Miracle-dz/UniFAR-FTUs huggingface dataset:
Modeling the ACVR1R206H mutation in human skeletal muscle stem cells

Abnormalities in skeletal muscle repair can lead to poor function and complications such as scarring or heterotopic ossification (HO). Here, we use fibrodysplasia ossificans progressiva (FOP), a disease of progressive HO caused by ACVR1R206H (Activin receptor type-1 receptor) mutation, to elucidate how ACVR1 affects skeletal muscle repair. Rare and unique primary FOP human muscle stem cells (Hu-MuSCs) isolated from cadaveric skeletal muscle demonstrated increased extracellular matric (ECM) marker expression, showed skeletal muscle-specific impaired engraftment and regeneration ability. Human induced pluripotent stem cell (iPSC)-derived muscle stem/progenitor cells (iMPCs) single-cell transcriptome analyses from FOP also revealed unusually increased ECM and osteogenic marker expression compared to control iMPCs. These results show that iMPCs can recapitulate many aspects of Hu-MuSCs for detailed in vitro study; that ACVR1 is a key regulator of Hu-MuSC function and skeletal muscle repair; and that ACVR1 activation in iMPCs or Hu-MuSCs may contribute to HO by changing the local tissue environment.
Human Islet MicroRNA-200c is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion.

MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets is not clear. Here we report increased expression of miR-200c in islets from T2D as compared with non-diabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on protein level in EndoC-βH1 cells overexpressing miR-200c and Luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c (LNA200c) increased glucose-stimulated insulin secretion in islets from T2D donors ∼3-fold. Our data reveal a vital role of the miR-200c-ETV5 axis in beta cell dysfunction and pathophysiology of T2D.
Clinical importance of high-mannose, fucosylated, and complex N-glycans in breast cancer metastasis

BACKGROUND. Although aberrant glycosylation is recognized as a hallmark of cancer, glycosylation in clinical breast cancer (BC) metastasis has not yet been studied. While preclinical studies show that the glycocalyx coating of cancer cells is involved in adhesion, migration, and metastasis, glycosylation changes from primary tumor (PT) to various metastatic sites remain unknown in patients. METHODS. We investigated N-glycosylation profiles in 17 metastatic BC patients from our rapid autopsy program. Primary breast tumor, lymph node metastases, multiple systemic metastases, and various normal tissue cores from each patient were arranged on unique single-patient tissue microarrays (TMAs). We performed mass spectrometry imaging (MSI) combined with extensive pathology annotation of these TMAs, and this process enabled spatially differentiated cell-based analysis of N-glycosylation patterns in metastatic BC. RESULTS. N-glycan abundance increased during metastatic progression independently of BC subtype and treatment regimen, with high-mannose glycans most frequently elevated in BC metastases, followed by fucosylated and complex glycans. Bone metastasis, however, displayed increased core-fucosylation and decreased high-mannose glycans. Consistently, N-glycosylated proteins and N-glycan biosynthesis genes were differentially expressed during metastatic BC progression, with reduced expression of mannose-trimming enzymes and with elevated EpCAM, N-glycan branching, and sialyation enzymes in BC metastases versus PT. CONCLUSION. We show in patients that N-glycosylation of breast cancer cells undergoing metastasis occurs in a metastatic site–specific manner, supporting the clinical importance of high-mannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC. FUNDING. NIH grants R01CA213428, R01CA213492, R01CA264901, T32CA193145, Dutch Province Limburg “LINK”, European Union ERA-NET TRANSCAN2-643638.
Investigation of Serum Pregnancy-Specific Beta-1-Glycoprotein and Relationship with Fetal Growth Restriction

Objective The most used definition for fetal growth restriction (FGR) is a fetus whose estimated weight is below the 10th percentile for its gestational age. Pregnancy-specific beta-1-glycoprotein (PSG-1) is an immunomodulator found in maternal serum during pregnancy. This study aimed to determine the serum levels of PSG-1 and clarify the potential role of this molecule in the etiopathogenesis of FGR. Methods Eighty women carrying fetuses with FGR and 80 healthy pregnant women were included in the study. Demographic data, laboratory values, and Doppler Ultrasonography (USG) results of all cases were recorded. Venous blood samples were taken from all cases before birth. PSG-1 values were studied by the ELISA method. An Independent Samples T-test was used to evaluate the results. The correlations between parameters were evaluated based on Spearman's rank correlation coefficient. P-values <0.05 were considered statistically significant. Results When the groups were evaluated for serum PSG-1 levels, the median serum PSG-1 level was lower in pregnant women carrying fetuses with FGR than in controls (0.05 < p>0.10). Median serum PSG-1 was lower in patients with absent end diastolic flow (AEDF) in the umbilical artery in Doppler ultrasound scans than in patients without AEDF, but the difference was not statistically significant (p>0.05). In patients with serum PSG-1 values below 12.93 with 50% sensitivity and 76% specificity, the risk of FGR was higher. Conclusions Serum PSG-1 levels may be lower in complicated pregnancies due to problems related to placental insufficiency and FGR.
APPRIS: selecting functionally important isoforms

Abstract APPRIS (https://appris.bioinfo.cnio.es) is a well-established database housing annotations for protein isoforms for a range of species. APPRIS selects principal isoforms based on protein structure and function features and on cross-species conservation. Most coding genes produce a single main protein isoform and the principal isoforms chosen by the APPRIS database best represent this main cellular isoform. Human genetic data, experimental protein evidence and the distribution of clinical variants all support the relevance of APPRIS principal isoforms. APPRIS annotations and principal isoforms have now been expanded to 10 model organisms. In this paper we highlight the most recent updates to the database. APPRIS annotations have been generated for two new species, cow and chicken, the protein structural information has been augmented with reliable models from the EMBL-EBI AlphaFold database, and we have substantially expanded the confirmatory proteomics evidence available for the human genome. The most significant change in APPRIS has been the implementation of TRIFID functional isoform scores. TRIFID functional scores are assigned to all splice isoforms, and APPRIS uses the TRIFID functional scores and proteomics evidence to determine principal isoforms when core methods cannot.
Characterization of Treatment Modalities for Patients With Syndromic Craniosynostosis in Relation to Degree of Midface Hypoplasia and Patient’s Age Using Longitudinal Follow-Up Data

Abstract: The purpose of this study was to investigate the type and frequency of use of treatment modalities (Tx-Mods) in patients with syndromic craniosynostosis (SC) using longitudinal follow-up data. A total of 28 patients with SC (24 Crouzon, 2 Apert, and 2 Antley-Bixler syndromes), who were treated at the Department of Orthodontics, Seoul National University Dental Hospital, Seoul, South Korea between 1998 and 2020, was included. According to the degree of midface hypoplasia (MH) at the initial visit (T1), the patients were divided into the mild-MH (78°≤SNA < 80°, n = 8), moderate-MH (76≤SNA < 78°, n = 7), and severe-MH (SNA < 76°, n = 13) groups. T1-age and Tx-Mods, including cal-varial surgery (CALS), orthopedic treatment (OPT), fixed orthodontic treatment, and midface advancement surgery in childhood (MAS-child) and adulthood (MAS-adult), were investigated. Complexity of MAS-adult was graded as follows: 0, no surgery; 1, orthognathic surgery; 2, distraction osteogenesis (DOG); 3, combination of distraction osteogenesis and orthognathic surgery. Then, statistical analysis was performed. Percentage distribution of Tx-Mods was 71.4% in CALS, 21.4% in MAS-child, 42.9% in OPT, 100% in fixed orthodontic treatment, and 89.3% in MAS-adult. 92.9% of patients underwent MAS more than once. The number of MAS increased according to the severity of MH (P < 0.05). The complexity of MAS-adult increased as T1-age and severity of MH increased (all P < 0.05); whereas it decreased when CALS and OPT were performed (all P < 0.05). However, MAS in childhood did not guarantee the avoidance of additional MAS in adulthood (P > 0.05). These findings may be used as basic guidelines for successful treatment planning and prognosis prediction in patients with SC.
Diminished error-related negativity and error positivity in children and adults with externalizing problems and disorders: a meta-analysis on error processing

Background: Deficits in error processing are reflected in an inability of people with externalizing problems to adjust their problem behaviour. The present study contains 2 meta-analyses, testing whether error processing — indexed by the event-related potentials error-related negativity (ERN) and error positivity (Pe) — is reduced in children and adults with externalizing problems and disorders compared to healthy controls. Methods: We conducted a systematic search in PubMed (1980 to December 2018), PsycInfo (1980 to December 2018) and Scopus (1970 to December 2018), identifying 328 studies. We included studies that measured error processing using the Eriksen flanker task, the go/no-go task or the stop-signal task in healthy controls and in adults or children with clearly described externalizing behavioural problems (e.g., aggression) or a clinical diagnosis on the externalizing spectrum (e.g., addiction). Results: Random-effect models (ERN: 23 studies, 1739 participants; Pe: 27 studies, 1456 participants) revealed a reduced ERN amplitude (Hedges’ g = 0.44, 95% confidence interval [CI] 0.29 to 0.58) and a reduced Pe amplitude (Hedges’ g = −0.27, 95% CI −0.44 to −0.09) during error processing in people with externalizing problems or disorders compared to healthy controls. Type of diagnosis, age and the presence of performance feedback or comorbidity did not moderate the results. The employed cognitive task was a moderator for Pe but not for ERN. The go/no-go task generated a greater amplitude difference in Pe than the Eriksen flanker task. Small-sample assessment revealed evidence of publication bias for both event-related potentials. However, a p curve analysis for ERN showed that evidential value was present; for Pe, the p curve analysis was inconclusive. Limitations: The moderators did not explain the potential heterogeneity in most of the analysis, suggesting that other disorder- and patient-related factors affect error processing. Conclusion: Our findings indicate the presence of compromised error processing in externalizing psychopathology, suggesting diminished activation of the prefrontal cortex during performance monitoring.
Capacity Planning for Web Services: Metrics, Models, and Methods

From the Publisher: The #1 guide to Web capacity planning  now completely updated! A quantitative analysis of Web service availability An integrated coverage of benchmarking, load testing, workload forecasting, and performance modeling of Web services Example and case studies show how to use each technique in the latest Web services, portals, search engines, mobile and streaming-media applications A quantitative framework for planning the capacity of Web services and understanding their behavior The world's #1 book on Web capacity planning now covers the latest Web services, e-business, and mobile applications! Capacity Planning for Web Services: Metrics, Models, and Methods introduces quantitative performance predictive models for every major Web scenario, showing precisely how to identify and address both potential and actual performance problems. Coverage includes: Web services: protocols, interaction models, and unique performance, reliability, and availability challenges State-of-the-art capacity planning methodologies Spreadsheets implement the solutions of the models presenteed in the book Specific issues and workloads associated with HTTP and TCP/IP protocols Benchmarking current performance at system and component levels From accommodating current usage peaks to defining service provider SLAs, Daniel A. Menasce and Virgilio Almeida cover every aspect of capacity planning  helping you optimize every tradeoff between cost and performance. "This bookis the best guide available to understanding the uniqinvolved in delivering today's Web services. "  Mark Crovella,Associate Professor, Boston University; Technical Director, Network Appliance ". asuperb starting point for anyone wishing to explore the world of Web performance. "  Jeffrey P. Buzen, President of CMG; Co-Founder, BGS Systems "There is no other book like this. It is a first. "  Peter J. Denning, Professor of Computer Science, George Mason University and former President of the ACM "Web servers have bursty andhighly-skewed load characteristics. This book presents a new way tomodel, analyze, and plan for these new performance problems. "  Jim Gray, Senior Researcher, Microsoft Research; 1998 ACM Turing Award Recipient ". a welcome approach to the performance analysis of today'sWeb-based Internet. no simple and practical treatment has been offered before, andtheirs is a timely contribution. "  Leonard Kleinrock, Professor of Computer Science, UCLA; Chairman and Founder, Nomadix, Inc.
Current Status of the Hypothesis of a Claustro-Insular Homolog in Sauropsids

The author previously worked extensively on the broad problem of the evolution of the vertebrate pallium. He proposed various Bauplan models covering at least gnathostomes, based in the definition of a set of pallial sectors with topologically invariant positional relationships and distinct molecular profiles. Out of one of these models, presented as the “updated tetrapartite pallium model,” a modified definition of the earlier lateral pallium sector (LPall) concept emerged, characterizing it in mammals as an unitary claustro-insular transitional (mesocortical) complex intercalated between the neocortex or dorsal pallium (DPall) above and olfactory cortex or ventral pallium (VPall) underneath. A distinctive molecular marker of the early-born deep claustral component of the LPall was found to be the transcription factor Nr4a2, which is not expressed significantly in the overlying insular cortex or in adjoining cortical territories. Given that earlier comparative studies had identified molecularly and topologically comparable VPall, LPall, and DPall sectors in the avian pallium, an avian Nr4a2 probe was applied, aiming to identify the reportedly absent avian claustro-insular complex. An early-born superficial subpopulation of the avian LPall that expresses this marker selectively through development was indeed found. This was proposed to be a claustrum homolog, whereas the remaining Nr4a2-negative avian LPall cells were assumed to represent a possible insular homolog. This last notion was subsequently supported by comparable selective expression of the mouse insular marker Cyp26b, also found restricted to the avian LPall. Some published data suggested that similar molecular properties and structure apply at the reptilian LPall. This analysis was reviewed in Puelles et al. [The pallium in reptiles and birds in the light of the updated tetrapartite pallium model. 2017]. Four years on, the present commentary discusses some international publications accrued in the interval that touch on the claustro-insular homology hypothesis. Some of them are opposed to the hypothesis whereas others corroborate or support it. This raises a number of secondary issues of general interest.
A stem-loop RNA RIG-I agonist protects against acute and chronic SARS-CoV-2 infection in mice

A stem-loop RNA (SLR) RIG-I agonist is effective in preventing and treating acute SARS-CoV-2 infection in mice. A single injection of SLR can clear chronic SARS-CoV-2 in immunocompromised mice. SLR is effective against the ancestral virus as well as variants of concern.
Insulin-like growth factor 2 mRNA binding protein 2 regulates proliferation, migration, and angiogenesis of keratinocytes by modulating heparanase stability

ABSTRACT Wound healing is related to proliferation, migration, and angiogenesis of keratinocytes. Insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) is an important N6-methyladenosine (m6A) reader, which is involved in multiple processes, including wound healing. However, the function and mechanism of IGF2BP2 in keratinocyte processes are largely uncertain. In the present study, expression levels of IGF2BP2 and heparanase (HPSE) were detected by quantitative reverse transcription polymerase chain reaction and western blotting assays. Cell proliferation was investigated by cell counting kit-8 (CCK-8) analysis. Cell migration was determined through wound healing assay. Angiogenesis was measured by tube formation assay and vascular endothelial growth factor (VEGF) level using enzyme linked immunosorbent assay (ELISA). The interaction between IGF2BP2 and HPSE was analyzed by RNA immunoprecipitation, pull-down and luciferase reporter analyses. The results showed that IGF2BP2 expression was enhanced in wound healing. IGF2BP2 downregulation constrained HaCaT cell proliferation, migration, and angiogenesis. IGF2BP2 knockdown decreased HPSE expression. IGF2BP2 could regulate HPSE stability by binding with 3ʹ untranslated region (UTR) of HPSE. HPSE upregulation attenuated silencing IGF2BP2-mediated suppression of proliferation, migration, and angiogenesis. As a conclusion, IGF2BP2 knockdown repressed proliferation, migration, and angiogenesis of HaCaT cells by decreasing HPSE stability.
Probabilistic prediction of urban water consumption using the SCEM-UA algorithm

Prediction of urban water consumption can help to improve the performance of water distribution systems. Despite the obvious presence of uncertainty in measurements and in assumed model types/structures, most of the existing water consumption prediction models are developed and used in a deterministic context. Methods for more realistic assessment of parameter and model prediction uncertainties have begun to appear in literature only recently. A novel application of the Shuffled Complex Evolution Metropolis algorithm (SCEM-UA) for the calibration of a water consumption prediction model is proposed here. The model is applied to a case study of the city of Catania (Italy) with the aim to predict daily water consumption. The SCEM-UA algorithm is used to calibrate the parameters of the artificial neural network based prediction model and in turn to determine the associated parameter and model prediction uncertainties. The results obtained using the SCEM-UA ANN approach were compared to the corresponding results obtained using other predictive models developed recently by the authors of the paper. When compared to the these models, the SCEM-UA ANN based water consumption prediction model shows similar predictive capability but also the ability to identify simultaneously the prediction uncertainty bounds associated with the posterior distribution of the parameter estimates.
Quantifying the relationship between dapagliflozin and loss of weight in type 1 diabetes mellitus patients

Dapagliflozin was the first oral treatment approved in type 1 diabetes mellitus (T1DM) patients, simultaneously improving body weight. However, the time course and dose effect of dapagliflozin on loss of weight in T1DM patients was still unknown. The present study aimed to investigate quantitative relationship between dapagliflozin and loss of weight in T1DM patients based on Model‐based Meta‐analysis.
A novel DLL4 mutation in Adams–Oliver syndrome with absence of the right pulmonary artery in newborn

Adams–Oliver syndrome (AOS), a rare inherited disorder, is characterized by scalp and terminal limb defects. Several genes associated with Notch pathway mutations have led to AOS. Here, we report a Thai male newborn presenting with aplasia cutis congenita and absence of a right pulmonary artery, which is suggestive of AOS. This was confirmed by the identification of a novel missense mutation in DLL4, a heterozygous one base pair change at nucleotide 82 (c.82G>C, p.Gly28Arg), which is in N‐terminal domain. This is the first DLL4‐related AOS case with arterial defect.
Life-time Actionable Pharmacogenetic Drug Use: A Population-based Cohort Study in 86 040 Young People With and Without Mental Disorders in Denmark

Objective To describe life-time use of current actionable pharmacogenetic (PGx) somatic and psychotropic drugs according to international PGx consortia in people with and without hospital-diagnosed mental disorders in the Danish population. Methods Population- and register-based observational drug utilization study in 56 065 individuals with mental disorders, i. e. attention-deficit/hyperactivity disorder, autism, bipolar disorder, depression and schizophrenia, and a random, representative sample of 29 975 individuals of the Danish population, born between 1981 and 2005. Individuals were followed from 1995 or birth until 2016 (for a maximum of 22 years). We report prevalence and incidence rates of PGx drug use by age, sex and mental disorders based on redeemed prescriptions between 1995 and 2016. Results Of the 69 PGx drugs, prescriptions of 39 drugs had been redeemed by the study population by 35 years of age. The use of at least 1 PGx drug varied between 23.1% in males without mental disorders and 97.2% in females with schizophrenia. Males with ADHD or autism were the youngest first-time PGx drug users at a mean of 11.6 years. The mean number of different PGx drugs used was 1.2 in males without mental disorders and 5.6 in individuals with schizophrenia. The prevalence of different PGx drugs linked to more than one gene was 25.3% in males without mental disorders to 94.1% in females with schizophrenia. Conclusion PGx drugs are commonly used by younger people, more often by individuals with mental disorders and by females. Panel-based PGx testing could contribute to treatment decisions at a very young age.