bluuebunny/crossref_metadata_2025 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

Increasing 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 brief

Peripheral 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.
Dissecting the cis-regulatory syntax of transcription initiation with deep learning
Authors: Cochran Kelly , Yin Melody , Mantripragada Anika , Schreiber Jacob , Marinov Georgi K , Shah Sagar R , Yu Haiyuan , Lis John T , Kundaje Anshul
Published: June 2024

Despite extensive characterization of mammalian Pol II transcription, the DNA sequence determinants of transcription initiation at a third of human promoters and most enhancers remain poorly understood. Hence, we trained and interpreted a neural network called ProCapNet that accurately models base-resolution initiation profiles from PRO-cap experiments using local DNA sequence. ProCapNet learns sequence motifs with distinct effects on initiation rates and TSS positioning and uncovers context-specific cryptic initiator elements intertwined within other TF motifs. ProCapNet annotates predictive motifs in nearly all actively transcribed regulatory elements across multiple cell-lines, revealing a shared cis-regulatory logic across promoters and enhancers mediated by a highly epistatic sequence syntax of cooperative and competitive motif interactions. ProCapNet models of RAMPAGE profiles measuring steady-state RNA abundance at TSSs distill initiation signals on par with models trained directly on PRO-cap profiles. ProCapNet learns a largely cell-type-agnostic cis-regulatory code of initiation complementing sequence drivers of cell-type-specific chromatin state critical for accurate prediction of cell-type-specific transcription initiation.
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

Safinamide (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

Oligodendrocyte 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 Image

MAIN POINTS

OPC 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.
Emergence of a dynamical state of coherent bursting with power-law distributed avalanches from collective stochastic dynamics of adaptive neurons
Authors: Chan Lik-Chun , Kok Tsz-Fung , Ching Emily S.C.
Published: June 2024

Spontaneous brain activity in the absence of external stimuli is not random but contains complex dynamical structures such as neuronal avalanches with power-law duration and size distributions. These experimental observations have been interpreted as supporting evidence for the hypothesis that the brain is operating at criticality and attracted much attention. Here, we show that an entire state of coherent bursting, with power-law distributed avalanches and features as observed in experiments, emerges in networks of adaptive neurons with stochastic input when excitation is sufficiently strong and balanced by adaptation. We demonstrate that these power-law distributed avalanches are direct consequences of stochasticity and the oscillatory population firing rate arising from coherent bursting, which in turn is the result of the balance between excitation and adaptation, and criticality does not play a role.
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

Tau 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

Antibody-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

The 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

In 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

ADHD 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

Social 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

Objectives

Neutrophil 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.

Methods

We 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.

Results

The 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).

Conclusion

In 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

Background

Lower 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.

Methods

We 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.

Results

Between 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).

Conclusions

In 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 Perspectives

What 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 Implications

Operator-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.
Impact of blood pressure control level on all-cause mortality and CVD mortality in patients with hypertension and its comorbidities: A prospective cohort study in Southwest China
Authors: Wu Yanli , Li Ling , Zhou Jie , Zhang Ji , Wang Yiying , Yu Lisha , Liu Tao
Published: June 2024

Background

Blood pressure (BP) control levels may be associated with the risk of all-cause mortality and CVD mortality. The goal of this study was to explore the association of BP control levels with the risk of all-cause mortality and CVD mortality in adults in Guizhou, China.

Methods

A 13-year prospective cohort study of 1,905 hypertension patients adults aged 18 years or older was conducted in Guizhou, southwest China from 2010 to 2023. Information of participants death were collected, cause of death was coded according to ICD-10 and codes I00-I99 was categorized as CVD-related deaths. Cox proportional hazard regression was used to examine the associations of BP control levels with all-cause mortality and CVD mortality.

Results

134 deaths occurred during a median follow-up of 11.72 years. The multivariable cox hazard regression models showed that compared with SBP≥140 mmHg and DBP≥90 mmHg group, participants with SBP <120 mmHg and DBP <80 mmHg, they had the lowest risk of all-cause mortality (HR=0.265, 95%CI:0.111,0.630) and the lower risk of CVD death (HR=0.274, 95%CI:0.092,0.814). Associations between BP control levels with all-cause mortality and CVD mortality were suggested to be even stronger among aged ≥65 years (P<0.05), but ideal BP levels were not significantly associated with CVD mortality in participants with comorbidity (P>0.05).

Conclusion

Optimal BP control levels(<120/80mmHg) is effective in reducing overall mortality and cardiovascular disease (CVD) mortality, even among older adults. however, for hypertension with comorbidities, mere BP control alone may not suffice, consideration should also be given to the treatment of other coexisting conditions.

NOVELTY AND RELEVANCE

What Is New?

To our knowledge, few studies have investigated the relationship between the levels of blood pressure control in hypertensive patients and all-cause mortality in the Chinese population. Furthermore, there exists divergent viewpoints regarding the extent of blood pressure management in geriatric patients diagnosed with hypertension.In this study, we used data from a prospective cohort study in Southwest China to investigate whether the level of blood pressure control of hypertension patients was associated with all-cause mortality and cardiovascular disease (CVD) death and test whether those associations were modified by age or comorbidity factors.

What Is Relevant?

Using data from a prospective cohort study in Southwest China, we found that maintaining optimal blood pressure control levels (<120/80mmHg) was found to significantly reduce overall mortality and cardiovascular disease (CVD) mortality, even among elderly individuals.

Clinical/Pathophysiological Implications?

The association between blood pressure and all-cause mortality serves as a guide for the management and control of hypertension in patients.
A New NAEC Level III Epilepsy Center for Adults in Southern San Joaquin Valley of CA – Initial Experience of the Kern Medical Epilepsy Center
Authors: Dao KT , Liu L , Ipe J , Poston C , Zalmay N , Ly B , Nguyen C , Braich S , Chacko C , Greenwood J , Heck CN , Ragoonanan L , Chen JCT , Lee D , Russin J , Lee B , Liu CY , Kunhi-Veedu HP
Published: June 2024

Epilepsy care has largely improved across the United States in the past decades, as reflected in Epilepsy Monitoring Units (EMU) bed availability, admissions, neurological procedures, and epileptologists. However, this has not been evident in many underserved areas. The vast majority of National Association of Epilepsy Centers (NAEC) accredited centers are located in major metropolitan areas, and some states lack epilepsy centers entirely. Kern Medical (KM) is the public safety-net hospital in Bakersfield, California (CA) that serves Kern and surrounding counties in the Central Valley. In 2018, an epilepsy center at KM was established with the support of the USC Epilepsy Care Consortium and received NAEC Level III accreditation to serve the over 34,000 patients who suffer from epilepsy in Kern County alone. Here, we review the initial 4-year experience of the KM Epilepsy Center by retrospectively analyzing a prospectively maintained database in light of the general NAEC data from 2012–2019. This experience demonstrates that epilepsy care can be coordinated across complex and competing health systems and socioeconomic barriers separated by large geographic distances through creative, physician-driven strategies of resource sharing and goal alignment across the health care ecosystem. However, considerable challenges remain in providing the requisite care to patients in need, even in highly resourced states like CA. This experience can inform future efforts to integrate epilepsy care across the region and beyond.
The causal role of male pubertal timing for the development of externalizing and internalizing traits: results from Mendelian randomization studies
Authors: Dinkelbach Lars , Peters Triinu , Grasemann Corinna , Hinney Anke , Hirtz Raphael
Published: June 2024

Preexisting epidemiological studies suggest that early pubertal development in males is associated with externalizing (e.g., conduct problems, risky behavior, and aggression) and internalizing (e.g., depression and anxiety) traits and disorders. However, due to problems inherent to observational studies, especially of reverse causation and residual confounding, it remains unclear whether these associations are causal. Mendelian randomization (MR) studies take advantage of the random allocation of genes at conception and can establish causal relationships. In the current study, N=76 independent genetic variants for male puberty timing (MPT) were derived from a large genome-wide association study (GWAS) on 205,354 participants and used as an instrumental variable in MR studies on 17 externalizing and internalizing traits and psychopathologies utilizing outcome GWAS with 16,400 to 1,045,957 participants. In these MR studies, earlier MPT was significantly associated with higher scores for the overarching phenotype of ‘Externalizing Traits’ (beta=-0.03, 95%-CI [-0.06, -0.01]). However, this effect was likely driven by an earlier age at first sex (beta=-0.17, 95%-CI [-0.21, - 0.13]), without evidence for an effect on further externalizing phenotypes. Regarding internalizing phenotypes, earlier MPT was associated with higher levels of the ‘Depressed Affect’ subdomain of neuroticism (beta=-0.04, 95%-CI [-0.07, -0.01]). Late MPT was related to higher scores of internalizing traits in early life (beta=0.04, 95%-CI [0.01, 0.08]). In conclusion, this MR study supports a causal effect of MPT on specific traits and behaviors. However, no evidence for an effect of MPT on long-term clinical outcomes (depression, anxiety disorders, alcohol dependency, cannabis abuse) was found.
Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression
Authors: McInnes Aaron N. , Olsen Sarah T. , Sullivan Christi R.P. , Cooper Dawson C. , Wilson Saydra , Sonmez Ayse Irem , Albott Sophia C. , Olson Stephen C. , Peterson Carol B. , Rittberg Barry R. , Herman Alexander , Bajzer Matej , Nahas Ziad , Widge Alik S.
Published: June 2024

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 – 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.
Time-resolved coupling between connectome harmonics and subjective experience under the psychedelic DMT
Authors: Vohryzek Jakub , Luppi Andrea , Atasoy Selen , Deco Gustavo , Timmermann Christopher , Carhart-Harris Robin L , Kringelbach Morten L
Published: June 2024

Exploring the intricate relationship between brain's structure and function, and how this affects subjective experience is a fundamental pursuit in neuroscience. Psychedelic substances offer a unique insight into the influences of specific neurotransmitter systems on perception, cognition and consciousness. Specifically, their impact on brain function propagates across the structural connectome, a network of white matter pathways linking different regions. To comprehensively grasp the effects of psychedelic compounds on brain function, we used a theoretically rigorous framework known as connectome harmonic decomposition. This framework provides a robust method to characterize how brain function intricately depends on the organized network structure of the human connectome. We show that the connectome harmonic repertoire under DMT is reshaped in line with other reported psychedelic compounds; psilocybin, LSD and ketamine. Furthermore, we show that the repertoire entropy of connectome harmonics increases under DMT, as with those other psychedelics. Importantly, we demonstrate for the first time that measures of energy spectrum difference and repertoire entropy of connectome harmonics indexes the intensity of subjective experience of the participants in a time-resolved manner reflecting close coupling between connectome harmonics and subjective experience.
Nanoliter-scale selection of optimized bioengineered peptide antibiotics that rescue mice with bacterial lung infection
Authors: Böhringer Nils , Wuisan Zerlina G. , Marner Michael , Kresna I Dewa Made , Mettal Ute , Schmitt Steven , Reiter Silke , Liu Yang , Brinkrolf Karina , Rupp Oliver , Schwengers Oliver , Findeisen Julia , Herold Susanne , Matt Ulrich , Schäberle Till F.
Published: June 2024

Increasing numbers of multi-drug resistant pathogens call for new chemical scaffolds, addressing novel targets, that can serve as lead structures for the development of life-saving drugs. For antibiotics, natural product-inspired molecules represent a most promising resource. Natural products evolved to high chemical complexity and occupy a chemical space different than synthetic libraries. However, clinical translation of promising natural products is often impeded by their relative inaccessibility to medicinal chemistry optimization,e.g.iterative synthesis of large series of derivatives. Here, this limitation is addressed with a randomized library of bicyclic heptapeptides based on the natural product darobactin that hits the clinically not addressed target BamA. Variants of the ribosomally synthesized and post-translationally modified peptides were generated using heterologous mutasynthesis. A parallelized screening assay is adapted in nanoliter-scale beads to test the darobactin derivatives against our sensor strain. Loss of fluorescence sorting prioritized 563 events out of the analyzed ∼500k beads. Re-testing confirmed 48 hit events, of which 40 proved to produce distinct darobactin-type molecules. Most promising structures were isolated and the growth inhibitory effects against Gram-negative pathogens validated. One of our current frontrunner compounds (i.e., darobactin B) was reinforced by the randomized screen. While microbiological investigations of the new derivatives is ongoing, darobactin B was profiled in later tier assays and compared to another promising, rationally-designed analog (i.e., darobactin B9, “D22”). Early ADMET profiling and efficacy tests in a mouse pneumonia model were performed. Darobactin B reduced bacterial load ofPseudomonas aeruginosaandKlebsiella pneumoniaeby intraperitoneal, as well as intratracheal administration. Our study showcases the potential of mutasynthetic libraries for high-throughput screening and identification of functional peptides for drug lead discovery.
Time-series sewage metagenomics can separate the seasonal, human-derived and environmental microbial communities, holding promise for source-attributed surveillance
Authors: Becsei Agnes , Fuschi Alessandro , Otani Saria , Kant Ravi , Weinstein Ilja , Alba Patricia , Steger Jozsef , Visontai David , Brinch Christian , de Graaf Miranda , Schapendonk Claudia M E , Battisti Antonio , De Cesare Alessandra , Oliveri Chiara , Troja Fulvia , Vapalahti Olli , Pasquali Frederique , Banyai Krisztian , Mako Magdolna , Pollner Peter , Merlotti Alessandra , Koopmans Marion , Csabai Istvan , Remondini Daniel , Aarestrup Frank M , Munk Patrick
Published: June 2024

Sewage metagenomics has risen to prominence in urban population surveillance of pathogens and antimicrobial resistance (AMR). Unknown species with similarity to known genomes cause database bias in reference-based metagenomics. To improve surveillance, we designed this study to recover sewage genomes and develop a quantification and correlation workflow for these genomes and AMR over time. We used longitudinal sewage sampling in seven treatment plants from five major European cities to explore the utility of catch-all sequencing of these population-level samples. Using metagenomic assembly methods, we recovered 2,332 metagenome-assembled genomes (MAGs) from prokaryotic species, 1,334 of which were previously undescribed. These genomes account for ~69% of sequenced DNA and provide insight into sewage microbial dynamics. Rotterdam (Netherlands) and Copenhagen (Denmark) showed strong seasonal microbial community shifts, while Bologna, Rome, (Italy) and Budapest (Hungary) had occasional blooms of Pseudomonas-dominated communities, accounting for up to ~95% of sample DNA. Seasonal shifts and blooms present challenges for effective sewage surveillance. We find that bacteria of known shared origin, like human gut microbiota, form communities, suggesting the potential for source-attributing novel species and their ARGs through network community analysis. This could significantly improve AMR tracking in urban environments.
Transfer of IgG from Long COVID patients induces symptomology in mice
Authors: Chen Hung-Jen , Appelman Brent , Willemen Hanneke , Bos Amelie , Prado Judith , Geyer Chiara. E. , Santos Ribeiro Patrícia Silva , Versteeg Sabine , Larsen Mads , Schüchner Eline , Bomers Marije K. , Lavell Ayesha H.A. ,   Amsterdam UMC COVID-19 biobank, Charlton Braeden , Wüst Rob , Wiersinga W. Joost , van Vugt Michèle , Vidarsson Gestur , Eijkelkamp Niels , den Dunnen Jeroen
Published: June 2024

SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by passively transferring total IgG from Long COVID patients to mice. Using Glial Fibrillary Acidic Protein (GFAP) and type-I interferon expression, we stratified patients into three Long COVID subgroups, each with unique plasma proteome signatures. Remarkably, IgG transfer from the two subgroups, which are characterized by higher plasma levels of neuronal proteins and leukocyte activation markers, induced pronounced and persistent sensory hypersensitivity with distinct kinetics. Conversely, IgG transfer from the third subgroup, which are characterized by enriched skeletal and cardiac muscle proteome profiles, reduced locomotor activity in mice without affecting their motor coordination. These findings demonstrate that transfer of IgG from Long COVID patients to mice replicates disease symptoms, underscoring IgG’s causative role in Long COVID pathogenesis. This work proposes a murine model that mirrors Long COVID’s pathophysiological mechanisms, which may be used as a tool for screening and developing targeted therapeutics.
Transcriptome-wide mapping of small-molecule RNA-binding sites in live cells
Authors: Tong Yuquan , Zanon Patrick R. A. , Yang Xueyi , Su Xiaoxuan , Childs-Disney Jessica L. , Disney Matthew D.
Published: June 2024

Small molecules targeting RNA can be valuable chemical probes and potential therapeutics. The interactions between small molecules, particularly fragments, and RNA, however, can be difficult to detect due to their modest affinities and short residence times. Here, we describe the procedures for mapping the molecular fingerprints of small molecules in vitro and throughout the human transcriptome in live cells, identifying both the targets bound by the small molecule and the sites of binding therein. For complete details on the use and execution of this protocol, please refer to1.
Advancing the genetic engineering toolbox by combiningAsCas12aknock-in mice with ultra-compact screening
Authors: Jin Wei , Deng Yexuan , La Marca John E. , Lelliott Emily J. , Diepstraten Sarah T. , Snetkova Valentina , Dorighi Kristel M. , Hoberecht Luke , Whelan Lauren , Liao Yang , Tai Lin , Healey Geraldine , Shi Wei , Kueh Andrew J. , Haley Benjamin , Fortin Jean-Philippe , Herold Marco J.
Published: June 2024

Cas12a is a gene-editing tool that simplifies multiplexed gene targeting through its RNase activity, enabling maturation of individual crRNAs from a pre-crRNA-encoding RNA. Here, we present a mouse model that constitutively expresses enhancedAcidaminococcus sp. Cas12a(enAsCas12a) linked to an mCherry fluorescent reporter. We demonstrate efficient single and multiplexed gene-editing in cells fromenAsCas12aKImice. To testin vivoactivity, we transduced haematopoietic stem cells fromEμ-MycT/+;enAsCas12aKI/+animals withTrp53-targeting pre-crRNAs followed by transplantation into irradiated recipient animals. Tumour development was accelerated and TRP53 protein lost. We generated compact, genome-wide Cas12a knockout libraries targeting each gene with four guide RNAs encoded on two (Menuetto) or one (Scherzo) vector. Introducing these libraries intoEμ-MycT/+;enAsCas12aKI/+lymphoma cells followed by treatment with an MCL-1 inhibitor (S63845) or TRP53-inducer (nutlin-3a) identified known and novel drug resistance genes. Finally, we demonstrate simultaneous gene knockouts (Trp53 or combined Bax/Bak) and activation (Cd19) in primary T cells and mouse dermal fibroblasts from crosses of ourenAsCas12aand CRISPR activation models (dCas9a-SAM). OurenAsCas12amouse model and accompanying libraries enhance genome engineering capabilities and complements current CRISPR technologies.
Improved gene targeting in vivo using EoHR, a small molecule inhibitor of 53BP1
Authors: Spencer Sarah J. , O’donoghue Finn , Ristovski Angelina , Glaser Astrid , Maniam Subashani , Mohsenipour Mitra , Soch Alita , Deans Andrew J. , Headey Stephen
Published: June 2024

Precise genome editing by programmable nucleases such as Cas9 has revolutionised medical research by enabling the creation of gene-edited or knock-in mouse models of disease. However, a major limitation of the approach is the inefficient process of homology driven recombination (HDR) from an exogenous DNA repair template. This is because error-prone, 53BP1-dependent non-homologous end joining (NHEJ) predominates at Cas9-induced double strand breaks (DSBs). Here we report the validation of a cell-permeable and non-toxic inhibitor of 53BP1 called EoHR. In vitro, EoHR prevents 53BP1 binding to dimethylated lysine 20 on histone H4, a marker of DSBs. In cells, EoHR prevents localisation of 53BP1 at nuclease mediated DSBs and promotes HDR at a Cas9-induced break. When tested in vivo during mouse Cas9-mediated gene editing, inclusion of EoHR at the time of microinjection more than doubled the recovery of correctly edited mice and halved the time to project success. Our work shows that inhibition of 53BP by EoHR is a simple and robust way to increase HDR at Cas9 breaks that can also dramatically increase the success rates of animal model generation.
Diagnostic Accuracy of Vision-Language Models on Japanese Diagnostic Radiology, Nuclear Medicine, and Interventional Radiology Specialty Board Examinations
Authors: Oura Tatsushi , Tatekawa Hiroyuki , Horiuchi Daisuke , Matsushita Shu , Takita Hirotaka , Atsukawa Natsuko , Mitsuyama Yasuhito , Yoshida Atsushi , Murai Kazuki , Tanaka Rikako , Shimono Taro , Yamamoto Akira , Miki Yukio , Ueda Daiju
Published: June 2024

Purpose

The performance of vision-language models (VLMs) with image interpretation capabilities, such as GPT-4 omni (GPT-4o), GPT-4 vision (GPT-4V), and Claude-3, has not been compared and remains unexplored in specialized radiological fields, including nuclear medicine and interventional radiology. This study aimed to evaluate and compare the diagnostic accuracy of various VLMs, including GPT-4 + GPT-4V, GPT-4o, Claude-3 Sonnet, and Claude-3 Opus, using Japanese diagnostic radiology, nuclear medicine, and interventional radiology (JDR, JNM, and JIR, respectively) board certification tests.

Methods

In total, 383 questions from the JDR test (358 images), 300 from the JNM test (92 images), and 322 from the JIR test (96 images) from 2019 to 2023 were consecutively collected. The accuracy rates of the GPT-4 + GPT-4V, GPT-4o, Claude-3 Sonnet, and Claude-3 Opus were calculated for all questions or questions with images. The accuracy rates of the VLMs were compared using McNemar’s test.

Results

GPT-4o demonstrated the highest accuracy rates across all evaluations with the JDR (all questions, 49%; questions with images, 48%), JNM (all questions, 64%; questions with images, 59%), and JIR tests (all questions, 43%; questions with images, 34%), followed by Claude-3 Opus with the JDR (all questions, 40%; questions with images, 38%), JNM (all questions, 51%; questions with images, 43%), and JIR tests (all questions, 40%; questions with images, 30%). For all questions, McNemar’s test showed that GPT-4o significantly outperformed the other VLMs (allP< 0.007), except for Claude-3 Opus in the JIR test. For questions with images, GPT-4o outperformed the other VLMs in the JDR and JNM tests (allP< 0.001), except Claude-3 Opus in the JNM test.

Conclusion

The GPT-4o had the highest success rates for questions with images and all questions from the JDR, JNM, and JIR board certification tests.

Secondary abstract

This study compared the diagnostic accuracy of vision-language models, including the GPT-4V, GPT-4o, and Claude-3, in Japanese radiological certification tests. GPT-4o demonstrated superior performance across diagnostic radiology, nuclear medicine, and interventional radiology tests, including image-based questions, highlighting its potential for medical image interpretation.