bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review of the reverse innovation series in globalization and health – where are we and what else is needed?
Authors: Harris Matthew , Dadwal Viva , Syed Shams B. 
Published: March 2020

AbstractFollowing advances in industrial strategy and organizational behaviour, as well as post-development debates in international relations, Globalization and Health launched the Reverse Innovation series in 2012, in order to forge an agenda to promote not just the innovativeness of low-income country health systems but to recognize current and advocate for future strengthened knowledge flow between the global south and global north. It was considered to be a timely antidote to a knowledge flow that has traditionally been characterised by unidirectionality of innovation and expertise. Since then, the series provides a repository of research, theory, commentary and debate through which a collective community of practice in Reverse Innovation might emerge and provide an evidence base to promote, support and mainstream this type of knowledge flow. In this Commentary, we review the series as a whole, explore what has been learnt and what needs to come next in terms of empirical research, business models, processes and theoretical contributions to inform reverse innovation.
Immune microenvironment in ductal carcinoma in situ: a comparison with invasive carcinoma of the breast
Authors: Kim Milim , Chung Yul Ri , Kim Hyun Jeong , Woo Ji Won , Ahn Soomin , Park So Yeon 
Published: March 2020

Abstract
Background
The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. This study was conducted to evaluate the immune microenvironment of DCIS including the composition of tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells and to compare it with that of invasive breast cancer.

Materials and methods
A total of 671 cases including three different disease groups of pure DCIS, DCIS with microinvasion (DCIS-M), and invasive carcinoma were included in this study. CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ immune cells were detected with immunohistochemistry using tissue microarrays and were analyzed in relation to clinicopathologic characteristics and different disease groups.

Results
In pure DCIS, high infiltrations of CD4+, CD8+, and FOXP3+ T cells and the presence of PD-L1+ immune cells were associated with high nuclear grade, comedo-type necrosis, hormone receptor (HR) negativity, and high Ki-67 proliferation index. All immune cell infiltrations were higher in invasive carcinoma than in pure DCIS regardless of the HR status. While CD4+ T cells were more abundant than CD8+ T cells in pure DCIS, CD8+ T cells were dominant in invasive carcinoma, especially in HR-negative tumors. Within individual cases of invasive carcinoma with DCIS component, all immune cell subset infiltration was higher in the invasive component than in the DCIS component; however, CD4+ TIL infiltration did not differ between the two components in HR-negative tumors. Comparing pure DCIS, DCIS-M, and DCIS associated with invasive carcinoma (DCIS-INV), CD4+ TIL infiltration revealed a gradual increase from pure DCIS to DCIS-M and DCIS-INV in the HR-negative group, whereas FOXP3+ TIL infiltration was significantly increased in DCIS-INV than in pure DCIS in the HR-positive group. The high infiltration of FOXP3+ TIL and the presence of PD-L1+ immune cells were associated with tumor recurrence in patients with pure DCIS.

Conclusions
Our study showed that the immune microenvironment differs significantly not only between DCIS and invasive carcinoma but also between pure DCIS, DCIS-M, and DCIS-INV depending on the HR status.
Diverse genetic mechanisms underlie worldwide convergent rice feralization
Authors: Qiu Jie , Jia Lei , Wu Dongya , Weng Xifang , Chen Lijuan , Sun Jian , Chen Meihong , Mao Lingfeng , Jiang Bowen , Ye Chuyu , Turra Guilherme Menegol , Guo Longbiao , Ye Guoyou , Zhu Qian-Hao , Imaizumi Toshiyuki , Song Beng-Kah , Scarabel Laura , Merotto Aldo , Olsen Kenneth M. , Fan Longjiang 
Published: March 2020

Abstract
Background
Worldwide feralization of crop species into agricultural weeds threatens global food security. Weedy rice is a feral form of rice that infests paddies worldwide and aggressively outcompetes cultivated varieties. Despite increasing attention in recent years, a comprehensive understanding of the origins of weedy crop relatives and how a universal feralization process acts at the genomic and molecular level to allow the rapid adaptation to weediness are still yet to be explored.

Results
We use whole-genome sequencing to examine the origin and adaptation of 524 global weedy rice samples representing all major regions of rice cultivation. Weed populations have evolved multiple times from cultivated rice, and a strikingly high proportion of contemporary Asian weed strains can be traced to a few Green Revolution cultivars that were widely grown in the late twentieth century. Latin American weedy rice stands out in having originated through extensive hybridization. Selection scans indicate that most genomic regions underlying weedy adaptations do not overlap with domestication targets of selection, suggesting that feralization occurs largely through changes at loci unrelated to domestication.

Conclusions
This is the first investigation to provide detailed genomic characterizations of weedy rice on a global scale, and the results reveal diverse genetic mechanisms underlying worldwide convergent rice feralization.
DeepMILO: a deep learning approach to predict the impact of non-coding sequence variants on 3D chromatin structure
Authors: Trieu Tuan , Martinez-Fundichely Alexander , Khurana Ekta 
Published: March 2020

AbstractNon-coding variants have been shown to be related to disease by alteration of 3D genome structures. We propose a deep learning method, DeepMILO, to predict the effects of variants on CTCF/cohesin-mediated insulator loops. Application of DeepMILO on variants from whole-genome sequences of 1834 patients of twelve cancer types revealed 672 insulator loops disrupted in at least 10% of patients. Our results show mutations at loop anchors are associated with upregulation of the cancer driver genesBCL2andMYCin malignant lymphoma thus pointing to a possible new mechanism for their dysregulation via alteration of insulator loops.
A comprehensive environmental scanning and strategic analysis of Iranian Public Hospitals: a prospective approach
Authors: Pourmohammadi Kimia , Bastani Peivand , Shojaei Payam , Hatam Nahid , Salehi Asiyeh 
Published: March 2020

AbstractObjectivesThis study was conducted to provide a strategic direction to public hospitals in Iran via environmental scanning in order to equip hospitals to plan and perform proactively and adapt with the everchanging environment.ResultsA mixed method study including in-depth interview and survey were used to determine influential environmental factors based on PESTLE (political, economic, social, technological, legal and environmental) and Douglas West framework to determine the effectiveness and feasibility of factors. Issues identified at micro environmental level were over prescription, inequality in distribution of healthcare services and high demands for luxurious health services. Issues identified at the macro environmental level were related to changes in disease patterns, inappropriate hospital budgeting, economic sanctions, government corruption and healthcare centralization. In order to tackle the issues identified, it is paramount to enhance bed distribution management, improve strategic policies for a more equitable payment system, and enhance the efficiency and effectiveness of services by implementing a strategic inventory control. Furthermore, the considerable impact of economic sanctions on financial resources of Iranian hospitals should not be ignored.
DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936
Authors: Seeboth Anne , McCartney Daniel L. , Wang Yunzhang , Hillary Robert F. , Stevenson Anna J. , Walker Rosie M. , Campbell Archie , Evans Kathryn L. , McIntosh Andrew M. , Hägg Sara , Deary Ian J. , Marioni Riccardo E. 
Published: March 2020

Abstract
Background
DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples.

Results
Here, we showed an association between age and log10-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p < 2 × 10−16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10−4) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log10-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HRmeta = 1.12; 95% CImeta = [1.02; 1.21]; pmeta = 0.021).

Conclusions
These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.
IGF-1C domain–modified hydrogel enhanced the efficacy of stem cells in the treatment of AMI
Authors: Yao Yong , Yang Liang , Feng Li-feng , Yue Zhi-wei , Zhao Nian-huan , Li Zongjin , He Zuo-xiang 
Published: March 2020

AbstractBackgroundDue to the low survival rate of cell transplantation, stem cell has not been widely used in clinical treatment of acute myocardial infarction (AMI). In this study, we immobilized the C domain peptide of insulin-like growth factor-1 on chitosan (CS-IGF-1C) to obtain bioactive hydrogel. The purpose was to investigate whether CS-IGF-1C hydrogel incorporated with human placenta–derived mesenchymal stem cells (hP-MSCs) can boost the survival of hP-MSCs and enhance their therapeutic effects.MethodshP-MSCs, which continuously expressed green fluorescent protein (GFP) and firefly luciferase (Fluc), were transplanted with CS-IGF-1C hydrogel into a mouse myocardial infarction model. Cell survival was detected by bioluminescence imaging (BLI), and cardiac function was measured by echocardiogram. Real-time PCR and histological analysis were used to explore the therapeutic mechanism of CS-IGF-1C hydrogel.ResultsCS-IGF-1C hydrogel could induce the proliferation of hP-MSCs and exert anti-apoptotic effects in vitro. The Calcine-AM/PI staining results showed that hP-MSCs seeded on CS-IGF-1C hydrogel could protect neonatal mouse ventricular cardiomyocytes (NMVCs) against oxidative stress. It was observed by BLI that CS-IGF-1C hydrogel injected into ischemic myocardium could improve the survival rate of hP-MSCs. Histology analysis indicated that co-transplantation of the CS-IGF-1C hydrogel and hP-MSCs could increase angiogenesis, reduce collagen deposition, ameliorate left ventricular expanded, and further promote the recovery of cardiac function. Besides, we found that the inflammatory response was inhibited and the expression of apoptosis-related genes was downregulated by CS-IGF-1C hydrogel.ConclusionsCS-IGF-1C hydrogel provides a conducive microenvironment for cells and significantly boosts the survival of hP-MSCs in mouse myocardial infarction model, which suggest that it may be a potential candidate for prolonging the therapeutic effect of hP-MSCs during AMI.
Loss of receptor tyrosine kinase-like orphan receptor 2 impairs the osteogenesis of mBMSCs by inhibiting signal transducer and activator of transcription 3
Authors: Lei Lizhen , Huang Zhuwei , Feng Jingyi , Huang Zijing , Tao Yiwei , Hu Xiaoli , Zhang Xiaolei 
Published: March 2020

Abstract
Background
Receptor tyrosine kinase-like orphan receptor 2 (Ror2) plays a key role in bone formation, but its signaling pathway is not completely understood. Signal transducer and activator of transcription 3 (Stat3) takes part in maintaining bone homeostasis. The aim of this study is to reveal the role and mechanism of Ror2 in the osteogenic differentiation from mouse bone marrow mesenchymal stem cells (mBMSCs) and to explore the effect of Stat3 on Ror2-mediated osteogenesis.

Methods
Ror2 CKO mice were generated via the Cre-loxp recombination system using Prrx1-Cre transgenic mice. Quantitative real-time PCR and western blot were performed to assess the expression of Stat3 and osteogenic markers in Ror2-knockdown mBMSCs (mBMSC-sh-Ror2). After being incubated in osteogenic induction medium for 3 weeks, Alizarin Red staining and western blot were used to examine the calcium deposit and osteogenic markers in Stat3 overexpression in mBMSC-sh-Ror2.

Results
Loss of Ror2 in mesenchymal or osteoblast progenitor cells led to a dwarfism phenotype in vivo. The mRNA expression of osteogenic markers (osteocalcin, osteopontin (OPN), and collagen I) in the ulna proximal epiphysis of Ror2 CKO mice was significantly decreased (P < 0.05). The mRNA and protein expression of Stat3 and osteogenic markers (Runx2, osterix, and OPN) decreased in mBMSC-sh-Ror2 cells (P < 0.05). The overexpression of Stat3 in mBMSC-sh-Ror2 cells rescued the calcium deposit and expression of Runx2, osterix, and OPN to a level comparable to normal mBMSCs.

Conclusions
Ror2 was essential for skeleton development by regulating mBMSCs’ osteogenesis and osteoblast differentiation. Loss of Ror2 may impair the osteogenesis of mBMSCs by inhibiting Stat3.
Mending a broken heart: current strategies and limitations of cell-based therapy
Authors: Liew Lee Chuen , Ho Beatrice Xuan , Soh Boon-Seng 
Published: March 2020

AbstractThe versatility of pluripotent stem cells, attributable to their unlimited self-renewal capacity and plasticity, has sparked a considerable interest for potential application in regenerative medicine. Over the past decade, the concept of replenishing the lost cardiomyocytes, the crux of the matter in ischemic heart disease, with pluripotent stem cell-derived cardiomyocytes (PSC-CM) has been validated with promising pre-clinical results. Nevertheless, clinical translation was hemmed in by limitations such as immature cardiac properties, long-term engraftment, graft-associated arrhythmias, immunogenicity, and risk of tumorigenicity. The continuous progress of stem cell-based cardiac therapy, incorporated with tissue engineering strategies and delivery of cardio-protective exosomes, provides an optimistic outlook on the development of curative treatment for heart failure. This review provides an overview and current status of stem cell-based therapy for heart regeneration, with particular focus on the use of PSC-CM. In addition, we also highlight the associated challenges in clinical application and discuss the potential strategies in developing successful cardiac-regenerative therapy.
Autophagy modulation altered differentiation capacity of CD146+ cells toward endothelial cells, pericytes, and cardiomyocytes
Authors: Hassanpour Mehdi , Rezaie Jafar , Darabi Masoud , Hiradfar Amirataollah , Rahbarghazi Reza , Nouri Mohammad 
Published: March 2020

Abstract
Background
To date, many attempts are employed to increase the regenerative potential of stem cells. In this study, we evaluated the hypothesis of whether an autophagy modulation could alter differentiation potency of CD146+ cells into mature pericyte, endothelial, and cardiomyocyte lineage.

Methods
In this study, CD146+cells were enriched from the human bone marrow aspirates and trans-differentiated into mature endothelial cells, pericytes, and cardiomyocytes after exposure to autophagy stimulator (50-μM Met)/inhibitor (15-μM HCQ). The protein levels of autophagy proteins were monitored by western blotting. NO content was measured using the Griess assay. Using real-time PCR assay and western blotting, we monitored the lineage protein and gene levels. Pro-inflammatory cytokine and angiocrine factors were measured by ELISA. The fatty acid change was determined by gas chromatography. We also measured exosome secretion capacity by measuring AChE activity and real-time PCR assay.

Result
Data revealed the modulation of autophagy factors, Beclin-1, P62, and LC3 II/I ratio in differentiating CD146+ cells after exposure to Met and HCQ (p < 0.05). The inhibition of autophagy increased NO content compared to the Met-treated cells (p < 0.05). Real-time PCR analysis showed that the treatment of CD146+ cells with autophagy modulators altered the expression of VE-cadherin, cTnI, and α-SMA (p < 0.05). Met increased the expression of VE-cadherin, α-SMA, and cTnI compared to the HCQ-treated cells (p < 0.05) while western blotting revealed the protein synthesis of all lineage-specific proteins under the stimulation and inhibition of autophagy. None statistically significant differences were found in the levels of Tie-1, Tie-2, VEGFR-1, and VEGFR-2 after autophagy modulation. Fatty acid profile analysis revealed the increase of unsaturated fatty acids after exposure to HCQ (p < 0.05). The treatment of cells with HCQ increased the levels of TNF-α and IL-6 compared to the Met-treated cells. Data revealed the increase of exosome biogenesis and secretion to the supernatant in cells treated with HCQ compared to the Met groups (p < 0.05).

Conclusions
In summary, autophagy modulation could alter differentiation potency of CD146+cells which is important in cardiac regeneration.
Fractional spectral differentiation matrices based on Legendre approximation
Authors: Ghorbani Asghar , Baleanu Dumitru 
Published: March 2020

AbstractA simple scheme is proposed for computing $N \times N$N×N spectral differentiation matrices of fractional order α for the case of Legendre approximation. The algorithm derived here is based upon a homogeneous three-term recurrence relation and is numerically stable. The matrices are then applied to numerically differentiate.
Study on microbubble of cellulose acetate microfilm of the Republic of China (AD 1912–1949) collected in the Second Historical Archives of China
Authors: Jia Zhihui , Li Yuhu , Qi Yunpeng , Zhou Yajun , Hu Daodao , Chao Xiaolian , Xing Huiping , Li Jing 
Published: March 2020

Abstract
The white spots known as microbubbles that are formed in cellulose acetate film, significantly affects the texture of the image. However, the formation of microbubbles and their corresponding microstructure are poorly understood. In this paper, cellulose acetate microfilm from the Republic of China (AD 1912–1949) collected in the Second Historical Archives of China was chosen as a prototype to investigate the causes of microbubble disease for the first time. A comparative study was conducted between the film samples with and without microbubbles. Herein, the microstructural analyses including optical and SEM microscopy were conducted. The crystals in the microbubbles proved to be triphenyl phosphate as identified by NMR spectroscopy and SEM–EDX. Comparative properties of the film substrate with and without microbubbles were measured by TG, XRD and FT-IR spectroscopy. The results show that formation of microbubbles was generally accompanied with the vinegar syndrome and was produced between the protective and emulsion layers with the different types of shapes along the closed structure (the diameter of ~ 0.1–2 mm). The formed microbubble was filled with plasticizer. Based on the above-mentioned results, the possible formation process of microbubble was proposed in the present study. The results can provide support for the cause of microbubbles and basis for the conservation of photographic films.
Gap models across micro- to mega-scales of time and space: examples of Tansley’s ecosystem concept
Authors: Shugart H. H. , Foster Adrianna , Wang Bin , Druckenbrod Dan , Ma Jianyong , Lerdau Manuel , Saatchi Sassan , Yang Xi , Yan Xiaodong 
Published: March 2020

Abstract
Background
Gap models are individual-based models for forests. They simulate dynamic multispecies assemblages over multiple tree-generations and predict forest responses to altered environmental conditions. Their development emphases designation of the significant biological and ecological processes at appropriate time/space scales. Conceptually, they are with consistent with A.G. Tansley’s original definition of “the ecosystem”.

Results
An example microscale application inspects feedbacks among terrestrial vegetation change, air-quality changes from the vegetation’s release of volatile organic compounds (VOC), and climate change effects on ecosystem production of VOC’s. Gap models can allocate canopy photosynthate to the individual trees whose leaves form the vertical leaf-area profiles. VOC release depends strongly on leaf physiology by species of these trees. Leaf-level VOC emissions increase with climate-warming. Species composition change lowers the abundance of VOC-emitting taxa. In interactions among ecosystem functions and biosphere/atmosphere exchanges, community composition responses can outweigh physiological responses. This contradicts previous studies that emphasize the warming-induced impacts on leaf function.
As a mesoscale example, the changes in climate (warming) on forests including pest-insect dynamics demonstrates changes on the both the tree and the insect populations. This is but one of many cases that involve using a gap model to simulate changes in spatial units typical of sampling plots and scaling these to landscape and regional levels. As this is the typical application scale for gap models, other examples are identified. The insect/climate-change can be scaled to regional consequences by simulating survey plots across a continental or subcontinental zone. Forest inventories at these scales are often conducted using independent survey plots distributed across a region. Model construction that mimics this sample design avoids the difficulties in modelling spatial interactions, but we also discuss simulation at these scales with contagion effects.

Conclusions
At the global-scale, successful simulations to date have used functional types of plants, rather than tree species. In a final application, the fine-scale predictions of a gap model are compared with data from micrometeorological eddy-covariance towers and then scaled-up to produce maps of global patterns of evapotranspiration, net primary production, gross primary production and respiration. New active-remote-sensing instruments provide opportunities to test these global predictions.