bluuebunny/crossref_metadata_2025_split huggingface dataset:
Αlpha-Synuclein Induced Immune Response Triggers Parkinson’s Disease-Like Symptoms
Authors: Parkinson Rebekah G. , Xu Tony , Martin Jacob , Xian Zizheng , Ziko Ilvana , Pettitt Jessica A. , RCom-H’Cheo-Forgues Alexandre , Buckland Rebecca , Gordon Sarah L. , Parish Christopher , Brüstle Anne , Dehorter Nathalie 
Published: June 2024

SUMMARYIncreasing evidence suggests that Parkinson’s disease is an autoimmune disorder, with findings of elevated peripheral blood mononuclear cell in patients, and antigenic properties of α-synuclein driving both the innate and adaptive immunity. Yet, how the interaction of α-synuclein and a specific immune response participates to Parkinson’s disease ontogenesis has remained unanswered. Here, we reveal that autoimmune response to an α-synuclein antigen underlies Parkinson’s disease. We demonstrate that autoimmunity mediated by CD4+T cell activation with α-synuclein α-syn61-75antigen is required to lead to immune cell infiltration and localized inflammation in the substantia nigra, triggering dopaminergic cell neurodegeneration and deficits in locomotion and gait kinematics. This study offers the first immune-induced mouse model that recapitulates all features of Parkinson’s disease to study the mechanisms triggering disease onset. It provides the basis for temporally tracking symptom development, exploring preventive strategies and prodromal therapeutic interventions in Parkinson’s Disease.In briefPeripheral α-synuclein immunization causes Parkinson’s disease-like symptoms in mice.Highlights- Both CD4+ T cells and α-synuclein are essential for Parkinson’s disease ontogenesis.- Peripheral injection of α-syn61-75induces significant CD4+ T cell infiltration in the mouse brain.- α-syn61-75immunization is associated with inflammation, α-synuclein aggregation and dopaminergic cell loss in the substantia nigra pars compacta.- Levodopa-sensitive motor symptoms are detected 8 weeks following α-syn61-75immunization in mice.- This study offers a novel autoimmune α-synuclein induced mouse model of Parkinson’s disease.
Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigrapars compactadopaminergic neuronsin vitro: a comparative study with tranylcypromine
Authors: Zarrilli Beatrice , Giacomet Cecilia , Cossa Francesca , Federici Mauro , Berretta Nicola , Mercuri Nicola B 
Published: June 2024

ABSTRACTSafinamide (SAF) is currently used to treat Parkinson’s disease (PD) symptoms based on its theoretical ability to potentiate the dopamine (DA) signal, blocking monoamine oxidase (MAO) B. The present work aims to highlight the functional relevance of SAF as an enhancer of the DA signal, by evaluating its ability to prolong recovery from DA-mediated firing inhibition of DAergic neurons of the substantia nigra pars compacta (SNpc), compared to another MAO antagonist, tranylcypromine (TCP). Using multielectrode array (MEA) and single electrode extracellular recordings of spontaneous spikes from presumed SNpc DAergic cells in vitro, we show that SAF (30 uM) mildly prolongs the DA-mediated firing inhibition, as opposed to the profound effect of TCP (10 uM). In patch-clamp recordings, we found that SAF (30 uM) significantly reduced the number of spikes evoked by depolarizing currents in SNpc DAergic neurons, in a sulpiride (1 uM) independent manner. According to our results, SAF marginally potentiates the DA signal in SNpc DAergic neurons, while exerting an inhibitory effect on the postsynaptic excitability acting on membrane conductances. Thus, we propose that the therapeutic effects of SAF in PD patients partially depends on MAO inhibition, while other MAO-independent sites of action could be more relevant.
Oligodendrocyte precursor cells exacerbate acute CNS inflammation via macrophage and T cell activation in a mouse model of multiple sclerosis
Authors: Ohashi Kana , Uemura Nagi , Nagayasu Kazuki , Kaneko Shuji , Maki Takakuni , Shirakawa Hisashi 
Published: June 2024

AbstractOligodendrocyte precursor cells (OPCs) are a type of glial cell that differentiates into mature oligodendrocytes, a cell type that contributes to myelination, but their roles in the pathologies are not fully understood. Activities other than differentiation into oligodendrocytes have recently been reported for OPCs present in the inflammatory milieu, but intervention studies using animal models are lacking. This study aimed to explore the role of OPCs in mouse MS model experimental autoimmune encephalomyelitis (EAE). Using inducible diphtheria toxin receptor-expressing transgenic mice, platelet-derived growth factor receptor A (PDGFRα)+OPCs were depleted in EAE mice. Surprisingly, OPC depletion in the acute phase improved clinical scores and reduced demyelination. Major histocompatibility complex (MHC) class II was reduced in the spinal cord, whereas astrocyte marker and blood–spinal cord barrier tight junction and adhesion molecule expressions were unaffected after OPC depletion. The numbers of T cells and IL17-expressing Th17 cells were decreased in the spinal cords of the OPC-depleted group. MHC class II expression in spinal cord macrophages was consistently decreased by OPC depletion. These data suggest that in the acute phase of EAE, OPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation. Although the precise mechanisms remain unclear, this implies that OPCs exist not only as the source for oligodendrocytes but also play a pivotal role in central nervous system (CNS) autoimmune inflammation.Table of Contents ImageMAIN POINTSOPC depletion in the acute phase of EAE improved clinical scores and reduced demyelination.OPC depletion in the spinal cord suppressed Antigen presentation via MHC class II.OPCs are involved in activation of infiltrated macrophages and induce subsequent T cell activation and neuroinflammation.
Fully Human Bifunctional Intrabodies Achieve Graded Reduction of Intracellular Tau and Rescue Survival ofMAPTMutation iPSC-derived Neurons
Authors: D’Brant Lianna , Rugenstein Natasha , Na Su Kyoung , Miller Michael J. , Czajka Timothy F , Trudeau Nicole , Fitz Emily , Tomaszek Lindsay , Fisher Elizabeth S. , Mash Ethan , Joy Shona , Lotz Steven , Borden Susan , Stevens Katherine , Goderie Susan K. , Wang Yue , Bertucci Taylor , Karch Celeste M. , Temple Sally , Butler David C. 
Published: June 2024

AbstractTau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), spurring development of tau-lowering therapeutic strategies. Here, we report fully human bifunctional anti-tau-PEST intrabodies that bind the mid-domain of tau to block aggregation and degrade tau via the proteasome using the ornithine decarboxylase (ODC) PEST degron. They effectively reduced tau protein in human iPSC-derived cortical neurons in 2D cultures and 3D organoids, including those with the disease-associated tau mutations R5L, N279K, R406W, and V337M. Anti-tau-hPEST intrabodies facilitated efficient ubiquitin-independent proteolysis, in contrast to tau-lowering approaches that rely on the cell’s ubiquitination system. Importantly, they counteracted the proteasome impairment observed in V337M patient-derived cortical neurons and significantly improved neuronal survival. By serial mutagenesis, we created variants of the PEST degron that achieved graded levels of tau reduction. Moderate reduction was as effective as high reduction against tau V337M-induced neural cell death.
Ex vivo human leukemia blood model illustrates limitations of cancer-targeting PEGylated nanoparticles
Authors: Ju Yi , Li Shiyao , Qi Tan Abigail Er , Pilkington Emily H. , Brannon Paul T. , Plebanski Magdalena , Cui Jiwei , Caruso Frank , Thurecht Kristofer J. , Tam Constantine , Kent Stephen J. 
Published: June 2024

AbstractAntibody-directed targeting of chemotherapeutic nanomaterials to primary human cancers could improve efficacy and reduce off-target toxicities. We developed an ex vivo model to study the targeting of primary human Chronic Lymphocytic Leukemia (CLL) in whole blood samples from 15 subjects with CLL. Anti-CD20 targeted polyethylene glycol (PEG)-based nanoparticles had generally efficient targeting of CLL cells and low off-target phagocytosis by neutrophils and monocytes. There was however substantial patient-patient variability (up to 164-fold difference in CLL targeting), driven in part by variance in pre-existing anti-PEG antibodies which reduced targeting effects. This suggests patients with lower PEG antibody levels may benefit more from targeted therapies. This was further exemplified by antibody-functionalized doxorubicin-containing PEGylated liposomes, which had relatively poor targeting of CLL in blood and high off-target uptake (significantly correlated with anti-PEG IgG levels in blood) and killing of almost all monocytes within 24 hours. Personalized low-fouling and non-PEGylated particle systems are needed to realize the potential of targeting chemotherapies. Overall, our human ex vivo model of tumor targeting by antibody-directed nanoparticles delineates limitations and opportunities of tumor-targeting nanomedicines.
Anterior insular activity signals perceptual conflicts induced by temporal and spatial context
Authors: Reichenbach Katrin , Rothkirch Marcus , Jaeckel Lucca , Sterzer Philipp , Weilnhammer Veith 
Published: June 2024

AbstractThe signals registered by our senses are inherently ambiguous. Subjective experience, by contrast, is informative: it portrays one interpretation of the sensory environment at a time while discarding competing alternatives. This is exemplified by bistable perception, where ambiguous sensory information induces prolonged intervals of alternating unambiguous perceptual states. According to predictive-processing accounts of bistable perception, perceptual experiences in the recent past constitute a predictive context that stabilizes perception, while sensory information that is in conflict with this predictive context evokes prediction errors. These prediction errors are thought to drive spontaneous perceptual switches. We asked whether this mechanism generalizes to conflicts between other forms of predictive context and sensory information.To this aim, we investigated the neural correlates of perceptual conflicts with temporal and spatial context during bistable perception using functional magnetic resonance imaging (fMRI). Twenty-six healthy participants viewed serial presentations of ambiguous structure-from-motion stimuli either in isolation (conflict with temporal context) or embedded in a similar but unambiguous surround stimulus (conflict with spatial context). The neural correlates of conflicts with temporal and spatial context overlapped in the anterior insula bilaterally. Model-based analyses similarly yielded common prediction error signals in the anterior insula bilaterally, right inferior frontal gyrus and right inferior parietal lobe. Together, these findings point to a generic role of these frontoparietal regions in detecting perceptual conflict and thus in the construction of unambiguous perceptual experiences.
Pasteurisation temperatures effectively inactivate influenza A viruses in milk
Authors: Schafers Jenna , Warren Caroline J. , Yang Jiayun , Zhang Junsen , Cole Sarah J. , Cooper Jayne , Drewek Karolina , Kolli B Reddy , McGinn Natalie , Qureshi Mehnaz , Reid Scott M. , Peacock Thomas P. , Brown Ian , James Joe , Banyard Ashley C. , Iqbal Munir , Digard Paul , Hutchinson Ed 
Published: June 2024

AbstractIn late 2023 an H5N1 lineage of high pathogenicity avian influenza virus (HPAIV) began circulating in American dairy cattle1. Concerningly, high titres of virus were detected in cows’ milk, raising the concern that milk could be a route of human infection. Cows’ milk is typically pasteurised to render it safe for human consumption, but the effectiveness of pasteurisation on influenza viruses in milk was uncertain. To assess this, we evaluated heat inactivation in milk for a panel of different influenza viruses. This included human and avian influenza A viruses (IAVs), an influenza D virus that naturally infects cattle, and recombinant IAVs carrying contemporary avian or bovine H5N1 glycoproteins. At pasteurisation temperatures, viral infectivity was rapidly lost and became undetectable before the times recommended for pasteurisation. We then showed that an H5N1 HPAIV in milk was effectively inactivated by a comparable treatment, even though its genetic material remained detectable. We conclude that industry standard pasteurisation conditions should effectively inactivate H5N1 HPAIV in cows’ milk, but that unpasteurised milk could carry infectious influenza viruses.
Validation of L-Type Calcium Channel Blocker Amlodipine as a Novel ADHD Treatment through Cross-Species Analysis, Drug-Target Mendelian Randomization, and clinical evidence from medical records
Authors: Þorsteinsson Haraldur , Baukmann Hannes A. , Sveinsdóttir Hildur S. , Halldórsdóttir Dagmar Þ. , Grzymala Bartosz , Hillman Courtney , Rolfe-Tarrant Jude , Parker Matthew O. , Cope Justin L. , Ravarani Charles N. J. , Schmidt Marco F. , Karlsson Karl Æ. 
Published: June 2024

AbstractADHD is a chronic neurodevelopmental disorder which significantly affects life outcomes. First-line treatments carry the risk of adverse side effects and present a high abuse potential, coupled with a 25% rate of non-response, necessitating novel treatments. Here, we validate amlodipine as an ADHD treatment using model rats and zebrafish and human genetic data. Amlodipine reduced hyperactivity in the Open Field Test in SHR rats and reduced both hyperactivity and impulsivity in the 5-Choice Serial Reaction Time Task inadgrl3.1-/-zebrafish. We show that amlodipine also passes the blood brain barrier and reduces telencephalic activation. Mendelian Randomization analysis using human genetic data revealed significant associations between ADHD and genetic variations in the subunits of L-type calcium channels (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3), and the combined genes targeted by amlodipine. Finally, we show that amlodipine mitigates key ADHD symptoms in a cohort of people with a high ADHD genetic liability. Given its well-tolerated profile, its efficacy in mitigating both hyperactivity and impulsivity across different species, coupled with genetic evidence from human data, the potential utility of amlodipine as a novel treatment for human ADHD is compelling.
Multimodality Integration of Neural Social Activation and Social and Language Scores Reveals Three Replicable Profound and Milder Autism Subtypes With Divergent Clinical Outcomes
Authors: Taluja Vani , Nazari Sanaz , Zahiri Javad , Garmire Lana , Pierce Karen , Xiao Yaqiong , Courchesne Eric 
Published: June 2024

ABSTRACTSocial affective and communication symptoms stand at the center of autism, and usually become apparent within the first 1-3 years of life. Symptom severity differs widely across toddlers and clinical outcomes, ranging from near-neurotypical to poor. The biological bases of this early and wide symptom diversity are largely unknown. While more than two dozen studies have attempted to subgroup early-age clinical heterogeneity, most studies fail to rigorously validate discovered subtypes using multiple methods, and none linked observed clinical subtypes with underlying functional neural signatures. Using a well-established approach for precision medicine patient subtyping (Similarity Network Fusion) and multiple rigorous validation methods, we integrated thoroughly replicated measures of social neurofunctional activation and social and language ability in 137 toddlers at early ages. Results identified three distinct social neural-clinical ASD subtypes, validated using multiple methods. One subtype was consistent with a ‘profound’ autism profile with negligible social neural activation, severe social and language symptoms, low social interest, and little clinical improvement. Another ASD subtype had a contrasting pattern with only mildly reduced social neural activity, near neurotypical social and language abilities, and substantial age-related clinical improvement. One principal implication of these results is that the “spectrum” of ASD heterogeneity is not truly a continuous spectrum from the neurobiological and clinical perspective. The profound autism subtype is the neurofunctional, clinical and developmental opposite of the mild ASD subtype, suggesting different etiological mechanisms. A second implication is that neurobiological and clinical subtype differences highlight the need to develop subtype-specific treatments, particularly for the profound subtype. Third, treatment studies with an undetermined mix of subtypes could fail or succeed based on how many patients from each subtype are included in the mix.
Effect of Neutrophil Elastase Inhibitor (Sivelestat Sodium) on Oxygenation in Patients with Sepsis Induced Acute Respiratory Distress Syndrome
Authors: Wu Tiejun , Wang Tao , Jiang Jinjiao , Tang Yue , Zhang Lina , Jiang Zhiming , Liu Fen , Kong Guiqing , Zhou Tingfa , Liu Ruijin , Guo Haipeng , Xiao Jie , Sun Wenqing , Li Yuye , Zhu Yingying , Liu Quan , Xie Weifeng , Qu Yan , Wang Xiaozhi 
Published: June 2024

AbstractObjectivesNeutrophil elastase (NE) plays an important role in the development of acute respiratory distress syndrome (ARDS). Sivelestat sodium, as a selective NE inhibitor, may improve the outcomes of patients with sepsis-induced ARDS in previous studies, but there is a lack of solid evidence. This trial aimed to evaluate the effect of sivelestat sodium on oxygenation in patients with sepsis-induced ARDS.MethodsWe conducted a multicenter, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with sepsis-induced ARDS admitted within 48 hours of the advent of symptoms. Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administrated as a 24-hour continuous intravenous infusion for a minimum duration of 5 days and a maximum duration of 14 days. The primary outcome was PaO2/FiO2ratio improvement on Day5 after randomization, defined by a greater than 50% improvement in PaO2/FiO2compared with that on ICU admission or PaO2/FiO2reached over 300 mmHg on Day5.ResultsThe study was stopped midway due to a potential between-group difference in mortality observed during the interim analysis. Overall, a total of 70 patients were randomized, of whom 34 were assigned to receive sivelastat sodium and 36 placebo. On day5, 19/34 (55.9%) patients in the sivelastat group had PaO2/FiO2ratio improvement compared with 7/36 (19.4%) patients in the placebo group (risk difference, 0.36; 95% CI, 0.14 to 0.56,p<0.001). The Kaplan-Meier curves showed a significantly improved 28-day survival rate in patients receiving sivelestat than those not (hazard ratio, 0.32; 95% CI, 0.11 to 0.95;p=0.041).ConclusionIn patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first five days and may be associated with decreased 28-day mortality.
Procedural Volume and Outcomes in Lower Extremity Peripheral Vascular Interventions: Insights from the National Cardiovascular Data Registry Peripheral Vascular Intervention Registry
Authors: Chunawala Zainali , Qamar Arman , Kennedy Kevin , Keshwani Neil , Pandey Ambarish , Kumbhani Dharam J. , Lee Cheong Jun , Mishkel Gregory , Secemsky Eric , Bhatt Deepak L. 
Published: June 2024

AbstractBackgroundLower extremity peripheral vascular interventions (PVI) are increasingly utilized for treatment of peripheral artery disease (PAD). However, the relationship between hospital- and operator-volume of PVI with in-hospital major adverse limb events (MALE) and major adverse cardiovascular events (MACE) is not well established.MethodsWe utilized the National Cardiovascular Data Registry PVI registry that included procedural data from 4/1/2014 – 9/3/2020 and assessed in-hospital MALE and MACE during hospitalization for PVI. Generalized linear mixed models were used to assess the volume-outcome relationships after adjustment of relevant covariates.ResultsBetween 2014 to 2020, a total of 60,834 PVI procedures were performed at 97 hospitals by 555 operators. In the adjusted analysis, there was no significant association between tertile of hospital volume and MALE (highest vs lowest-volume: OR 0.89, 95% CI 0.73–1.08, p=0.24) or tertile of hospital-volume and MACE (highest vs lowest-volume: OR 1.26, 95% CI 0.98 – 1.62, p=0.066). Notably, undergoing PVI with high volume operators was associated with lower odds of in-hospital MALE (highest vs lowest-volume: OR 0.72, 95% CI 0.54–0.94, p=0.017). However, no association was observed between operator-volume tertiles and MACE (highest vs lowest-volume: OR 0.71, 95% CI 0.48–1.04, p=0.082).ConclusionsIn contemporary practice, a strong relationship was observed between operator volume and adjusted PVI outcomes. Highest volume operators had lower rates of in-hospital MALE compared with lowest volume operators. However, there was no observed relationship between tertiles of hospital volume of PVI and associated outcomes.Clinical PerspectivesWhat is New?Procedural volume has been defined as a surrogate to define quality of care in many cardiovascular settings.In patients undergoing peripheral vascular intervention, highest volume operators were associated with lower incidence of in-hospital major adverse limb events.However, there was no observed association between hospital volume of peripheral vascular interventions and outcomes.Clinical ImplicationsOperator-volume may be a valuable surrogate to assess peripheral vascular interventions quality across different centers and could potentially outweigh the significance of institutional volume in the context of the procedural safety and outcomes.