bluuebunny/crossref_metadata_2025_split huggingface dataset:
A TALS-likeRTTNmutation impedes neural rosette formation in human cortical organoids
Authors: Guguin Justine , Chen Ting-Yu , Besson Alicia , Cuinat Silvestre , Bertiaux Eloïse , Boutaud Lucile , Ardito Nolan , Murguiondo Miren Imaz , Cabet Sara , Hamel Virginie , Thomas Sophie , Pain Bertrand , Edery Patrick , Putoux Audrey , Tang Tang K. , Mazoyer Sylvie , Delous Marion 
Published: April 2024

AbstractThe Taybi-Linder syndrome (TALS) is a rare genetic disorder characterized by a severe microcephaly with abnormal gyral pattern, severe growth retardation, bone abnormalities and a reduced life span for the most severe cases. It is caused by mutations inRNU4ATACwhose transcript, the small nuclear RNA U4atac, is a core component of the minor spliceosome involved in the excision of minor introns spread over ∼750 genes.Here, we report a patient presenting with TALS features but no mutation inRNU4ATAC; instead, she carries theRTTNc.2953A>G variant at the homozygous state. This variant, already reported in patients with syndromic microcephaly, encodes the missense p.Arg985Gly amino acid change. It is also known to affectRTTNpre-mRNA splicing, with the expression of two forms lacking either exon 23 (in-frame) or exons 22-23 (out-of-frame). By using the engineeredRTTNdepleted RPE1 cellular model, we analysed independently the impact of the missense and in-frame deletion of exon 23RTTNisoforms on the localisation and function of the protein at the centrosome, and showed that the pathogenicity of the c.2953A>G variant is mostly due to the latter. In patient fibroblasts, we observed a reduction of the centriole length and an alteration of ciliary function, while the analysis of neuronal stem cells (NSC) derived from CRISPR/Cas9-edited induced pluripotent stem cells revealed major cell cycle and mitotic abnormalities, leading to aneuploidy, cell cycle arrest and increased cell death. Finally, by generating cortical organoids, we discovered a new function of RTTN in the self-organisation of NSC into neural rosettes. We observed a delayed apico-basal polarization of NSC, accompanied with decreased cell division and increased apoptosis. Altogether, these defects lead to a marked decrease of rosette number and size inRTTN-mutated organoids, thus impeding their overall growth.To conclude, our study gives new insights on microcephaly-related pathophysiological mechanisms underlying the only recurrentRTTNmutation, that could also open a path to better understand those involved inRNU4ATAC-associated Taybi-Linder syndrome.
Mutational pressure drives enhanced release of proteasome-generated public CD8+T cell epitopes from SARS-CoV-2 RBD of Omicron and its current lineages
Authors: Kudriaeva Anna A. , Butenko Ivan O. , Saratov George A. , Ri Maxim , Mokrushina Yuliana A. , Bondarev Alexey A. , Evpak Alena S. , Smirnov Ivan V. , Matyushkina Daria S. , Gabibov Alexander G. , Govorun Vadim M. , Belogurov Alexey A. 
Published: April 2024

SUMMARYThe COVID-19 pandemic was the most dramatic in the newest history with nearly 7 million deaths and global impact on mankind. Here we report binding index of 305 HLA class I molecules from 18,771 unique haplotypes of 28,104 individuals to 821 peptides experimentally observed from spike protein RBD of 5 main SARS-CoV-2 strains hydrolyzed by human proteasomes with constitutive and immune catalytic phenotypes. Our data read that mutations in the hACE2-binding region RBD496-513of Omicron B.1.1.529 strain results in a dramatic increase of proteasome-mediated release of two public HLA class I epitopes. Global population analysis of HLA class I haplotypes, specific to these peptides, demonstrated decreased mortality of human populations enriched in these haplotypes from COVID-19 after but not before December, 2021, when Omicron became dominant SARS-CoV-2 strain. Noteworthy, currently circulating BA.2.86 and JN.1 lineages contain no amino acid substitutions in RBD496-513thus preserving identified core epitopes.
A Randomized, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of VIR-2482 in Healthy Adults for Prevention of Influenza A Illness (PENINSULA)
Authors: Tan Susanna K. , Cebrik Deborah , Plotnik David , Agostini Maria L. , Boundy Keith , Hebner Christy M. , Yeh Wendy W. , Pang Phillip S. , Moya Jaynier , Fogarty Charles , Darani Manuchehr , Hayden Frederick G. 
Published: April 2024

AbstractBackgroundInfluenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin, and may protect against seasonal and pandemic influenza.MethodsThis double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular (IM) injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction (RT-PCR)–confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention (CDC)–defined ILI or World Health Organization (WHO)–defined ILI, respectively.ResultsVIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with RT-PCR–confirmed influenza A versus placebo (relative risk reduction [RRR], 3.8% [95% CI: −67.3, 44.6] and 15.9% [95% CI: −49.3, 52.3], respectively). At the 1200 mg dose, the RRRs in influenza A illness were 57.2% [95% CI: −2.5, 82.2] using CDC-ILI and 44.1% [95% CI: −50.5, 79.3] using WHO-ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection-site reactions were mild and similar across groups.ConclusionVIR-2482 1200 mg IM was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness.Trial registrationClinicalTrials.govidentifier,NCT05567783Key pointsProphylactic administration of 1200 mg of VIR-2482, an engineered human monoclonal antibody targeting a highly conserved epitope on the stem region of influenza A hemagglutinin, did not significantly reduce risk of influenza-like illness from influenza A virus in healthy adults.
Reward enhances motor adaptation learning in acute stroke patients
Authors: Paul Theresa , Wiemer Valerie M. , Günther Jonas , Lehnberg Finn M. , Grafton Scott T. , Fink Gereon R. , Volz Lukas J. 
Published: April 2024

AbstractThe majority of motor recovery occurs within the first weeks after stroke and has been hypothesized to rely on similar mechanisms as motor learning. However, it remains unknown whether acute stroke patients are capable of error-based motor adaptation learning and, if so, whether such learning may be enhanced by reinforcement feedback. Here, we show for the first time that acute stroke patients exhibit successful error-based motor adaptation with their paretic hand by replicating well-known phenomena such as savings and retention of adaptation learning. Notably, reward and punishment feedback exerted dissociative modulatory effects on motor adaptation. Contrary to findings in healthy subjects and chronic stroke patients, punishment did not enhance learning rates during early adaptation but led to poorer performance than reward. Most importantly, reward feedback enhanced both initial learning and retention, emphasizing the potential of reward and discouraging punishment feedback in early neurorehabilitation after stroke.
Modulation of subcortical activity along the migraine cycle during cognitive executive load
Authors: Ruiz-Tagle Amparo , Caetano Gina , Fouto Ana , Esteves Inês , Cabaço Inês , Da Silva Nuno , Vilela Pedro , Alves Pedro Nascimento , Martins Isabel Pavão , Gouveia Raquel Gil , Figueiredo Patrícia 
Published: April 2024

ABSTRACTObjectiveTo analyze cognition and brain activation during an executive task in migraine patients studied in the different phases of the migraine cycle, compared with healthy participants.BackgroundCognitive difficulties reported during migraine attacks remain poorly understood, despite evidence that the lateral frontoparietal network undergoes reversible disturbances and decreased activation during attacks. Recent findings in resting state functional magnetic resonance imaging suggest that brain areas involved in this network interact with subcortical regions during spontaneous migraine attacks.MethodsPatients with low-frequency episodic menstrual migraine without aura were assessed with functional magnetic resonance imaging while performing a working memory task, along the four phases of natural migraine cycles, including spontaneous attacks, namely: peri-ictal (preictal, ictal, postictal) phases and interictally (in-between attacks). Healthy controls were assessed during the corresponding phases of their menstrual cycles.ResultsThe protocol was completed by 24 female participants aged 21 to 47 years: 10 with migraine (four sessions each) and 14 controls (two sessions each). Patients and controls showed similar performance on the working memory task and displayed increased brain activity in regions linked to this function, namely the middle frontal gyrus, inferior parietal lobe, and anterior cingulate cortex, during all phases of the migraine/menstrual cycle. Migraine patients exhibited a significant decrease in hypothalamic activity during the postictal phase when compared to perimenstrual controls (p= 0.007), interictal (p= 0.002) and preictal (p= 0.034) migraine phases.ConclusionCognitive areas were actively recruited during a working memory task in different phases of the migraine cycle. In addition, migraine patients displayed significantly lower neural activity at the subcortical level in the peri-ictal period. These findings, combined with previous research showing activation in cortical areas, suggest subcortical-cortical interaction during the peri-ictal phases, which may act as a compensatory mechanism when the individual faces a cognitively demanding task during migraine attacks.
Molecular epidemiology of invasive Group A Streptococcal infections before and after the COVID-19 pandemic in Switzerland
Authors: Andrianaki Angeliki M. , Franz Jessica , Andreoni Federica , Bergada-Pijuan Judith , Scheier Thomas C. , Duwe Tanja , Pfister Marc , Seth-Smith Helena , Roloff Tim , Kolesnik-Goldmann Natalia , Burkhard Sara H. , Cusini Alexia , Karrer Urs , Rüegg Christian , Schibli Adrian , Schrenzel Jacques , Musumeci Stefano , Kouyos Roger D. , Egli Adrian , Brugger Silvio D. , Zinkernagel Annelies S. 
Published: April 2024

AbstractGroup AStreptococcus(GAS, akaStreptococcus pyogenes) poses a significant public health concern, causing a diverse spectrum of infections with high mortality rates. Following the COVID-19 pandemic, a resurgence of invasive GAS (iGAS) infections has been documented, necessitating efficient outbreak detection methods. Whole genome sequencing (WGS) serves as the gold standard for GAS molecular typing, albeit constrained by time and costs. This study aimed to characterize the post-pandemic increased prevalence of iGAS on the molecular epidemiological level in order to assess whether new, more virulent variants have emerged, as well as to assess the performance of the rapid and cost-effective Fourier-transform infrared (FT-IR) spectroscopy as an alternative to WGS for detecting and characterizing GAS transmission routes. A total of 66 iGAS strains isolated from nine Swiss hospitals during the COVID-19 post-pandemic increased GAS prevalence were evaluated and compared to 15 strains collected before and 12 during the COVID-19 pandemic. FT-IR measurements and WGS were conducted for network analysis. Demographic, clinical, and epidemiological data were collected. Skin and soft tissue infection was the most common diagnosis, followed by primary bacteremia and pneumonia. Viral co-infections were found in 25% of cases and were significantly associated with more severe disease requiring intensive care unit admission. WGS analysis did not reveal emerging GAS genetic distinct variants after the COVID-19 pandemic, indicating the absence of a pandemic-induced shift. FT-IR spectroscopy exhibited limitations in differentiating genetically distant GAS strains, yielding poor overlap with WGS-derived clusters. Theemm1/ST28 gebotype was predominant in our cohort and was associated with five of the seven deaths recorded, in accordance with the molecular epidemiological data before the pandemic. Additionally, no notable shift in antibiotic susceptibility patterns was observed. Our data suggest that mainly non-pathogen related factors contributed to the recent increased prevalence of iGAS.
Effect of Eligibility Criteria on Patients’ Survival and Serious Adverse Events in Colorectal Cancer Drug Trials
Authors: Wang Chang , Chen Aokun , He Xing , Balian Patrick , George Thomas J. , Wang Fei , Bian Jiang , Guo Yi 
Published: April 2024

AbstractThis study investigates the impact of clinical trial eligibility criteria on patient survival and serious adverse events (SAEs) in colorectal cancer (CRC) drug trials using real-world data. We utilized the OneFlorida+ network’s data repository, conducting a retrospective analysis of CRC patients receiving FDA-approved first-line metastatic treatments. Propensity score matching created balanced case-control groups, which were evaluated using survival analysis and machine learning algorithms to assess the effects of eligibility criteria. Our study included 68,375 patients, with matched case-control groups comprising 1,126 patients each. Survival analysis revealed ethnicity and race, along with specific medical history (eligibility criteria), as significant survival outcome predictors. Machine learning models, particularly the XgBoost regressor, were employed to analyze SAEs, indicating that age and study groups were notable factors in SAEs occurrence. The study’s findings highlight the importance of considering patient demographics and medical history in CRC trial designs.
Implementation and Assessment of the HIV Enhanced Access Testing in the Emergency Department (HEATED) Program in Nairobi, Kenya: A Quasi-Experimental Prospective Study
Authors: Aluisio Adam R. , Smith-Sreen Joshua , Offorjebe Agatha , Maina Wamutitu , Pirirei Sankei , Kinuthia John , Bukusi David , Waweru Harriet , Bosire Rose , Ojuka Daniel K. , Eastment McKenna C. , Katz David A. , Mello Michael J. , Farquhar Carey 
Published: April 2024

ABSTRACTBackgroundPersons seeking emergency injury care are often from underserved key populations (KPs) and priority populations (PPs) for HIV programming. While facility-based HIV Testing Services (HTS) in Kenya are effective, emergency department (ED) delivery is limited, despite the potential to reach underserved persons.MethodsThis quasi-experimental prospective study evaluated implementation of the HIV Enhanced Access Testing in Emergency Departments (HEATED) at Kenyatta National Hospital ED in Nairobi, Kenya. The HEATED program was designed using setting specific data and utilizes resource reorganization, services integration and HIV sensitization to promote ED-HTS. KPs included sex workers, gay men, men who have sex with men, transgender persons and persons who inject drugs. PPs included young persons (18-24 years), victims of interpersonal violence, persons with hazardous alcohol use and those never previously HIV tested. Data were obtained from systems-level records, enrolled injured patient participants and healthcare providers. Systems and patient-level data were collected during a pre-implementation period (6 March - 16 April 2023) and post-implementation (period 1, 1 May - 26 June 2023). Additional, systems-level data were collected during a second post-implementation (period 2, 27 June – 20 August 2023). Evaluation analyses were completed across reach, effectiveness, adoption, implementation and maintenance framework domains.ResultsAll 151 clinical staff were reached through trainings and sensitizations on the HEATED program. Systems-level ED-HTS increased from 16.7% pre-implementation to 23.0% post-implementation periods 1 and 2 (RR=1.31, 95% CI:1.21-1.43; p<0.001) with a 62.9% relative increase in HIV self-test kit provision. Among 605 patient participants, facilities-based HTS increased from 5.7% pre-implementation to 62.3% post-implementation period 1 (RR=11.2, 95%CI:6.9-18.1; p<0.001). There were 440 (72.7%) patient participants identified as KPs (5.6%) and/or PPs (65.3%). For enrolled KPs/PPs, HTS increased from 4.6% pre-implementation to 72.3% post-implementation period 1 (RR=13.8, 95%CI:5.5-28.7, p<0.001). Systems and participant level data demonstrated successful adoption and implementation of the HEATED program. Through 16-weeks post-implementation a significant increase in ED-HTS delivery was maintained as compared to pre-implementation.ConclusionsThe HEATED program increased ED-HTS and augmented delivery to KPs/PPs, suggesting that broader implementation could improve HIV services for underserved persons, already in contact with health systems.
Etiologies of bloody diarrhea in children presenting with acute gastroenteritis to US emergency departments
Authors: Fonseca-Romero Paola , Ahmed Sharia M. , Brintz Ben J. , Vierkant D. Matthew , Bard Jennifer Dien , Cohen Daniel M. , Festekjian Ara , Leber Amy L. , Jackson Jami T. , Kanwar Neena , Larsen Chari , Selvarangan Rangaraj , Chapin Kimberle C. , Pavia Andrew T. , Leung Daniel T. 
Published: April 2024

AbstractAmong 111 children presenting with bloody diarrhea in a multicenter study of molecular testing in US emergency departments, we found viral pathogens in 18%, bacteria in 48%, protozoa in 2%, and no pathogens detected in 38%.
Dual targeting of GPX4 and TXNRD1 triggers eradication of AML cells through induction of apoptosis and ferroptosis
Authors: Favreau Cécile , Savy Coline , Bourgoin Maxence , Botton Thomas , Bailly Sarah , Granger Florence , Birck Catherine , Zerhouni Marwa , Kerreneur Emeline , Vigroux Alban , Gautheret Jade Dussart , Arcangeli Marie-Laure , Porterszman Arnaud , Cluzeau Thomas , Rocchi Stephane , Jacquel Arnaud , Benhida Rachid , Auberger Patrick , Martin Anthony R , Robert Guillaume 
Published: April 2024

ABSTRACTMyeloDysplastic Syndromes (MDS) are a group of heterogeneous hematological disorders characterized by bone marrow failure and abnormal hematopoietic cell expansion, often progressing to acute myeloid leukemia (AML). Current treatments for AML and high-risk MDS have limited efficacy, requiring the exploration of new therapeutic approaches. Recent research highlighted the potential of inducing cell death through ferroptosis, either independently or alongside traditional chemotherapy, as promising approaches for treating MDS/AML cells. We described here two novel compounds, HA344 and #231, capable of targeting both ferroptosis and apoptosis, leading to the effective eradication of cell lines and primary blasts from MDS/AML patients, while sparing normal hematopoietic cells. RNASeq analysis identified oxidation reduction and apoptotic processes as highly significant induced pathways in two different AML cell lines. Using click-chemistry approaches coupled to mass spectrometry, we identified glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1) as the main targets of HA344 and #231 in a large panel of AML cells. Accordingly, both compounds inhibited GPX4 and TXNRD1 activity in the micromolar range and triggered GPX4 degradation. Moreover, using recombinant GPX4 carrying or not a selenium (GPX4-Se and GPX4-S), we confirmed by mass spectrometry that HA344 and #231 bind more efficiently GPX4-Se than GPX4-S. In conclusion, these compounds might represent a new pharmacological approach in the treatment of MDS and AML, offering a potential avenue for future therapies.
Blended Genome Exome (BGE) as a Cost Efficient Alternative to Deep Whole Genomes or Arrays
Authors: DeFelice Matthew , Grimsby Jonna L. , Howrigan Daniel , Yuan Kai , Chapman Sinéad B. , Stevens Christine , DeLuca Samuel , Townsend Megan , Buxbaum Joseph , Pericak-Vance Margaret , Qin Shengying , Stein Dan J. , Teferra Solomon , Xavier Ramnik J. , Huang Hailiang , Martin Alicia R. , Neale Benjamin M. 
Published: April 2024

AbstractGenomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation has recently been shown to yield 99% of association signals detected by WGS. However, a method free from ascertainment biases of arrays or the need for merging different data types that still benefits from deeper exome coverage to enhance novel coding variant detection does not exist. We developed a new, combined, “Blended Genome Exome” (BGE) in which a whole genome library is generated, an aliquot of that genome is amplified by PCR, the exome regions are selected and enriched, and the genome and exome libraries are combined back into a single tube for sequencing (33% exome, 67% genome). This creates a single CRAM with a low-coverage whole genome (2-3x) combined with a higher coverage exome (30-40x). This BGE can be used for imputing common variants throughout the genome as well as for calling rare coding variants. We tested this new method and observed >99% r2concordance between imputed BGE data and existing 30x WGS data for exome and genome variants. BGE can serve as a useful and cost-efficient alternative sequencing product for genomic researchers, requiring ten-fold less sequencing compared to 30x WGS without the need for complicated harmonization of array and sequencing data.
Continuous monitoring of glucose levelsin vivowith a micro-organ based microfluidic biosensor
Authors: Puginier Emilie , Pirog Antoine , Poulletier de Gannes Florence , Gaitan Julien , Hurtier Annabelle , Monchablon Marie , Raoux Matthieu , Renaud Sylvie , Lang Jochen 
Published: April 2024

ABSTRACTContinuous monitoring of glucose levels has improved diabetes therapy. Current approaches rely on enzyme-linked electrochemical probes but do not allow a fully autonomous artificial pancreas. In contrast, monitoring the activity of a few electrogenic pancreatic islets in a biosensor may harness the computational power of the different endocrine cell types in the micro-organ, shaped for nutrient detection during evolution, and provide a more appropriate read-out. Extracellular electrophysiology captures slow potentials (SPs), which reflect coupled islet β-cell activity and is thus a method of choice for long-term monitoring of native islet activityin vitro.We have now developed a microfluidic microelectrode chip containing a few islets and linked to interstitial fluids in live rats by subcutaneous microdialysis. The electrical activity in terms of slow potentials monitored by this biosensor reactsex vivoproportionally to glucose levels off-line in serum or dialysed interstitial fluid. On-line monitoringin vivoreveals an excellent correlation between islet slow potential frequency, and to a lesser degree to slow potential amplitudes, to glucose concentrations with little variation between animals. The microorgan-based biosensor harness multiple parametersin vivoand provides a read-out closer to physiology. This demonstrates the usefulness of such biosensors for sensor-based therapy of diabetes.