bluuebunny/crossref_metadata_2025_split huggingface dataset:
FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers
Authors: Hoellerbauer Pia , Kufeld Megan , Arora Sonali , Mitchell Kelly , Girard Emily J , Herman Jacob A , Olson James M , Paddison Patrick J 
Published: May 2024

Abstract
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42’s cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42’s substrate recognition and targeting by SCF (SKP1–CUL1–F-box protein) ubiquitin ligase complex. However, none of FBXO42’s previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome–microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.
Upstream open reading frames: new players in the landscape of cancer gene regulation
Authors: Dasgupta Anwesha , Prensner John R 
Published: May 2024

Abstract
The translation of RNA by ribosomes represents a central biological process and one of the most dysregulated processes in cancer. While translation is traditionally thought to occur exclusively in the protein-coding regions of messenger RNAs (mRNAs), recent transcriptome-wide approaches have shown abundant ribosome activity across diverse stretches of RNA transcripts. The most common type of this kind of ribosome activity occurs in gene leader sequences, also known as 5′ untranslated regions (UTRs) of the mRNA, that precede the main coding sequence. Translation of these upstream open reading frames (uORFs) is now known to occur in upwards of 25% of all protein-coding genes. With diverse functions from RNA regulation to microprotein generation, uORFs are rapidly igniting a new arena of cancer biology, where they are linked to cancer genetics, cancer signaling, and tumor-immune interactions. This review focuses on the contributions of uORFs and their associated 5′UTR sequences to cancer biology.
Advances in single-cell long-read sequencing technologies
Authors: Gupta Pallavi , O’Neill Hannah , Wolvetang Ernst J , Chatterjee Aniruddha , Gupta Ishaan 
Published: May 2024

Abstract
With an increase in accuracy and throughput of long-read sequencing technologies, they are rapidly being assimilated into the single-cell sequencing pipelines. For transcriptome sequencing, these techniques provide RNA isoform-level information in addition to the gene expression profiles. Long-read sequencing technologies not only help in uncovering complex patterns of cell-type specific splicing, but also offer unprecedented insights into the origin of cellular complexity and thus potentially new avenues for drug development. Additionally, single-cell long-read DNA sequencing enables high-quality assemblies, structural variant detection, haplotype phasing, resolving high-complexity regions, and characterization of epigenetic modifications. Given that significant progress has primarily occurred in single-cell RNA isoform sequencing (scRiso-seq), this review will delve into these advancements in depth and highlight the practical considerations and operational challenges, particularly pertaining to downstream analysis. We also aim to offer a concise introduction to complementary technologies for single-cell sequencing of the genome, epigenome and epitranscriptome. We conclude by identifying certain key areas of innovation that may drive these technologies further and foster more widespread application in biomedical science.
Nanopore Current Events Magnifier (nanoCEM): a novel tool for visualizing current events at modification sites of nanopore sequencing
Authors: Guo Zhihao , Ni Ying , Tan Lu , Shao Yanwen , Ye Lianwei , Chen Sheng , Li Runsheng 
Published: May 2024

Abstract
Summary: Nanopore sequencing technologies have enabled the direct detection of base modifications in DNA or RNA molecules. Despite these advancements, the tools for visualizing electrical current, essential for analyzing base modifications, are often lacking in clarity and compatibility with diverse nanopore pipelines. Here, we present Nanopore Current Events Magnifier (nanoCEM, https://github.com/lrslab/nanoCEM), a Python command-line tool designed to facilitate the identification of DNA/RNA modification sites through enhanced visualization and statistical analysis. Compatible with the four preprocessing methods including ‘f5c resquiggle’, ‘f5c eventalign’, ‘Tombo’ and ‘move table’, nanoCEM is applicable to RNA and DNA analysis across multiple flow cell types. By utilizing rescaling techniques and calculating various statistical features, nanoCEM provides more accurate and comparable visualization of current events, allowing researchers to effectively observe differences between samples and showcase the modified sites.
Homorepeat variability within the human population
Authors: Mier Pablo , Andrade-Navarro Miguel A , Morett Enrique 
Published: May 2024

Abstract
Genetic variation within populations plays a crucial role in driving evolution. Unlike the average protein sequence, the evolution of homorepeats can be influenced by DNA replication slippage, when DNA polymerases either add or skip repeats of nucleotides. While there are some diseases known to be caused by abnormal changes in the length of amino acid homorepeats, naturally occurring variations in homorepeat length remain relatively unexplored. In our study, we examined the variation in amino acid homorepeat length of human individuals by analyzing 125 748 exomes, as well as 15 708 whole genomes. Our analyses revealed significant variability in homorepeat length across the human population, indicating that these motifs are prone to mutations at higher rates than non repeat sequences. We focused our study on glutamine homorepeats, also known as polyQ sequences, and found that shorter polyQ sequences tend to exhibit greater length variation, while longer ones primarily undergo deletions. Notably, polyQ sequencesthat are more conserved across primates tend to show less variation within the human population, indicating stronger selective pressure to maintain their length. Overall, our results demonstrate that there is large natural variation in the length of homorepeats within the human population, with no apparent impact on observable traits.
Risk factors for prevalent and incident hypertension in rheumatoid arthritis: data from the Canadian Early Arthritis Cohort
Authors: Hadwen Brook , Stranges Saverio , Pope Janet E , Bartlett Susan , Boire Gilles , Bessette Louis , Hitchon Carol A , Hazlewood Glen , Keystone Edward C , Schieir Orit , Thorne Carter , Tin Diane , Valois Marie-France , Bykerk Vivian , Barra Lillian ,   CATCH Investigators, Akhavan Pooneh , Bessette Louis , Boire Gilles , Bykerk Vivian , Colmegna Ines , Fallavollita Sabrina , Haaland Derek , Haraoui Boulos , Hazlewood Glen , Hitchon Carol , Jamal Shahin , Joshi Raman , Keystone Ed , Kuriya Bindee , Panopalis Peter , Pope Janet , Thorne Carter , Villeneuve Edith , Zummer Michel 
Published: May 2024

Abstract

Objective
Hypertension (HTN) is a common comorbidity in RA. This study aimed to explore the prevalence and incidence of HTN and baseline factors associated with incident HTN in early RA (ERA).

Methods
Data were from the Canadian Early Arthritis Cohort (CATCH), an inception cohort of ERA patients having &lt;1 year of disease duration. HTN was determined by patient- or physician-reported diagnosis, the use of anti-hypertensives and/or blood pressure. Multivariable logistic regression was performed to determine baseline factors associated with prevalent and incident HTN in this population.

Results
The study sample included 2052 ERA patients [mean age 55 years (s.d. 14), 71% female). The prevalence of HTN at study enrolment was 26% (23% in females and 34% in males). In both sexes, prevalent HTN was associated with older age, diabetes and hyperlipidaemia. HTN was associated with being overweight or high alcohol consumption in females. Of the RA patients who did not have HTN at enrolment, 24% (364/1518) developed HTN during the median follow-up period of 5 years (range 1–8). Baseline factors significantly associated with incident HTN were older age, being overweight, excess alcohol consumption and having hyperlipidaemia. Incident HTN was associated with high alcohol consumption in males and with hyperlipidaemia in females. RA-associated disease factors and treatments were not significantly associated with prevalent or incident HTN.

Conclusions
Early RA patients had a high incidence of hypertension with the highest risk in older patients with traditional cardiovascular risk factors.
Mandarin-speaking Children With Cochlear Implants Face Challenges in Using F0 Expansion to Express Contrastive Focus
Authors: Tang Ping , Xu Rattanasone Nan , Demuth Katherine , Wang Liyan , Yuen Ivan 
Published: May 2024

Objectives:
Children with cochlear implants (CIs) face challenges in perceiving fundamental frequency (F0) information because CIs do not transmit F0 effectively. In Mandarin, F0 can contrast meanings at the word level, that is, via lexical tones with distinct F0 contours, and signal contrastive relations between words at the utterance-level, that is, via contrastive focus with expanded F0 range and longer duration. Mandarin-speaking children with CIs have been reported to face challenges in producing distinct F0 contours across tones, but early implantation facilitates tonal acquisition. However, it is still unclear if utterance-level prosody, such as contrastive focus, is also challenging for these children, and if early implantation also offers benefits for focus production. Therefore, this study asked how accurately children with CIs can produce contrastive focus, and if early implantation leads to more accurate focus production, with acoustic patterns approaching that of children with typical hearing (TH).

Design:
Participants included 55 Mandarin-speaking children (3 to 7 years) with CIs and 55 age-matched children with TH. Children produced noun phrases with and without contrastive focus, such as RED-COLORED cat versus red-colored cat. Three adult native listeners perceptually scored the productions as correct or incorrect. The “correct” productions were then acoustically analyzed in terms of F0 range and duration.

Results:
Based on the perceptual scores, children with CIs produced focus with significantly lower accuracy (38%) than their TH peers (84%). The acoustic analysis on their “correct” productions showed that children with TH used both F0 and duration to mark focus, producing focal syllables with an expanded F0 range and long duration, and postfocal syllables with a reduced F0 range and short duration. However, children with CIs differed from children with TH in that they produced focal syllables with long duration but not an expanded F0 range, although they produced postfocal syllables with a reduced F0 range and short duration like their TH peers. In addition, early implantation correlated with the percept of more accurate focus productions and better use of F0 range in focal marking.

Conclusions:
This study finds that Mandarin-speaking children with CIs are still learning to apply appropriate acoustic cues to contrastive focus. The challenge appears to lie in the use of an expanded F0 range to mark focus, probably related to the limited transmission of F0 information through the CI devices. These findings thus have implications for parents and those working with children with CIs, showing that utterance-level prosody also requires speech remediation, and underscores the critical role of identifying problems early in the acquisition of F0 functions in Mandarin, not only at the word level but also at the utterance-level.
Evaluating adherence to American Diabetes Association standards of care in diabetes and impacts of social determinants of health on patients at two nurse practitioner–owned clinics
Authors: Tuohy Christine A. , Liziewski Kathryn E. , White Patricia A. , Wright Wendy L. 
Published: May 2024

ABSTRACTBackground:The COVID-19 pandemic created barriers in the management of type 2 diabetes mellitus (T2DM) and worsened social determinants of health (SDOH). A New Hampshire primary care office worked to adhere to T2DM standards of care and began screening for SDOH. This project assessed adherence to quality metrics, hemoglobin A1C, and SDOH screening as telehealth utilization decreased.Local Problem:A1C values have increased at the practice, especially since COVID-19. The practice also began screening for SDOH at every visit, but there was need to assess how needs were being documented and if/how they were addressed.Methods:A retrospective chart review of patients with T2DM was performed. Demographic data and T2DM metrics were collected and compared with previous years and compared new versus established patients. Charts were reviewed to evaluate documentation of SDOH and appropriate referral.Interventions:The practice transitioned from an increased utliization of telehealth back to prioritizing in-office visits. The practice also began routinely screening for SDOH in 2020; however, this process had not been standardized or evaluated.Results:Adherence to nearly all quality metrics improved. Glycemic control improved after a year of nurse practitioner (NP) care, especially in new patients. All patients were screened for SDOH, but documentation varied, and affected patients had higher A1Cs, despite receiving comparable care.Conclusion:Nurse practitioners at this practice are adhering to American Diabetes Association guidelines, and A1C values improve under their care. Social determinants of health continue to act as unique barriers that keep patients from improving glycemic control, highlighting the need for individualized treatment of SDOH in T2DM care.
The EBI2 receptor is coexpressed with CCR5 in CD4+ T cells and boosts HIV-1 R5 replication
Authors: Guigues Adeline , Gimenez Sandrine , Mettling Clément , Maurel Damien , Doumazane Etienne , Prézeau Laurent , François Vincent , Corbeau Pierre 
Published: May 2024

Objective:
CCR5, a G protein-coupled receptor (GPCR), is used by most HIV strains as a coreceptor. In this study, we looked for other GPCR able to modify HIV-1 infection.

Design:
We analyzed the effects of one GPCR coexpressed with CCR5, EBI2, on HIV-1 replicative cycle.

Methods:
We identified GPCR expressed in primary CD4+CCR5+ T cells by multi-RT-qPCR. We studied GPCR dimerization by FRET technology. Cell lines expressing EBI2 were established by transduction with HIV vectors. HIV-1 entry was quantified with virions harboring β-lactamase fused to the viral protein vpr, early and late HIV-1 transcriptions by qPCR, NFkB nuclear activation by immunofluorescence and transfection, and viral production by measuring p24 concentration in culture supernatant by ELISA.

Results:
We showed that EBI2 is naturally expressed in primary CD4+CCR5+ T cells, and that CCR5 and EBI2 heterodimerize. We observed that this coexpression reduced viral entry by 50%. The amount of HIV reverse transcripts was similar in cells expressing or not EBI2. Finally, the presence of EBI2 induced the translocation of NFkB and activated HIV-1 genome expression. Globally, the result was a drastic HIV-1 R5, but not X4, overproduction in EBI2–transduced cells.

Conclusion:
EBI2 expression in CD4+CCR5+ cells boosts HIV-1 R5 productive infection. As the natural ligand for EBI2 is present in blood and lymphoid tissues, the constant EBI2 activation might increase HIV replication in CD4+ T cells. It might be of interest to test the effect of EBI2 antagonists on the residual viral production persisting in patients aviremic under treatment.
Macrophages activation syndrome in patients infested with parasites about 3 cases with different outcomes
Authors: El Mrimar Nadia , Rhars rhars Amal , sokori Kaoutar , Raghani Abdeljalil , ezzariga Nihal , Chachi chachi Mostafa , Aghrouch Mohamed , Lemkhente Zohra 
Published: May 2024

Hemophagocytic syndrome (HPS) also known as macrophage activation syndrome (MAS) is a rare and life-threatening condition characterized by a hyperinflammatory response, leading to the uncontrolled activation of macrophages and the subsequent hemophagocytosis of erythrocytes, leukocytes, and platelets. This can result in cytopenias, organomegaly, and multiorgan failure.
The list of infectious agents that predispose to hemophagocytic syndrome has expanded since the first description of infection- associated hemophagocytosis (IAHS).
Visceral leishmaniasis (VL), also known as kala-azar, is a severe and potentially fatal parasitic disease caused by protozoa of the Leishmania genus. It is characterized by irregular bouts of fever, weight loss, hepatosplenomegaly, and anemia. One of the complications associated with this disease is HPS. Malaria is a worldwide problem. Plasmodium falciparum infection, particularly if the diagnosis wasn't at time, may result in a multi-organ failure. In the literature, Plasmodium falciparum infection was rarely cited as the root cause of HPS.
In this article, we report 3 cases of parasite infestations complicated with MAS. We illustrate the clinical manifestations, diagnostic challenges, and management of this severe condition. Additionally we provide a comprehensive review of the current understanding of MAS in parasite, with a focus on the epidemiology, clinical manifestations, pathophysiology, diagnosis, and treatment options. Furthermore, we aim to discuss the latest advancements in research and the potential for new therapeutic approaches.
Accurate Inference of the Polyploid Continuum using Forward-time Simulations
Authors: Dunn Tamsen , Sethuraman Arun 
Published: May 2024

AbstractMultiple rounds of whole-genome duplication (WGD) followed by diploidization have occurred throughout the evolutionary history of angiosperms. To understand how these cycles occur, much work has been done to model the genomic consequences and evolutionary significance of WGD. The machinations of diploidization are strongly influenced by the mode of speciation (allo or autopolyploidy). However, there is no discrete boundary between allo and autopolyploidy, which is best described as a continuum. Here we present a forward-time polyploid genome evolution simulator called SpecKS. SpecKS models polyploid speciation as originating from a 2D continuum, whose dimensions account for both the level of genetic differentiation between the ancestral parental genomes, as well the time lag between ancestral speciation and their subsequent reunion in the derived polyploid. Using extensive simulations, we demonstrate that changes in initial conditions along either dimension of the 2D continuum deterministically affect the shape of theKshistogram. Our findings indicate that the error in the common method of estimating WGD time from theKshistogram peak scales with the degree of allopolyploidy, and we present an alternative, accurate estimation method that is independent of the degree of allopolyploidy. Lastly, we use SpecKS to derive tests that infer both the lag time between parental divergence and WGD time, and the diversity of the ancestral species, from an inputKshistogram. We apply the latter test to transcriptomic data from over 200 species across the plant kingdom, the results of which are concordant with the prevailing theory that the majority of angiosperm lineages are derived from diverse parental genomes and may be of allopolyploid origin.
A mechanistic model of Rtc-regulated RNA repair suggests molecular targets to potentiate antibiotic effects
Authors: Hindley Hollie J. , Kotta-Loizou Ioly , Buck Martin , Engl Christoph , Weiße Andrea Y. 
Published: May 2024

AbstractRNA is susceptible to damage from various internal and external factors. Given the integral role of RNA, its repair is essential for maintaining proper cell function. A highly conserved RNA repair system, the Rtc system, maintains core RNA components of the translational apparatus. Rtc expression is induced upon various stresses, including exposure to ribosome-targeting antibiotics. Its expression enables cells to rescue growth and survive treatment by conferring transient resistance to these antibiotics. The mechanisms by which Rtc-induced resistance arises are largely unknown. Here, we develop and analyse a computational model of Rtc-regulated maintenance of long-lived RNAs that form part of the translational apparatus. We investigate the mechanistic action of Rtc leading to transient resistance and find that its regulatory structure promotes heterogeneity across bacterial populations, where a resistant sub-population can co-exist with non-expressing, susceptible cells. The finding suggests a complex response underlying adaptive resistance conferred by Rtc with individual cell fates determining antibiotic efficacy. We further analyse the molecular determinants that lead to growth rescue vs suppression and identify components within the Rtc system that may be targeted to potentiate antibiotic effects. Our results provide novel tools for the systems analysis of Rtc-regulated RNA repair and pinpoint testable hypotheses to advance knowledge of RNA repair and its physiological implications.
Imaginary past of a quantum particle moving on imaginary time
Authors: Uranga A. , Akhmatskaya E. , Sokolovski D. 
Published: May 2024

The analytical continuation of classical equations of motion to complex times suggests that a tunneling particle spends in the barrier an imaginary duration i|T|. Does this mean that it takes a finite time to tunnel, or should tunneling be seen as an instantaneous process? It is well known that examination of the adiabatic limit in a small additional AC field points towards |T| being the time it takes to traverse the barrier. However, this is only half the story. We probe the transmitted particle's history, and find that it very little of the field's past behavior, as if the transit time were close to zero. The ensuing contradiction suggests that the question is ill posed, and we explain why.

Published by the American Physical Society
2024