Miracle-dz/UniFAR-FTUs huggingface dataset:
Detoxification vs non-detoxification before starting an anti-CGRP monoclonal antibody in medication overuse headache

Abstract Background Medication overuse headache significantly contributes to the chronification process and treatment refractoriness of migraine. Currently, abrupt discontinuation of the overused medication still represents the best management strategy for these patients, challenging public health system resources. Methods In this prospective study, chronic migraine and medication overuse headache sufferers with at least 28 days of analgesic consumption per month were included. Assessment of efficacy outcomes at three months were compared among patients who underwent in-hospital abrupt discontinuation of overused acute medication (YES-DETOX group) and patients who did not (NO-DETOX group) before starting an anti-CGRP monoclonal antibody. Results Of 401 patients who received either erenumab or galcanezumab, 28% (n = 111) satisfied inclusion criteria (YES-DETOX n = 28; NO-DETOX n = 83). After three months of treatment, 59% (n = 65; 47/83 YES-DETOX; 18/28 NO-DETOX) patients reverted from medication overuse headache and 51% (n = 57; 42/83 YES-DETOX; 15/28 NO-DEOTX) achieved ≥50% reduction in monthly headache days; yet no statistical differences were observed between the two groups (p = 0.4788 and p = 0.8393, respectively). Monthly consumption of pain medication was the only baseline prognostic factor in multivariate analysis in the overall cohort (p = 0.016). Conclusion Our results support the emerging evidence that anti-CGRP monoclonal antibodies may be effective in medication overuse headache patients irrespective of detoxification, yet further studies are needed to draw definitive conclusions.
Evidence of islet CADM1-mediated immune cell interactions during human type 1 diabetes

BACKGROUND Pathophysiology of type 1 diabetes (T1D) is illustrated by pancreatic islet infiltration of inflammatory lymphocytes, including CD8+ T cells; however, the molecular factors mediating their recruitment remain unknown. We hypothesized that single-cell RNA-sequencing (scRNA-Seq) analysis of immune cell populations isolated from islets of NOD mice captured gene expression dynamics providing critical insight into autoimmune diabetes pathogenesis. METHODS Pancreatic sections from human donors were investigated, including individuals with T1D, autoantibody-positive (aAb+) individuals, and individuals without diabetes who served as controls. IHC was performed to assess islet hormones and both novel and canonical immune cell markers that were identified from unbiased, state-of-the-art workflows after reanalyzing murine scRNA-Seq data sets. RESULTS Computational workflows identified cell adhesion molecule 1–mediated (Cadm1-mediated) homotypic binding among the most important intercellular interactions among all cell clusters, as well as Cadm1 enrichment in macrophages and DCs from pancreata of NOD mice. Immunostaining of human pancreata revealed an increased number of CADM1+glucagon+ cells adjacent to CD8+ T cells in sections from T1D and aAb+ donors compared with individuals without diabetes. Numbers of CADM1+CD68+ peri-islet myeloid cells adjacent to CD8+ T cells were also increased in pancreatic sections from both T1D and aAb+ donors compared with individuals without diabetes. CONCLUSION Increased detection of CADM1+ cells adjacent to CD8+ T cells in pancreatic sections of individuals with T1D and those who were aAb+ validated workflows and indicated CADM1-mediated intercellular contact may facilitate islet infiltration of cytotoxic T lymphocytes and serve as a potential therapeutic target for preventing T1D pathogenesis. FUNDING The Johns Hopkins All Children’s Foundation Institutional Research Grant Program, the National Natural Science Foundation of China (grant 82071326), and the Deutsche Forschungsgemeinschaft (grants 431549029–SFB1451, EXC2030–390661388, and 411422114-GRK2550).
Downregulation of sperm-associated antigen 5 inhibits melanoma progression by regulating forkhead box protein M1/A disintegrin and metalloproteinase 17/NOTCH1 signaling

ABSTRACT Sperm-associated antigen 5 (SPAG5) has been identified as a driver in several type of cancers. In this study, we aimed to reveal the role of SPAG5 in melanoma and clarify whether FOXM1 (forkhead box protein M1) /ADAM17 (A disintegrin and metalloproteinase 17) /NOTCH1 signaling was involved. The expression of SPAG5 in malignant melanoma (MM) tissues and matched normal tissues was detected using qRT-PCR, immunohistochemistry and Western blotting. Cell viability was tested using CCK-8 (Cell Count Kit-8), colony formation and EdU staining. Cell migration and epithelial to mesenchymal transition (EMT) were measured using transwell chambers and immunofluorescent staining. Cell cycle distribution and tumorigenesis were assessed by flow cytometry and in vivo tumor-bearing experiments, respectively. The results demonstrated that the expression of SPAG5 was increased in MM tissues and cells. Downregulation of SPAG5 inhibited cell viability, migration, invasion and EMT, and induced a G1-phase arrest. In addition, downregulation of SPAG5 decreased the expression of FOXM1, thereafter inhibiting the expression of ADAM17, NOTCH1 and HES1. Furthermore, deletion of SPAG5 expression decreased the tumorigenesis of MM A375 cells. In conclusion, this study demonstrated that SPAG5 was overexpressed in MM. Downregulation of SPAG5 repressed MM cell growth and EMT, which might be induced by inactivation of the FOXM1/ADAM17/NOTCH1 signaling. Graphical abstract
Changes in anemia and anthropometry during adolescence predict learning outcomes: findings from a 3-year longitudinal study in India

ABSTRACT Background Anemia and poor physical growth during adolescence have far-ranging consequences, but limited longitudinal evidence exists on how changes in these factors relate to changes in learning skills as adolescents mature. Objectives We examined the association between changes in anemia and physical growth during adolescence and learning outcomes. Methods We used longitudinal data from the Understanding the Lives of Adolescents and Young Adults (UDAYA) project, which surveyed adolescents aged 10–19 y in northern India in 2015–2016 and 2018–2019 (n = 5963). We used multilevel mixed-effects logistic regression models to examine associations between changes in anemia/thinness/stunting status (4 groups: never, improved, new, and persistent) and reading (ability to read a story) and math proficiency (ability to solve division problems) at follow-up. Results Persistent anemia and stunting were higher among girls than among boys (46% compared with 8% and 37% compared with 14%, respectively), but persistent thinness was lower (7% compared with 16%). Improvement in anemia, thinness, and stunting was 1.4–1.7 times higher among boys than among girls. Boys who were anemic in both waves were 74% [adjusted odds ratio (AOR): 0.26; 95% CI: 0.12, 0.59] and 65% (AOR: 0.35; 95% CI: 0.16, 0.76) less likely to be able to read a story and solve division problems, respectively, than boys who were nonanemic in both waves. Persistent thinness in boys was negatively associated with both reading (AOR: 0.37; 95% CI: 0.21, 0.66) and math proficiency (AOR: 0.27; 95% CI: 0.16, 0.46). Persistent stunting contributed to lower reading and math proficiency in boys and girls (AORs: 0.29–0.46). Boys whose anemia or thinness status improved and girls whose stunting status improved had similar learning skills at follow-up as those who were never anemic/thin/stunted. Conclusions Persistent anemia, thinness, and short stature during adolescence were associated with poor learning. Programs targeted at adolescents should contribute to nurturing environments that foster healthy growth and learning.
Grape seed tannin extract and polyunsaturated fatty acids affect in vitro ruminal fermentation and methane production.

Condensed tannins (CT), one of the most ubiquitous compounds in the plant kingdom, can modulate ruminal nutrient metabolism. Objectives were to study potential interactions of CT and polyunsaturated fatty acids (PUFA) on ruminal fermentation, biohydrogenation (BH), and methane production. Ruminal fluid obtained from lactating Holstein Friesian cows was used. All experiments were carried out as a completely randomized design with the same mixed diet: control (60:40 forage:concentrate) without supplement (CON), 2.5% soybean oil (SBO), and SBO + grape seed tannin extract (GSTE) at 0.2, 0.4, 0.6 or 0.8% dietary DM (ST0.2, ST0.4, ST0.6 and ST0.8, respectively). Compared with CON (84.7 mM), total VFA concentration was not affected by SBO, but decreased (P < 0.001) with ST0.8 vs. ST0.6 (75.3 vs. 78.3 mM). Relative to CON, methane production was depressed (P < 0.001) by 17.7 and 28.0% in ST0.4 and ST0.8. The highest (P < 0.001) mean concentrations of c9,t11 CLA and C18:1 t11 were observed with ST0.4 compared with CON, but there was no difference between SBO and CT-containing diets. Disappearance of C18:2 c9,c12 was 49.1 vs. 50.3% in CON vs. SBO while it ranged from 39.9-46.3% in CT-containing diets after 2 h incubation (P < 0.001). Concentrations of c9,t11 CLA with supplemental SBO and ST0.8 nearly peaked (P < 0.001) at 2 h incubation, but this fatty acid peaked (P > 0.05) at 6 h incubation and remained higher (P < 0.001) (15.9-17.0 µg/mL) at 24 h incubation with ST0.2, ST0.4 and ST0.6 compared with other diets (13.5-14.5 µg/mL). Compared with CON (50.6 µg/mL), concentration of C18:1 t11 with SBO and CT-containing diets reached a peak (P < 0.001) (241-265 µg/mL) at 12 h incubation. Concentration of C18:0 was 171-231% higher (P < 0.001) with SBO and CT relative to CON at 24 h incubation. Overall, these results demonstrated that PUFA in SBO are more effective in modulating ruminal BH and CH4 production when combined with CT. However, high doses of added CT can reduce ruminal VFA concentration. Thus, a level of 0.4% GSTE added to diets containing 2.5% PUFA from plant origin might be suitable for optimizing ruminal fermentation and BH of C18:2 c9,c12 to fatty acid intermediates that could have beneficial effects to human health.
Circular RNA circCHFR downregulation protects against oxidized low-density lipoprotein-induced endothelial injury via regulation of microRNA-15b-5p/growth arrest and DNA damage inducible gamma

ABSTRACT Atherosclerosis is the leading cause of coronary heart disease. In recent years, circ_0029589 (circCHFR) has been found to be associated with atherosclerosis development. However, the molecular mechanism of circCHFR action in atherosclerosis development is unknown. This study was aimed to investigate the function and action mechanism of circCHFR in atherosclerosis development. An atherosclerosis cell model was created by exposing human vascular endothelial cells (HUVECs) to oxidized low-density lipoprotein. The expression of circCHFR, microRNA(miR)-15b-5p, growth arrest and DNA damage inducible gamma (GADD45G), and their associated proteins was evaluated using quantitative reverse transcription-polymerase chain reaction and Western blotting. Additionally, cell viability, apoptosis, and cytokine levels were determined using Cell Counting Kit-8 (CCK8) assay, flow cytometry, and enzyme-linked immunosorbent assay, respectively. circCHFR expression was upregulated in patients with atherosclerosis and oxidized low-density lipoprotein (ox-LDL)-exposed HUVECs, whereas miR-15b-5p expression was downregulated. circCHFR silencing significantly improved viability and reduced apoptosis of HUVECs. In addition, the pro-apoptotic protein Bax and atherosclerosis-associated cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α) were significantly downregulated, whereas the anti-apoptotic protein Bcl-2 was upregulated. Further, we discovered that circCHFR serves as a molecular sponge of miR-15b-5p. GADD45G was found to be an important target of miR-15b-5p; miR-15b-5p mimic inhibited GADD45G expression, reduced apoptosis and proinflammatory cytokine secretion, and improved cell survival. However, these effects of miR-15b-5p on (ox-LDL) induced HUVECs were reversed with GADD45G plasmid co-transfection. In conclusion, circCHFR promotes atherosclerosis progression via the miR-15b-5p/GADD45G axis and may be an important target for atherosclerosis treatment.
Prognostic significance of serum chloride level in heart failure patients with preserved ejection fraction

The prognostic value of serum chloride level has been reported primarily in patients with heart failure with reduced ejection fraction, and hence, there is limited evidence in patients of heart failure with preserved ejection fraction (HFpEF). This study was conducted to clarify the relationship between serum chloride level and clinical outcomes in patients with HFpEF with acute decompensated heart failure (ADHF).
Gene manipulation in the Mucorales fungus Rhizopus oryzae using TALENs with exonuclease overexpression

Abstract The Mucorales fungal genus Rhizopus is used for the industrial production of organic acids, enzymes and fermented foods. The metabolic engineering efficiency of Rhizopus could be improved using gene manipulation; however, exogenous DNA rarely integrates into the host genome. Consequently, a genetic tool for Mucorales fungi needs to be developed. Recently, programmable nucleases that generate DNA double-strand breaks (DSBs) at specific genomic loci have been used for genome editing in various organisms. In this study, we examined gene disruption in Rhizopus oryzae using transcription activator-like effector nucleases (TALENs), with and without exonuclease overexpression. TALENs with an overexpressing exonuclease induced DSBs, followed by target site deletions. Although DSBs are repaired mainly by nonhomologous end joining in most organisms, our results suggested that in R. oryzae microhomology-mediated end joining was the major DSB repair system. Our gene manipulation method using TALENs coupled with exonuclease overexpression contributes to basic scientific knowledge and the metabolic engineering of Rhizopus.
The Interferon-Inducible Human PLSCR1 Protein Is a Restriction Factor of Human Cytomegalovirus

Because several IFN-stimulated genes (ISGs) have been reported to suppress HCMV replication, HCMV replication is thought to be regulated by an IFN-mediated host defense mechanism, but the mechanism remains unclear. PLSCR1 expression is induced in response to viral infection and IFN treatment, and PLSCR1 has been reported to play an important role in IFN-dependent antiviral responses. ABSTRACT Human phospholipid scramblase 1 (PLSCR1) is strongly expressed in response to interferon (IFN) treatment and viral infection, and it has been suggested to play an important role in IFN-dependent antiviral responses. In this study, we showed that the levels of human cytomegalovirus (HCMV) plaque formation in OUMS-36T-3 (36T-3) cells with high basal expression of PLSCR1 were significantly lower than those in human embryonic lung (HEL) cells with low basal expression of PLSCR1. In addition, the levels of HCMV plaque formation and replication in PLSCR1-knockout (KO) 36T-3 cells were significantly higher than those in parental 36T-3 cells and were comparable to those in HEL cells. Furthermore, compared to that in PLSCR1-KO cells, the expression of HCMV major immediate early (MIE) proteins was repressed and/or delayed in parental 36T-3 cells after HCMV infection. We also showed that PLSCR1 expression decreased the levels of the cAMP-responsive element (CRE)-binding protein (CREB)•HCMV immediate early protein 2 (IE2) and CREB-binding protein (CBP)•IE2 complexes, which have been suggested to play important roles in the IE2-mediated transactivation of the viral early promoter through interactions with CREB, CBP, and IE2. Interestingly, PLSCR1 expression repressed CRE- and HCMV MIE promoter-regulated reporter gene activities. These observations reveal, for the first time, that PLSCR1 negatively regulates HCMV replication by repressing the transcription from viral MIE and early promoters, and that PLSCR1 expression may contribute to the IFN-mediated suppression of HCMV infection. IMPORTANCE Because several IFN-stimulated genes (ISGs) have been reported to suppress HCMV replication, HCMV replication is thought to be regulated by an IFN-mediated host defense mechanism, but the mechanism remains unclear. PLSCR1 expression is induced in response to viral infection and IFN treatment, and PLSCR1 has been reported to play an important role in IFN-dependent antiviral responses. Here, we demonstrate that HCMV plaque formation and major immediate early (MIE) gene expression are significantly increased in PLSCR1-KO human fibroblast cells. PLSCR1 reduces levels of the CREB•IE2 and CBP•IE2 complexes, which have been suggested to play important roles in HCMV replication through its interactions with CREB, CBP, and IE2. In addition, PLSCR1 expression represses transcription from the HCMV MIE promoter. Our results indicate that PLSCR1 plays important roles in the suppression of HCMV replication in the IFN-mediated host defense system.
Respiratory reoxidation of NADH is a key contributor to high oxygen requirements of oxygen-limited cultures of Ogataea parapolymorpha

Abstract While thermotolerance is an attractive trait for yeasts used in industrial ethanol production, oxygen requirements of known thermotolerant species are incompatible with process requirements. Analysis of oxygen-sufficient and oxygen-limited chemostat cultures of the facultatively fermentative, thermotolerant species Ogataea parapolymorpha showed its minimum oxygen requirements to be an order of magnitude larger than those reported for the thermotolerant yeast Kluyveromyces marxianus. High oxygen requirements of O. parapolymorpha coincided with a near absence of glycerol, a key NADH/NAD+ redox-cofactor-balancing product in many other yeasts, in oxygen-limited cultures. Genome analysis indicated absence of orthologs of the Saccharomyces cerevisiae glycerol-3-phosphate-phosphatase genes GPP1 and GPP2. Co-feeding of acetoin, whose conversion to 2,3-butanediol enables reoxidation of cytosolic NADH, supported a 2.5-fold increase of the biomass concentration in oxygen-limited cultures. An O. parapolymorpha strain in which key genes involved in mitochondrial reoxidation of NADH were inactivated did produce glycerol, but transcriptome analysis did not reveal a clear candidate for a responsible phosphatase. Expression of S. cerevisiae GPD2, which encodes NAD+-dependent glycerol-3-phosphate dehydrogenase, and GPP1 supported increased glycerol production by oxygen-limited chemostat cultures of O. parapolymorpha. These results identify dependence on respiration for NADH reoxidation as a key contributor to unexpectedly high oxygen requirements of O. parapolymorpha.
Selection and evaluation of suitable reference genes for quantitative gene expression analysis during infection of Cucumis sativus with Pectobacterium brasiliense

Bacterial soft rot caused by Pectobacterium brasiliense (Pbr) has resulted in severe economic losses of cucumber production in northern China. Quantitative reverse transcription PCR (RT‐qPCR) is widely used to determine the fold change in the expression of genes of interest, and an appropriate reference gene played a critical role in the evaluation of genes expression. However, the suitable reference genes for transcript normalization during the interaction between cucumber and Pbr have not yet been systematically validated. In this study, we aimed to identify the suitable reference genes for accurate and reliable normalization of cucumber and Pbr RT‐qPCR data.
Racial Disparities in Diabetes-Related Emergency Department Visits and Hospitalizations Among Cancer Survivors

PURPOSE: Black and Hispanic individuals with diabetes receive less recommended diabetes care after cancer diagnosis than non-Hispanic Whites (NHW). We sought to determine whether racial/ethnic minorities with diabetes and cancer were at increased risk of diabetes-related emergency department (ED) visits and hospitalizations compared with NHW. METHODS: Using SEER cancer registry data linked to Medicare claims from 2006 to 2014, we included Medicare beneficiaries age 66+ years diagnosed with incident nonmetastatic breast, prostate, or colorectal cancer between 2007 and 2012 who had diabetes. Our primary outcome was any diabetes-related ED visit or hospitalization 366-731 days after cancer diagnosis. Using Fine-Gray subdistribution hazard models, we examined whether risk of ED visits or hospitalizations was higher for racial/ethnic minorities compared with NHW. RESULTS: We included 40,059 beneficiaries with mean age 75.5 years (standard deviation 6.3), 45.6% were women, and 28.9% were non-White. Overall, 825 (2.1%) had an ED visit and 3,324 (8.3%) had a hospitalization related to diabetes in the 366-731 days after cancer diagnosis. Compared with NHW, Black individuals were more likely to have ED visits (2.9% v 2.0%; P < .0001) and hospitalizations (11.7% v 7.8%; P < .0001). Adjusting for potential confounders, Black (adjusted hazard ratio, 1.22; 95% CI, 1.12 to 1.35) individuals had a higher risk of any ED visit or hospitalization compared with NHW. CONCLUSION: Black individuals with diabetes and cancer were at increased risk for diabetes-related ED visits and hospitalizations in the second year after cancer diagnosis compared with NHW even after accounting for confounders. Black cancer survivors face an increased risk of ED visits and hospitalization for diabetes in the second year after cancer diagnosis compared with Whites.
The incorporation of β-tricalcium phosphate nanoparticles within silk fibroin composite scaffolds for enhanced bone regeneration: An in vitro and in vivo study

To investigate the osteogenesis of β-tricalcium phosphate nanoparticles-incorporated silk fibroin (SF/β-TCP) composite scaffolds, SF-based scaffolds with different β-TCP proportion (2/1, 1/1, and 1/2) were fabricated by freeze-drying technology in the present study. Structural and physicochemical properties of SF-based scaffolds were evaluated by using scanning electron microscope, X-ray diffraction, Fourier transformed infrared spectroscopy (ATR-FTIR) and transmission electron microscope. Biocompatibility and osteogenesis of SF/β-TCP scaffolds were investigated by using bone marrow mesenchymal stem cells (BMSCs). Eight New Zealand rabbits were selected, while four 8-mm-diameter calvarial defects were created in each rabbit to place SF/β-TCP scaffolds. The harvested specimens at 4 and 12 weeks were used to evaluate the bone forming ability by micro-CT and histological examination. The results suggested incorporation of β-TCP displayed flake-like pore morphology with proper pore sizes. With the increasing proportion of β-TCP, composite scaffolds exhibited higher compressive strength, lower swelling ratio and degradation rate, as well as enhanced biomineralization capacity. Alkaline phosphatase activity and collagen type I expression levels of BMSCs were significantly increased in the presence of β-TCP nanoparticles. All composite scaffolds with different β-TCP proportion had good bone formation ability at 12 weeks. Among them, SF/β-TCP (1/2) scaffold exhibited the favorable osteogenesis capability which had great potential for applications in bone regeneration.
Truncal‐based perforator flaps for autologous breast reconstruction: A review of 975 flaps and their clinical application

When autologous breast reconstruction is desired and deep inferior epigastric artery perforator (DIEP) flap is inadequate or unavailable, other perforator flaps in the truncal region should not be disregarded. This study aimed to review all truncal‐based perforator flaps used for autologous breast reconstruction to identify clinical indications and outcomes of alternate perforator flaps.