
April 2021

Multiple spontaneous visceral arterial dissections in a patient with Tolosa-Hunt syndrome on corticosteroid therapy.

Ann Vasc Surg 2021 Apr 7. Epub 2021 Apr 7.

Department of Vascular Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China. Electronic address:

Multiple spontaneous visceral arterial dissections are an infrequent occurrence. The etiology, risk factors and natural history of these dissections have not been elucidated, and the optimal therapeutic strategy has not been established. We report a rare case of multiple spontaneous visceral arterial dissections involving the celiac artery, splenic artery, superior mesenteric artery, and right renal artery in a patient with Tolosa-Hunt syndrome on short-term corticosteroid therapy. The patient was subjected to conservative treatment and endovascular repair, achieving good clinical and radiological outcomes during the long-term follow-up period.
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http://dx.doi.org/10.1016/j.avsg.2021.01.107DOI Listing
April 2021

Serum LRG1 as a novel biomarker for cardioembolic stroke.

Clin Chim Acta 2021 Apr 7. Epub 2021 Apr 7.

Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao266000, China. Electronic address:

Background: In recent years, LRG1 was found to be closely related to atrial fibrillation, heart failure, and myocardial remodeling after myocardial infarction. While its role in cerebral infarction was still controversial. We aimed to explore the value of LRG1 to identify the cardioembolic stroke.

Methods: 283 acute ischemic stroke(AIS) patients and 169 controls were enrolled. The AIS patients were divided into a CE(cardiogenic embolism) group and a non-CE group. Serum LRG1 levels were quantified by ELISA.

Results: The serum LRG1 levels were decreased in the AIS patients. CE group had higher serum LRG1 levels than the non-CE group. LRG1 was an independent risk factor for cardioembolic stroke. The area under the curve (AUC) was 0.768 with a sensitivity of 72.5% and specificity of 69.5%, which was not second to BNP and LAD. The combined predictive model we designed, including LRG1, BNP, and LAD, greatly improved the prediction effect. A positive correlation was shown between LRG1 and stroke severity in the CE group. Those who experienced poor outcomes had higher serum LRG1 levels compared with good ones.

Conclusion: Serum LRG1 was a promising indicator to predict cardioembolic stroke, as well as stroke severity and the 3-month prognosis of it.
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http://dx.doi.org/10.1016/j.cca.2021.04.002DOI Listing
April 2021

Development of new therapeutic options for the treatment of uveal melanoma.

FEBS J 2021 Apr 10. Epub 2021 Apr 10.

The University of Sydney, Sydney Pharmacy School, Faculty of Medicine and Health, Sydney, NSW, 2006, Australia.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies. Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers. The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible.
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http://dx.doi.org/10.1111/febs.15869DOI Listing
April 2021

Surfactant cocamide monoethanolamide causes eye irritation by activating nociceptor TRPV1.

Br J Pharmacol 2021 Apr 10. Epub 2021 Apr 10.

State Key Laboratory of Natural Medicines and Department of TCM pharmacology, School of Traditional Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China, 211198.

Background And Purpose: Cocamide monoethanolamide (CMEA) is commonly used as a surfactant-foam booster in cosmetic formulations. Upon contact with the eye or other sensitive skin areas, CMEA elicits sting and lasting irritation. We hypothesized a specific molecular interaction with TRPV1 by which CMEA caused eye irritation.

Experimental Approach: Eye irritancy is evaluated using eye-wiping test in rabbit and mouse. Intracellular Ca concentrations and action potentials are measured using Ca imaging and current clamp, respectively. Voltage clamp, site-direct mutagenesis and molecular modeling identify the binding pocket of CMEA on TRPV1.

Key Results: CMEA-induced eye irritation is ameliorated by selective ablation of TRPV1 and rodents exhibit much stronger responses to CMEA than rabbits. In trigeminal ganglion neurons, CMEA induces Ca influx and neuronal excitability, effects mitigated by TRPV1 inhibitor and absent in TRPV1 knockout neurons. In HEK-293 cell expressing TRPV1, CMEA increases whole-cell currents by increasing channel open probability (EC = 10.2 μM) without affecting TRPV2, 3, 4 and TRPA1 activities. Lauric acid monoethanolamide (LAMEA), the most abundant constituent in CMEA, is the most efficacious and potent TRPV1 activator. LAMEA binds to the capsaicin-binding pocket of TRPV1. Both rabbit TRPV1 that possesses the T550I variant and the human TRPV1 mutant exhibit much lower sensitivity to LAMEA.

Conclusions And Implication: CMEA directly activates TRPV1 to produce eye irritation, and rabbit, the traditional animal model used for eye irritancy test is a poor model for evaluating human eye irritants structurally related to CMEA. Our study identifies potential alternatives to CMEA as non-irritating surfactants.
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http://dx.doi.org/10.1111/bph.15491DOI Listing
April 2021

A general chemical crosslinking strategy for structural analyses of weakly interacting proteins applied to preTCR-pMHC complexes.

J Biol Chem 2021 Jan 8;296:100255. Epub 2021 Jan 8.

Laboratory of Immunobiology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA; Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

T lymphocytes discriminate between healthy and infected or cancerous cells via T-cell receptor-mediated recognition of peptides bound and presented by cell-surface-expressed major histocompatibility complex molecules (MHCs). Pre-T-cell receptors (preTCRs) on thymocytes foster development of αβT lymphocytes through their β chain interaction with MHC displaying self-peptides on thymic epithelia. The specific binding of a preTCR with a peptide-MHC complex (pMHC) has been identified previously as forming a weak affinity complex with a distinct interface from that of mature αβTCR. However, a lack of appropriate tools has limited prior efforts to investigate this unique interface. Here we designed a small-scale linkage screening protocol using bismaleimide linkers for determining residue-specific distance constraints between transiently interacting protein pairs in solution. Employing linkage distance restraint-guided molecular modeling, we report the oriented solution docking geometry of a preTCRβ-pMHC interaction. The linkage model of preTCRβ-pMHC complex was independently verified with paramagnetic pseudocontact chemical shift (PCS) NMR of the unlinked protein mixtures. Using linkage screens, we show that the preTCR binds with differing affinities to peptides presented by MHC in solution. Moreover, the C-terminal peptide segment is a key determinant in preTCR-pMHC recognition. We also describe the process for future large-scale production and purification of the linked constructs for NMR, X-ray crystallography, and single-molecule electron microscopy studies.
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http://dx.doi.org/10.1016/j.jbc.2021.100255DOI Listing
January 2021

Novel functions of cytoplasmic aminoacyl-tRNA synthetases shaping the hallmarks of cancer.

Enzymes 2020 26;48:397-423. Epub 2020 Sep 26.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, United States. Electronic address:

With the intense protein synthesis demands of cancer, the classical enzymatic role of aminoacyl-tRNA synthetases (aaRSs) is required to sustain tumor growth. However, many if not all aaRSs also possess regulatory functions outside of the domain of catalytic tRNA aminoacylation, which can further contribute to or even antagonize cancers in non-translational ways. These regulatory functions of aaRS are likely to be manipulated in cancer to ensure uncontrolled growth and survival. This review will largely focus on the unique capacities of individual and sometimes collaborating synthetases to influence the hallmarks of cancer, which represent the principles and characteristics of tumorigenesis. An interesting feature of cytoplasmic aaRSs in higher eukaryotes is the formation of a large multi-synthetase complex (MSC) with nine aaRSs held together by three non-enzymatic scaffolding proteins (AIMPs). The MSC-associated aaRSs, when released from the complex in response to certain stimulations, often participate in pathways that promote tumorigenesis. In contrast, the freestanding aaRSs are associated with activities in both directions-some promoting while others inhibiting cancer. The AIMPs have emerged as potent tumor suppressors through their own distinct mechanisms. We propose that the tumor-suppressive roles of AIMPs may also be a consequence of keeping the cancer-promoting aaRSs within the MSC. The rich connections between cancer and the synthetases have inspired the development of innovative cancer treatments that target or take advantage of these novel functions of aaRSs.
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http://dx.doi.org/10.1016/bs.enz.2020.06.005DOI Listing
September 2020

Remodeling of Arctic char (Salvelinus alpinus) lipidome under a stimulated scenario of Arctic warming.

Glob Chang Biol 2021 Apr 10. Epub 2021 Apr 10.

Toxicology Centre, University of Saskatchewan, Saskatoon, SK, Canada.

Arctic warming associated with global climate change poses a significant threat to populations of wildlife in the Arctic. Since lipids play a vital role in adaptation of organisms to variations in temperature, high-resolution mass spectrometry based lipidomics can provide insights into adaptive responses of organisms to a warmer environment in the Arctic and help to illustrate potential novel roles of lipids in the process of thermal adaption. In this study, we studied an ecologically and economically important species-Arctic char (Salvelinus alpinus), with a detailed multi-tissue analysis of the lipidome in response to chronic shifts in temperature by use of a validated lipidomics workflow. In addition, dynamic alterations in the hepatic lipidome during the time-course of shifts in temperature were also characterized. Our results showed that early life stages of Arctic char were more susceptible to variations in temperature. One-year-old Arctic char responded to chronic increases in temperature with coordinated regulation of lipids, including headgroup-specific remodeling of acyl chains in glycerophospholipids (GP) and extensive alterations in composition of lipids in membranes, such as less lyso-GPs, and more ether-GPs and sphingomyelin (SM). Glycerolipids (e.g., triacylglycerol, TG) also participated in adaptive responses of the lipidome of Arctic char. Eight-week-old Arctic char exhibited rapid adaptive alterations of the hepatic lipidome to stepwise decreases in temperature, while showing blunted responses to gradual increases in temperature, implying an inability to adapt rapidly to warmer environments. Three common PEs (PE 36:6|PE 16:1_20:5, PE 38:7|PE 16:1_22:6, and PE 40:7|PE 18:1_22:6) were finally identified as candidate lipid biomarkers for temperature shifts via machine learning approach. Overall, this work provides additional information to a better understanding of underlying regulatory mechanisms of the lipidome of Arctic organisms in the face of near-future warming.
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http://dx.doi.org/10.1111/gcb.15638DOI Listing
April 2021

Lentinan protects against pancreatic β-cell failure in chronic ethanol consumption-induced diabetic mice via enhancing β-cell antioxidant capacity.

J Cell Mol Med 2021 Apr 9. Epub 2021 Apr 9.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.

Chronic ethanol consumption is a well-established independent risk factor for type 2 diabetes mellitus (T2DM). Recently, increasing studies have confirmed that excessive heavy ethanol exerts direct harmful effect on pancreatic β-cell mass and function, which may be a mechanism of pancreatic β-cell failure in T2DM. In this study, we evaluated the effect of Lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic β-cell apoptosis and dysfunction caused by ethanol and the possible mechanisms implicated. Functional studies reveal that LNT attenuates chronic ethanol consumption-induced impaired glucose metabolism in vivo. In addition, LNT ameliorates chronic ethanol consumption-induced β-cell dysfunction, which is characterized by reduced insulin synthesis, defected insulin secretion and increased cell apoptosis. Furthermore, mechanistic assays suggest that LNT enhances β-cell antioxidant capacity and ameliorates ethanol-induced oxidative stress by activating Nrf-2 antioxidant pathway. Our results demonstrated that LNT prevents ethanol-induced pancreatic β-cell dysfunction and apoptosis, and therefore may be a potential pharmacological agent for preventing pancreatic β-cell failure associated with T2DM and stress-induced diabetes.
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http://dx.doi.org/10.1111/jcmm.16529DOI Listing
April 2021

FABP5 enhances malignancies of lower-grade gliomas via canonical activation of NF-κB signaling.

J Cell Mol Med 2021 Apr 9. Epub 2021 Apr 9.

Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Low-grade gliomas (LGGs) are grade III gliomas based on the WHO classification with significant genetic heterogeneity and clinical properties. Traditional histological classification of gliomas has been challenged by the improvement of molecular stratification; however, the reproducibility and diagnostic accuracy of LGGs classification still remain poor. Herein, we identified fatty acid binding protein 5 (FABP5) as one of the most enriched genes in malignant LGGs and elevated FABP5 revealed severe outcomes in LGGs. Functionally, lentiviral suppression of FABP5 reduced malignant characters including proliferation, cloning formation, immigration, invasion and TMZ resistance, contrarily, the malignancies of LGGs were enhanced by exogenous overexpression of FABP5. Mechanistically, epithelial-mesenchymal transition (EMT) was correlated to FABP5 expression in LGGs and tumour necrosis factor α (TNFα)-dependent NF-κB signalling was involved in this process. Furthermore, FABP5 induced phosphorylation of inhibitor of nuclear factor kappa-B kinase α (IKKα) thus activated nuclear factor kappa-B (NF-κB) signalling. Taken together, our study indicated that FABP5 enhances malignancies of LGGs through canonical activation of NF-κB signalling, which could be used as individualized prognostic biomarker and potential therapeutic target of LGGs.
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http://dx.doi.org/10.1111/jcmm.16536DOI Listing
April 2021

A Ratiometric Fluorescent Biosensor Reveals Dynamic Regulation of Long-Chain Fatty Acyl-CoA Esters Metabolism.

Angew Chem Int Ed Engl 2021 Apr 10. Epub 2021 Apr 10.

Central China Normal University, Chemistry, CHINA.

Despite increasing awareness of the biological impacts of long-chain fatty acyl-CoA esters (LCACoAs), our knowledge about the subcellular distribution and regulatory functions of these acyl-CoA molecules is limited by a lack of methods for detecting LCACoAs in living cells. Here, we report development of a genetically encoded fluorescent sensor that enables ratiometric quantification of LCACoAs in living cells and subcellular compartments. We demonstrate how this FadR-cpYFP fusion "LACSer sensor" undergoes LCACoA-induced conformational changes reflected in easily detectable fluorescence responses, and show proof-of-concept for real-time monitoring of LCACoAs in human cells. Subsequently, we applied LACSer to investigate how disruption of ACSL enzymes differentially reduces cytosolic and mitochondrial LCACoA levels, and show how genetic disruption of an acyl-CoA binding protein (ACBP) alters mitochondrial accumulation of LCACoAs. Thus, our LACSer sensor achieves spatiotemporally precise detection of dynamic changes in endogenous LCACoA levels in living cells and yields mechanistic insights about metabolism and cellular regulation .
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http://dx.doi.org/10.1002/anie.202101731DOI Listing
April 2021

Capturing Cytokines with Advanced Materials: A Potential Strategy to Tackle COVID-19 Cytokine Storm.

Adv Mater 2021 Apr 10:e2100012. Epub 2021 Apr 10.

Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.

The COVID-19 pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused great impact on the global economy and people's daily life. In the clinic, most patients with COVID-19 show none or mild symptoms, while approximately 20% of them develop severe pneumonia, multiple organ failure, or septic shock due to infection-induced cytokine release syndrome (the so-called "cytokine storm"). Neutralizing antibodies targeting inflammatory cytokines may potentially curb immunopathology caused by COVID-19; however, the complexity of cytokine interactions and the multiplicity of cytokine targets make attenuating the cytokine storm challenging. Nonspecific in vivo biodistribution and dose-limiting side effects further limit the broad application of those free antibodies. Recent advances in biomaterials and nanotechnology have offered many promising opportunities for infectious and inflammatory diseases. Here, potential mechanisms of COVID-19 cytokine storm are first discussed, and relevant therapeutic strategies and ongoing clinical trials are then reviewed. Furthermore, recent research involving emerging biomaterials for improving antibody-based and broad-spectrum cytokine neutralization is summarized. It is anticipated that this work will provide insights on the development of novel therapeutics toward efficacious management of COVID-19 cytokine storm and other inflammatory diseases.
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http://dx.doi.org/10.1002/adma.202100012DOI Listing
April 2021

The risk of pulmonary tuberculosis after traumatic brain injury.

Sci Rep 2021 Apr 9;11(1):7840. Epub 2021 Apr 9.

Department of Medical Research, Chi Mei Medical Center, No 901, Zhonghua Road, Yongkang District, Tainan City 710, Taiwan.

After traumatic brain injury (TBI), an inflammatory response in the brain might affect the immune system. The risk of pulmonary infection reportedly increases in patients with TBI. We aimed to evaluate the risk of tuberculosis (TB) in patients with TBI in Taiwan. All participants were selected from the intensive care unit (ICU). Patients with TBI were defined as patients in ICU with intracranial injury, and comparison cohort were patients in ICU without TBI diagnosis. There was a significant difference in TB risk between the patients with TBI and the comparison cohort according to age and the Charlson's comorbidity index (CCI) score. Thus, we divided patients based on CCI into three groups for further analysis: mild (CCI = 0), moderate (CCI = 1/2), severe (CCI > 2). Mild-CCI group had a lower TB incidence rate (0.74%) and longer time to TB development (median: 2.43) than the other two groups. Moderate-CCI group had 1.52-fold increased risk of TB infection (p < 0.0001) compared with mild-CCI group. In the severe-CCI group, patients aged ≥ 80 years had 1.91-fold risk of TB compared with mild-CCI group (p = 0.0481). Severe-CCI group had significantly higher mortality than the mild-CCI group (p = 0.0366). Patients with TBI and more comorbidities had higher risk of TB infection with higher mortality rate.
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http://dx.doi.org/10.1038/s41598-021-87332-6DOI Listing
April 2021

Astrocytes in cocaine addiction and beyond.

Mol Psychiatry 2021 Apr 9. Epub 2021 Apr 9.

Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.

Drug addiction remains a key biomedical challenge facing current neuroscience research. In addition to neural mechanisms, the focus of the vast majority of studies to date, astrocytes have been increasingly recognized as an "accomplice." According to the tripartite synapse model, astrocytes critically regulate nearby pre- and postsynaptic neuronal substrates to craft experience-dependent synaptic plasticity, including synapse formation and elimination. Astrocytes within brain regions that are implicated in drug addiction exhibit dynamic changes in activity upon exposure to cocaine and subsequently undergo adaptive changes themselves during chronic drug exposure. Recent results have identified several key astrocytic signaling pathways that are involved in cocaine-induced synaptic and circuit adaptations. In this review, we provide a brief overview of the role of astrocytes in regulating synaptic transmission and neuronal function, and discuss how cocaine influences these astrocyte-mediated mechanisms to induce persistent synaptic and circuit alterations that promote cocaine seeking and relapse. We also consider the therapeutic potential of targeting astrocytic substrates to ameliorate drug-induced neuroplasticity for behavioral benefits. While primarily focusing on cocaine-induced astrocytic responses, we also include brief discussion of other drugs of abuse where data are available.
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http://dx.doi.org/10.1038/s41380-021-01080-7DOI Listing
April 2021

Spatio-temporal evolution and influencing mechanism of the COVID-19 epidemic in Shandong province, China.

Sci Rep 2021 Apr 9;11(1):7811. Epub 2021 Apr 9.

College of Urban and Environmental Sciences, Northwest University, Xi'an, 710127, China.

The novel coronavirus pneumonia (COVID-19) outbreak that emerged in late 2019 has posed a severe threat to human health and social and economic development, and thus has become a major public health crisis affecting the world. The spread of COVID-19 in population and regions is a typical geographical process, which is worth discussing from the geographical perspective. This paper focuses on Shandong province, which has a high incidence, though the first Chinese confirmed case was reported from Hubei province. Based on the data of reported confirmed cases and the detailed information of cases collected manually, we used text analysis, mathematical statistics and spatial analysis to reveal the demographic characteristics of confirmed cases and the spatio-temporal evolution process of the epidemic, and to explore the comprehensive mechanism of epidemic evolution and prevention and control. The results show that: (1) the incidence rate of COVID-19 in Shandong is 0.76/100,000. The majority of confirmed cases are old and middle-aged people who are infected by the intra-province diffusion, followed by young and middle-aged people who are infected outside the province. (2) Up to February 5, the number of daily confirmed cases shows a trend of "rapid increase before slowing down", among which, the changes of age and gender are closely related to population migration, epidemic characteristics and intervention measures. (3) Affected by the regional economy and population, the spatial distribution of the confirmed cases is obviously unbalanced, with the cluster pattern of "high-low" and "low-high". (4) The evolution of the migration pattern, affected by the geographical location of Wuhan and Chinese traditional culture, is dominated by "cross-provincial" and "intra-provincial" direct flow, and generally shows the trend of "southwest → northeast". Finally, combined with the targeted countermeasures of "source-flow-sink", the comprehensive mechanism of COVID-19 epidemic evolution and prevention and control in Shandong is revealed. External and internal prevention and control measures are also figured out.
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http://dx.doi.org/10.1038/s41598-021-86188-0DOI Listing
April 2021

Creating enzymes and self-sufficient cells for biosynthesis of the non-natural cofactor nicotinamide cytosine dinucleotide.

Nat Commun 2021 Apr 9;12(1):2116. Epub 2021 Apr 9.

Laboratory of Biotechnology, Dalian Institute of Chemical Physics, CAS, Dalian, PR China.

Nicotinamide adenine dinucleotide (NAD) and its reduced form are indispensable cofactors in life. Diverse NAD mimics have been developed for applications in chemical and biological sciences. Nicotinamide cytosine dinucleotide (NCD) has emerged as a non-natural cofactor to mediate redox transformations, while cells are fed with chemically synthesized NCD. Here, we create NCD synthetase (NcdS) by reprograming the substrate binding pockets of nicotinic acid mononucleotide (NaMN) adenylyltransferase to favor cytidine triphosphate and nicotinamide mononucleotide over their regular substrates ATP and NaMN, respectively. Overexpression of NcdS alone in the model host Escherichia coli facilitated intracellular production of NCD, and higher NCD levels up to 5.0 mM were achieved upon further pathway regulation. Finally, the non-natural cofactor self-sufficiency was confirmed by mediating an NCD-linked metabolic circuit to convert L-malate into D-lactate. NcdS together with NCD-linked enzymes offer unique tools and opportunities for intriguing studies in chemical biology and synthetic biology.
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http://dx.doi.org/10.1038/s41467-021-22357-zDOI Listing
April 2021

Smooth muscle-specific HuR knockout induces defective autophagy and atherosclerosis.

Cell Death Dis 2021 Apr 9;12(4):385. Epub 2021 Apr 9.

The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Human antigen R (HuR) is a widespread RNA-binding protein involved in homeostatic regulation and pathological processes in many diseases. Atherosclerosis is the leading cause of cardiovascular disease and acute cardiovascular events. However, the role of HuR in atherosclerosis remains unknown. In this study, mice with smooth muscle-specific HuR knockout (HuR) were generated to investigate the role of HuR in atherosclerosis. HuR expression was reduced in atherosclerotic plaques. As compared with controls, HuR mice showed increased plaque burden in the atherosclerotic model. Mechanically, HuR could bind to the mRNAs of adenosine 5'-monophosphate-activated protein kinase (AMPK) α1 and AMPKα2, thus increasing their stability and translation. HuR deficiency reduced p-AMPK and LC3II levels and increased p62 level, thereby resulting in defective autophagy. Finally, pharmacological AMPK activation induced autophagy and suppressed atherosclerosis in HuR mice. Our findings suggest that smooth muscle HuR has a protective effect against atherosclerosis by increasing AMPK-mediated autophagy.
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http://dx.doi.org/10.1038/s41419-021-03671-2DOI Listing
April 2021

Bayesian estimation of cell type-specific gene expression with prior derived from single-cell data.

Genome Res 2021 Apr 9. Epub 2021 Apr 9.

University of Pittsburgh;

When assessed over a large number of samples, bulk RNA sequencing provides reliable data for gene expression at the tissue level. Single-cell RNA sequencing (scRNA-seq) deepens those analyses by evaluating gene expression at the cellular level. Both data types lend insights into disease etiology. With current technologies, however, scRNA-seq data are known to be noisy. Moreover, constrained by costs, scRNA-seq data are typically generated from a relatively small number of subjects, which limits their utility for some analyses, such as identification of gene expression quantitative trait loci (eQTLs). To address these issues, while maintaining the unique advantages of each data type, we develop a Bayesian method (bMIND) to integrate bulk and scRNA-seq data. With a prior derived from scRNA-seq data, we propose to estimate sample-level cell type-specific (CTS) expression from bulk expression data. The CTS expression enables large-scale sample-level downstream analyses, such as detection of CTS differentially expressed genes (DEGs) and eQTLs. Through simulations, we demonstrate that bMIND improves the accuracy of sample-level CTS expression estimates and power to discover CTS-DEGs when compared to existing methods. To further our understanding of two complex phenotypes, autism spectrum disorder and Alzheimer's disease, we apply bMIND to gene expression data of relevant brain tissue to identify CTS-DEGs. Our results complement findings for CTS-DEGs obtained from snRNA-seq studies, replicating certain DEGs in specific cell types while nominating other novel genes for those cell types. Finally, we calculate CTS-eQTLs for eleven brain regions by analyzing Genotype-Tissue Expression Project data, creating a new resource for biological insights.
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http://dx.doi.org/10.1101/gr.268722.120DOI Listing
April 2021

SKP2-Promoted Ubiquitination of FOXO3 Promotes the Development of Asthma.

J Immunol 2021 Apr 9. Epub 2021 Apr 9.

The 6th Department of Pediatrics, Linyi People's Hospital, Linyi 276000, People's Republic of China

Asthma is a respiratory disease with a dramatically increasing incidence globally. The present study explored the roles of S-phase kinase-associated protein 2 (SKP2) and forkhead box O3 (FOXO3) in asthma and their involvement in the Krüppel-like factor 15-lipoprotein receptor-related protein 5 (KLF15-LRP5) axis. SKP2 expression in patients with asthma and OVA-induced asthmatic Sprague Dawley rats was detected by reverse transcription quantitative PCR and Western blot assays. Alterations in SKP2 and LRP5 expression were evaluated in OVA-induced asthmatic rats, followed by measurement of inflammatory cytokines using ELISA and airway resistance using a methacholine challenge test. We applied TGF-β1 to establish the airway smooth muscle cell (ASMC) proliferation model of asthma. The FOXO3 ubiquitination and changes in cell biological behaviors were detected using immunoprecipitation, MTT, and Annexin V/propidium iodide assays. Flow cytometry was adopted to detect cell cycle, and ELISA was used to measure the concentrations of IL-4, IL-5, IL-13, and IgE in rat bronchoalveolar lavage fluid. SKP2 was highly expressed and FOXO3 was poorly expressed in patients with asthma and in OVA-induced asthmatic rats. SKP2 silencing decreased IL-4, IL-5, IL-13, and IgE expression in rat bronchoalveolar lavage fluid, whereas SKP2 enhanced FOXO3 ubiquitination to upregulate KLF15, which bound to the LRP5 promoter in TGF-β1-induced ASMCs and increased LRP5 expression. SKP2 enhanced airway hyperresponsiveness and inflammation in the OVA-induced rat model and augmented TGF-β1-induced ASMC proliferation by inhibiting the FOXO3/KLF15/LRP5 axis. Additionally, overexpressed SKP2 resulted in reduced numbers of ASMCs in the G1 phase but increased numbers in the G2/M phase. Collectively, we show that SKP2 promotes FOXO3 ubiquitination to suppress the KLF15-LRP5 axis, thereby exacerbating asthma.
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http://dx.doi.org/10.4049/jimmunol.2000387DOI Listing
April 2021

Haploidentical Transplantation with Modified Post-transplantation Cyclophosphamide for Patients with Primary Aplastic Anemia: A Multicenter Experience.

Transplant Cell Ther 2021 Apr 24;27(4):331.e1-331.e7. Epub 2021 Jan 24.

Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address:

Aplastic anemia (AA) is a life-threatening hematological disorder that can be cured by hematopoietic stem cell transplantation. Haploidentical transplantation becomes an alternative choice for patients in the absence of a matched sibling donor. We used a retrospective study aimed to confirm the feasibility of busulfan-based modified post-transplantation cyclophosphamide (PTCY) strategy in haploidentical hematopoietic stem cell transplantation for AA patients. We analyzed the outcomes of 27 patients from 3 clinical centers who had undergone haploidentical transplantation between October 2018 and July 2020. The modified condition regimen consisted of anti-thymoglobulin/antilymphocyte globulin, fludarabine, busulfan and low-dose cyclophosphamide, and high-dose cyclophosphamide, mycophenolate mofetil (MMF) and tacrolimus were administered as graft versus host disease (GVHD) prophylaxis after transplantation. The median follow-up time was 370 (range 65-721) days. One patient developed primary graft failure, and successful engraftment was observed in 96.29% (95% confidence interval [CI], 93.45%-97.91%) of patients. The median times for neutrophil and platelet engraftment were 13 (range 11-18) days and 13 (range 11-28) days, respectively. The most common regimen-related toxicity was bladder toxicity, followed by stomatitis and gastrointestinal toxicity. The cumulative incidence of grade II-IV aGVHD was 25.93% (95% CI, 5.84%-52.64%), whereas the cumulative incidence of grade III-IV aGVHD was 7.4% (95% CI, 0%-52.16%). Chronic GVHD was observed in 3 patients by the end of follow-up. All 27 patients are alive, with a failure-free survival rate of 96.30% (95% CI, 6.49%-99.47%) and GVHD relapse-free survival rate of 88.89% (95% CI, 69.39%-96.28%). Virus reactivation was comparable, with rates of 53.54% for cytomegalovirus (CMV) reactivation and 41.57% for Epstein-Barr virus, but the CMV diseases and post-transplantation lymphoproliferative disorder were rare. Our study using haploidentical transplantation with modified PTCY demonstrated an encouraging result with prolonged survival and reduced complications for aplastic anemia patients.
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http://dx.doi.org/10.1016/j.jtct.2021.01.018DOI Listing
April 2021

Associations among phthalate exposure, DNA methylation of TSLP, and childhood allergy.

Clin Epigenetics 2021 Apr 9;13(1):76. Epub 2021 Apr 9.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Cheng-Hsing Campus, No. 1, University Road, Tainan City, Taiwan.

Background: Dysregulation of thymic stromal lymphopoietin (TSLP) expressions is linked to asthma and allergic disease. Exposure to phthalate esters, a widely used plasticizer, is associated with respiratory and allergic morbidity. Dibutyl phthalate (DBP) causes TSLP upregulation in the skin. In addition, phthalate exposure is associated with changes in environmentally induced DNA methylation, which might cause phenotypic heterogeneity. This study examined the DNA methylation of the TSLP gene to determine the potential mechanism between phthalate exposure and allergic diseases.

Results: Among all evaluated, only benzyl butyl phthalate (BBzP) in the settled dusts were negatively correlated with the methylation levels of TSLP and positively associated with children's respiratory symptoms. The results revealed that every unit increase in BBzP concentration in the settled dust was associated with a 1.75% decrease in the methylation level on upstream 775 bp from the transcription start site (TSS) of TSLP (β =  - 1.75, p = 0.015) after adjustment for child's sex, age, BMI, parents' smoking status, allergic history, and education levels, PM, formaldehyde, temperature; and relative humidity. Moreover, every percentage increase in the methylation level was associated with a 20% decrease in the risk of morning respiratory symptoms in the children (OR 0.80, 95% CI 0.65-0.99).

Conclusions: Exposure to BBzP in settled dust might increase children's respiratory symptoms in the morning through decreasing TSLP methylation. Therefore, the exposure to BBzP should be reduced especially for the children already having allergic diseases.
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http://dx.doi.org/10.1186/s13148-021-01061-1DOI Listing
April 2021

Thin endometrium is associated with the risk of hypertensive disorders of pregnancy in fresh IVF/ICSI embryo transfer cycles: a retrospective cohort study of 9,266 singleton births.

Reprod Biol Endocrinol 2021 Apr 9;19(1):55. Epub 2021 Apr 9.

Center for Reproductive Medicine, Shandong University, No.157 Jingliu Road, Jinan, 250021, China.

Background: Thin endometrial thickness (EMT) has been suggested to be associated with reduced incidence of pregnancy rate after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment, but the effect of thin endometrium on obstetric outcome is less investigated. This study aims to determine whether EMT affects the incidence of obstetric complications in fresh IVF/ICSI-embryo transfer (ET) cycles.

Methods: We conducted a retrospective cohort study collecting a total of 9266 women who had singleton livebirths after fresh IVF/ICSI-ET treatment cycles at the Center for Reproductive Medicine Affiliated to Shandong University between January 2014 and December 2018. The women were divided into three groups according to the EMT: 544 women with an EMT ≤8 mm, 6234 with an EMT > 8-12 mm, and 2488 with an EMT > 12 mm. The primary outcomes were the incidence of obstetric complications including hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), placental abruption, placenta previa, postpartum hemorrhage (PPH) and cesarean section. Multivariable logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between the EMT measured on the day of human chorionic gonadotropin (HCG) trigger and the risk of the outcomes of interest.

Results: The HDP incidence rate of pregnant women was highest in EMT ≤ 8 mm group and significantly higher than those in EMT from > 8-12 mm and EMT > 12 mm group, respectively (6.8% versus 3.6 and 3.5%, respectively; P = 0.001). After adjustment for confounding variables by multivariate logistic regression analysis, a thin EMT was still statistically significant associated with an increased risk of HDP. Compared with women with an EMT > 8-12 mm, women with an EMT ≤8 mm had an increased risk of HDP (aOR = 1.853, 95% CI 1.281-2.679, P = 0.001).

Conclusion: A thin endometrium (≤8 mm) was found to be associated with an increased risk of HDP after adjustment for confounding variables, indicating that the thin endometrium itself is a risk factor for HDP. Obstetricians should remain aware of the possibility of HDP when women with a thin EMT achieve pregnancy through fresh IVF/ICSI-ET treatment cycles.
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http://dx.doi.org/10.1186/s12958-021-00738-9DOI Listing
April 2021

Protective effect of selenomethionine on T-2 toxin-induced liver injury in New Zealand rabbits.

BMC Vet Res 2021 Apr 9;17(1):153. Epub 2021 Apr 9.

College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471000, Henan, China.

Background: T-2 toxin is a mycotoxin produced by Fusarium species that is highly toxic to animals. Recent studies have indicated that Selenomethionine (SeMet) have protective effect against mycotoxins-induced toxicity. The aim of the present study was to investigate the protective effect of SeMet on T-2-toxin-induced liver injury in rabbit and explore its molecular mechanism. Fifty rabbits (30 d, 0.5 ± 0.1 kg) were randomly divided into 5 groups: control group, T-2 toxin group, low, medium and high dose SeMet treatment group. The SeMet-treated group was orally pretreated with SeMet (containing selenium 0.2 mg/kg, 0.4 mg/kg and 0.6 mg/kg) for 21 days. On the 17th day, T-2 toxin group and SeMet-treated group were orally administered with T-2 toxin (0.4 mg/kg body weight) for 5 consecutive days.

Results: The results showed that low-dose SeMet significantly improved T-2 toxin-induced liver injury. We found that low-dose SeMet can reduce the level of oxidative stress and the number of hepatocyte apoptosis. Moreover, the levels of Bax, caspase-3 and caspase-9 were significantly reduced and the levels of Bcl-2 were increased.

Conclusions: Therefore, we confirmed that low-dose SeMet may protect rabbit hepatocytes from T-2 toxin by inhibiting the mitochondrial-caspase apoptosis pathway.
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http://dx.doi.org/10.1186/s12917-021-02866-1DOI Listing
April 2021

LINC00221 silencing prevents the progression of hepatocellular carcinoma through let-7a-5p-targeted inhibition of MMP11.

Cancer Cell Int 2021 Apr 9;21(1):202. Epub 2021 Apr 9.

Department of Oncology, Shaanxi Province, Affiliated Hospital of the Shaanxi University of Traditional Chinese Medicine, No. 2, Weiyang West Road, Xianyang, 712000, People's Republic of China.

Background: Microarray profiles of hepatocellular carcinoma (HCC) identified that long intergenic noncoding RNA 00221 (LINC00221) was upregulated. Herein, we aimed to identify the functional significance and underlying mechanisms of LINC00221 in HCC.

Methods And Results: Human HCC samples had increased expression of LINC00221. Effects of LINC00221 on HCC cellular functions were analyzed using gain- and loss-function approaches. LINC00221 knockdown repressed HCC cell growth, migration, and invasion and enhanced their apoptosis. This anti-tumor effect was validated in vivo. Online prediction showed the potential binding relationship between LINC00221 and let-7a-5p, as well as that between let-7a-5p and matrix metalloproteinase 11 (MMP11). The results of luciferase, RNA immunoprecipitation, and RNA pull-down assays identified that LINC00221 interacted with let-7a-5p to increase expression of MMP11. Furthermore, we demonstrated that LINC00221 silencing increased let-7a-5p and inhibited MMP11 expression, thereby delaying the progression of HCC in vitro.

Conclusions: Silencing of LINC00221 could prevent HCC progression via upregulating let-7a-5p and downregulating MMP11. As such, LINC00221 inhibition presents a promising antitumor strategy for the treatment of HCC.
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http://dx.doi.org/10.1186/s12935-021-01819-wDOI Listing
April 2021

Are need for affect and cognition culture dependent? Implications for global public health campaigns: a cross-sectional study.

BMC Public Health 2021 Apr 9;21(1):693. Epub 2021 Apr 9.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Cultural differences in affective and cognitive intrinsic motivation could pose challenges for global public health campaigns, which use cognitive or affective goals to evoke desired attitudes and proactive health-promoting actions. This study aimed to identify cross-cultural differences in affective and cognitive intrinsic motivation and discuss the potential value of this information for public health promotion.

Methods: A cross-sectional survey using cross-culturally validated need for affect (NFA) and need for cognition (NFC) scales was carried out among 1166 Chinese participants, and the results were compared with published data from 980 American participants. Additionally, we assessed a highly prevalent symbolic geriatric health condition, hearing loss, in 500 Chinese community-dwelling seniors. The Chinese NFA scale was developed following the translation-back translation procedure, and the psychometric evaluation was performed by applying confirmatory factor analysis (CFA), exploratory structural equation modeling (ESEM), correlation analysis and multigroup invariance test. MANOVA and Hedge's g statistic were employed to compare the NFA and NFC levels between individuals from different countries and between Chinese seniors with and without hearing loss. The relation of early hearing intervention intention to NFA and NFC was also explored in the Chinese sample.

Results: A basic two-factor model of NFA adequately fit the sample data from Chinese and American cultures. The questionnaire demonstrated reasonable invariance of the factor structure and factor loadings across the groups. Those in the primary Chinese sample had lower NFA and NFC than their American peers. This difference held in the senior sample. Moreover, Chinese seniors with hearing loss had even lower NFA and NFC than those without hearing loss. Their early hearing intervention intention was low but was associated with intrinsic motivation.

Conclusions: The Need for Affect (NFA) construct may be generalized beyond its Western origins. There was a general lack of affective and cognitive intrinsic motivation in Chinese individuals, particularly in seniors with hearing loss, compared with their American peers. These differences point to a potential challenge in framing effective messages for some cultures in the geriatric public health domain. Ideally, recognizing and understanding this challenge will inspire the consideration of novel persuasive strategies for these audiences.
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http://dx.doi.org/10.1186/s12889-021-10689-wDOI Listing
April 2021

Venous thromboembolism in patients with multiple myeloma receiving daratumumab-based regimens: a analysis of phase 3 clinical trials.

Leuk Lymphoma 2021 Apr 9:1-8. Epub 2021 Apr 9.

Department of Internal Medicine, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, USA.

It is unknown if daratumumab could affect venous thromboembolism (VTE) risks in patients with multiple myeloma (MM). In this study, individual participant data from three trials comparing daratumumab (DARA) and non-DARA regimens, the CASTOR, PULLOX and MAIA trial, were pooled into two groups. A total of 896 and 899 patients received DARA and non-DARA regimens, respectively. After a median follow-up of 13.9 and 13.5 months, there was no significant difference in VTE incidence between the two groups (hazard ratio 0.80, 95% confidence interval 0.57-1.13,  = 0.17). The two groups shared similar VTE risk factors. The SAVED score and IMPEDE-VTE score are two validated VTE risk-stratification tools in MM. In the DARA group, the SAVED score had better performance than the IMPEDE-VTE score in identifying high risk patients.
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http://dx.doi.org/10.1080/10428194.2021.1910687DOI Listing
April 2021

A specific RIP3 subpopulation of microglia promotes retinopathy through a hypoxia-triggered necroptotic mechanism.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China;

Retinal neovascularization is a leading cause of severe visual loss in humans, and molecular mechanisms of microglial activation-driven angiogenesis remain unknown. Using single-cell RNA sequencing, we identified a subpopulation of microglia named sMG2, which highly expressed necroptosis-related genes Rip3 and Mlkl. Genetic and pharmacological loss of function demonstrated that hypoxia-induced microglial activation committed to necroptosis through the RIP1/RIP3-mediated pathway. Specific deletion of Rip3 gene in microglia markedly decreased retinal neovascularization. Furthermore, hypoxia induced explosive release of abundant FGF2 in microglia through RIP3-mediated necroptosis. Importantly, blocking signaling components of the microglia necropotosis-FGF2 axis largely ablated retinal angiogenesis and combination therapy with simultaneously blocking VEGF produced synergistic antiangiogenic effects. Together, our data demonstrate that targeting the microglia necroptosis axis is an antiangiogenesis therapy for retinal neovascular diseases.
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http://dx.doi.org/10.1073/pnas.2023290118DOI Listing
March 2021