bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of second booster compared to first booster and protection conferred by previous SARS CoV-2 infection against symptomatic Omicron BA.2 and BA.4/5 in France
Authors: Tamandjou Cynthia , Auvigne Vincent , Schaeffer Justine , Vaux Sophie , du Châtelet Isabelle Parent 
Published: January 2023

AbstractIn face of evidence of rapid waning of vaccine effectiveness against Omicron and its sub-lineages, a second booster with mRNA vaccines was recommended for the most vulnerable in France. We used a test negative design to estimate the effectiveness of the second booster relative to the first booster and the protection conferred by a previous SARS-CoV-2 infection, against symptomatic Omicron BA.2 or BA.4/5. We included symptomatic ≥60 years old individuals tested for SARS-CoV-2 in March 21-October 30, 2022. Compared to a 181-210 days old first booster, a second booster restored protection with a relative effectiveness of 39% [95%CI: 38% - 41%], 7-30 days post-vaccination This gain in protection was lower than the one observed with the first booster, at equal time points since vaccination. High levels of protection were associated to previous SARS-CoV-2 infection, especially if the infection was recent and occurred when an antigenic-related variant was dominant.HighlightsA second Wuhan-like mRNA booster brought additional protection against symptomatic Omicron BA.2 or BA.4/5 infections, relative to a first booster given 181 to 210 days ago.The gain in protection offered by a second booster was lower to the protection observed with a first booster, at equal time points since these booster doses.Previous infection, in a vaccinated population, offered high levels and long-lasting protection against symptomatic Omicron BA.2 or BA.4/5 infections.
‘It’s about dying, not just a broken leg’ - Qualitative findings on paramedics’ perception of end-of-life situations in rescue scenarios in Germany
Authors: Rieder Nicola , Banse Christian , Schade Franziska , Nauck Friedemann 
Published: January 2023

ABSTRACTIn Germany, paramedics and emergency physicians arrive separately on scene (‘rendez-vous-system’), which aims to save resources when no physician is needed. Usually, paramedics arrive firstly on scene, and are obliged by law to perform all possible action to maintain a patient’s life. Especially in end-of-life (EoL) situations, this can cause conflicts, as those patients may require a decent consideration between ‘saving life’ and ‘allowing to die’. Whereas the emergency physicians’ perspective on this issue is relatively well examined, until today, in Germany, little is known about the (non-physician) paramedics’ perception.AimTo explore paramedics’ perception of rescue scenarios involving patients with advanced, incurable, severe diseases facing their EoL and to scientifically classify this cross-sectional field through experts from different research fields.MethodSeven semi-structured narrative interviews with paramedics and one focus group with representatives from the Center for Medical Law in Goettingen were conducted and analysed using qualitative content analysis.ResultsSix key categories emerged from the data. Rescue scenarios in EoL situations are perceived as highly complex situations that are narrowed down through deviating goals of care (1), limited options for action (2), an emotional overload of all involved actors (3), consequences of a neglected (care) planning in advance (4) and various background structures, such as current societal and demographic changes (5) and systemic challenges (6). Complexity also arises from the multiple influences of the different categories/ their content on one another.DiscussionBeing confronted with patients that do not wish for further life-maintaining treatment marks a significant shift concerning the range of rescue scenarios, resulting from (i.a.) demographic developments and structural dynamics in health care. Therefore, in addition to specific actions restoring paramedics’ ability to act in rescue scenarios in EoL situations, a general discussion of the emergency services’ area of responsibility as well as the (emergency) medical treatment and care of patients with advanced, incurable, severe diseases is required.
Development of a clinical decision-support tool for Management of Adolescent knee Pain (The MAP-Knee Tool)
Authors: Riel Henrik , Bruun Malene Kjær , Djurtoft Chris , Jensen Martin Bach , Kaalund Søren , van Leeuwen Guido , Overgaard Charlotte , Rahbek Ole , Rathleff Michael Skovdal 
Published: January 2023

AbstractObjectiveThis study aimed to develop a clinical decision-support tool (The MAP-Knee Tool) to improve the management of adolescents with non-traumatic knee pain.MethodsThis multi-step study consisted of five steps ((1-4) initial development and (5) end-user testing with adolescents with or without non-traumatic knee pain and medical doctors). It ended with the first version of the MAP-Knee Tool for the six most common non-traumatic knee pain conditions. The tool includes four components: 1) tool for diagnosing, 2) credible explanations of the diagnoses based on two systematic literature searches and an Argumentative Delphi process with international experts, 3) prognostic factors based on an individual participant data meta-analysis, and 4) option grid including an unbiased presentation of management options based on the available evidence.ResultsWe included seven children/adolescents (8-15 years old) and seven medical doctors for the end-user testing. All four components were revised accordingly, and the text was condensed as the initial draft was too comprehensive.ConclusionWe developed a clinical decision-support tool for clinicians and adolescents with non-traumatic knee pain to support the consultation in clinical practice.Practice ImplicationsThe tool targets clinicians and adolescents with four components that may decrease diagnostic uncertainty and increase shared decision-making.
Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients
Authors: Badla Beshr Abdulaziz , Hanifa Mohamed Samer , Jain Ruchi , El Naofal Maha , Halabi Nour , Yaslam Sawsan , Ramaswamy Sathishkumar , Taylor Alan , Alfalasi Roudha , Shenbagam Shruti , Khansaheb Hamda , Al Suwaidi Hanan , Nowotny Norbert , Popatia Rizwana , Khayat Abdulla Al , Alsheikh-Ali Alawi , Loney Tom , AlDabal Laila Mohamed , Tayoun Ahmad Abou 
Published: January 2023

AbstractStudies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 ± SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediated and bacterial infection-susceptibility genes, when compared to control, mildly affected, or asymptomatic COVID-19 patients (N = 25), or to general populations representing Asia and the Middle East. Genetic variants tended to associate with mortality, intensive care admission, and ventilation support. Our findings confirm the association of interferon pathway genes with severe COVID-19 and highlight the importance of extending genetic studies to diverse populations given implications for pan-ethnic therapeutic and genetic screening options.Author SummaryBased on the hypothesis that rare monogenic variants contribute to the severity of SARS-CoV-2 infection outcomes, we performed whole exome sequencing in young, previously healthy patients with severe COVID-19 of Asian or Middle Eastern origins. We found an enrichment of rare missense and truncating variants in immune-related genes, mainly associated with interferon pathways and susceptibility to bacterial infections, which can be therapeutic targets. Genetic findings tended to correlate with mortality, intensive care unit (ICU) admission, high dependency unit (HDU) admission, and invasive ventilation.
A cross-sectional survey examining the association of clinician characteristics with perceived changes in cervical cancer screening and colposcopy practice during the COVID-19 pandemic
Authors: Fuzzell Lindsay , Brownstein Naomi C. , Fontenot Holly B. , Lake Paige , Michel Alexandra , Whitmer Ashley , Rossi Sarah L. , McIntyre McKenzie , Vadaparampil Susan T. , Perkins Rebecca 
Published: January 2023

AbstractBackgroundThe COVID-19 pandemic led to reductions in cervical cancer screening and colposcopy. Therefore, in this mixed method study we explored perceived pandemic-related practice changes to cervical cancer screenings and colposcopies.MethodsIn 2021, a national sample of 1,251 clinicians completed surveys, including 675 clinicians who performed colposcopy; a subset (n=55) of clinicians completed qualitative interviews.ResultsNearly half of all clinicians reported they were currently performing fewer cervical cancer screenings (47%) and colposcopies (44% of those who perform the procedure) than before the pandemic. About one-fifth (18.6%) of colposcopists reported performing fewer LEEPs than prior to the pandemic. Binomial regression analyses indicated that older, non-White, internal medicine and family medicine clinicians (compared to OB-GYNs), and those practicing in community health centers (compared to private practice) had higher odds of reporting reduced screening. Among colposcopists, males, internal medicine physicians, those practicing in community health centers, and in the South had higher odds of reporting reduced colposcopies. Qualitative interviews highlighted pandemic-related care disruptions and lack of tracking systems to identify overdue screenings.ConclusionsReductions in cervical cancer screening and colposcopy among nearly half of clinicians more than one year into the pandemic raise concerns that inadequate screening and follow-up will lead to future increases in preventable cancers.FundingThis study was funded by the American Cancer Society, who had no role in the study’s design, conduct, or reporting.
Magnetic seizure therapy and electroconvulsive therapy increase aperiodic activity
Authors: Smith Sydney E. , Kosik Eena L. , van Engen Quirine , Kohn Jordan , Hill Aron T. , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Hadas Itay , Voytek Bradley 
Published: January 2023

AbstractMajor depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical “slowing” of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.
Axial regionalization inTiktaalik roseaeand the origin of quadrupedal locomotion
Authors: Stewart T.A. , Lemberg J.B. , Hillan E.J. , Magallanes I. , Daeschler E.B. , Shubin N.H. 
Published: January 2023

SummaryThe origin of quadrupedal locomotion in tetrapods entailed the evolution of a regionalized axial skeleton with sacral ribs. These ribs provide linkage between the pelvis and vertebral column and contribute to body support and propulsion by the hind limb. The closest relatives of limbed vertebrates are not known to possess such a connection and, therefore, have typically been described as primarily supporting their bodies against the substrate with pectoral fins. However, data on the axial skeletons of stem tetrapods are sparce, with key features of specimens potentially concealed by matrix. Here we provide micro-computed tomography data of the axial skeleton ofTiktaalik roseaeand show that its vertebrae and ribs are regionalized along the craniocaudal axis, including expanded and ventrally curved ribs in the sacral region. The sacral ribs would have contacted the expanded iliac blade of the pelvis in a soft tissue connection. No atlas-axis complex is observed, however the basioccipital-exoccipital complex is deconsolidated from the rest of the neurocranium, suggesting increased mobility at occipital-vertebral junction. Thus, axial regionalization that allowed for innovations in head mobility, body support and buttressing the pelvic fin evolved prior to the origin of limbs.
Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes
Authors: Ma Liang , Singh Jasleen , Schekman Randy 
Published: January 2023

AbstractFusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a “cold shock” domain (CSD) of YBX1 through a 5’ proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.
Protein aggregation in plant mitochondria inhibits translation and induces an NAC017-dependent ethylene-associated unfolded protein response
Authors: Song Ce , Li Yuanyuan , Hou Yuqi , Yang Mengmeng , Li Tiantian , Liu Yinyin , Xu Chang , Liu Jinjian , Millar A. Harvey , Wang Ningning , Li Lei 
Published: January 2023

AbstractLoss of Lon1 in plant mitochondria led to stunted plant growth and accumulation of nuclear-encoded mitochondrial proteins, including Lon1 substrates, while mitochondrial-encoded proteins typically decreased in abundance. Lon1 mutants contained protein aggregates in the mitochondria matrix which were enriched in PPR-containing proteins and ribosomal subunits of the translation apparatus and were slowed in mitochondrial RNA splicing, editing and general translation rate. Transcriptome analysis showed multiple organellar unfolded protein responses involving ethylene biosynthesis were induced by either Lon1 loss, mitochondrial ribosomal protein loss, translation or respiratory inhibition and most were regulated by the mitochondrial retrograde signaling pathway dependent on the transcription factor NAC017. The short hypocotyl inlon1mutants during skotomorphogenesis was partially rescued by ethylene inhibitors and mutants showed higher ethylene production rates than wildtype. Together this provides multiple steps in the link between loss of Lon1 and its whole plant phenotype.Single Sentence SummaryLon1 knockout inhibits mitochondrial-encoded gene translation and induces retrograde signaling involving unfolded protein responses.
Molecular identification of ALDH1A1 and SIRT2 in the astrocytic putrescine-to-GABA metabolic pathway
Authors: Bhalla Mridula , Shin Jeong Im , Ju Yeon Ha , Park Yongmin Mason , Yoo Seonguk , Lee Hyeon Beom , Lee C Justin 
Published: January 2023

ABSTRACTGABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter in the CNS. In astrocytes, GABA is synthesized by degradation of putrescine by monoamine oxidase B (MAO-B), a process which is known to mediate tonic inhibition of neuronal excitability. This astrocytic tonic GABA and related enzymes are also reported to be involved in memory impairment in Alzheimer’s Disease, and therefore are potential therapeutic targets to rescue memory in AD patients. However, the enzymes downstream of MAO-B in this pathway have not been elucidated yet. To fill this gap in knowledge, we performed transcriptomic and literature database analysis and identified Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and a histone deacetylase enzyme Sirtuin2 (SIRT2) as plausible candidate enzymes in primary cultured astrocytes. Immunostaining, metabolite analyses, and sniffer patch clamp performed in the presence or absence of suitable inhibitors, or with genetic ablation of the candidate enzymes recapitulated their participation in GABA production. We propose ALDH1A1 and SIRT2 as potential therapeutic targets against Alzheimer’s Disease.
Production of β-PheRS fragments correlates with food avoidance and slow growth, and is suppressed by the appetite-inducing hormone CCHa2
Authors: Brunßen Dominique , Suter Beat 
Published: January 2023

AbstractThe housekeeping tRNA synthetases play many non-canonical roles with diverse functions. The phenylalanyl-tRNA synthetase (PheRS/FARS) is an α2β2tetramere. Recently, human patients with mutations inFARSB, the homolog ofβ-PheRSin Drosophila, have been reported to display problems gaining weight. Here, we show in Drosophila that overexpressing the β subunit in the context of the complete PheRS leads to larval roaming, food avoidance, slow growth, and a developmental delay that can last several days and even prevents pupation. Narrowing down the tissue involved in this behavioral and developmental effect revealed that expression in CCHa2+and Pros+cells induced this phenotype. Simultaneous expression of β-PheRS, α-PheRS, and the appetite-inducing CCHa2 peptide rescued these phenotypes, linking thisβ-PheRSactivity to the appetite-controlling pathway. The fragmentation dynamics of the excessive β-PheRS points to a β-PheRS fragment as a likely candidate inducer of these phenotypes. Fragmentation of PheRS (FARS) has also been observed in humans and mutations in humanβ-PheRS (FARSB)can lead to problems in gaining weight. This study, therefore, points to a potential mechanism for the human phenotype and to possible novel approaches to research ways to correct the balance between hunger and satiety signals in the context of obesity.
Not all Notch pathway mutations are equal in the embryonic mouse retina
Authors: Bosze Bernadett , Suarez-Navarro Julissa , Cajias Illiana , Brzezinski Joseph A. , Brown Nadean L 
Published: January 2023

AbstractIn the vertebrate retina, combinations of Notch ligands, receptors, and ternary complex components determine the destiny of retinal progenitor cells by regulatingHeseffector gene activity. Owing to reiterated Notch signaling in numerous tissues throughout development, there are multiple vertebrate paralogues for nearly every node in this pathway. These Notch signaling components can act redundantly or in a compensatory fashion during development. To dissect the complexity of this pathway during retinal development, we used seven germline or conditional mutant mice and two spatiotemporally distinct Cre drivers. We perturbed the Notch ternary complex and multipleHesgenes with two overt goals in mind. First, we wished to determine if Notch signaling is required in the optic stalk/nerve head for Hes1 sustained expression and activity. Second, we aimed to test ifHes1, 3and5genes are functionally redundant during early retinal histogenesis. With our allelic series, we found that disrupting Notch signaling consistently blocked mitotic growth and overproduced ganglion cells, but we also identified two significant branchpoints for this pathway. In the optic stalk/nerve head, sustained Hes1 is regulated independent of Notch signaling, whereas during photoreceptor genesis both Notch-dependent and -independent roles forRbpjandHes1impact photoreceptor genesis in opposing manners.
Vectored Immunoprophylaxis and Treatment of SARS-CoV-2 Infection
Authors: Tada Takuya , Dcosta Belinda M. , Minnee Julia , Landau Nathaniel R. 
Published: January 2023

SummaryVectored immunoprophylaxis was first developed as a means to establish engineered immunity to HIV through the use of an adeno-associated viral vector expressing a broadly neutralizing antibody. We have applied this concept to establish long-term prophylaxis against SARS-CoV-2 by adeno-associated and lentiviral vectors expressing a high affinity ACE2 decoy receptor. Administration of decoy-expressing AAV vectors based on AAV2.retro and AAV6.2 by intranasal instillation or intramuscular injection protected mice against high-titered SARS-CoV-2 infection. AAV and lentiviral vectored immunoprophylaxis was durable and active against recent SARS-CoV-2 Omicron subvariants. The AAV vectors were also effective when administered up to 24 hours post-infection. Vectored immunoprophylaxis could be of value for immunocompromised individuals for whom vaccination is not practical and as a means to rapidly establish protection from infection. Unlike monoclonal antibody therapy, the approach is expected to remain active despite continued evolution viral variants.
Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp
Authors: Neininger-Castro Abigail C. , Hayes James B. , Sanchez Zachary C. , Taneja Nilay , Fenix Aidan M. , Moparthi Satish , Vassilopoulos Stéphane , Burnette Dylan T. 
Published: January 2023

ABSTRACTSarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the “Z-Bodies” of sarcomere precursors and the “Z-Lines” of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance. Previous measurements of α-actinin-2 organization have been largely accomplished manually, which is time-consuming and has hampered research progress. Here, we introduce sarcApp, an image analysis tool that quantifies several components of the cardiac sarcomere and their alignment in muscle cells and tissue. We first developed sarcApp to utilize deep learning-based segmentation and real space quantification to measure α-actinin-2 structures and determine the organization of both precursors and sarcomeres/myofibrils. We then expanded sarcApp to analyze “M-Lines” using the localization of myomesin and a protein that connects the Z-Lines to the M-Line (titin). sarcApp produces 33 distinct measurements per cell and 24 per myofibril that allow for precise quantification of changes in sarcomeres, myofibrils, and their precursors. We validated this system with perturbations to sarcomere assembly. We found perturbations that affected Z-Lines and M-Lines differently, suggesting that they may be regulated independently during sarcomere assembly.