bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reimagining community relationships for organizational learning: a scoping review with implications for a learning health system
Authors: Milligan Crystal , Berta Whitney 
Published: June 2021

AbstractBackgroundCommunities represent a highly relevant source of knowledge with regard to not only healthcare performance but also sociocultural context, yet their role in learning health systems has not been studied. Situating the learning health system as an organization, this paper explores the phenomenon of organizational learning from or with communities (defined as one of ‘the people,’ such as a town, a specific patient group or another group directly receiving a healthcare service).MethodsWe conducted a scoping review to determine what is known about organizational learning from or with communities that the organization serves, and to contribute to a more comprehensive evidence base for building and operating learning health systems. In March 2019, we systematically searched six academic databases and grey literature, applying no date limits, for English language materials that described organizational learning in relation to knowledge transfer between an organization and a community. Numerous variables were charted in Excel and synthesized using frequencies and thematic analysis. We updated this search in August 2020.ResultsIn total, 42 documents were included in our analysis. We found a disproportionate emphasis on learning explicit knowledge from community rather than on tacit knowledge or learning in equal partnership with community. Our review also revealed inconsistently defined concepts, tenuously linked with their theoretical and empirical foundations. Our findings provide insight to understand the organization-community learning relationship, including motives and power differentials; types of knowledge to be learned; structures and processes for learning; and transformative learning outcomes.ConclusionsOur review makes a singular contribution to organizational learning literatures by drawing from diverse research disciplines such as health services, business and education to map what is known about learning from or with community. Broadly speaking, learning health systems literature would benefit from additional research and theory-building within a sociological paradigm so as to establish key concepts and associations to understand the nature of learning with community, as well as the practices that make it happen.
A phenome-wide association study of genetically mimicked statins
Authors: Li Shun , Schooling C. M. 
Published: June 2021

Abstract
Background
Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c).

Methods
We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c.

Results
As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition.

Conclusions
Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.
Identification and genetic diversity of hepatitis E virus in domestic swine from Slovakia
Authors: Jackova Anna , Dudasova Katarina , Salamunova Slavomira , Mandelik Rene , Novotny Jaroslav , Vilcek Stefan 
Published: June 2021

Abstract
Background
Hepatitis E virus (HEV) is agent causing hepatitis worldwide. Originally considered to be limited to developing countries, this virus was also detected in developed countries. In recent years an increasing number of reports indicate that farmed domestic pigs are widely infected with HEV in several European countries. The HEV status in Slovakia is still missing.

Results
In this study, the circulation of HEV among domestic swine in Slovakia and genetic diversity of the virus was studied. Overall HEV RNA was detected in 53/388 (13.7, 95% CI: 10.40–17.48%) pig rectal swabs in five production stages (age categories) with statistically significant differences among all the stages. The highest HEV prevalence was observed in weaners 24/81 (29.6, 95% CI: 19.99–40.81%) and then significantly declined in growers and fatteners. No HEV was detected in suckling piglets and sows. Twenty-eight partial sequences of ORF1 (242 bp) and seventeen of ORF2 (304 bp) were analysed. Phylogenetic analysis and p-distance comparisons confirmed in both ORFs that all Slovak HEV sequences belong to the genotype HEV-3, major clade 3abchij with higher identity to 3a and 3i subtypes. Three sequences were outside of all lastly updated HEV-3 subtypes.

Conclusion
This is the first report to fill the information gap about HEV infection in pigs in Slovakia. The results suggested a lower prevalence of HEV in Slovak pig farms than observed in other European countries. While most HEV isolates were typed as HEV-3 clade 3abchij, three sequences were unclassified.
Metabolic engineering of Escherichia coli for de novo production of 3-phenylpropanol via retrobiosynthesis approach
Authors: Liu Zhenning , Zhang Xue , Lei Dengwei , Qiao Bin , Zhao Guang-Rong 
Published: June 2021

Abstract
Background
3-Phenylpropanol with a pleasant odor is widely used in foods, beverages and cosmetics as a fragrance ingredient. It also acts as the precursor and reactant in pharmaceutical and chemical industries. Currently, petroleum-based manufacturing processes of 3-phenypropanol is environmentally unfriendly and unsustainable. In this study, we aim to engineer Escherichia coli as microbial cell factory for de novo production of 3-phenypropanol via retrobiosynthesis approach.

Results
Aided by in silico retrobiosynthesis analysis, we designed a novel 3-phenylpropanol biosynthetic pathway extending from l-phenylalanine and comprising the phenylalanine ammonia lyase (PAL), enoate reductase (ER), aryl carboxylic acid reductase (CAR) and phosphopantetheinyl transferase (PPTase). We screened the enzymes from plants and microorganisms and reconstructed the artificial pathway for conversion of 3-phenylpropanol from l-phenylalanine. Then we conducted chromosome engineering to increase the supply of precursor l-phenylalanine and combined the upstream l-phenylalanine pathway and downstream 3-phenylpropanol pathway. Finally, we regulated the metabolic pathway strength and optimized fermentation conditions. As a consequence, metabolically engineered E. coli strain produced 847.97 mg/L of 3-phenypropanol at 24 h using glucose-glycerol mixture as co-carbon source.

Conclusions
We successfully developed an artificial 3-phenylpropanol pathway based on retrobiosynthesis approach, and highest titer of 3-phenylpropanol was achieved in E. coli via systems metabolic engineering strategies including enzyme sources variety, chromosome engineering, metabolic strength balancing and fermentation optimization. This work provides an engineered strain with industrial potential for production of 3-phenylpropanol, and the strategies applied here could be practical for bioengineers to design and reconstruct the microbial cell factory for high valuable chemicals.
Long noncoding RNA ILF3-AS1 aggravates papillary thyroid carcinoma progression via regulating the miR-4306/PLAGL2 axis
Authors: Zeng Zhaohui , Teng Qiangfeng , Xiao Jinhong 
Published: June 2021

AbstractBackgroundIt have been proven that long non-coding RNAs (lncRNAs) serve as regulators in carcinogenesis. Interleukin enhancer binding factor 3 antisense RNA 1 (ILF3-AS1) has been illuminated as a prognostic factor in some cancers. Nevertheless, its expression pattern and possible functions in papillary thyroid carcinoma (PTC) have not been studied.MethodsThe expression of ILF3-AS1 was measured by RT-qPCR and ISH. Colony formation assay and EdU assay were used to probe cell proliferation. TUNEL assay was used for analysis of cell apoptosis. Immunofluorescence and western blot were conducted to evaluate the expression change of E-cadherin and N-cadherin. The RNA interaction was demonstrated by mechanism experiments, including pull down assay and dual luciferase reporter assay.ResultsILF3-AS1 expression was evidently upregulated in PTC cell lines. ILF3-AS1 knockdown restrained the proliferation, migration and invasion of PTC cells. Mechanical investigation revealed that miR-4306 could interact with ILF3-AS1. PLAGL2 was a downstream target of miR-4306. The effects of ILF3-AS1 knockdown on the cellular processes were abrogated by miR-4306 downregulation or pleiomorphic adenoma gene-like 2 (PLAGL2) overexpression.ConclusionILF3-AS1 plays tumor-promoting role in PTC via targeting miR-4306/PLAGL2 axis.
Down-regulation of BCL2L13 renders poor prognosis in clear cell and papillary renal cell carcinoma
Authors: Meng Fei , Zhang Luojin , Zhang Mingjun , Ye Kaiqin , Guo Wei , Liu Yu , Yang Wulin , Zhai Zhimin , Wang Hongzhi , Xiao Jun , Dai Haiming 
Published: June 2021

AbstractBackgroundBCL2L13belongs to theBCL2super family, with its protein product exhibits capacity of apoptosis-mediating in diversified cell lines. Previous studies have shown thatBCL2L13has functional consequence in several tumor types, including ALL and GBM, however, its function in kidney cancer remains as yet unclearly.MethodsMultiple web-based portals were employed to analyze the effect ofBCL2L13in kidney cancer using the data from TCGA database. Functional enrichment analysis and hubs ofBCL2L13co-expressed genes in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) were carried out on Cytoscape. Evaluation ofBCL2L13protein level was accomplished through immunohistochemistry on paraffin embedded renal cancer tissue sections. Western blotting and flow cytometry were implemented to further analyze the pro-apoptotic function ofBCL2L13in ccRCC cell line 786-0.ResultsBCL2L13expression is significantly decreased in ccRCC and pRCC patients, however, mutations and copy number alterations are rarely observed. The poor prognosis of ccRCC that derived from down-regulatedBCL2L13is independent of patients’ gender or tumor grade. Furthermore,BCL2L13only weakly correlates with the genes that mutated in kidney cancer or the genes that associated with inherited kidney cancer predisposing syndrome, while actively correlates withSLC25A4. As a downstream effector ofBCL2L13in its pro-apoptotic pathway,SLC25A4is found as one of the hub genes that involved in the physiological function ofBCL2L13in kidney cancer tissues.ConclusionsDown-regulation ofBCL2L13renders poor prognosis in ccRCC and pRCC. This disadvantageous factor is independent of any well-known kidney cancer related genes, soBCL2L13can be used as an effective indicator for prognostic evaluation of renal cell carcinoma.
Characterization of the substrate binding site of an iron detoxifying membrane transporter from Plasmodium falciparum
Authors: Sharma Pragya , Tóth Veronika , Hyland Edel M. , Law Christopher J. 
Published: June 2021

AbstractBackgroundPlasmodiumspecies are entirely dependent upon their host as a source of essential iron. Although it is an indispensable micronutrient, oxidation of excess ferrous iron to the ferric state in the cell cytoplasm can produce reactive oxygen species that are cytotoxic. The malaria parasite must therefore carefully regulate the processes involved in iron acquisition and storage. A 273 amino acid membrane transporter that is a member of the vacuolar iron transporter (VIT) family and an orthologue of the yeast Ca2+-sensitive cross complementer (CCC1) protein plays a major role in cytosolic iron detoxification ofPlasmodiumspecies and functions in transport of ferrous iron ions into the endoplasmic reticulum for storage. While this transporter, termed PfVIT, is not critical for viability of the parasite evidence from studies of mice infected with VIT-deficientPlasmodiumsuggests it could still provide an efficient target for chemoprophylactic treatment of malaria. Individual amino acid residues that constitute the Fe2+binding site of the protein were identified to better understand the structural basis of substrate recognition and binding by PfVIT.MethodsUsing the crystal structure of a recently published plant VIT as a template, a high-quality homology model of PfVIT was constructed to identify the amino acid composition of the transporter’s substrate binding site and to act as a guide for subsequent mutagenesis studies. To test the effect of mutation of the substrate binding-site residues on PfVIT function a yeast complementation assay assessed the ability of overexpressed, recombinant wild type and mutant PfVIT to rescue an iron-sensitive deletion strain (ccc1∆) ofSaccharomyces cerevisiaeyeast from the toxic effects of a high concentration of extracellular iron.ResultsThe combined in silico and mutagenesis approach identified a methionine residue located within the cytoplasmic metal binding domain of the transporter as essential for PfVIT function and provided insight into the structural basis for the Fe2+-selectivity of the protein.ConclusionThe structural model of the metal binding site of PfVIT opens the door for rational design of therapeutics to interfere with iron homeostasis within the malaria parasite.
Nanoparticles prepared from pterostilbene reduce blood glucose and improve diabetes complications
Authors: Zhao Xi , Shi Anhua , Ma Qiong , Yan Xueyan , Bian Ligong , Zhang Pengyue , Wu Junzi 
Published: June 2021

Abstract
Background
Diabetes complications are the leading cause of mortality in diabetic patients. The common complications are decline in antioxidant capacity and the onset of micro-inflammation syndrome. At present, glucose-responsive nanoparticles are widely used, as they can release insulin-loaded ultrafine particles intelligently and effectively reduce blood sugar. However, the toxicology of this method has not been fully elucidated. The plant extracts of pterostilbene (PTE) have a wide range of biological applications, such as antioxidation and inflammatory response improvement. Therefore, we have proposed new ideas for the cross application of plant extracts and biomaterials, especially as part of a hypoglycaemic nano-drug delivery system.

Results
Based on the PTE, we successfully synthesised poly(3-acrylamidophenyl boric acid-b-pterostilbene) (p[AAPBA-b-PTE]) nanoparticles (NPs). The NPs were round in shape and ranged between 150 and 250 nm in size. The NPs possessed good pH and glucose sensitivity. The entrapment efficiency (EE) of insulin-loaded NPs was approximately 56%, and the drug loading (LC) capacity was approximately 13%. The highest release of insulin was 70%, and the highest release of PTE was 85%. Meanwhile, the insulin could undergo self-regulation according to changes in the glucose concentration, thus achieving an effective, sustained release. Both in vivo and in vitro experiments showed that the NPs were safe and nontoxic. Under normal physiological conditions, NPs were completely degraded within 40 days. Fourteen days after mice were injected with p(AAPBA-b-PTE) NPs, there were no obvious abnormalities in the heart, liver, spleen, lung, or kidney. Moreover, NPs effectively reduced blood glucose, improved antioxidant capacity and reversed micro-inflammation in mice.

Conclusions
p(AAPBA-b-PTE) NPs were successfully prepared using PTE as raw material and effectively reduced blood glucose, improved antioxidant capacity and reduced the inflammatory response. This novel preparation can enable new combinations of plant extracts and biomaterials to adiministered through NPs or other dosage forms in order to regulate and treat diseases.

Graphic abstract
Is expected substance type associated with timing of drug checking service utilization?: A cross-sectional study
Authors: Beaulieu Tara , Wood Evan , Tobias Samuel , Lysyshyn Mark , Patel Priya , Matthews Jennifer , Ti Lianping 
Published: June 2021

Abstract
Background
Drug checking is a harm reduction intervention aiming to reduce substance use-related risks by improving drug user knowledge of the composition of unregulated drugs. With increasing fears of fentanyl adulteration in unregulated drugs, this study sought to examine whether the expected type of drug checked (stimulant vs. opioid) was associated with timing of drug checking service utilization (pre-consumption vs. post-consumption).

Methods
Data were derived from drug checking sites in British Columbia between October 31, 2017 and December 31, 2019. Pearson’s Chi-square test was used to examine the relationship between expected sample type (stimulant vs. opioid) and timing of service utilization. Odds ratios (OR) were calculated to assess the strength of this relationship. The Mantel–Haenszel (MH) test was used to adjust for service location.

Results
A total of 3561 unique stimulant and opioid samples were eligible for inclusion, including 691 (19.40%) stimulant samples; and 2222 (62.40%) samples that were tested pre-consumption. Results indicated a positive association between testing stimulant samples and testing pre-consumption (OR = 1.45; 95% CI 1.21–1.73). Regions outside of the epicenter of the province’s drug scene showed a stronger association with testing pre-consumption (ORMH = 2.33; 95% CI 1.51–3.56) than inside the epicenter (ORMH = 1.33; 95% CI 1.09–1.63).

Conclusion
Stimulant samples were more likely to be checked pre-consumption as compared with opioid samples, and stimulant samples were more likely to be tested pre-consumption in regions outside the epicenter of the province’s drug scene. This pattern may reflect a concern for fentanyl-adulterated stimulant drugs.
Regulation of exosome secretion by cellular retinoic acid binding protein 1 contributes to systemic anti-inflammation
Authors: Lin Yi-Wei , Nhieu Jennifer , Wei Chin-Wen , Lin Yu-Lung , Kagechika Hiroyuki , Wei Li-Na 
Published: June 2021

AbstractBackgroundIntercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear.MethodsCellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets.ResultsThis study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients’ data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway.ConclusionsThis study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation.
Nomogram for short-term outcome assessment in AChR subtype generalized myasthenia gravis
Authors: Zhao Rui , Wang Ying , Huan Xiao , Zhong Huahua , Zhou Zhirui , Xi Jianying , Da Yuwei , Lei Lin , Chang Ting , Ruan Zhe , Luo Lijun , Li Shengnan , Yang Huan , Li Yi , Luo Sushan , Zhao Chongbo 
Published: June 2021

Abstract
Background
An accurate prediction for prognosis can help in guiding the therapeutic options and optimizing the trial design for generalized myasthenia gravis (gMG). We aimed to develop and validate a predictive nomogram to assess the short-term outcome in patients with the anti-acetylcholine receptor (AChR) subtype gMG.

Methods
We retrospectively reviewed 165 patients with AChR subtype gMG who were immunotherapy naïve at the first visit from five tertiary centers in China. The short-term clinical outcome is defined as the achievement of minimal symptom expression (MSE) at 12 months. Of them, 120 gMG patients from Huashan Hospital were enrolled to form a derivation cohort (n = 96) and a temporal validation cohort (n = 24) for the nomogram. Then, this nomogram was externally validated using 45 immunotherapy naïve AChR subtype gMG from the other four hospitals. Multivariate logistic regression was used to screen independent factors and construct the nomogram.

Results
MSE was achieved in 70 (72.9%), 20 (83.3%), and 33 (73.3%) patients in the training, temporal validation, and external validation cohort, respectively. The duration ≤ 12 months (p = 0.021), ocular score ≤ 2 (p = 0.006), QMG score > 13 (p = 0.008), and gross motor score ≤ 9 (p = 0.006) were statistically associated with MSE in AChR subtype gMG. The nomogram has good performance in predicting MSE as the concordance indexes are 0.81 (95% CI, 0.72–0.90) in the development cohort, 0.944 (95% CI, 0.83–1.00) in the temporal validation cohort, and 0.773 (95% CI, 0.63–0.92) in the external validation cohort.

Conclusion
The nomogram achieved an optimal prediction of MSE in AChR subtype gMG patients using the baseline clinical characters.