Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiac Alternans: Mechanisms and Clinical Utility in Arrhythmia Prevention

S udden cardiac death (SCD) is frequently the initial manifestation of a cardiac arrhythmia, resulting in about 350 000 deaths annually in the United States. Devices such as the implantable cardioverter-defibrillator (ICD) seek to restore normal rhythm and may abort SCD. However, given the complex spatiotemporal dynamics of cardiac electrophysiology, predicting the onset of an arrhythmia and preventing the transition from a stable to an unstable rhythm is highly challenging. Deciphering the mechanisms that lead to an unstable heart rhythm and developing therapies to prevent unstable rhythms is an urgent clinical need. In 1908, Heinrich Hering first described ECG alternans, a pattern of beat-to-beat oscillation in the ECG waveform. Subsequently, repolarization alternans (RA), or alternans that manifests during ventricular repolarization, has been associated with an increased risk for ventricular tachyarrhythmic events (VTEs) and SCD under a wide range of pathophysiologic substrates including ischemic and nonischemic cardiomyopathy and recent acute coronary syndromes. RA may also be seen in structurally normal hearts under conditions of significant metabolic stress and chronotropic stimulation. Early pioneering work has shown that different regions of the heart may alternate out of phase to form spatially discordant RA, and that phenomenon alone was a key factor promoting arrhythmogenesis by predisposing the heart to reentrant wave propagation. Furthermore, in in silico studies, it was demonstrated that spatially discordant alternans led to markedly increased dispersion in repolarization (DR) that formed an ideal substrate for an ectopic trigger beat to instigate spiral-wave breakups leading to the onset of lethal arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF). This review provides a contemporary perspective of the subcellular and cellular mechanisms that give rise to cardiac alternans and potential therapeutic approaches based on this mechanistic understanding.
The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist for long periods in the human body has been a controversial question. The objective of this study was to see if we could find B. burgdorferi in a Lyme disease patient after a long clinical course and after long-term antibiotic treatment. Therefore, we investigated the potential presence of B. burgdorferi antigens and DNA in human autopsy tissues from a well-documented serum-, PCR-, and culture-positive Lyme disease patient, a 53-year-old female from northern Westchester County in the lower Hudson Valley Region of New York State, who had received extensive antibiotic treatments during extensive antibiotic treatments over the course of her 16-year-long illness. We also asked what form the organism might take, with special interest in the recently found antibiotic-resistant aggregate form, biofilm. We also examined the host tissues for the presence of inflammatory markers such as CD3+ T lymphocytes. Autopsy tissue sections of the brain, heart, kidney, and liver were analyzed by histological and immunohistochemical methods (IHC), confocal microscopy, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), and whole-genome sequencing (WGS)/metagenomics. We found significant pathological changes, including borrelial spirochetal clusters, in all of the organs using IHC combined with confocal microscopy. The aggregates contained a well-established biofilm marker, alginate, on their surfaces, suggesting they are true biofilm. We found B. burgdorferi DNA by FISH, polymerase chain reaction (PCR), and an independent verification by WGS/metagenomics, which resulted in the detection of B. burgdorferi sensu stricto specific DNA sequences. IHC analyses showed significant numbers of infiltrating CD3+ T lymphocytes present next to B. burgdorferi biofilms. In summary, we provide several lines of evidence that suggest that B. burgdorferi can persist in the human body, not only in the spirochetal but also in the antibiotic-resistant biofilm form, even after long-term antibiotic treatment. The presence of infiltrating lymphocytes in the vicinity of B. burgdorferi biofilms suggests that the organism in biofilm form might trigger chronic inflammation.
Copy Number Variation of Multiple Genes in SAPHO Syndrome

Objective. SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a type of rare chronic aseptic inflammation of unknown etiology. To date, no research to our knowledge has reported copy number variation (CNV) of genes that could affect predisposition to SAPHO syndrome. We investigated the association between CNV profile and SAPHO syndrome. Methods. We used array comparative genomic hybridization (CGH) to screen for CNV in a nuclear family including 2 patients and a healthy control. We then validated the copy numbers of candidate genes found in the array CGH assay and other candidate genes by TaqMan real-time PCR in 360 case and control samples. Results. Ten regions from 8 chromosomes were found to have abnormal gene copies in the nuclear family, so the CNV of candidate genes (ADAM5, CSF2RA, IL3RA, and 9 other genes) were tested by TaqMan PCR. Significant copy number loss of CSF2RA (p = 0.000) and NOD2 (p = 0.005), and significant copy number gain of MEGF6 (p = 0.002) and ADAM5 (p = 0.000) were seen in patients with SAPHO compared with controls at the a = 0.05 level. There were no differences in the other 8 candidate genes between patient and control samples (p > 0.05). Conclusion. Our study established the first association between CNV in CSF2RA, NOD2, MEGF6, and ADAM5 and SAPHO syndrome. These findings may offer insight into the pathogenesis of SAPHO and provide the basis for improved diagnosis and treatment.
Uncanny Valley Effects on Friendship Decisions in Virtual Social Networking Service

Drawing on the uncanny valley effects (UVE) hypothesis and related works on avatar-based interactions, this study investigates the role of UVE (i.e., a feeling of eeriness), induced by avatar realism and animacy, on the perceived trustworthiness (PT) of an avatar user, and subsequent decisions to befriend that avatar user in a virtual social networking service (SNS). Specifically, the current study examines whether (1) the realism (hyperrealistic vs. cartoonish) and animacy (animate vs. still) of avatars, rendered through a 3D scanning technology, will induce a feeling of eeriness as a result of UVE; (2) the degree to which perceivers experience a feeling of eeriness will negatively bias the PT of an avatar user; and (3) PT, determined by UVE, will serve a role as a gating mechanism for the decision whether to befriend the unknown avatar user in a virtual SNS. Results from a two (realism: cartoonish vs. hyperrealistic) × two (animacy: still vs. animate) between-subjects online experiment (N = 134) indicated that a feeling of eeriness, induced by the realism and animacy of avatars, negatively biased the PT of the avatar user, and this, in turn, led avatar perceivers to reject a friend request sent from the unknown avatar user. These results call into the question the effectiveness of rendering avatar realism in social virtual environments. Overall, the findings of our research provide theoretical as well as practical implications for the design of avatars in virtual SNSs.
High Fidelity Deep Sequencing Reveals No Effect of ATM, ATR, and DNA-PK Cellular DNA Damage Response Pathways on Adenovirus Mutation Rate

Most DNA viruses exhibit relatively low rates of spontaneous mutation. However, the molecular mechanisms underlying DNA virus genetic stability remain unclear. In principle, mutation rates should not depend solely on polymerase fidelity, but also on factors such as DNA damage and repair efficiency. Most eukaryotic DNA viruses interact with the cellular DNA damage response (DDR), but the role of DDR pathways in preventing mutations in the virus has not been tested empirically. To address this goal, we serially transferred human adenovirus type 5 in cells in which the telangiectasia-mutated PI3K-related protein kinase (ATM), the ATM/Rad3-related (ATR) kinase, and the DNA-dependent protein kinase (DNA-PK) were chemically inactivated, as well as in control cells displaying normal DDR pathway functioning. High-fidelity deep sequencing of these viral populations revealed mutation frequencies in the order of one-millionth, with no detectable effect of the inactivation of DDR mediators ATM, ATR, and DNA-PK on adenovirus sequence variability. This suggests that these DDR pathways do not play a major role in determining adenovirus genetic diversity.
Tumor-derived extracellular vesicles: molecular parcels that enable regulation of the immune response in cancer

ABSTRACT Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound vesicles released by cells that contain bioactive cargoes including proteins, lipids and nucleic acids. Multiple subpopulations of EVs have now been recognized and these include exosomes and microvesicles. EVs have been thought to facilitate intercellular and distal communication to bring about various processes that enable tumor progression and metastases. Here, we describe the current knowledge of the functional cargo contained within EVs, with a focus on tumor microvesicles, and review the emerging theory of how EVs support immune suppression in cancer. Summary: This article reviews current literature on cargoes contained within extracellular vesicles (EVs) and the emerging theory of how they support immune suppression in cancer.
Failed B cell survival factor trials support the importance of memory B cells in multiple sclerosis

Clinical trials are probably the most informative experiments to help an understanding of multiple sclerosis (MS) biology. Recent successes with CD20‐depleting antibodies have focused attention towards B cell subsets as important mediators in MS. The trial of tabalumab (NTC00882999), which inhibits B cell activation factor (BAFF), is reported and reviewed and this trial is contrasted with the trial on the inhibition of a proliferation‐inducing ligand (APRIL) and BAFF using atacicept (NCT00642902). Both tabalumab and atacicept induce depletion of mature B cells and inhibit antibody formation, but they fail to deplete memory B cells and do not inhibit relapsing MS. Atacicept is reported to augment memory B cell responses and may precipitate relapse, suggesting the importance of APRIL. However, BAFF inhibition can enhance peripheral blood memory B cell responses, which was not associated with augmented relapse. Although other interpretations are possible, these data further support the hypothesis that memory B cells may be of central importance in relapsing MS, as they are the major CD20+ B cell subset expressing APRIL receptors. They also suggest that quantitative and/or qualitative differences in B cell responses or other factors, such as an immune‐regulatory effect associated with APRIL, may be important in determining whether MS reactivates following neutralization of peripheral B cell maturation and survival factors.
Genomic Analysis of Dysembryoplastic Neuroepithelial Tumor Spectrum Reveals a Diversity of Molecular Alterations Dysregulating the MAPK and PI3K/mTOR Pathways.

Dysembryoplastic neuroepithelial tumors (DNT) lacking key diagnostic criteria are challenging to diagnose and sometimes fall into the broader category of mixed neuronal-glial tumors (MNGT) or the recently described polymorphous low-grade neuroepithelial tumor of the young (PLNTY). We examined 41 patients with DNT, MNGT, or PLNTY for histologic features, genomic findings, and progression-free survival (PFS). Genomic analysis included sequence and copy number variants and RNA-sequencing. Classic DNT (n = 26) was compared with those with diffuse growth without cortical nodules (n = 15), 6 of which exhibited impressive CD34 staining classifying them as PLNTY. Genomic analysis was complete in 33, with sequence alterations recurrently identified in BRAF, FGFR1, NF1, and PDGFRA, as well as 7 fusion genes involving FGFR2, FGFR1, NTRK2, and BRAF. Genetic alterations did not distinguish between MNGTs, DNTs, or PLNTYs; however, FGFR1 alterations were confined to DNT, and PLNTYs contained BRAF V600E or FGFR2 fusion genes. Analysis of PFS showed no significant difference by histology or genetic alteration; however, numbers were small and follow-up time short. Further molecular characterization of a PLNTY-related gene fusion, FGFR2-CTNNA3, demonstrated oncogenic potential via MAPK/PI3K/mTOR pathway activation. Overall, DNT-MNGT spectrum tumors exhibit diverse genomic alterations, with more than half (19/33) leading to MAPK/PI3K pathway alterations.
Crisis in the schools : crisis, crisis intervention training, and school counselor burnout

"In the course of a school year, schools may face a number of crisis situations, including suicidality, child abuse and neglect, violence, and natural disasters that may impact individual students or create school-wide crises (Collins & Collins, 2005; Mathai, 2002). Each of these crises can pose a threat to student and school safety and, therefore, requires swift and precise action. In addition to the potential lethality of these situations, they also can take an emotional toll on school personnel, potentially leading to increased levels of burnout (Collins & Collins). Despite the prevalence of crisis situations in schools, there is a dearth of literature referencing school crisis intervention. To date, researchers have not considered important issues such as training in crisis intervention, adequacy of preparation, and self-perceived skills that are necessary to provide crisis intervention in the schools. Because schools serve as the primary provider of child and adolescent mental health services (Burns et al. 1995; Hoagwood & Erwin, 1997), limited training in crisis intervention may leave the professional school counselor less than adequately prepared for the crises they encounter in their schools (Allen et al., 2002). The current study examined the impact of crisis related issues (type, frequency, and training) on school counselor burnout in order to describe any potential links between level and perceived adequacy of training, perception of crisis intervention efficacy, frequency of crises encountered, self-perceived crisis intervention skills, and level of burnout experienced. Specifically, results indicated that school counselors worked with a variety of individual crisis situations multiple times during the previous year, but may have gaps in their training experiences regarding crisis topics. On average, participants found crisis training helpful, and some types of crisis training were negatively correlated with levels of burnout. Findings of this study may inform further research on the potential relationships between crisis training, crisis frequency, and school counselor burnout. Counselor educators and school counselors may use these findings to explore ways to best prepare school counselors for crisis intervention. This exploration may ultimately help current and future school counselors both provide effective crisis intervention and prevent their own burnout. "--Abstract from author supplied metadata.
Assessment of crustal element and trace metal concentrations in atmospheric particulate matter over a coastal city in the Eastern Arabian Sea

ABSTRACT Major/crustal elements (Al, Ca, Mg, K, and Fe) and trace metals (Mn, Cr, Cu, Pb, Zn, and Ni) in atmospheric particulate matter at three sites in Goa (a coastal city in the Eastern Arabian Sea) were assessed during winter (December) and summer (March–May) months of 2015. A significant spatial and temporal variability was observed in PM10 mass concentration, crustal element, and trace metal composition at the sampling area (pristine, urban, and industrial locations). Using a diagnostic crustal element ratio (Fe/Al, Ca/Al, and Mg/Al), mineral dust components were characterized and found to show large spatial and temporal variability. The concentration levels of trace metals were further assessed for enrichment factor (EF) analysis, wherein reported elements were classified into two major groups. The first group consists of Cr, Cu, and Pb with 10< EF < 100 compared to continental crustal values (w.r.t. Al), suggesting a dominant contribution from anthropogenic sources with minor contribution from natural sources; the second group consists of Zn and Ni showing very high EF (>100)—these are solely derived from anthropogenic sources. Source identification for trace metals was further assessed based on principle component analysis (PCA). PCA highlights that the major contribution of trace metals is from anthropogenic emissions at all three locations. However, contributions from mineral dust were observed at pristine and urban locations during winter months. The reported data of trace metal concentrations in aerosols give baseline information on the atmospheric supply of micronutrients to the Arabian Sea, which has implications for the various surface ocean biogeochemical processes. Implications: This paper reports on crustal and trace metal composition and concentration level in atmospheric aerosols over a coastal city located on the Eastern Arabian Sea. This study highlights the role of various factors (meteorology and emission sources) controlling the abundance of metals over a coastal site. The contribution from various sources (anthropogenic vis-à-vis natural) has also been identified using enrichment factor analysis as well as principle component analysis. This study has implications for the supply of micronutrients to the coastal Arabian Sea, which can significantly impact various surface ocean biogeochemical processes.
Immunogenicity of 2 and 3 Doses of the Quadrivalent Human Papillomavirus Vaccine up to 120 Months Postvaccination: Follow-up of a Randomized Clinical Trial

Abstract Background Several countries have implemented a 2-dose (2D) human papillomavirus (HPV) vaccination schedule for adolescents based on immunobridging studies. We compared immunogenicity of 2D vs 3-dose (3D) schedules of the quadrivalent vaccine (4vHPV) up to 10 years after the first dose. Methods Girls aged 9–13 years were randomized to receive 2D or 3D and were compared with women aged 16–26 receiving 3D at day 1 and months 7, 24, and 120 after the first dose. Antibody levels for HPV6/11/16/18 were evaluated using the competitive Luminex immunoassay (cLIA) and total immunoglobulin G assay. Geometric mean titers (GMTs) and seropositivity rates were compared between the different groups at different time points. Noninferiority of GMT ratios was defined as the lower bound of the 2-sided 95% confidence interval (CI) being greater than 0.5. Kinetics of antibody titers over time among study groups were examined. Results At 120 months, data from 35 2D girls, 38 3D girls, and 30 3D women were used for analyses. cLIA seropositivity rates were above 95% for all HPV vaccine types and all schedules, except HPV18, with the lowest seropositivity observed among 3D women (60.0%; 95% CI, 40.6%–77.3%). GMT ratios (cLIA) for both 2D and 3D girls were noninferior to 3 doses in women for HPV6/11/16/18. Trends were comparable between assays. Conclusions GMTs for HPV6/11/16/18 after 2D or 3D of 4vHPV in girls were noninferior to 3D in adult women up to 120 months postvaccination. This study demonstrates long-term immunogenicity of the 2D HPV vaccine schedule.
Regulatory changes in TaSNAC8‐6A are associated with drought tolerance in wheat seedlings

Summary Wheat is a staple crop produced in arid and semi‐arid areas worldwide, and its production is frequently compromised by water scarcity. Thus, increased drought tolerance is a priority objective for wheat breeding programmes, and among their targets, the NAC transcription factors have been demonstrated to contribute to plant drought response. However, natural sequence variations in these genes have been largely unexplored for their potential roles in drought tolerance. Here, we conducted a candidate gene association analysis of the stress‐responsive NAC gene subfamily in a wheat panel consisting of 700 varieties collected worldwide. We identified a drought responsive gene, TaSNAC8‐6A, that is tightly associated with drought tolerance in wheat seedlings. Further analysis found that a favourable allele TaSNAC8‐6A In‐313, carrying an insertion in the ABRE promoter motif, is targeted by TaABFs and confers enhanced drought‐inducible expression of TaSNAC8‐6A in drought‐tolerant genotypes. Transgenic wheat and Arabidopsis TaSNAC8‐6A overexpression lines exhibited enhanced drought tolerance through induction of auxin‐ and drought‐response pathways, confirmed by transcriptomic analysis, that stimulated lateral root development, subsequently improving water‐use efficiency. Taken together, our findings reveal that natural variation in TaSNAC8‐6A and specifically the TaSNAC8‐6A In‐313 allele strongly contribute to wheat drought tolerance and thus represent a valuable genetic resource for improvement of drought‐tolerant germplasm for wheat production.
Anti-Inflammatory Activity of a Peptide from Skipjack (Katsuwonus pelamis)

In this paper, the effect of skipjack (Katsuwonus pelamis) enzymatic peptide (SEP), which was prepared and purified from a byproduct of skipjack, on inflammation, ulcerative colitis and the regulation of intestinal flora was studied in a mouse ulcerative colitis model and a transgenic zebrafish inflammation model. The aggregation of transgenic granulocyte neutrophils in zebrafish from a normal environment and from a sterile environment was calculated, and the anti-inflammatory activity of SEP was evaluated. To evaluate the anti-ulcerative colitis activity of SEP, DSS-induced colitis mice were given SEP, salicylazosulfapyridine (SASP), or SASP + SEP. Then, the concentrations of IL-6, IL-10 and TNF-α in the serum were detected, the HE-stained colon tissue was examined by microscopy the species composition and abundance distribution of the intestinal flora was analyzed. The results showed that 500 μg/mL SEP treatment significantly alleviated neutrophil granulocyte aggregation in the zebrafish inflammation model; Diarrhea, hematochezia and body weight loss were alleviated to a certain extent in mice gavaged with SEP and SASP, and the combination of SASP with SEP was the most effective in mice. The damage to villi in the intestine was completely repaired, and the levels of IL-6, IL-10 and TNF-α, which are associated with inflammation, were all reduced. In addition, the proportion of intestinal probiotics or harmless bacteria increased, while that of pathogenic bacteria decreased, and the effect of the combined treatment was the most pronounced. These results show that SEP could relieve inflammation, cure ulcerative colitis, regulate intestinal flora and enhance the therapeutic effect of the clinical drug SASP. This study provides a theoretical basis for the development of SEP as an anti-inflammatory adjuvant therapy and intestinal flora regulator.