bluuebunny/crossref_metadata_2025 huggingface dataset:
What lurks in the shadows of the openness hyperbole for biopharmaceuticals?
Authors: Neethu R. , Minssen Timo
Published: March 2019

Recent advances in transparency initiative signify laudable developments. Yet, a closer look on the legal developments indicates that commercially confidential information and personal data will continue to pose persisting challenges for clinical trial transparency and drug development. This article depicts these developments with a particular focus on European Medicines Agency (EMA) and Biologics. We argue that in order to promote the development of innovative biologics and biosimilars, the EMA will need to carefully consider and address such challenges.
Direct and indirect effects of forest microclimate on pathogen spillover
Authors: Dillon Whalen W. , Meentemeyer Ross K.
Published: March 2019

Disease dynamics are governed by variation of individuals, species, and environmental conditions across space and time. In some cases, an alternate reservoir host amplifies pathogen loads and drives disease transmission to less competent hosts in a process called pathogen spillover. Spillover is frequently associated with multi‐host disease systems where a single species is more tolerant of infection and more competent in pathogen transmission compared to other hosts. Pathogen spillover must be driven by biotic factors, including host and community characteristics, yet biotic factors interact with the abiotic environment (e.g., temperature) to create disease. Despite its fundamental role in disease dynamics, the influence of the abiotic environment on pathogen spillover has seldom been examined. Improving our understanding of disease processes such as pathogen spillover hinges on disentangling the effects of interrelated biotic and abiotic factors over space and time. We applied 10 yr of fine‐scale microclimate, disease, and tree community data in a path analysis to investigate the relative influence of biotic and abiotic factors on pathogen spillover for the emerging infectious forest disease sudden oak death (SOD). Disease transmission in SOD is primarily driven by the reservoir host California bay laurel, which supports high foliar pathogen loads that spillover onto neighboring oak trees and create lethal canker infections. The foliar pathogen load and susceptibility of oaks is expected to be sensitive to forest microclimate conditions. We found that biotic factors of pathogen load and tree diversity had relatively stronger effects on pathogen spillover compared to abiotic microclimate factors, with pathogen load increasing oak infection and tree diversity reducing oak infection. Abiotic factors still had significant effects, with greater heat exposure during summer months reducing pathogen loads and optimal pathogen conditions during the wet season increasing oak infection. Our results offer clues to possible disease dynamics under future climate change where hotter and drier or warmer and wetter conditions could have opposing effects on pathogen spillover in the SOD system. Disentangling direct and indirect effects of biotic and abiotic factors affecting disease processes can provide key insights into disease dynamics including potential avenues for reducing disease spread and predicting future epidemics.
Invasive earthworm and soil litter response to the experimental removal of white‐tailed deer and an invasive shrub
Authors: Mahon Michael B. , Crist Thomas O.
Published: March 2019

Recent studies have shown that complex species interactions can regulate above‐ and belowground processes in terrestrial systems. Ungulate herbivory and invasive species are known to have strong effects on plant communities in some systems, but their impacts on soil biota and belowground processes are lesser known. Growing evidence suggests white‐tailed deer (Odocoileus virginianus) and invasive plants facilitate increased abundance of exotic earthworms in temperate forests of the eastern United States. We conducted an experimental study that manipulated deer access and the presence of an invasive understory shrub in an eastern deciduous forest of southwestern Ohio,USA, from 2013 to 2017. Earthworm density and biomass, and standing litter biomass were measured in five paired deer access and exclosure plots, each with a split‐plot removal of Amur honeysuckle (Lonicera maackii). Earthworm density declined in response to the experimental exclusion of deer, with earthworm density decreasing over time in the deer exclosure plots relative to deer access plots. Deer exclusion produced greater variation in earthworm species composition relative to access plots. Multivariate analyses indicated that larger earthworms in the genusLumbricuswere associated with deer exclosure plots, while smaller endogeic species were ubiquitous in both treatments. Standing litter biomass decreased over time in the deer‐access plots. In contrast, honeysuckle removal had little effect on earthworm density and standing litter biomass. There was an interaction between deer and honeysuckle treatments on earthworm biomass, with honeysuckle removal reducing earthworm biomass when deer were excluded. Our results demonstrate strong effects of herbivores on invasive earthworms and ecosystem processes, but indicate a weaker influence of invasive shrubs. Further, our findings suggest that the effects of deer overabundance in forest ecosystems are potentially reversible with long‐term intervention.
CD1b presents self and Borrelia burgdorferi diacylglycerols to human T cells
Authors: Reinink Peter , Souter Michael N. T. , Cheng Tan‐Yun , van Gorkom Tamara , Lenz Stefanie , Kubler‐Kielb Joanna , Strle Klemen , Kremer Kristin , Thijsen Steven F.T. , Steere Allen C. , Godfrey Dale I. , Pellicci Daniel G. , Moody D. Branch , Van Rhijn Ildiko
Published: March 2019

Lyme disease is a common multisystem disease caused by infection with a tick‐transmitted spirochete, Borrelia burgdorferi and related Borrelia species. The monoglycosylated diacylglycerol known as B. burgdorferi glycolipid II (BbGL‐II) is a major target of antibodies in sera from infected individuals. Here, we show that CD1b presents BbGL‐II to human T cells and that the TCR mediates the recognition. However, we did not detect increased frequency of CD1b‐BbGL‐II binding T cells in the peripheral blood of Lyme disease patients compared to controls. Unexpectedly, mapping the T cell specificity for BbGL‐II‐like molecules using tetramers and activation assays revealed a concomitant response to CD1b‐expressing APCs in absence of BbGL‐II. Further, among all major classes of self‐lipid tested, BbGL‐II responsive TCRs show strong cross‐reactivity to diacylglycerol, a self‐lipid antigen with structural similarities to BbGL‐II. Extending prior work on MHC and CD1b, CD1c, and CD1d proteins, this study provides evidence for cross‐reactive CD1b‐restricted T cell responses to bacterial and self‐antigens, and identifies chemically defined targets for future discovery of self and foreign antigen cross‐reactive T cells.
Characterization of corn, cassava, and commercial flours: Use of amylase‐rich flours of germinated corn and sweet potato in the reduction of the consistency of the gruels made from these flours—Influence on the nutritional and energy value
Authors: Tambo Tene Stephano , Klang Julie Mathilde , Ndomou Houketchang Serge Cyrille , Teboukeu Boungo Gires , Womeni Hilaire Macaire
Published: March 2019

Malnutrition appears in weaning age and is usually due to weaning food which is of low nutritional value. This problem led us to investigate the study of the physicochemical and functional properties of cassava flours and corn flours, and the fluidification of the gruels made from these flours by germinated yellow corn and sweet white potato flours. To do this, the approximate chemical composition, physical and functional properties, and ability of amylase‐rich flours to digest the starch in order to reduce consistency were evaluated. From these analyses, it emerges that the chemical composition, and physical and functional properties are influenced by the nature and the treatment undergone by the flours. It appears that the amylase‐rich flours that we used at a concentration of 1%–3% during the preparation of the gruels significantly reduced their consistencies. Given their strong liquefying power, this reduction was more marked with germinated corn flour where 1% permits to obtain desired consistency with 21.50 g of DM of bitter cassava flour, thereby multiplying the energy density and nutritional value of this flour by 5.18. It also appears that the action of flours rich in amylases was depending on the concentration, the nature of the flour, its composition, and the treatment undergone. In view of all these results, we can therefore consider the formulation of a weaning food with the consistency, and energy and nutritional value necessary for the proper growth of children.
Late Palaeozoic tectonic evolution of the southern North China Craton: Constraints from detrital zircon dating and Hf–O isotopic compositions of the Benxi Formation, Sanmenxia area, North China Craton
Authors: Wang An‐Qi , Yang De‐Bin , Yang Hao‐Tian , Mu Mao‐Song , Quan Yi‐Kang , Hao Le‐Ran , Xu Wen‐Liang
Published: March 2019

This study presents new detrital zircon laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) U–Pb ages and in situ Hf–O isotopic data in order to constrain the depositional age and provenance of the Benxi Formation in the Sanmenxia area of the southern North China Craton (NCC). Detrital zircons in quartz sandstone drillcore from the Benxi Formation are euhedral–subhedral, oscillatory zoned, and have high Th/U ratios (0.03–1.60, generally greater than 0.3) that are indicative of a magmatic origin. Detrital zircons from samples 13H16A and 13H16B yield seven (2544, 1788, 1123, 955, 737, 441, and 344 Ma) and six main age populations (2440, 1583, 951, 759, 434, and 348 Ma), respectively. The εHf(t) values of the Neoarchean–Paleoproterozoic zircons range from −11.3 to +13.9, and these zircons have δ18O values that range from 5.68‰ to 8.83‰. The Neoproterozoic zircons have variable εHf(t) (−9.2 to +12.5) and δ18O (5.58‰ to 9.85‰) values, whereas the Palaeozoic zircons have εHf(t) values between −19.9 and +13.4 and δ18O values of 5.23‰–9.43‰. The Benxi Formation was deposited during the late Carboniferous and contains sediments derived from igneous rocks of the North Qinling Orogen combined with a small amount of material derived from Precambrian basement of the NCC. The northward subduction of the South Qinling Orogen caused the uplift and erosion of the North Qinling Orogen during the late Carboniferous.
Mineral phase equilibria and zircon geochronology constrain multiple metamorphic events of high‐pressure pelitic granulites in south‐easternTibetan Plateau
Authors: Ji Lei , Liu Fulai , Wang Fang , Santosh M. , Tian Zhonghua , Sun Zaibo
Published: March 2019

The Ailao Shan (ALS) metamorphic belt separates the Indochina Block to the west from the South China Block and is an important region for understanding the history of evolution of the Palaeo‐Tethys in relation to the collision of the Indian and Eurasian plates and the formation of the Tibetan Plateau. The multiple metamorphic events andP–T–tpaths of the ALS belt remain debated. Here, we present the results of an integrated study of the petrography, mineral chemistry, phase equilibria modelling, and zircon U–Pb geochronology of high‐grade metasedimentary rocks from this belt. Abundant metamorphic zircon grains with mineral inclusions of Sil/Ky + Bt + Pl + Qz ± Mnz record two metamorphic events, the first one during the Triassic (227–220 Ma), although intense shearing overlapped during the Cenozoic and mineral assemblages of this thermal event were not preserved. The second metamorphic event occurred during the Palaeogene (49 –23 Ma) and involved three stages: (a) a peak high‐pressure (HP) granulite‐facies metamorphism (M1) with a mineral assemblage of Ky + Grt1 + Bt1 + Pl + Qz ± Kfs; (b) a postpeak near‐isothermal decompression (M2) characterized by Sil1–2 + Grt2 + Bt1 + Pl + Qz + Kfs + Ilm and the decompression reactions of Grt + Ky + Qz = 3An and Ky = Sil; and (c) a late decompressional cooling (M3) with a mineral assemblage of Sil3 + Grt3 + Bt2 + Pl + Qz + Mnz ± Kfs, followed by a series of hydration reactions. The metamorphic evolution occurred along a clockwiseP–T–tpath with peakP–Tconditions of 13.5–14.0 kbar and 810–820°C. Our new data, combined with those from previous studies, reveal that the Diancang Shan–Ailao Shan Complex Belt is not a single suture that represents the closure of the Palaeo‐Tethyan Ocean during the Triassic, but that it also represents a typical continent–continent collisional orogenic belt that formed during the Eocene–Oligocene prior to the strong left‐lateral, ductile deformation along the Ailao Shan–Red River shear zone.
Machine learning approaches to studying the role of cognitive reserve in conversion from mild cognitive impairment to dementia
Authors: Facal David , Valladares‐Rodriguez Sonia , Lojo‐Seoane Cristina , Pereiro Arturo X. , Anido‐Rifon Luis , Juncos‐Rabadán Onésimo
Published: March 2019

Objectives

The overall aim of the present study was to explore the role of cognitive reserve (CR) in the conversion from mild cognitive impairment (MCI) to dementia. We used traditional and machine learning (ML) techniques to compare converter and nonconverter participants. We also discuss the predictive value of CR proxies in relation to the ML model performance.

Methods

In total, 169 participants completed the longitudinal study. Participants were divided into a control group and three MCI subgroups, according to the Petersen criteria for diagnosis. Information about the participants was compared using nine ML classification techniques. Seven relevant performance metrics were computed in order to evaluate the accuracy of prediction regarding converter and nonconverter participants.

Results

ML algorithms applied to socio‐demographic, basic health, and CR proxy data enabled prediction of conversion to dementia. The best performing models were the gradient boosting classifier (accuracy (ACC) = 0.93; F1 = 0.86, and Cohen κ = 0.82) and random forest classifier (ACC = 0.92; F1 = 0.79, and Cohen κ = 0.71). Use of ML techniques corroborated the protective role of CR as a mediator of conversion to dementia, whereby participants with more years of education and higher vocabulary scores survived longer without developing dementia.

Conclusions

We used ML approaches to explore the role of CR in conversion from MCI to dementia. The findings indicate the potential value of ML algorithms for detecting risk of conversion to dementia in cognitive aging and CR studies. Further research is required to develop an ML‐based procedure that can be used to make robust predictions.
Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment‐resistant late‐life depression
Authors: Trevizol Alisson Paulino , Goldberger Kyle W. , Mulsant Benoit H. , Rajji Tarek K. , Downar Jonathan , Daskalakis Zafiris J. , Blumberger Daniel M.
Published: March 2019

Background

The management of late‐life depression is challenged by high rates of treatment‐resistance and adverse effects, along with medical comorbidities and polypharmacy. Together with the limited data on managing treatment‐resistant depression in older adults, there is a need for investigating the efficacy of nonpharmacological treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) is one modality that may better serve this patient population.

Methods

The present study examines data from two previous clinical trials (NCT00305045 and NCT01515215) to explore the efficacy of bilateral and unilateral high‐frequency left‐sided (HFL) rTMS in older adults suffering from treatment‐resistant depression. A total of 43 adults aged 60 or older with a current major depressive episode were randomized to bilateral sequential, unilateral HFL, or sham. Bilateral sequential stimulation involved low‐frequency (1 Hz) right dorsolateral prefrontal cortex (DLPFC) stimulation followed immediately by high‐frequency (10 Hz) left DLPFC. The unilateral condition was HFL stimulation alone, and the placebo condition was either HFL or sequential bilateral form of sham. The primary outcome was remission of depression.

Results

Participants receiving bilateral rTMS experienced greater remission rates (40%) compared with unilateral (0%) or sham (0%) groups. Response to rTMS in the Hamilton Depression Rating Scale scores similarly favored the efficacy of bilateral rTMS.

Conclusion

This study suggests that sequential bilateral treatment may be an optimal form of rTMS when used for treatment‐resistant depression in older adults. Further large‐scale comparative effectiveness trials of bilateral rTMS in this population are warranted.
Awareness and its relationships with neuropsychiatric symptoms in people with Korsakoff syndrome or other alcohol‐related cognitive disorders living in specialized nursing homes
Authors: Gerridzen Ineke J. , Joling Karlijn J. , Depla Marja F. , Veenhuizen Ruth B. , Verschuur Els M.L. , Twisk Jos W.R. , Hertogh Cees M.P.M.
Published: March 2019

Objectives

Impaired awareness of functional deficits is often observed in people with Korsakoff syndrome (KS) and may result in refusal of care, although this area has been understudied. This study aimed to investigate levels of impaired awareness and their relationships with neuropsychiatric symptoms (NPS) in people with KS residing in specialized nursing homes.

Methods

A cross‐sectional, observational study was conducted among 215 residents with KS or other alcohol‐related cognitive disorders. Awareness was measured with the Patient Competency Rating Scale (PCRS). NPS and subsyndromes were measured with the Neuropsychiatric Inventory–Questionnaire (NPI‐Q). Adjusted multilevel regression analyses were performed to examine the relationships between the level of awareness and NPS.

Results

The mean level of impaired awareness was 39.3 (SD = 19.9) indicating moderate impairment. Twenty‐nine percent of the residents had no or mildly impaired awareness; 37% were moderately impaired, and 34% were severely impaired. Residents with moderately impaired awareness showed more severe apathy than residents with no or mildly impaired awareness (difference 1.23; 95% CI 1.02‐1.48; p = 0.03). No associations were found between the level of awareness and other NPI outcomes. Cognitive functioning seems to have the strongest impact on the association between level of awareness and NPS in KS residents.

Conclusions

Impaired awareness of functional deficits is highly common in KS residents; however, apart from apathy, is not significantly related with NPS. Additional research should further examine, which interventions are effective in dealing with impaired awareness in these people, particularly when apathy is present.
Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis
Authors: Wang Chan , Zheng Xiaodong , Jiang Peng , Tang Ruqi , Gong Yuhua , Dai Yaping , Wang Lan , Xu Ping , Sun Wenjuan , Wang Lu , Han Chongxu , Jiang Yuzhang , Wei Yiran , Zhang Kui , Wu Jian , Shao Youlin , Gao Yueqiu , Yu Jianjiang , Hu Zhigang , Zang Zhidong , Zhao Yi , Wu Xudong , Dai Na , Liu Lei , Nie Jinshan , Jiang Bo , Lin Maosong , Li Li , Li You , Chen Sufang , Shu Lixin , Qiu Fang , Wu Qiuyuan , Zhang Mingming , Chen Ru , Jawed Rohil , Zhang Yu , Shi Xingjuan , Zhu Zhen , Pei Hao , Huang Lihua , Zhao Weifeng , Tian Ye , Zhu Xiang , Qiu Hong , Gershwin M. Eric , Chen Weichang , Seldin Michael F. , Liu Xiangdong , Sun Liangdan , Ma Xiong
Published: March 2019

Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.
Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR‐23a‐3p and Up‐regulate Programmed Death Ligand 1 Expression in Macrophages
Authors: Liu Jiatao , Fan Lulu , Yu Hanqing , Zhang Ju , He Yong , Feng Dechun , Wang Fang , Li Xiaoqiu , Liu Qingqing , Li Yuhuan , Guo Zhenli , Gao Bin , Wei Wei , Wang Hua , Sun Guoping
Published: March 2019

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD‐L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose‐regulated protein 78, activating transcription factor 6, protein kinase R–like ER kinase, and inositol‐requiring enzyme 1α) was up‐regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress–related proteins positively correlated with CD68+ macrophage recruitment and PD‐L1 expression in HCC tissues. High‐throughput sequencing analysis identified miR‐23a‐3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)‐treated HCC cells (Exo‐TMs). miR‐23a‐3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo‐TMs up‐regulated the expression of PD‐L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR‐23a‐3p regulates PD‐L1 expression through the phosphatase and tensin homolog (PTEN)–phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR‐23a‐3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD‐L1 expression in macrophages. Finally, coculture of T cells with Exo‐TM–stimulated macrophages decreased CD8+ T‐cell ratio and interleukin‐2 production but increased T‐cell apoptosis in vitro. Conclusion: ER‐stressed HCC cells release exosomes to up‐regulate PD‐L1 expression in macrophages, which subsequently inhibits T‐cell function through an exosome miR‐23a–PTEN–AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.
AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta‐analysis using TRIBE, MAVERICC and FIRE3
Authors: Tokunaga Ryuma , Cao Shu , Naseem Madiha , Battaglin Francesca , Lo Jae Ho , Arai Hiroyuki , Loupakis Fotios , Stintzing Sebastian , Puccini Alberto , Berger Martin D , Soni Shivani , Zhang Wu , Mancao Christoph , Salhia Bodour , Mumenthaler Shannon M , Weisenberger Daniel J. , Liang Gangning , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Millstein Joshua , Lenz Heinz‐Josef
Published: March 2019

AMP‐activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway‐related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE‐3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first‐line chemotherapy). The association between AMPK pathway‐related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta‐analysis approach. Our meta‐analysis showed that AMPK pathway had significant associations with progression‐free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = −0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = −0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway‐related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies.
“It Broadens Our Horizon”: English Learners Learn Through Global Literature and Cultural Discussion
Authors: Wang Yang
Published: March 2019

In this qualitative case study, the author explored how reading global literature books and interacting with U.S. literacy teachers influenced Chinese college students’ intercultural understandings and English‐language learning. Students read the selected picture books, discussed in small groups, conducted freewritings, made video clips, and created e‐books and PowerPoint presentations. The author found that students learned about different cultures, developed global awareness, and showed their respect and empathy for cultural differences. Reading global picture books and engaging in cultural discussion about the books helped students reflect on their own culture, think critically, and advocate for others. Students became interested in global literature books and developed English‐language skills by interacting with literature and U.S. teachers. Educational implications for English‐language and literacy teachers are provided.
Total flavonoids, extracted from Polygonum knotweed L, exert beneficial hepatoprotection against liver injury
Authors: Xu Lingyuan , Huang Guikun , Guo Xiaobao , Zhou Qiji , He Silu
Published: March 2019

Hepatic function is of great concern in metabolic and immunological homeostasis. Traditionally, medical management to liver damage may benefit from phytomedicine, such as Chinese herbs. In southern China, Polygonum perfoliatum L can contribute to alleviating pathological symptoms of liver disease, such as hepatitis. However, bioactive compounds of hepatoprotection in this herb are still less to be investigated. In this study, clinical data of patients with drug‐induced liver injury were collected on the basis of serological analyses. In addition, we extracted and identified total flavonoids from Polygonum perfoliatum L (TFPPL) before implementing biochemical experiments in vivo. In human data, the blood contents of liver function enzymes were visibly elevated, and the percentage of immune cells were abnormally changed. The data from the animal study showed that TFPPL‐treated carbon tetrachloride‐exposed mice resulted in reduced absolute liver mass and lowered blood levels of liver functional enzymes (alanine transaminase and aspartate transaminase). In enzyme‐linked immunosorbent assay, the comparable data indicated that serological tumor necrosis factor α (TNF‐α), interleukin 6, and heat shock protein 90 (Hsp90) contents were reduced in TFPPL‐treated mice. In histopathological observations, TFPPL‐treated mice exhibited reduced hepatocellular Hsp90, TNF‐α, nuclear factor κ‐light‐chain‐enhancer of activated B cells‐p65 positive cells, and lowered Bax and caspase‐3‐labeled cells in the livers. Further, intrasplenic integrin β1, 5′‐nucleotidase, and antigen KI‐67 positive cells were increased after TFPPL treatments. Taken together, our present findings demonstrate that herb‐extracted TFPPL exert potential hepatoprotective activities against chemical‐induced liver damage in mice, possibly through the pharmacological mechanisms of inhibiting inflammatory stress and apoptosis, inactivating Hsp90 bioactivity in the liver, and improving splenic immunocompetence.
miR‐193b‐5p regulates chondrocytes metabolism by directly targeting histone deacetylase 7 in interleukin‐1β‐induced osteoarthritis
Authors: Zhang Chengyun , Zhang Zhiqi , Chang Zongkun , Mao Guping , Hu Shu , Zeng Anyu , Fu Ming
Published: March 2019

There is increasing evidence regarding the pivotal roles of microRNAs (miRNAs) and histone deacetylases (HDACs) in the development of osteoarthritis (OA). This study aimed to determine whether miR‐193b‐5p regulates HDAC7 expression directly to affect cartilage degeneration. Expression levels of miR‐193b‐5p, HDAC7, matrix metalloproteinase 3 (MMP3), and MMP13 were determined in normal and OA cartilage and primary human chondrocytes (PHCs) stimulated with interleukin‐1β (IL‐1β). PHCs were transfected with a miR‐193b‐5p mimic or inhibitor to verify whether miR‐193b‐5p influences the expression of HDAC7 and MMPs. A luciferase reporter assay was performed to demonstrate the binding between miR‐193b‐5p and the 3′‐untranslated region (UTR) of HDAC7. Expression of miR‐193b‐5p was reduced in IL‐1β‐stimulated PHCs and in OA cartilage compared to that in normal cartilage. Luciferase reporter assay exhibited the repressed activity of the reporter construct containing the 3′UTR of HDAC7. Both miR‐193b‐5p overexpression and HDAC7 inhibition decreased the expression of MMP3 and MMP13, whereas the inhibition of miR‐193b‐5p enhanced HDAC7, MMP3, and MMP13 expression. miR‐193b‐5p downregulates HDAC7 directly and, as a result, inhibits MMP3 and MMP13 expression, which suggests that miR‐193b‐5p has a protective role in OA.
Distinguishing the optimal binding mechanism of an E3 ubiquitin ligase: Covalent versus noncovalent inhibition
Authors: Bjij Imane , Khan Shama , Ramharak Pritika , Cherqaoui Driss , Soliman Mahmoud E. S.
Published: March 2019

The development of covalent drugs, specifically in cancer therapeutics, has recently sparked interest among the pharmaceutical research community. While representing a significant fraction of the drugs in the market, very few have been deliberately designed to interact covalently with their biological target. One of the enzymes that have been both covalently and noncovalently targeted is the Neural Precursor Cell Expressed Developmentally Downregulated gene 4‐1 (Nedd4‐1). This enzyme has been found to have multiple physiological implications, including its involvement in cancer invasion. A critical gap still remains in the molecular understanding of the structural mechanism upon the covalent and noncovalent binding to Nedd4‐1. In this study, we explore the most optimal binding mechanism in the inhibition of the catalytic site of the Nedd4‐1. Our results exhibited a greater stability in the covalent complex compared with the noncovalent complex. This was supported by the secondary structure elements that were more dominant in the covalently inhibited complex. This complex disclosed an optimal free binding energy landscape, induced by the catalytic site energy contributions that showed to be more favorable. The insights demonstrating the above binding mechanism of Nedd4‐1 establishes covalent inhibition as the preferred method of inhibition of the enzyme. This investigation aids in the understanding of the structural mechanism of Nedd4‐1 inhibition and would assist in the design of more potent covalent inhibitors at the catalytic site of Nedd4‐1.
Retracted: microRNA‐203 promotes proliferation, differentiation, and migration of osteoblasts by upregulation of Msh homeobox 2
Authors: Liu Haochuan , Chen Bing , Li Yi
Published: March 2019

Despite the improvements in fracture healing, about 10% of patients undergo abnormal healing. As a tumor suppressor, upregulation of microRNA (miR)‐203 has been observed in osteogenic differentiation. Herein, we aimed to explore the functional role of miR‐203 in osteoblasts as well as the underlying mechanisms. The expression of miR‐203 in MC3T3‐E1 cells that underwent osteogenic differentiation was determined by quantitative reverse transcription PCR (qRT‐PCR). The effects of aberrantly expressed miR‐203 on cell viability, migration, and expressions of proteins associated with proliferation, migration, and osteogenic differentiation were measured by using a Cell Counting Kit‐8 assay, Transwell cell migration assay, and western blot/qRT‐PCR, respectively. The possible downstream factor of miR‐203 was subsequently studied. Finally, involvements of the mitogen‐activated protein kinase (MAPK)/activator of transcription (STAT) pathways were assessed by western blot. We found that the miR‐203 level was increased in osteogenic differentiation of MC3T3‐E1 cells with increasing duration time (28th day, p < 0.001). After cell transfection, we interestingly found that miR‐203 overexpression could increase cell viability (p < 0.05), promote proliferation, migration (p < 0.05), and osteogenic differentiation, and upregulate Msh homeobox 2 (Msx2) expression. Furthermore, Msx2 knockdown was proved to abrogate the effects of miR‐203 overexpression on MC3T3‐E1 cells. Finally, phosphorylated levels of key kinases in the MAPK/STAT pathways were increased by miR‐203 overexpression via upregulating Msx2 expression. In conclusion, miR‐203 overexpression promoted proliferation, migration, and osteogenic differentiation of MC3T3‐E1 cells through upregulating Msx2 along with activation of the MAPK/STAT pathways.
Scavenger receptor Class B type I as a potential risk stratification biomarker and therapeutic target in cardiovascular disease
Authors: Sahebi Reza , Hassanian Seyed Mahdi , Ghayour‐Mobarhan Majid , Farrokhi Effat , Rezayi Majid , Samadi Sara , Bahramian Shabbou , Ferns Gordon A. , Avan Amir
Published: March 2019

Cardiovascular disease (CVD) is the leading cause of mortality globally. There are few useful markers available for CVD risk stratification that has proven clinical utility. Scavenger receptor B type I (SR‐BI) is a cell surface protein that plays a major role in cholesterol homeostasis through its interaction with high‐density lipoprotein‐cholesterol (HDL‐C) esters (CE). HDL delivers CE to the liver through selective uptake by the SR‐BI. SR‐BI also regulates the inflammatory response. It has been shown that SR‐BI overexpression has beneficial, protective effects in atherogenesis, and there is considerable interest in developing antiatherogenic strategies that involve SR‐BI‐mediated increases in reverse cholesterol transport through HDL and/or low‐density lipoprotein. Further investigations are essential to explore the clinical utility of this approach. Moreover, there is growing evidence showing associations between genetic variants with modulation of SR‐BI function that may, thereby, increase CVD risk. The aim of the current review was to provide an overview of the possible molecular mechanisms by which SR‐BI may affect CVD risk, and the clinical implications of this, with particular emphasis on preclinical studies on genetic changes of SR‐BI and CVD risk.
A direct comparison of four high‐risk human papillomavirus tests versus the cobas test: Detecting CIN2+ in low‐resource settings
Authors: Xue Peng , Gao Li‐Li , Yin Jian , Han Li‐Li , Zhao Jing , Li Li , Seery Samuel , Han Xue‐Yan , Li Ting‐Yuan , Jiang Yu , Chen Wen , Shen Jie
Published: March 2019

Low‐cost, accurate high‐risk human papillomavirus (HR‐HPV) tests are needed for cervical cancer screening in limited‐resource settings. More than 200 cervical cytological specimens from hospital patients were collected and analyzed for a real‐world study. We evaluated the analytical and clinical performance of four widely used HR‐HPV test (Tellgen, Hybribio, Liferiver, and Sansure) based on real‐time polymerase chain reaction technology platforms, compared with the cobas test. Cervical intraepithelial neoplasia grade 2 or worse lesions (CIN2+) were set as the disease endpoint, and all the five HPV tests were performed with equal sensitivity (McNemar's test; P = 0.971) and specificity (McNemar's test; P = 0.953). All genotyping using the INNO‐LiPA HPV test showed that HPV‐16, ‐52, and ‐54 were the most common types among CIN2+ cases. Overall, the four HR‐HPV tests analyzed appear to be as effective as the cobas HPV test in both agreement and clinical performance. Therefore, each of these low‐cost HPV test kits could be implemented in limited‐resource settings to accelerate the control of cervical cancer. However, we suggest that there is a need to further standardize and optimize testing around clinical sensitivity and specificity.
Different motivations for knowledge sharing and hiding: The role of motivating work design
Authors: Gagné Marylène , Tian Amy Wei , Soo Christine , Zhang Bo , Ho Khee Seng Benjamin , Hosszu Katrina
Published: March 2019

Little research to date has focused on understanding employee motivation to share and hide knowledge. Using self‐determination theory, we tested the premise that knowledge sharing and hiding might be differentially motivated and that work design characteristics might influence the motivation to share knowledge with colleagues. In a panel survey of Australian knowledge workers and in a Chinese knowledge‐intensive organization, we asked knowledge workers, using time‐lagged designs, about perceptions of work design, motivation to share knowledge, and self‐reported knowledge sharing and hiding behaviors. Results, largely replicated across both samples, indicated that cognitive job demands and job autonomy were positively related to future reports of knowledge‐sharing frequency and usefulness via autonomous motivation to share knowledge. Unexpectedly, task interdependence was positively related to the three forms of knowledge hiding (evasive and rationalized hiding, and playing dumb) via external regulation to share knowledge. Implications for the design of jobs that motivate knowledge sharing and demotivate knowledge hiding are discussed.
Pitfalls of using the risk ratio in meta‐analysis
Authors: Bakbergenuly Ilyas , Hoaglin David C. , Kulinskaya Elena
Published: March 2019

For meta‐analysis of studies that report outcomes as binomial proportions, the most popular measure of effect is the odds ratio (OR), usually analyzed as log(OR). Many meta‐analyses use the risk ratio (RR) and its logarithm because of its simpler interpretation. Although log(OR) and log(RR) are both unbounded, use of log(RR) must ensure that estimates are compatible with study‐level event rates in the interval (0, 1). These complications pose a particular challenge for random‐effects models, both in applications and in generating data for simulations. As background, we review the conventional random‐effects model and then binomial generalized linear mixed models (GLMMs) with the logit link function, which do not have these complications. We then focus on log‐binomial models and explore implications of using them; theoretical calculations and simulation show evidence of biases. The main competitors to the binomial GLMMs use the beta‐binomial (BB) distribution, either in BB regression or by maximizing a BB likelihood; a simulation produces mixed results. Two examples and an examination of Cochrane meta‐analyses that used RR suggest bias in the results from the conventional inverse‐variance–weighted approach. Finally, we comment on other measures of effect that have range restrictions, including risk difference, and outline further research.
Perspectives on effective digital content management in organizations
Authors: Venkitachalam Krishna , Bosua Rachelle
Published: March 2019

Modern corporations face enormous digital transformation challenges in order to incorporate digital content into its corporate memory. At the same time over the last decade and a half, there is growing evidence of the advent of different types of mechanisms to manage digital organizational content. The management of digital content is particularly important to support knowledge worker practices to access, share, and reuse content in knowledge intensive organizations. Despite the availability of technological solutions in the marketplace to integrate content, managers are often overwhelmed by the choices they need to make to effectively manage digital content in their organizations. Extant literature indicates that in an increasingly digitized world, there is no clear understanding of the digital content considerations for informed decision making in organizations. Based on our research experiences in knowledge management, particularly knowledge codification in digital infrastructures, we provide certain perspectives on the four considerations for effective management of digital content in large organizations. We present four short exhibits to illustrate these four core considerations, which we label as the “4Cs” (i.e., content contribution, categorization, control, and centralization) for effective digital content management in large organizations.
Molecular‐weight‐dependent redox cycling of humic substances of paddy soils over successive anoxic and oxic alternations
Authors: Tan Wenbing , Wang Guoan , Zhao Xinyu , Dang Qiuling , Li Renfei , Xi Beidou , Jiang Jie , Zhang Hui , Li Dan , Cui Dongyu , Jia Yufu
Published: March 2019

Humic substances (HSs) are critical to regulating methane cycling in temporary anoxic systems because their redox‐active functional groups can sustainably shuttle electrons from microorganisms to oxygen (O2) over successive anoxic and oxic alternations. Whether the relative amount of these redox‐active functional groups involved in redox cycles is associated with the overall chemical structures of HS still remains poorly understood. In this study, variations in the reducing capacities (RCs) of HSs extracted from paddy soils were monitored over consecutive cycles of reduction by iron‐reducing microorganisms and oxidation by O2. Our results show that about 10–40% of the microbially reduced redox‐active moieties within HS, which were reoxidised by O2, cannot restore the same redox state as those before microbial reduction. The restoration extents of RCs of HSs after microbial reduction and O2 reoxidation were greatly negatively correlated with average molecular weight (AMW). The microbially reduced HSs having large AMWs (>1,000 Da) were more kinetically difficult to restore by O2 from a reduced state to an oxidised state than were those having small AMWs (<1,000 Da) possibly because the former, which underwent process of microbial reduction and O2 reoxidation, were more easily sheltered by other parts of HS structures than were the latter. Nevertheless, the unsheltered redox‐active groups that accounted for about 50–85% in HSs can be fully reversible and sustainable to switch between a reduced state and an oxidised state over successive redox cycles. Our results can help to understand the redox dynamics of HSs in biogeochemical cycles in environments.
Green tea–induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase‐3 suppresses prostate cancer progression through histone‐modifying enzymes
Authors: Deb Gauri , Shankar Eswar , Thakur Vijay S. , Ponsky Lee E. , Bodner Donald R. , Fu Pingfu , Gupta Sanjay
Published: March 2019

Green tea polyphenols (GTPs) and their major constituent, epigallocatechin‐3‐gallate (EGCG), have been reported to demonstrate many interesting biological activities, including anticancer properties. Recent studies on prostate cancer provide strong evidence that epigenetic mechanisms are major players in the regulation of matrix metalloproteinases (MMPs) and their binding partner tissue inhibitor of MMPs (TIMPs) involved in prostate cancer progression. Here we demonstrate that GTP/EGCG mediate epigenetic reactivation of TIMP‐3 that plays a key role in suppressing invasiveness and cancer progression. Treatment of human prostate cancer DUPRO and LNCaP cells with 10 µg/mL GTP and 20 µM EGCG induced TIMP‐3 mRNA and protein expression. This transcriptional activation of TIMP‐3 was associated with the decrease in the expression of both enhancers of zeste homolog 2 (EZH2) and its catalytic product trimethylation of histone H3 at lysine 27 (H3K27me3) repressive marks at the TIMP‐3 promoter with an accompanying increase in histone H3K9/18 acetylation. In addition, GTP/EGCG treatment significantly reduced class I histone deacetylase (HDAC) activity/expression and EZH2 and H3K27me3 levels in prostate cancer cells. EGCG/GTP exposure also reduced MMP‐2/MMP‐9 gelatinolytic activity and abrogated invasion and migration capabilities in these cells. Silencing of EZH2 and class I HDACs strikingly increased the expression of TIMP‐3 independent of DNA methylation. Furthermore, clinical trials performed on patients undergoing prostatectomy consuming 800 mg EGCG (Polyphenon E) up to 6 weeks and grade‐matched controls demonstrate an increase in plasma TIMP‐3 levels. A marked reduction in class I HDACs activity/expression and EZH2 and H3K27me3 levels were noted in GTP‐supplemented prostate tissue. Our findings highlight that TIMP‐3 induction, as a key epigenetic event modulated by green tea in restoring the MMP:TIMP balance suppresses prostate cancer progression.
Simple Modeling to Inform Harvest Strategy Policy for a Data-Moderate Crab Fishery
Authors: Grubert Mark A. , Walters Carl J. , Buckworth Rik C. , Penny Shane S.
Published: March 2019

Attempts to model the giant mud crab Scylla serrata fishery in the Northern Territory (Australia), have often been complex and the results difficult to interpret, leading to divergent estimates of fishing mortality. This has hindered the development of meaningful management policy. Additionally, analyses based on the entire Northern Territory fishery have masked the extreme variation in catches observed along the Gulf of Carpentaria coast. We applied a structurally simple model to visualize the historical patterns in stock size, recruitment, fishing mortality, and fishing mortality at maximum sustainable yield in the western Gulf of Carpentaria mud crab fishery (WGOCMCF) from 1983 to 2017. We also projected future catch and female spawning stock biomass (FSSB) under positive, neutral, and negative recruitment scenarios for three closure periods contained in the fishery harvest strategy (which start in October, if triggered) and compared these with the results of equivalent closures beginning in September. This exercise was undertaken because of known and significant changes in the proportion of fishing effort across different months as well as large variations in the proportion of females harvested each month (with both factors being particularly low in December). These differences were annualized and incorporated into the yearly time step of the model. Predicted catch and FSSB were similar for shorter closure periods (3 or 6 weeks), irrespective of the starting month. However, initiating a 3-month closure in September rather than October could lead to a 16–17% increase in FSSB under negative and average recruitment anomalies, imposing a 9–10% reduction in predicted catch. Based on our experience applying a simple model to the WGOCMCF, we also describe processes and practices that could improve the quality of assessment data for this and other data-moderate crab fisheries.