julilili42/papers huggingface dataset:
Addressing vaccine hesitancy and misinformation amidst Japan’s self-amplifying mRNA COVID-19 vaccine rollout
2024-11-05

Abstract As of 1 October 2024, Japan implemented a revised coronavirus disease 2019 (COVID-19) vaccination strategy, shifting from a fully publicly funded model to one where costs are partially or fully borne by recipients. This new annual program targets individuals aged 65 and above, and those aged 60–64 at higher risk of severe illness, requiring them to cover some vaccination expenses. For others, the vaccine remains voluntary and self-funded. Notably, this program includes the world’s first self-amplifying mRNA COVID-19 vaccine, zapomeran (Kostaive®, Meiji Seika Pharma Co., Ltd.) approved on 28 November 2023. This vaccine’s innovative self-amplifying feature has ignited debates across media platforms, with widespread public division and confusion. The new vaccine encodes replicase proteins and the spike protein antigen, allowing for reduced doses of 5 μg compared to traditional mRNA vaccines that require 30 μg. However, concerns have been raised, primarily around four misconceptions: shedding, perpetual mRNA replication, integration into human DNA, and its non-approval situation outside Japan. Despite these scientifically unfounded concerns, they have fueled vaccine hesitancy, influenced by misleading information spreading rapidly on social media. Alarmingly, biased statements from an academic university and an academic society aggravate this hesitancy. Japan’s history has experienced vaccine hesitancies in human papillomavirus and diphtheria–tetanus–pertussis vaccination cases. To prevent a public health crisis, it is crucial that governmental bodies and academic groups actively counter misinformation, advocating for evidence-based understanding and encouraging vaccination among those most at risk.
Inferior Overall Survival After Haploidentical Donor Lymphocyte Infusions in Relapsed Myeloid Neoplasms
2024-11-05

ABSTRACT Objectives Allogeneic hematopoietic stem cell transplantation (HSCT) effectively treats high‐risk myeloid neoplasms, but relapses post‐HSCT, particularly in acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS), pose significant challenges. Donor lymphocyte infusion (DLI) has been utilized, but its effectiveness, especially in haploidentical settings, remains insufficiently clarified, and graft‐versus‐host disease (GvHD) poses a substantial risk. Methods In this retrospective cohort study, 57 patients with AML or MDS who received DLI after allogeneic HSCT at our center from 2002 to 2023 were analyzed. Herein, only preemptively or therapeutically applied DLI were included, and endpoints included overall survival (OS), progression‐free survival (PFS), and GvHD incidence post‐DLI. Results Median OS after DLI was 517 days, with a 1‐year OS of 62.5%. Factors associated with longer OS included patient age, HLA‐identical donor, post‐HSCT treatment naivety, and preemptive DLI indication. Haploidentical DLI was associated with inferior OS compared to HLA‐identical DLI; however, PFS and GvHD incidence post‐DLI did not differ significantly. Conclusions Our study findings indicate that OS rate is inferior in patients with relapsed AML or MDS treated with haploidentical DLI in comparison to those who received HLA‐identical DLI. Given the limitations of haploidentical DLI, alternative strategies, such as higher cell doses or combination treatment approaches, warrant further investigation.
A Defined Diet Combined with Sonicated Inoculum Provides a High Incidence, Moderate Severity Form of Experimental Autoimmune Encephalomyelitis (EAE)
2024-11-05

A defined fiber/high-sugar diet with sonicated inoculum provides for a moderate severity, high incidence, and less variable EAE. The resulting uniformity in animal response and associated cytokine patterns, and the strong link to a defined diet, suggest that this may be a more clinically translatable protocol for the induction of EAE. This is consistent with reported effects of low-fermentable diets on immune modulation in human patients with autoimmune diseases.
Flavopiridol Restores Granulopoiesis in an Experimental Model of Severe Congenital Neutropenia
2024-11-05

Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways that cause maturation arrest of granulocytic progenitors. The largest group of CN patients harbors autosomal dominant ELANE mutations (ELANE-CN). We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of ELANE-CN and identified signaling pathways deregulated by ELANE mutations in iPSC-derived hematopoietic stem and progenitor cells, potentially leading to defective granulopoiesis. We further performed an in silico drug repurposing analysis of the transcriptomics data and selected flavopiridol, an FDA-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic. We found that treatment with low-dose flavopiridol (up to 10-fold lower than that usually used to treat cancer patients) rescued defective granulopoiesis in primary CD34+ cells of CN patients with different inherited gene mutations, including ELANE, HAX1, SRP54 and JAGN1, in vitro and in two zebrafish CN models in vivo (hax1-CN and jagn1b-CN) without any toxic effects on hematopoietic stem cells or granulocytes and leading to fully functional granulocytes. We have previously shown that the expression levels of the transcription factor CEBPA are severely reduced in hematopoietic cells and myeloid progenitors of CN patients. Rescue of defective granulopoiesis by transduction of CD34+ cells from CN patients with CEBPA further supports its key role in the pathogenesis of CN. CEBPA is known to counteract CDK2 and CDK4 activity to induce granulopoiesis and we found that flavopiridol restored granulopoiesis caused by reduced CEBPA expression in vitro and in zebrafish embryos in vivo. These data provide insight into the mechanism of action of flavopiridol in rescuing defective granulopoiesis in CN. Thus, we described for the first time a therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.
Autosomal Recessive COPZ1 Mutations Cause Isolated Severe Neutropenia or Complex Syndrome with Severe Neutropenia
2024-11-05

We have identified new autosomal recessive mutations in the COPZ1 gene in three severe congenital neutropenia (CN) patients from two unrelated families. In one family, two siblings with a stop-codon COPZ1 mutation (NP_057141:p.Gln141Ter) suffered from CN, lymphopenia, anemia, thrombocytopenia, and syndromic organ involvement, including hepatosplenomegaly, atypical autism with mental retardation, varying degrees of bone defects, and dermatitis. An unrelated patient with a missense COPZ1 mutation (NP_057141:p.Gly132Arg) exhibited isolated CN and chilblains. The COPZ1 gene encodes the zeta 1 subunit of the coatomer protein complex I (COPI), which is phylogenetically highly conserved, with two identified mutation positions in the conserved region. The protein structure of human COPZ1 is still unknown, and computational analysis using bovine COPZ1 and COPG1 proteins predicted that truncated COPZ1 exhibits substantial structural instability and reduced interaction with COPG1, whereas missense COPZ1 retains interaction with COPG1. Consistent with structural defects, truncated COPZ1 blocked retrograde protein transport from the Golgi to the ER in human fibroblasts, suggesting a detrimental effect on COPI complex functions. We also found that truncated or missense COPZ1 mutations caused impaired granulocytic differentiation of human CD34+ cells in vitro with a more pronounced phenotype in COPZ1 truncated cells. In zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated COPZ1 downregulated JAK-STAT-C/EBPE-G-CSFR signaling and hypoxia-responsive pathways while inducing interferon-stimulated genes (ISGs) and STING, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species (ROS) levels in CD34+ cells. Missense COPZ1 protein also deregulated interferon signaling. Therapeutically, by applying connectivity map analysis, we discovered that treatment with the HIF1α activator IOX2 successfully restored granulopoiesis in truncated Copz1 zebrafish embryos and human CD34+ cells. Furthermore, transduction with COPZ2 cDNA effectively corrected granulocytic differentiation defects in COPZ1-mutated CD34+ cells. In summary, our findings elucidate the distinct pathogenic mechanisms and clinical presentations associated with truncated versus missense COPZ1 mutations and underscore the potential of HIF1α activation as a promising therapeutic approach for CN.
Validation and next-generation update of a DNA methylation–based recurrence predictor for meningioma: A multicenter prospective study
2024-11-06

Abstract Background We previously developed a DNA methylation–based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays. Methods Genome-wide methylation profiles were generated with the Illumina EPICArray. The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. An nomogram was generated by incorporating our methylation predictor with WHO grade and the extent of resection. Results A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and an external cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperform the 2021 WHO grade in predicting early postoperative recurrence. Dichotomizing patients into grade-specific risk subgroups was predictive of outcomes within both WHO grades 1 and 2 tumors (P &amp;lt; .05), whereas all WHO grade 3 tumors were considered high-risk. Multivariable Cox regression demonstrated the benefit of adjuvant radiotherapy (RT) in high-risk cases specifically, reinforcing its informative role in clinical decision-making. Finally, our next-generation predictor contains nearly 10-fold fewer features than the original model, allowing for targeted arrays. Conclusions This next-generation DNA methylation–based meningioma outcome predictor significantly outperforms the 2021 WHO grading in predicting time to recurrence. We make this available as a point-and-click tool that will improve prognostication, inform patient selection for RT, and allow for molecularly stratified clinical trials.
The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells
2024-11-06

Abstract Age-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD. Here, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. Intriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity, caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. This suggests that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers, however iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress.
Acoustic correlates of GIVENness in Icelandic: Revisiting the Radical Deaccentuation hypothesis
2024-11-06

This paper discusses whether there is a direct link between GIVENness-related deaccentuation and ellipsis. The idea that ellipsis can only target already-deaccented material with “distinguished low-flat intonation” (Chomsky &amp;amp; Lasnik 1993: 564) is known as the Radical Deaccentuation (RD) account (see e.g. Tancredi 1992). Icelandic represents a challenge for RD, as it permits (clausal) ellipsis (Wood et al. 2016, 2020) yet does not seem to display deaccentuation (Nolan &amp;amp; Jónsdóttir 2001, Dehé 2009). We conducted a prosodic production experiment to investigate the acoustic correlates of post-focal GIVENness in pre-elliptic clauses in Icelandic to determine if Icelandic undermines the RD theory. We found that Icelandic exhibits prosodic attenuation in pre-elliptic clauses, such that pitch accents of given items are realized, yet they exhibit lower overall F0, and shorter duration. We also found a difference in prosodic constituency between all-new and pre-elliptic clauses, such that the given part in only the pre-elliptic condition is structur-ally integrated to the prosodic domain of the focused item. Our empirical findings are compatible with a weaker version of RD, namely one which treats ‘deaccentuation’ as a cover term for any acoustic effect related to the prosodic marking of GIVENness.
Inhibition of the Notch signal transducer CSL by Pkc53E-mediated phosphorylation to fend off parasitic immune challenge in Drosophila
2024-11-06

Notch signalling activity regulates hematopoiesis in Drosophila and vertebrates alike. Parasitoid wasp infestation of Drosophila larvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here, we show that the Drosophila CSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation. As this phosphorylation interferes with the DNA binding of Su(H), it reversibly precludes its activity. Accordingly, phospho-deficient Su(H) S269A mutants are immune-compromised. A screen for kinases involved in Su(H) phosphorylation identified Pkc53E, required for normal hematopoiesis as well as for parasitoid immune response. Genetic and molecular interactions support the specificity of the Su(H)-Pkc53E relationship. Moreover, phorbol ester treatment inhibits Su(H) activity in vivo and in human cell culture. We conclude that Pkc53E targets Su(H) during parasitic wasp infestation, thereby remodelling the blood cell population required for wasp egg encapsulation.
Impact of dietary zinc on stimulated zinc secretion MRI in the healthy and malignant mouse prostate
2024-11-06

Previous studies have shown that the zinc-responsive MRI probe, GdL1, can distinguish healthy versus malignant prostate tissues based upon differences in zinc content and secretion. In this study, mice were fed chow containing low, normal, or high zinc content for 3 weeks before imaging glucose stimulated zinc secretion (GSZS) by MRI. The distribution of zinc in prostate tissue in these three groups was imaged by synchrotron radiation X-ray fluorescence (SR-XRF). A zinc deficiency caused systemic and organ-level dysregulation, weight loss, and altered zinc bioavailability. Zinc efflux from the prostate increased in parallel to dietary zinc in healthy mice but not in TRAMP mice, consistent with a lowered capacity to store dietary zinc in malignant cells. This differential zinc efflux suggests that a dietary supplement of zinc prior to a GSZS study may enhance image contrast between healthy and malignant prostate tissue, thereby improving the accuracy of prostate cancer detection in man.
One Third of Alcohol Use Disorder Diagnoses are Missed by ICD Coding
2024-11-07

Background/Significance: Alcohol use carries significant morbidity and mortality, yet accurate identification of alcohol use disorder (AUD) remains a multi-layered problem for both researchers and clinicians. Objective: To fine-tune a language model to AUD in the clinical narrative and to detect AUDs not accounted for by ICD-9 coding in the MIMIC-III database. Materials and Methods: We applied clinicalBERT to unique patient discharge summaries. For classification, patients were divided into nonoverlapping groups stratified by the presence/absence of AUD ICD diagnosis for model training (80%), validation (10%), and testing (10%). For detection, the model was trained (80%) and validated (20%) on 1:1 positive/negative patients, then applied to remaining negative patient population. Physicians adjudicated 600 samples from the full model confidence spectrum to confirm AUD by Diagnostic and Statistical Manual of Mental Disorders-V criteria. Results: The model exhibited the following characteristics (mean, standard deviation): precision (0.9, 0.02), recall (0.65, 0.03), F-1 (0.75, 0.02), area under the receiver operating curve (0.97, 0.01), and area under the precision-recall curve (0.86, 0.01). Adjudication produced an estimated 4% under-documentation rate for the total study population. As model confidence increased, AUD under-documentation rate rose to 30% of the number of patients identified as positive by ICD-9 coding. Conclusion: Our model improves the identification of patients meeting AUD criteria, outperforming ICD codes in detecting cases of AUD. Detection discrepancy between ICD and free-text highlights clinician under documentation , not under recognition. Adjudication revealed model over-sensitivity to language around substance use, withdrawal, and chronic liver disease; future study requires application to a broader set of patient age and acuity. This model has the potential to improve rapid identification of patients with AUD and enhance treatment allocation.
SMAS: Structural MRI-Based AD Score using Bayesian VAE
2024-11-07

Abstract This study introduces the Structural MRI-based Alzheimer’s Disease Score (SMAS), a novel index intended to quantify Alzheimer’s Disease (AD)-related morphometric patterns using a deep learning Bayesian-supervised Variational Autoencoder (Bayesian-SVAE). SMAS index was constructed using baseline structural MRI data from the DELCODE study and evaluated longitudinally in two independent cohorts: DEL-CODE (n=415) and ADNI (n=190). Our findings indicate that SMAS has strong associations with cognitive performance (DELCODE: r=-0.83; ADNI: r=-0.62), age (DEL-CODE: r=0.50; ADNI: r=0.28), hippocampal volume (DEL-CODE: r=-0.44; ADNI: r=-0.66), and total grey matter volume (DELCODE: r=-0.42; ADNI: r=-0.47), suggesting its potential as a biomarker for AD-related brain atrophy. Moreover, our longitudinal studies suggest that SMAS may be useful for early identification and tracking of AD. The model demonstrated significant predictive accuracy in distinguishing cognitively healthy individuals from those with AD (DELCODE: AUC=0.971 at baseline, 0.833 at 36 months; ADNI: AUC=0.817 at baseline, improving to 0.903 at 24 months). Notably, over a 36-month period, SMAS index outperformed existing measures such as SPARE-AD and hippocampal volume. Relevance map analysis revealed significant morphological changes in key AD-related brain regions—including the hippocampus, posterior cingulate cortex, precuneus, and lateral parietal cortex—highlighting that SMAS is a sensitive and interpretable biomarker of brain atrophy, suitable for early AD detection and longitudinal monitoring of disease progression.
Real-Time Spatiotemporal Filtering for Artifact-Free EEG during Electrical Neurostimulation
2024-11-07

A bstract Combining electrical neurostimulation with electroencephalography (EEG) for adaptive neurostimulation remains challenging due to the presence of stimulation artifacts in the recorded signal. Interpretation of EEG activity concurrent with stimulation requires real-time filtering of this noisy signal. While traditional frequency domain filters can suppress activity within frequency bands, they fail to differentiate sources in situations when there is a shared frequency characteristic between brain activity and stimulation signal. Here we present a new real-time denoising approach that combines spatial filtering and dynamic filter application. The spatiotemporal filter can suppress stimulation artifacts that share frequency bands with the brain signal in real-time while preserving the full spectral power. The spatial filter is also dynamically updated to account for possible changes in artifact topography. Finally, the filter is robust to changes of stimulation intensity, frequency and duration, enabling reliable denoising performance for inclusion in brain state-based closed-loop stimulation.