bluuebunny/crossref_metadata_2025_split huggingface dataset:
Participation in patient support forums may put rare disease patient data at risk of re-identification
Authors: Gow James , Moffatt Colin , Blackport Jamie 
Published: August 2020

Abstract
Background
Rare disease patients often struggle to find both medical advice and emotional support for their diagnosis. Consequently, many rare disease patient support forums have appeared on hospital webpages, social media sites, and on rare disease foundation sites. However, we argue that engagement in these groups may pose a healthcare data privacy threat to many participants, since it makes a series of patient indirect identifiers ‘readily available’ in combination with rare disease conditions. This information produces a risk of re-identification because it may allow a motivated attacker to use the unique combination of a patient’s identifiers and disease condition to re-identify them in anonymized data.

Results
To assess this risk of re-identification, patient direct and indirect identifiers were mined from patient support forums for 80 patients across eight rare diseases. This data mining consisted of scanning patient testimonials, social media sites, and public records for the collection of identifiers linked to a rare disease patient. The number of people in the United States that may share each patient’s combination of marital status, 3-digit ZIP code, age, and sex, as well as their rare disease condition, was then estimated, as such information is commonly found in health records which have undergone de-identification by HIPAA’s ‘Safe Harbor.’ The study showed that by these estimations, nearly 75% of patients could be at high risk for re-identification in healthcare datasets in which they appear, due to their unique combination of identifiers.

Conclusions
The results of this study show that these rare disease patients, due to their choice to provide support for their community, are putting all their healthcare data at risk of re-identification. This paper demonstrates how simple adjustments to participation guidelines in such support forums, in combination with improved privacy measures at the organizational level, could mitigate this risk of re-identification. Additionally, this paper suggests the potential for future investigation into consideration of certain ‘risky’ International Classification of Diseases (ICD) codes as quasi-identifiers in de-identified datasets to further protect patients’ privacy, while maintaining the utility of such rare disease support groups.
Multi-level consistent changes of the ECM pathway identified in a typical keratoconus twin’s family by multi-omics analysis
Authors: Hao Xiao-dan , Chen Xiu-nian , Zhang Yang-yang , Chen Peng , Wei Chao , Shi Wei-yun , Gao Hua 
Published: August 2020

AbstractBackgroundKeratoconus (KC) is a common, degenerative disorder of the cornea, and genetic factors play a key role in its development. However, the genetic etiology of KC is still unclear. This study used the family of twins as material, using, for the first time, multi-omics analysis, to systematically display the changes in KC candidate factors in patients at the DNA, RNA, and protein levels. These can evaluate candidate pathogenic factors in depth and lock onto pathogenic targets.ResultsThe twins in this study presented classic phenotypes, clear diagnoses, complete case data, and clinical samples, which are excellent materials for genetically studying KC. Whole-exome sequencing was conducted on both the twins and their parents. Transcriptome sequencing was conducted on proband’s and health individual’s primary human corneal fibroblast cells. Quantitative Real-time PCR and western blot were used to validate the differential gene expressions between the proband and controls. By integrating genomics, transcriptome, and protein level data, multiple consecutive events of KC were systematically analyzed to help better understand the molecular mechanism and genetic basis of KC. The results showed that the accumulation of rare, micro-effect risk variants was the pathogenic factor in this Chinese KC family. Consistent changes in extracellular matrices (ECMs) at the DNA and RNA levels suggested that ECM related changes play a key role in KC pathogenesis. The major gene variants (WNT16,CD248,COL6A2,COL4A3andADAMTS3) may affect the expression of related collagens or ECM proteins, thus reducing the amount of ECM in corneas and resulting in KC.ConclusionsThis study, the first to explore the genetic etiology of KC via multi-omics analysis under the polygenetic model, has provided new insights into the genetic mechanisms underlying KC and an effective strategy for studying KC pathogenesis in the future.
Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit
Authors: De Bruyn Astrid , Gunst Jan , Goossens Chloë , Vander Perre Sarah , Guerra Gonzalo G. , Verbruggen Sascha , Joosten Koen , Langouche Lies , Van den Berghe Greet 
Published: August 2020

Abstract
Background
In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits.

Methods
In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators.

Results
In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1–5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04–0.04] mmol/L to 0.75 [0.04–2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings.

Conclusion
Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.
Cryptosporidium parvum upregulates miR-942-5p expression in HCT-8 cells via TLR2/TLR4-NF-κB signaling
Authors: Zhang Guiling , Zhang Yajun , Niu Ziwen , Wang Chenrong , Xie Fujie , Li Juanfeng , Zhang Sumei , Qi Meng , Jian Fuchun , Ning Changshen , Zhang Longxian , Wang Rongjun 
Published: August 2020

Abstract
Background
Micro (mi)RNAs are small noncoding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. This study investigated host miRNA activity in the innate immune response to Cryptosporidium parvum infection.

Methods
In vitro infection model adopts HCT-8 human ileocecal adenocarcinoma cells infected with C. parvum. The expression of miR-942-5p was estimated using quantitative real-time polymerase chain reaction (qPCR). The TLRs-NF-κB signaling was confirmed by qPCR, western blotting, TLR4- and TLR2-specific short-interfering (si)RNA, and NF-κB inhibition.

Results
HCT-8 cells express all known toll-like receptors (TLRs). Cryptosporidium parvum infection of cultured HCT-8 cells upregulated TLR2 and TLR4, and downstream TLR effectors, including NF-κB and suppressed IκBα (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha). The expression of miR-942-5p was significantly upregulated at 4, 8, 12 and 24 h post-infection, and especially at 8 hpi. The results of TLR4- and TLR2-specific siRNA and NF-κB inhibition showed that upregulation of miR-942-5p was promoted by p65 subunit-dependent TLR2/TLR4-NF-κB pathway signaling.

Conclusions
miR-942-5p of HCT-8 cells was significantly upregulated after C. parvum infection, especially at 8 hpi, in response to a p65-dependent TLR2/TLR4-NF-κB signaling. TLR4 appeared to play a dominant role.
N6-Adenosine methylation on mRNA is recognized by YTH2 domain protein of human malaria parasite Plasmodium falciparum
Authors: Govindaraju Gayathri , Kadumuri Rajashekar Varma , Sethumadhavan Devadathan Valiyamangalath , Jabeena C. A. , Chavali Sreenivas , Rajavelu Arumugam 
Published: August 2020

Abstract
Background
Plasmodium falciparum exhibits high translational plasticity during its development in RBCs, yet the regulation at the post-transcriptional level is not well understood. The N6-methyl adenosine (m6A) is an important epigenetic modification primarily present on mRNA that controls the levels of transcripts and efficiency of translation in eukaryotes. Recently, the dynamics of m6A on mRNAs at all three developmental stages of P. falciparum in RBCs have been profiled; however, the proteins that regulate the m6A containing mRNAs in the parasites are unknown.

Results
Using sequence analysis, we computationally identified that the P. falciparum genome encodes two putative YTH (YT521-B Homology) domain-containing proteins, which could potentially bind to m6A containing mRNA. We developed a modified methylated RNA immunoprecipitation (MeRIP) assay using PfYTH2 and find that it binds selectively to m6A containing transcripts. The PfYTH2 has a conserved aromatic amino acid cage that forms the methyl-binding pocket. Through site-directed mutagenesis experiments and molecular dynamics simulations, we show that F98 residue is important for m6A binding on mRNA. Fluorescence depolarization assay confirmed that PfYTH2 binds to methylated RNA oligos with high affinity. Further, MeRIP sequencing data revealed that PfYTH2 has more permissive sequence specificity on target m6A containing mRNA than other known eukaryotic YTH proteins. Taken together, here we identify and characterize PfYTH2 as the major protein that could regulate m6A containing transcripts in P. falciparum.

Conclusion
Plasmodium spp. lost the canonical m6A-specific demethylases in their genomes, however, the YTH domain-containing proteins seem to be retained. This study presents a possibility that the YTH proteins are involved in post-transcriptional control in P. falciparum, and might orchestrate the translation of mRNA in various developmental stages of P. falciparum. This is perhaps the first characterization of the methyl-reading function of YTH protein in any parasites.
Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study
Authors: Do Minh Duc , Mai Thao Phuong , Do Anh Duy , Nguyen Quang Dinh , Le Nghia Hieu , Le Linh Gia Hoang , Hoang Vu Anh , Le Anh Ngoc , Le Hung Quoc , Richette Pascal , Resche-Rigon Matthieu , Bardin Thomas 
Published: August 2020

AbstractObjectiveThe aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese.MethodsAll patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated.ResultsOn comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8–40.1],P < 0.0001), female sex (OR 333 [40–43,453],P < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120–125,847],P < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101–122],P < 0.0001), diuretics intake (OR 304 [35–40,018],P < 0.0001), eGFR < 60 ml/min/1.73 m2(OR 100 [32–353],P < 0.0001), history of allopurinol-induced skin reaction (OR 78 [6–10,808],P = 0.004), and HLA-B*58:01 carriage (OR 147 [45–746],P < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs (n = 74), risk factors were eGFR < 60 ml/min/1.73 m2(OR 4.9 [1.61–14.6],P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2–3777],P = 0.01), and asymptomatic hyperuricemia (OR 27 [2–3777],P = 0.01).ConclusionThis study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.
Exposure to perfluorooctanoic acid (PFOA) decreases neutrophil migration response to injury in zebrafish embryos
Authors: Pecquet Alison M. , Maier Andrew , Kasper Susan , Sumanas Saulius , Yadav Jagjit 
Published: August 2020

Abstract
Objective
Perfluorooctanoic acid (PFOA) is a ubiquitous environmental contaminant and a known immune suppressant in humans and experimental animal models. Studies on PFOA have focused on suppression of the adaptive immune response; however, little is known of the impact on innate immunity, especially during embryogenesis. Therefore, we utilized the zebrafish chemotaxis assay coupled with in situ hybridization for myeloperoxidase expression to determine the effects of PFOA exposure on neutrophil migration in the developing zebrafish embryo. Zebrafish embryos are a well-established in vivo model that exhibit high homology with the development of human innate immunity.

Results
Treatment of zebrafish with increasing concentrations of PFOA identified the lethal concentration in 50% of the embryos (LC50) to be 300 mg/L. Utilizing the zebrafish chemotaxis assay, this study showed that wounding induced significant neutrophil migration to the site of injury, and that neutrophil number in the wound region was significantly reduced in response to 48-h PFOA exposure (well below doses causing acute mortality). This study demonstrates that the developing embryo is sensitive to PFOA exposure and that PFOA can modify the innate immune system during embryonic development. These results lay the groundwork for future investigation on the mechanisms underlying PFOA-induced developmental immunotoxicity.
The effect of royal jelly and tocotrienol-rich fraction along with calorie restriction on hypothalamic endoplasmic reticulum stress and adipose tissue inflammation in diet-induced obese rats
Authors: Irandoost Pardis , Mesri Alamdari Naimeh , Saidpour Atoosa , Shidfar Farzad , Farsi Farnaz , Asghari Jafarabadi Mohammad , Alivand Mohammad Reza , Vafa Mohammadreza 
Published: August 2020

Abstract
Objectives
Endoplasmic reticulum (ER) stress causes adipose tissue dysfunction and chronic inflammation in obesity. Royal jelly (RJ) and tocotrienol-rich fraction (TRF) are reported to ameliorate inflammation. However, the improving effects of RJ and TRF on inflammation from ER stress modulating view have not been assessed so far. Hence, we investigated the effect of RJ and TRF on ER stress and some adipose tissue-derived inflammatory markers in the high-fat diet (HFD)-induced obesity. Wistar obese rats randomly allocated into 5 groups: HFD, calorie restriction diet (CRD), RJ + CRD, TRF + CRD, RJ + TRF + CRD. After 8-week intervention, adipose tissues and hypothalamus were dissected and serum was collected.

Results
RJ reduced glucose-regulated protein-78 (GRP78) expression as ER stress indicator in WAT and hypothalamus compared to CRD. Besides, RJ diminished the expression of inflammatory markers in white adipose tissue (WAT) and also decreased the serum concentration of them. TRF reduced inflammatory markers in the serum without remarkable effects on ER stress. Overall, RJ has protective effect against adipose tissue dysfunction and inflammation then suggested as a therapeutic approach to reduce some obesity-related complications. The impact of TRF in this regard is lower than RJ and limited to systemic inflammation improvement without remarkable changes in adipose tissue inflammation.
Ectocarpus: an evo-devo model for the brown algae
Authors: Coelho Susana M. , Peters Akira F. , Müller Dieter , Cock J. Mark 
Published: August 2020

AbstractEctocarpusis a genus of filamentous, marine brown algae. Brown algae belong to the stramenopiles, a large supergroup of organisms that are only distantly related to animals, land plants and fungi. Brown algae are also one of only a small number of eukaryotic lineages that have evolved complex multicellularity. For many years, little information was available concerning the molecular mechanisms underlying multicellular development in the brown algae, but this situation has changed with the emergence ofEctocarpusas a model brown alga. Here we summarise some of the main questions that are being addressed and areas of study usingEctocarpusas a model organism and discuss how the genomic information, genetic tools and molecular approaches available for this organism are being employed to explore developmental questions in an evolutionary context.
Ursodeoxycholic acid augmentation in treatment-refractory schizophrenia: a case report
Authors: Khosravi Mohsen 
Published: August 2020

Abstract
Background
Treatment-resistance is recognized as a significant dilemma in schizophrenia, which has been reported to involve approximately one-third of patients with schizophrenia.

Case presentation
This case report described a 12-week treatment course for a 39-year-old Persian man with treatment-refractory schizophrenia, who showed a significant improvement in terms of positive, negative, and cognitive symptoms after taking ursodeoxycholic acid 300 mg capsules twice a day. Also, ursodeoxycholic acid was well tolerated, and he did not exhibit any side effects during treatment, based on interview and physical examination.

Conclusion
Ursodeoxycholic acid augmentation seems to be an effective treatment strategy for patients with treatment-refractory schizophrenia. However, further investigations in this field need to be carried out through randomized controlled trials.
Dental follicle stem cells rescue the regenerative capacity of inflamed rat dental pulp through a paracrine pathway
Authors: Hong Hong , Chen Xiaochuan , Li Kun , Wang Nan , Li Mengjie , Yang Bo , Yu Xiaoqi , Wei Xi 
Published: August 2020

Abstract
Background
Pulpitis is a common dental disease characterized by sustained inflammation and impaired pulp self-repair. Mesenchymal stem cell-based minimally invasive vital pulp therapy (MSC-miVPT) is a potential treatment method, but its application is limited by the difficulty in acquiring MSCs. We recently revealed the immunomodulatory effects of rat dental follicle stem cells (rDFSCs) on acute lung injury. The present study focused on the paracrine effects of rDFSCs on the inflammation and regeneration of rat injured dental pulp to detect whether DFSCs are a potential candidate for MSC-miVPT.

Methods
Conditioned medium from rDFSCs (rDFSC-CM) was applied to lipopolysaccharide (LPS)-induced inflammatory rat dental pulp cells (rDPCs). The inflammation and regeneration of rDPCs were detected by RT-qPCR, Western blotting, immunofluorescence staining, Cell Counting Kit-8 (CCK-8) assay, flow cytometry, wound-healing assay, and Masson’s staining. The effects of rDFSC-CM on inflamed rat dental pulp were further evaluated by hematoxylin-eosin and immunohistochemical staining.

Results
rDFSC-CM downregulated the ERK1/2 and NF-κB signaling pathways, which resulted in suppression of the expression of IL-1β, IL-6, and TNF-α and promotion of the expression of IL-4 and TGF-β, and these findings lead to the attenuation of rDPC inflammation. rDFSC-CM enhanced the in vitro proliferation, migration, and odontogenic differentiation of inflammatory rDPCs and their in vivo ectopic dentinogenesis. Furthermore, rDFSC-CM inhibited inflammatory cell infiltration in rat pulpitis and triggered Runx2 expression in some of the odontoblast-like cells surrounding the injured site, and these effects were conducive to the repair of inflamed dental pulp.

Conclusions
rDFSC-CM exhibits therapeutic potential by rescuing the regeneration of the inflamed rat dental pulp through an immunomodulatory mechanism, indicating the application prospects of DFSCs in biological regenerative endodontics.
Rhein laden pH-responsive polymeric nanoparticles for treatment of osteoarthritis
Authors: Hu Bo , Gao Feng , Li Chunbao , Zhang Boqing , An Mingyang , Lu Ming , Liu Yufeng , Liu Yujie 
Published: August 2020

AbstractOsteoarthritis (OA) is a condition associated with severe inflammation, cartilage destruction and degeneration of joints. Rhein (Rh) is an effective anti-inflammatory drug with proven efficacy in in-vitro and in-vivo models. pH sensitive Rh and NH4HCO3 laden poly (lactic-co-glycolic acid (PLGA) nanoparticles (NPs) (Rh-PLGA-NPs@NH4) are developed for an effective treatment of OA. The Rh-PLGA-NPs@NH4 are prepared along with Rh-PLGA-NPs as a control by double emulsion method. Rh-PLGA-NPs@NH4 was characterized for their size, shape, morphology and encapsulation efficiency (EE). The effect of pH on release of Rh from Rh-PLGA-NPs@NH4 was studied at different pH. Further, the cytotoxicity effect of Rh-PLGA-NPs@NH4 on THP-1 cells were evaluated. Anti-inflammatory efficacy was evaluated on LPS stimulated THP-1 cells and the release of pro-inflammatory cytokines was evaluated and compared with control. The size of Rh-PLGA-NPs@NH4 and Rh-PLGA-NPs was found to be 190.7 ± 1.2 nm and 134.6 ± 2.4 nm respectively with poly dispersity (PDI) 0.14 and 0.15. The zeta potential of Rh-PLGA-NPs@NH4 was found to be -22 ± 1.12 mV. Rh-PLGA-NPs@NH4 were uniform, smooth and spherical shape as confirmed using electron microscopy analysis. Rh-PLGA-NPs@NH4 release the Rh more effectively in the low pH of synovial fluid environment (SFE). Rh-PLGA-NPs@NH4 also significantly affect inflammatory cytokines TNF-α and IL-1β and reduced their release in LPS stimulated THP-1 cells. Reactive oxygen species (ROS), a mediator responsible for the cartilage collapse was also found to be reduced. Results proposes that Rh-PLGA-NPs could provide therapeutic solution to those patients who suffer from chronic joint ailments by reducing the progression of OA.