bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparing tonic and phasic calcium in the dendrites of vulnerable midbrain neurons
Authors: Chen Rita Yu-Tzu , Evans Rebekah C. 
Published: August 2023

AbstractSeveral midbrain nuclei degenerate in Parkinson’s Disease (PD). Many of these nuclei share the common characteristics that are thought to contribute to their selective vulnerability, including pacemaking activity and high levels of calcium influx. In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. It is well established that the low-threshold L-type calcium current is a main contributor to tonic calcium in SNc dopaminergic neurons and is hypothesized to contribute to their selective vulnerability. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in the tonic and phasic activity of PPN neurons and the corresponding dendritic calcium signal and directly compare these characteristics to SNc neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the calcium load in PPN neurons during pacemaking did not depend on L-type channels. However, we find that blocking L-type channels reduces phasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells.
Cortico-hippocampal representational similarity contributes to learning of multiple motor sequences
Authors: Yoon Seojin , Kim Sungshin 
Published: August 2023

AbstractCortico-hippocampal interaction is integral to memory consolidation during sleep or wakeful rest. However, the extent of its engagement in non-declarative motor memory during skill learning remains largely undefined. Specifically, it remains unclear how neural representations in cortical and hippocampal regions are related to learning multiple motor sequences. Here, we conducted an fMRI experiment in which participants learned four distinct motor sequences in a pseudo-random order with interleaved rest periods. We found pattern separation in the sensorimotor regions was significant, particularly in the anterior motor cortex, related to early learning performance. However, there was no pattern separation in the hippocampus during the rest periods. Intriguingly, the representational similarity between the motor cortex during task periods and the hippocampus during rest periods was highly correlated with overall learning performance. These findings suggest a new role of hippocampal replay in motor sequence learning, that is, learning a more abstract relational structure of sequences instead of representing sequences per se.
ASTA-P: a pipeline for the detection, quantification and statistical analysis of complex alternative splicing events
Authors: Tiwari Kanupriya , Nielsen Lars Keld 
Published: August 2023

AbstractAlternative splicing dramatically increases the repertoire of the human transcriptome and plays a critical role in cellular differentiation. Long read sequencing has dramatically improved our ability to explore isoform diversity directly. However, short read sequencing still provides advantages in terms of sequencing depth at low cost, which is important in comparative quantitative studies. Here, we present a pipeline called ASTA-P for profiling, quantification, and differential splicing analysis of tissue-specific, arbitrarily complex alternative splicing patterns. We discover novel events by supplementing existing annotation with reconstructed transcripts and use spliced RNA-seq reads to quantify splicing changes accurately based on their unique assignments. We used simulated RNA-seq data to demonstrate that ASTA-P provides a good trade-off between discovery and accuracy compared with several popular methods. Further, we applied ASTA-P to analyse AS patterns in real data from hiPSC derived cranial neural crest cells capturing the transition from primary neural cells into migratory cranial neural crest cells, differentiated by their expression of the transcription factor, SOX10. Our analysis revealed a significant splicing complexity, i.e., numerous AS events that cannot be described using the conventionally analysed 2D splicing event patterns. Such events are misclassified when analysed using current differential splicing analysis methods. Thus, ASTA-P provides a new approach for studying both conventional and complex splicing across different cellular conditions and the dynamic regulation of AS. The pipeline is available athttps://github.com/uqktiwar/ASTAP/tree/main
The Atad5 RFC-like complex is the major unloader of proliferating cell nuclear antigen inXenopusegg extracts
Authors: Kawasoe Yoshitaka , Shimokawa Sakiko , Gillespie Peter J. , Blow J. Julian , Tsurimoto Toshiki , Takahashi Tatsuro S. 
Published: August 2023

AbstractProliferating cell nuclear antigen (PCNA) is a homo-trimeric clamp complex that serves as the molecular hub for various DNA transactions, including DNA synthesis and post-replicative mismatch repair. Its timely loading and unloading are critical for genome stability. PCNA loading is catalyzed by Replication factor C (RFC) and the Ctf18 RFC-like complex (Ctf18-RLC), and its unloading is catalyzed by Atad5/Elg1-RLC. However, RFC, Ctf18-RLC, and even some subcomplexes of their shared subunits are capable of unloading PCNAin vitro, leaving an ambiguity in the division of labor in eukaryotic clamp dynamics. By using a system that specifically detects PCNA unloading, we show here that Atad5-RLC, which accounts for only approximately 3% of RFC/RLCs, nevertheless provides the major PCNA unloading activity inXenopusegg extracts. RFC and Ctf18-RLC each account for approximately 40% of RFC/RLCs, while immunodepletion of neither Rfc1 nor Ctf18 detectably affects the rate of PCNA unloading in our system. PCNA unloading is dependent on the ATP-binding motif of Atad5, independent of nicks on DNA and chromatin assembly, and inhibited effectively by PCNA-interacting peptides. These results support a model in which Atad5-RLC preferentially unloads DNA-bound PCNA molecules that are free from their interactors.
Effectiveness of mass dengue vaccination in the state of Paraná, Brazil: integrating case-cohort and case-control designs
Authors: Diaz-Quijano Fredi Alexander , de Carvalho Denise Siqueira , Raboni Sonia Mara , Shimakura Silvia Emiko , de Mello Angela Maron , da Costa-Ribeiro Magda Clara Vieira , Silva Lineu , da Cruz Magalhães Buffon Marilene , Maluf Eliane Mara Cesario Pereira , Graeff Gabriel , Almeida Gustavo , Preto Clara , Luhm Karin Regina 
Published: August 2023

AbstractWe aimed to estimate the effectiveness of CYD-TDV in preventing symptomatic dengue cases during a campaign targeting individuals aged 15-27 years in selected municipalities in Paraná, Brazil. Additionally, we examined whether a history of dengue, as recorded by the surveillance system, modified the vaccine’s effectiveness.MethodsWe conducted a case-cohort analysis comparing the frequency of vaccination, with at least one dose of CYD-TDV, in individuals confirmed to have dengue by RT-PCR, identified by the surveillance system during 2019 and 2020, with the vaccination coverage in the target population. Moreover, with a case-control design using weighted controls, we assessed the history of dengue as a modifier of the vaccine’s effectiveness. The analyses were performed using a logistic random-effects regression model, with data clustered in municipalities and incorporating covariates such as the incidence of dengue before the campaign, age, and sex.ResultsDuring the study period, 1,869 cases of dengue were identified. The vaccination frequency among these cases was significantly lower than the overall vaccination coverage of the participating municipalities (50.4% vs. 57.2%, respectively; adjusted odds ratio: 0.79; 95% confidence interval: 0.72–0.87). In individuals with a history of dengue, vaccination was more than 70% effective in reducing the incidence of dengue. However, vaccination was not associated with significantly reducing the overall dengue case risk in individuals without a history of dengue.ConclusionVaccination significantly decreased dengue cases in the target population. The case-control design suggested that this reduction was primarily driven by the benefits seen in individuals with a history of dengue. Previous dengue diagnosis recorded by epidemiological surveillance could serve as a criterion for the recommendation of CYD-TDV, especially in endemic regions with limited serological testing facilities.
Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19
Authors: Ripoll Juan G. , Tulledge-Scheitel Sidna M. , Stephenson Anthony A. , Ford Shane , Pike Marsha L. , Gorman Ellen K. , Hanson Sara N. , Juskewitch Justin E. , Miller Alex J. , Zaremba Solomiia , Ovrom Erik A. , Razonable Raymund R. , Ganesh Ravindra , Hurt Ryan T. , Fischer Erin N. , Derr Amber N. , Eberle Michele R. , Larsen Jennifer J. , Carney Christina M. , Theel Elitza S. , Parikh Sameer A. , Kay Neil E. , Joyner Michael J. , Senefeld Jonathon W. 
Published: August 2023

ABSTRACTAlthough severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. Additionally, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19 specific therapeutics (standard of care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard of care group, which corresponded to a relative risk reduction of 65% (P=0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19 specific therapies reduced the risk of disease progression leading to hospitalization.IMPORTANCEAs SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged which evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19 specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.
A Systematic Review on the Effect of Diabetes Mellitus on the Pharmacokinetics of Tuberculosis Drugs
Authors: Cevik Muge , Sturdy Ann , Maraolo Alberto Enrico , Dekkers Bart G.J. , Akkerman Onno W. , Gillespie Stephen H. , Alffenaar Jan-Willem C. 
Published: August 2023

AbstractObjectivesThe coexistence of TB and DM (TB-DM) has been associated with an increased risk of treatment failure, death, delayed culture conversion and drug resistance. As plasma concentrations may influence clinical outcomes, we evaluated the evidence on the PK of TB drugs in DM individuals to guide management.MethodsWe performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).ResultsOut of 4173 potentially relevant articles, we identified 16 studies assessing rifampicin PK, 9 on isoniazid, 8 on pyrazinamide and 3 on ethambutol. Two studies reported on second line anti-TB drugs. According to our analysis, RIF Tmax was significantly prolonged in patients with DM compared to non-DM patients. We found no significant differences for RIF Cmax, AUC0-24or C2hr, INH C2hr, PZA C2hr, PZA Tmaxand ETB Tmax. While RIF C2hr was slightly reduced in TB-DM patients, this finding was not statistically significant.ConclusionsThis review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among studies. Given the association between lower plasma concentrations and poor clinical outcomes among DM patients, we recommend a higher dose limit to correct for larger bodyweight of patients with DM.
Changes in respiratory infection trends during the COVID-19 pandemic in the haematologic malignancy patients
Authors: RYOO Jiwon , Kim Seok Chan , Lee Jongmin 
Published: August 2023

AbstractBackgroundThe coronavirus disease 2019 (COVID-19) pandemic globally changed respiratory infection patterns. However, its impact on community-acquired pneumonia (CAP) in high risk patients with haematological malignancies (HM) is uncertain. We aimed to examine CAP aetiology changes in patients with HM pre- and post-COVID-19 pandemic.MethodsThis retrospective study included 524 HM patients hospitalised with CAP between March 2018 and February 2022. Those who underwent bronchoscopy within 24 hours after admission to identify CAP aetiology were included. Data on patient characteristics, laboratory findings, and results of bronchioalveolar lavage fluid cultures and PCR tests were analysed to compare etiological changes and identify in-hospital mortality risk factors.ResultsPatients were divided into pre-COVID-19 (44.5%) and post-COVID-19 (55.5%) groups. This study found a significant decrease in viral CAP in the post-COVID-19 era, particularly for influenza A, parainfluenza, adenovirus, and rhinovirus (3.0% vs. 0.3%, respectively, P = 0.036; 6.5% vs. 0.7%, respectively, P = 0.001; 5.6% vs. 1.4%, respectively, P = 0.015; 9.5% vs. 1.7%, respectively, P < 0.001). Bacterial, fungal, and unknown CAP aetiologies remain unchanged. Higher Sequential Organ Failure Assessment scores and lower platelet count correlated with in-hospital mortality after adjusting for potential confounding factors.ConclusionThe incidence of CAP in HM patients did not decrease after COVID-19. Additionally, CAP aetiology among patients with HM changed following the COVID-19 pandemic, with a significant reduction in viral pneumonia while bacterial and fungal pneumonia persisted. Further studies are required to evaluate the impact of COVID-19 on the prognosis of patients with HM and CAP.
Atypical memory B cells form a pre-plasmacellular reservoir for steady-state IgD responses to common nasopharyngeal antigens
Authors: Tachó-Piñot Roser , Bashour Habib , Filipska Martyna , Tejedor-Vaquero Sonia , de Campos-Mata Leire , Sáez-Gordón Alba , Perera-Bel Júlia , Guzman Mauricio , Marcos-Fa Xavi , Canales-Herrerias Pablo , Domínguez-Barragán Jorge , Arcós-Ribas Berta , Slabodkin Andrei , Chernigovskaya Maria , de la Concepción María Luisa Rodríguez , Gutierrez-Marcos José , García-García Ana , Nascimento-Osorio Andrés , Pascal Mariona , Alsina Laia , Aróstegui Juan I. , Mehandru Saurabh , Cunningham-Rundles Charlotte , Carrillo Jorge , Magri Giuliana , Greiff Victor , Cerutti Andrea 
Published: August 2023

AbstractThe human nasopharyngeal mucosa includes organized lymphoepithelial structures continually engaged in frontline immune responses to aerodigestive antigens. Advancing our understanding of these responses might lead to the development of new strategies for the prevention and treatment of common immune disorders such as allergies. Here we identified a hitherto elusive tonsillar subset of atypical IgD class-switched IgD+IgM-memory (IgD-ME) B cells that were clonally related to IgD+IgM−germinal center (IgD-GC) B cells and IgD-secreting IgD+IgM−plasma cells (IgD-PCs) but not anergic IgD+IgM−B cells. Consistent with their pre-plasmacellular properties, IgD-ME B cells served as preferential precursors of IgD-PCs over IgD-GC B cells. IgD antibodies from IgD+IgM−cells acquired reactivity to multiple oral, airborne and commensal antigens through a mutation-dependent pathway involving both innate and adaptive signals. Thus, IgD-ME B cells may form a ready-to-use pre-plasmacellular reservoir for steady-state IgD responses likely aimed at enhancing nasopharyngeal homeostasis.One Sentence SummaryTonsillar atypical memory B cells form a ready-to-use pre-plasmacellular repertoire for IgD responses to common aerodigestive antigens.
Building a realistic, scalable memory model with independent engrams using a homeostatic mechanism
Authors: Kaster Marvin , Czappa Fabian , Butz-Ostendorf Markus , Wolf Felix 
Published: August 2023

AbstractMemory formation is usually associated with Hebbian learning, using synaptic plasticity to change the synaptic strengths but omitting structural changes. Recent work suggests that structural plasticity can also lead to silent memory engrams, reproducing a conditioned learning paradigm with neuron ensembles. However, this work is limited by its way of synapse formation, enabling the formation of only one memory engram. Overcoming this, our model allows the formation of many engrams simultaneously while retaining high neurophysiological accuracy, e.g., as found in cortical columns. We achieve this by substituting the random synapse formation with the Model of Structural Plasticity (Butz and van Ooyen, 2013). As a homeostatic model, neurons regulate their activity by growing and pruning synaptic elements based on their current activity. Utilizing synapse formation based on the Euclidean distance between the neurons with a scalable algorithm allows us to easily simulate 4 million neurons with 343 memory engrams. These engrams do not interfere with one another by default, yet we can change the simulation parameters to form long-reaching associations. Our model paves the way for simulations addressing further inquiries, ranging from memory chains and hierarchies to complex memory systems comprising areas with different learning mechanisms.
Opportunities for risk-taking during play alters cognitive performance and prefrontal inhibitory signalling in rats of both sexes
Authors: Bijlsma Ate , Birza Evelien E. , Pimentel Tara C. , Maranus Janneke P.M. , van Gaans Marieke J.J.M , Lozeman-van t Klooster José G. , Baars Annemarie J.M. , Achterberg E.J. Marijke , Lesscher Heidi M.B. , Wierenga Corette J. , Vanderschuren Louk J.M.J. 
Published: August 2023

AbstractSocial play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision-making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes, and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered PFC synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.
Treatment with a selective histone deacetylase (HDAC) 1 and 2 inhibitor in aged mice rejuvenates multiple organ systems
Authors: Tammaro Alessandra , Daniels Eileen G. , Hu Iman M. , ‘t Hart Kelly C. , Reid Kim , Juni Rio P. , Butter Loes M. , Vasam Goutham , Kamble Rashmi , Jongejan Aldo , Aviv Richard I. , Roelofs Joris J.T.H. , Aronica Eleonora , Boon Reinier A. , Menzies Keir J. , Houtkooper Riekelt H. , Janssens Georges E. 
Published: August 2023

ABSTRACTThe process of aging increases the risk of developing age-related diseases, which come at great societal healthcare costs and suffering to individuals. Meanwhile, targeting the basic mechanisms of aging can reduce the risk of developing age-related diseases during aging, essentially resulting in a ‘healthy aging’ process. Multiple aging pathways exist, which over past decades have systematically been confirmed through gene knockout or overexpression studies in mammals and the ability to increase healthy lifespan. In this work, we perform transcriptome-based drug screening to identify small molecules that mimic the transcriptional profiles of long-lived genetic interventions in mammals. We identify one small molecule whose transcriptional effects mimic diverse known genetic longevity interventions: compound 60 (Cmpd60), which is a selective inhibitor of histone deacetylase 1 (HDAC1) and 2 (HDAC2). In line with this, in a battery of molecular, phenotypic, and bioinformatic analyses, in multiple disease cell and animal models, we find that Cmpd60 treatment rejuvenates multiple organ systems. These included the kidney, brain, and heart. In renal aging, Cmpd60 reduced partial epithelial-mesenchymal transition (EMT)in vitroand decreased fibrosisin vivo. For the aging brain, Cmpd60 reduced dementia-related gene expressionin vivo, effects that were recapitulated when treating the APPSWE-1349 Alzheimer mouse. In cardiac aging, Cmpd60 treatment activated favorable developmental gene expressionin vivoand in line with this, improved ventricular cardiomyocyte contraction and relaxation in a cell model of cardiac hypertrophy. Our work establishes that a systemic, two-week treatment with an HDAC1/2 inhibitor serves as a multi-tissue, healthy aging intervention in mammals. This holds potential for translation towards therapeutics that promote healthy aging in humans.