bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phospholipase D3 contributes to Alzheimer’s disease risk via disruption of Aβ clearance and microglia response to amyloid plaques
Authors: Rosene Matthew J. , Hsu Simon , You Shih Feng , Brase Logan , Verbeck Anthony , Martinez Rita , Wallace Clare E. , Li Zeran , Yan Ping , Dräger Nina M. , Sattler Sydney M. , Iyer Abhirami K , Macauley Shannon L , Holtzman David M. , Benitez Bruno A. , Kampmann Martin , Cruchaga Carlos , Harari Oscar , Cirrito John R. , Lee Jin-Moo , Goate Alison M. , Karch Celeste M. 
Published: February 2022

AbstractAlzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. AD is also the result of complex genetic architecture that can be leveraged to understand pathways central to disease processes. We have previously identified coding variants in the phospholipase D3 (PLD3) gene that double the late-onset AD risk. However, the mechanism by which PLD3 impacts AD risk is unknown. One AD risk variant, PLD3 p.A442A, disrupts a splicing enhancer-binding site and reduces PLD3 splicing in human brains. Using differentiated induced pluripotent stem cells from a PLD3 p.A442A carrier and CRISPR-reverted, isogenic control, we show that PLD3 p.A442A cortical neurons exhibit a PLD3 splicing defect and a significant increase in Aβ42 and Aβ40, both of which are corrected upon reversion of the risk allele in isogenic control neurons. Thus, PLD3 p.A442A is sufficient to alter PLD3 splicing and Aβ metabolism. While the normal function of PLD3 is poorly understood, PLD3 is highly expressed in neurons and brain regions most susceptible to amyloid pathology. PLD3 expression is significantly lower in AD brains than controls, suggesting that PLD3 may play a role in sporadic AD. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD. In a mouse model of amyloid accumulation, loss of Pld3 increases interstitial fluid (ISF) Aβ and reduces Aβ turnover. AAV-mediated overexpression of PLD3 in the hippocampus decreased ISF Aβ levels and accelerated Aβ turnover. To determine whether PLD3-mediated reduction of ISF Aβ impacts amyloid accumulation, we measured amyloid plaque abundance and size after significant Aβ deposition. We found that in the absence of Pld3, amyloid plaques were less compact and more diffuse. Additionally, we observed reduced recruitment of microglia to amyloid plaques in the absence of Pld3. PLD3 may impact amyloid accumulation and AD risk through disrupted microglia function as PLD3 is enriched in disease associated microglia in human brains. Together, our findings demonstrate that PLD3 regulates Aβ clearance through cell-autonomous and non-cell-autonomous pathways in a manner that likely contributes to AD risk.
Patterns of Medication Use and Prescription Fills for Cardioprotective Anti-Hyperglycemic Agents in the United States
Authors: Nargesi Arash A , Clark Callahan , Chen Lian , Liu Mengni , Reddy Abraham , Amodeo Samuel , Oikonomou Evangelos K , Suchard Marc A , McGuire Darren K , Lin Zhenqiu , Inzucchi Silvio , Khera Rohan 
Published: February 2022

ABSTRACTImportanceSelected glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose cotransporter-2 inhibitors (SGLT2i) have cardioprotective effects in patients with type 2 diabetes and elevated cardiovascular risk. Prescription of these agents by clinicians and their consistent use by patients are essential to realize their benefits.ObjectiveTo assess the patterns of use and prescription fills of GLP-1RAs and SGLT-2i.DesignCross-sectional for medication use and prospective for prescription fills in 2018-2020SettingNationwide de-identified US administrative claims database of Medicare Advantage and commercially insured adults.ParticipantsIndividuals 18 years of age and older with type 2 diabetesExposuresComorbidities representing guideline-directed indications of atherosclerotic cardiovascular disease (ASCVD) for GLP-1RAs, and ASCVD, heart failure, and diabetic nephropathy for SGLT2i.Main Outcomes and MeasuresMedication use and monthly fill rates for 12 months following initiation of therapy by calculating the proportion of days with consistent medication use.ResultsAmong 587,657 individuals with type 2 diabetes, 80,196 (13.6%) were prescribed GLP-1RAs and 68,149 (11.5%) SGLT2i during 2018-2020. This represented 12.9% and 10.5% of individuals with indications for each medication, respectively. Based on monthly counts of new prescriptions, there were no changes in the uptake of either drug class during 2019-2020. Among new initiators, fill rate was 52.5% for GLP-1RAs and 52.9% for SGLT2i one year after initiation. One-year fill rates were higher for patients with commercial insurance than those with Medicare Advantage plans for both GLP-1RAs (59.3% vs 51.0%, p-value<0.001) and SGLT2i (63.4% vs 50.3%, p-value<0.001). After adjusting for comorbidity profile, there were higher prescription fills for patients with commercial insurance (versus Medicare Advantage, OR 1.17, 95% CI [1.06-1.29] for GLP-1RAs, and 1.59 [1.42-1.77] for SGLT2i); and higher income (top quartile versus others, OR 1.09 [1.06-1.12] for GLP-1RAs, and 1.06 [1.03-1.10] for SGLT2i).Conclusions and RelevanceIn 2018-2020, use of GLP-1RAs and SGLT2i remained limited to fewer than 1 in 8 individuals with type 2 diabetes meeting criteria for evidence-based guideline and professional society recommendations, with one-year fill rates around 50%. The low and inconsistent use of these medications compromises their longitudinal health outcomes benefits in a period of expanding indications for their use.
Number of plasma exchanges and outcome in myasthenic crisis
Authors: Hansen Michael , Neilson Lee , Parikh Melanie , Katirji Bashar 
Published: February 2022

AbstractBackgroundPlasma exchange is an effective therapy for myasthenic crisis (MC); yet the number of exchanges needed is unknown. We set out to examine the relationship between the number of plasma exchanges and clinical outcome in patients experiencing MC.MethodsWe retrospectively reviewed patient episodes with ICD 9 and ICD 10 codes for myasthenia gravis and myasthenia gravis exacerbation/crisis in patients admitted to a single center tertiary care referral center from July 2008 to July 2017. These episodes were screened for patients with impending myasthenia gravis crisis and manifest crisis who received plasmapheresis during their hospital course. We performed statistical analyses to determine if increased number of plasma exchanges improves the primary outcome (hospital length of stay), as well as the secondary outcome (disposition to home, skilled nursing facility, long term acute care hospital, or death).ResultsThere is neither clinically observable nor statistically significant improvement in length of stay or disposition on discharge in patients who received six or greater sessions of plasmapheresis.ConclusionsThis study provides class IV evidence that extending the number of plasma exchanges beyond five does not correlate with decreased hospital length of stay or improved discharge disposition in patients experiencing myasthenic crisis.
Extension of Community Healthcare Outcomes in Parkinson Disease (Parkinson ECHO): A Feasibility Study
Authors: Neilson Lee E. , Wilhelm Jennifer , McDonnell Margaret McLain , Mann Lisa , Kraakevik Jeff A. 
Published: February 2022

AbstractParkinson’s disease is the second most common neurodegenerative disorder and presents with a heterogeneous group of symptoms. Managing these symptoms requires coordinated care from a neurology specialist and a primary care provider. Access to neurology care is limited for those patients with Parkinson’s disease who reside in rural areas given financial and mobility constraints along with the rarity of specialty providers. To close this gap, we developed and implemented a telehealth-based Project ECHO® (Extension for Community Healthcare Outcomes) program, “Parkinson ECHO,” to provide education and support for rural clinicians and allied health members. We assessed the feasibility of this tele-mentoring educational offering and the effect it had on clinician confidence in diagnosing and treating Parkinson’s disease. Participants from across Oregon (n=33), of whom 70% served rural and/or medically underserved communities, attended the biweekly sessions. The sessions focused on a topic within Parkinson’s disease diagnosis or management followed by case discussions. We assessed clinician confidence and acceptability using surveys before and after their participation in the program. The COVID-19 pandemic was an unexpected obstacle in executing this project, delaying the program by several months and likely accounting for a lower number of attendees for the last two sessions. Nevertheless, we found Parkinson ECHO did significantly increase participant confidence levels in diagnosing and managing Parkinson’s disease.
Coagulation abnormalities in children with uncorrected congenital heart defects seen at a teaching hospital in a developing country
Authors: Majiyagbe Omotola O. , Akinsete Adeseye M. , Adeyemo Titilayo A. , Ekure Ekanem N. , Okoromah Christy A. N. 
Published: February 2022

AbstractBackgroundCoagulation abnormality is a significant complication and cause of mortality in children with uncorrected congenital heart defects (CHD). The aim of this study was to determine the prevalence of coagulation abnormalities and the associated factors in children with uncorrected CHD.MethodA cross sectional study conducted to determine the prevalence of coagulation abnormalities among 70 children with uncorrected CHD aged six months to 17 years and 70 age and sex matched apparently healthy controls. Coagulation abnormality was determined using complete blood count, prothrombin time, activated partial thromboplastin time and D-dimer assay.ResultsThe prevalence of coagulation abnormalities among children with CHD and controls was 37.1% and 7.1% respectively. Children with Cyanotic CHD had a significantly higher prevalence of coagulation abnormalities compared to children with Acyanotic CHD (57.1% versus 17.1%). Haematocrit and oxygen saturation levels were significantly associated with coagulation abnormalities.ConclusionThis study affirms that coagulation abnormality is high in children with uncorrected CHD. Oxygen saturation and haematocrit are factors of coagulation abnormalities. Routine coagulation screening is recommended especially in children with cyanotic congenital heart defects to improve their quality of life and reduce morbidity and mortality while awaiting definitive surgeries.
Embodiment of Supernumerary Robotic Limbs in Virtual Reality
Authors: Arai Ken , Saito Hiroto , Fukuoka Masaaki , Ueda Sachiyo , Sugimoto Maki , Kitazaki Michiteru , Inami Masahiko 
Published: February 2022

ABSTRACTThe supernumerary robotic limb system expands the motor function of human users by adding extra artificially designed limbs. It is important for us to embody the system as if it is a part of one’s own body and to maintain cognitive transparency in which the cognitive load is suppressed. Embodiment studies have been conducted with an expansion of bodily functions through a “substitution” and “extension.” However, there have been few studies on the “addition” of supernumerary body parts. In this study, we developed a supernumerary robotic limb system that operates in a virtual environment, and then evaluated whether the extra limb can be regarded as a part of one’s own body using a questionnaire and whether the perception of peripersonal space changes with a visuotactile crossmodal congruency task. We found that the participants can embody the extra-limbs after using the supernumerary robotic limb system. We also found a positive correlation between the perceptual change in the crossmodal congruency task and the subjective feeling that the number of one’s arms had increased (supernumerary limb sensation). These results suggest that the addition of an extra body part may cause the participants to feel that they had acquired a new body part that differs from their original body part through a functional expansion.
The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context
Authors: Marchiano Fabio , Haering Margaux , Habermann Bianca Hermine 
Published: February 2022

ABSTRACTMitochondria are subcellular organelles present in almost all eukaryotic cells, which play a central role in cellular metabolism. Different tissues, health and age conditions are characterised by a difference in mitochondrial structure and composition. The visual data mining platform mitoXplorer 1.0 was developed to explore the expression dynamics of genes associated with mitochondrial functions that could help explain these differences. It however lacked functions aimed at integrating mitochondria in the cellular context and thus, identifying regulators that help mitochondria adapt to cellular needs. To fill this gap, we upgraded the mitoXplorer platform to version 2.0 (mitoXplorer 2.0). In this upgrade we implemented two novel integrative functions, Network Analysis and the transcription factor- (TF-) Enrichment, to specifically help identify signalling or transcriptional regulators of mitochondrial processes. In addition, we implemented several other novel functions to allow the platform to go beyond simple data visualisation, such as an enrichment function for mitochondrial processes, a function to explore time-series data, the possibility to compare datasets across species as well as an IDconverter to help facilitate data upload. We demonstrate the usefulness of these functions in 3 specific use cases. mitoXplorer 2.0 is freely available without login at http://mitoxplorer2.ibdm.univ-mrs.fr.
Seasonal IVIG contains high infectivity neutralizing and hemagglutination inhibition activity against seasonal flu virus strains selected for vaccines (2020-22)
Authors: Díez José María , Casals Daniel , Romero Carolina , Gajardo Rodrigo 
Published: February 2022

AbstractIVIG solutions (10%) were tested for infectivity neutralization and hemagglutination inhibition against the influenza strains (two A and two B) recommended by the WHO for inclusion in vaccines for Northern and Southern hemispheres 2020-2022. The IVIG batches used were manufactured (June 2020) from plasma pools collected in the US. Potent neutralization and inhibition of hemagglutination were seen with these IVIG batches. This raises the possibility that IVIG could be added to existing therapies, especially in immunocompromised patients, to fight serious influenza infections. Further study of the potential of IVIG in influenza is warranted.
A model of autonomous interactions between hippocampus and neocortex driving sleep-dependent memory consolidation
Authors: Singh Dhairyya , Norman Kenneth A. , Schapiro Anna C. 
Published: February 2022

AbstractHow do we build up our knowledge of the world over time? Many theories of memory formation and consolidation have posited that the hippocampus stores new information, then “teaches” this information to neocortex over time, especially during sleep. But it is unclear, mechanistically, how this actually works — how are these systems able to interact during periods with virtually no environmental input to accomplish useful learning and shifts in representation? We provide a framework for thinking about this question, with neural network model simulations serving as demonstrations. The model contains hippocampus and neocortical areas, which replay memories and interact with one another completely autonomously during simulated sleep. Oscillations are leveraged to support error-driven learning that leads to useful changes in memory representation and behavior. The model has a non-Rapid Eye Movement (NREM) sleep stage, where dynamics between hippocampus and neocortex are tightly coupled, with hippocampus helping neocortex to reinstate high-fidelity versions of new attractors, and a REM sleep stage, where neocortex is able to more freely explore existing attractors. We find that alternating between NREM and REM sleep stages, which alternately focuses the model’s replay on recent and remote information, facilitates graceful continual learning. We thus provide an account of how the hippocampus and neocortex can interact without any external input during sleep to drive useful new cortical learning and to protect old knowledge as new information is integrated.
Anatomical variability, multi-modal coordinate systems, and precision targeting in the marmoset brain
Authors: Ose Takayuki , Autio Joonas A. , Ohno Masahiro , Frey Stephen , Uematsu Akiko , Kawasaki Akihiro , Takeda Chiho , Hori Yuki , Nishigori Kantaro , Nakako Tomokazu , Yokoyama Chihiro , Nagata Hidetaka , Yamamori Tetsuo , Van Essen David C. , Glasser Matthew F. , Watabe Hiroshi , Hayashi Takuya 
Published: February 2022

AbstractLocalising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and posterior commissures (AC-PC) and CIFTI grayordinates. We found that the horizontal plane of the stereotactic coordinate was significantly rotated in pitch relative to the AC-PC coordinate system (10 degrees, frontal downwards), and had a significant bias and uncertainty due to positioning procedures. We also found that many common cranial and brain landmarks (e.g., bregma, intraparietal sulcus) vary in location across subjects and are substantial relative to average marmoset cortical area dimensions. Combining the neuroimaging-based targeting pipeline with robot-guided surgery enabled proof-of-concept targeting of deep brain structures with an accuracy of 0.2 mm. Altogether, our findings demonstrate substantial intersubject variability in marmoset brain and cranial landmarks, implying that subject-specific neuroimaging-based localization is needed for precision targeting in marmosets. The population-based templates and atlases in grayordinates, created for the first time in marmoset monkeys, should help bridging between macroscale and microscale analyses.HighlightsAchieved sub-millimeter localization accuracy of subject-wise brain regionPropose a dedicated non-invasive multi-modal subject-specific registration pipelineConstruct brain coordinate system in AC-PC and grayordinate spacesEstablish multi-modal MRI and CT brain and cortical templates, MarmosetRIKEN20Quantify intersubject variabilities in marmoset brainSignificant bias and uncertainty exist in marmoset stereotactic positioning
Increased academic performance and prolonged career duration among principal investigators in ecology and evolutionary biology in Taiwan
Authors: Hsu Gen-Chang , Lin Wei-Jiun , Sun Syuan-Jyun 
Published: February 2022

AbstractAcademic job markets have become increasingly challenging worldwide, yet it remains poorly characterized how competitively-successful candidates should be and what the underlying determinants of their success are. Focusing on the field of ecology and evolutionary biology, we analyzed the academic performance (measured as h-index) as well as the duration before recruitment as a new faculty member and promotion to full professor of 145 principal investigators (PI) over the past 34 years in Taiwan. We found that PIs had higher performance and longer duration before recruitment more recently. Performance before promotion remained stable, whereas the duration increased over time. The origin and prestige of doctorate had no effect on the performance or duration either before recruitment or before promotion. We also found that the difference in performance before and after recruitment (“After” performance — “Before” performance) decreased in recent years, with PIs recruited in earlier years maintaining their performance after recruitment while those recruited in later years exhibiting a performance drop. While PIs performed equally well before and after recruitment irrespective of doctorate origin, those with domestic PhD degrees showed a decrease in performance after promotion compared to their counterparts with foreign degrees. Taken together, our findings reveal a prolonged career duration for researchers as a result of intensifying competition in academia, and highlight the increasingly crucial role of academic performance, rather than PhD degree itself, in determining academic success.
Surface engineering enhances the therapeutic potential of extracellular vesicles following acute myocardial infarction
Authors: Mentkowski Kyle I. , Tarvirdizadeh Touba , Manzanero Cody A. , Eagler Lisa A. , Lang Jennifer K. 
Published: February 2022

Structured AbstractObjectivesThe objective of the study was to assess the therapeutic efficacy of targeting remote zone cardiomyocytes with cardiosphere-derived cell (CDC) extracellular vesicles (EVs) in acute myocardial infarction.BackgroundCardiomyocyte (CM) cell death plays a significant role in left ventricular (LV) remodeling and cardiac dysfunction following myocardial infarction (MI). While EVs secreted by CDCs have shown efficacy in promoting cardiac repair in preclinical models of MI, their translational potential is limited by their biodistribution. We hypothesized that targeting therapeutic EVs to CMs would result in further reduction of cardiomyocyte (CM) cell death in vivo and improvement in cardiac function post-MI.MethodsCDC-derived EVs were engineered to express a CM-specific binding peptide (CMP) on their surface and characterized for size, morphology, and protein expression. Mice with acute MI underwent delivery of human CDC EVs, CMP-EVs and placebo in a double-blind study. LVEF was assessed by echo at 1- and 28-days post-MI and tissue samples processed for assessment of EV biodistribution and histological endpoints.ResultsCMP-EVs demonstrated superior cardiac targeting and retention when compared with control EVs 24 hours post MI. While intramyocardial administered CDC-EVs improved LVEF compared with placebo at 4 weeks, mice treated with CMP-EVs demonstrated a significant improvement in LVEF compared with non-targeted EVs. Likely accounting for their augmented therapeutic efficacy, CMP-EVs demonstrated enhanced reduction of remote zone cardiomyocyte apoptosis.ConclusionsTargeting CMP-EVs to CMs post-MI improved cardiac function compared with unmodified EVs demonstrating a strategy to further optimize therapeutic EV delivery to increase efficacy and decease off-target effects.Condensed AbstractExtracellular vesicles (EVs) offer several potential advantages over small molecule therapeutics for cardiovascular disease (CVD). However, their potential is limited by their biodistribution and lack of specificity. We engineered cardiosphere-derived cells (CDCs) to express Lamp2b fused to a cardiomyocyte specific peptide (CMP), generating EVs with increased cardiomyocyte uptake and cardiac retention. CMP-EVs enhanced cardiac function following acute MI and further reduced remote zone apoptosis when compared with unmodified CDC-EVs. This work highlights a role for targeting therapeutic EVs to cardiomyocytes following injury and serves as a proof-of-concept study for the utility of EV surface engineering in the treatment of CVD.