bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns
Authors: Rahayel Shady , Mišić Bratislav , Zheng Ying-Qiu , Liu Zhen-Qi , Abdelgawad Alaa , Abbasi Nooshin , Caputo Anna , Zhang Bin , Lo Angela , Kehm Victoria , Kozak Michael , Yoo Han Soo , Dagher Alain , Luk Kelvin C. 
Published: December 2021

Abstract
Parkinson’s disease is a progressive neurodegenerative disorder characterized by the intracellular accumulation of insoluble alpha-synuclein aggregates into Lewy bodies and neurites. Increasing evidence indicates that Parkinson’s disease progression results from the spread of pathologic alpha-synuclein through neuronal networks. However, the exact mechanisms underlying the propagation of abnormal proteins in the brain are only partially understood. The objective of this study was first to describe the long-term spatiotemporal distributions of Lewy-related pathology in mice injected with alpha-synuclein preformed fibrils and then to recreate these patterns using a computational model that simulates in silico the spread of pathologic alpha-synuclein.
In this study, 87 2–3-month-old non-transgenic mice were injected with alpha-synuclein preformed fibrils to generate a comprehensive post-mortem dataset representing the long-term spatiotemporal distributions of hyperphosphorylated alpha-synuclein, an established marker of Lewy pathology, across the 426 regions of the Allen Mouse Brain Atlas. The mice were injected into either the caudoputamen, nucleus accumbens or hippocampus, and followed over 24 months with pathologic alpha-synuclein quantified at seven intermediate time points. The pathologic patterns observed at each time point in this high-resolution dataset were then compared to those generated using a Susceptible-Infected-Removed (SIR) computational model, an agent-based model that simulates the spread of pathologic alpha-synuclein for every brain region taking simultaneously into account the effect of regional brain connectivity and Snca gene expression.
Our histopathological findings showed that differentially targeted seeding of pathological alpha-synuclein resulted in unique propagation patterns over 24 months and that most brain regions were permissive to pathology. We found that the SIR model recreated the observed distributions of pathology over 24 months for each injection site. Null models showed that both Snca gene expression and connectivity had a significant influence on model fit.
In sum, our study demonstrates that the combination of normal alpha-synuclein concentration and brain connectomics contributes to making brain regions more vulnerable to the pathological process, providing support for a prion-like spread of pathologic alpha-synuclein. We propose that this rich dataset and the related computational model will help test new hypotheses regarding mechanisms that may alter the spread of pathologic alpha-synuclein in the brain.
Neuronal synchrony abnormalities associated with subclinical epileptiform activity in early-onset Alzheimer’s disease
Authors: Ranasinghe Kamalini G , Kudo Kiwamu , Hinkley Leighton , Beagle Alexander , Lerner Hannah , Mizuiri Danielle , Findlay Anne , Miller Bruce L , Kramer Joel H , Gorno-Tempini Maria Luisa , Rabinovici Gil D , Rankin Katherine P , Garcia Paul A , Kirsch Heidi E , Vossel Keith , Nagarajan Srikantan S 
Published: December 2021

Abstract
Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer’s disease, a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with Alzheimer’s disease. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with Alzheimer’s disease. Using magnetoencephalography (MEG) at rest, we studied 30 Alzheimer’s disease patients without subclinical epileptiform activity, 20 Alzheimer’s disease patients with subclinical epileptiform activity and 35 age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with Alzheimer’s disease by long-term video-EEG and a 1-h resting MEG with simultaneous EEG. Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8–12 Hz) and delta–theta (2–8 Hz) oscillatory frequencies. We found that Alzheimer’s disease patients with subclinical epileptiform activity have greater reductions in alpha imaginary coherence and greater enhancements in delta–theta imaginary coherence than Alzheimer’s disease patients without subclinical epileptiform activity, and that these changes can distinguish between Alzheimer’s disease patients with subclinical epileptiform activity and Alzheimer’s disease patients without subclinical epileptiform activity with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini-Mental State Examination in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next-generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction together with cognitive and clinical correlates in patients with Alzheimer’s disease.
Influenza vaccination induces autoimmunity against orexinergic neurons in a mouse model for narcolepsy
Authors: Bernard-Valnet Raphaël , Frieser David , Nguyen Xuan Hung , Khajavi Leila , Quériault Clémence , Arthaud Sébastien , Melzi Silvia , Fusade-Boyer Maxime , Masson Frederick , Zytnicki Matthias , Saoudi Abdelhadi , Dauvilliers Yves , Peyron Christelle , Bauer Jan , Liblau Roland S 
Published: December 2021

Abstract
Narcolepsy with cataplexy or narcolepsy type 1 is a disabling chronic sleep disorder resulting from the destruction of orexinergic neurons in the hypothalamus. The tight association of narcolepsy with HLA-DQB1*06:02 strongly suggest an autoimmune origin to this disease. Furthermore, converging epidemiological studies have identified an increased incidence for narcolepsy in Europe following Pandemrix® vaccination against the 2009–2010 pandemic ‘influenza’ virus strain. The potential immunological link between the Pandemrix® vaccination and narcolepsy remains, however, unknown. Deciphering these mechanisms may reveal pathways potentially at play in most cases of narcolepsy.
Here, we developed a mouse model allowing to track and study the T-cell response against ‘influenza’ virus haemagglutinin, which was selectively expressed in the orexinergic neurons as a new self-antigen. Pandemrix® vaccination in this mouse model resulted in hypothalamic inflammation and selective destruction of orexin-producing neurons. Further investigations on the relative contribution of T-cell subsets in this process revealed that haemagglutinin-specific CD4 T cells were necessary for the development of hypothalamic inflammation, but insufficient for killing orexinergic neurons. Conversely, haemagglutinin-specific CD8 T cells could not initiate inflammation but were the effectors of the destruction of orexinergic neurons. Additional studies revealed pathways potentially involved in the disease process. Notably, the interferon-γ pathway was proven essential, as interferon-γ-deficient CD8 T cells were unable to elicit the loss of orexinergic neurons.
Our work demonstrates that an immunopathological process mimicking narcolepsy can be elicited by immune cross-reactivity between a vaccine antigen and a neuronal self-antigen. This process relies on a synergy between autoreactive CD4 and CD8 T cells for disease development. This work furthers our understanding of the mechanisms and pathways potentially involved in the development of a neurological side effect due to a vaccine and, likely, to narcolepsy in general.
Decline in Pneumococcal Disease in Young Children During the Coronavirus Disease 2019 (COVID-19) Pandemic in Israel Associated With Suppression of Seasonal Respiratory Viruses, Despite Persistent Pneumococcal Carriage: A Prospective Cohort Study
Authors: Danino Dana , Ben-Shimol Shalom , van der Beek Bart Adriaan , Givon-Lavi Noga , Avni Yonat Shemer , Greenberg David , Weinberger Daniel M , Dagan Ron 
Published: December 2021

Abstract

Background
The incidence of invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from nonpharmaceutical interventions. We used multiple ongoing cohort surveillance projects in children &lt;5 years to test this hypothesis.

Methods
The first SARS-CoV-2 cases were detected in February 2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory infections necessitating chest X-rays (NA-LRIs), nasopharyngeal pneumococcal carriage in nonrespiratory visits, nasopharyngeal respiratory virus detection (by polymerase chain reaction), and nationwide IPD. Monthly rates (January 2020 through February 2021 vs mean monthly rates 2016–2019 [expected rates]) adjusted for age and ethnicity were compared.

Results
CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios [IRRs]: .07 and .19, respectively); NA-LRIs and nonpneumonia IPD were also reduced by a lesser magnitude (IRRs: .46 and .42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distributions were similar to previous years. The decline in pneumococcus-associated disease was temporally associated with a full suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels.

Conclusions
Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic in Israel were not predominantly related to reduced pneumococcal carriage and density but were strongly associated with the disappearance of specific respiratory viruses.
Nutritional Supplementation Would Be Cost-Effective for Reducing Tuberculosis Incidence and Mortality in India: The Ration Optimization to Impede Tuberculosis (ROTI-TB) Model
Authors: Sinha Pranay , Lakshminarayanan Subitha L , Cintron Chelsie , Narasimhan Prakash Babu , Locks Lindsey M , Kulatilaka Nalin , Maloomian Kimberly , Prakash Babu Senbagavalli , Carwile Madeline E , Liu Anne F , Horsburgh C Robert , Acuna-Villaorduna Carlos , Linas Benjamin P , Hochberg Natasha S 
Published: December 2021

Abstract

Background
Undernutrition is the leading cause of tuberculosis (TB) in India and is associated with increased TB mortality. Undernutrition also decreases quality of life and economic productivity.

Methods
We assessed the cost-effectiveness of providing augmented rations to undernourished Indians through the government’s Targeted Public Distribution System (TPDS). We used Markov state transition models to simulate disease progression and mortality among undernourished individuals in 3 groups: general population, household contacts (HHCs) of people living with TB, and persons living with human immunodeficiency virus (HIV). The models calculate costs and outcomes (TB cases, TB deaths, and disability-adjusted life years [DALYs]) associated with a 2600 kcal/day diet for adults with body mass index (BMI) of 16–18.4 kg/m2 until they attain a BMI of 20 kg/m2 compared to a status quo scenario wherein TPDS rations are unchanged. We employed deterministic and probabilistic sensitivity analyses to test result robustness.

Results
Over 5 years, augmented rations could avert 81% of TB cases and 88% of TB deaths among currently undernourished Indians. Correspondingly, this intervention could forestall 78% and 48% of TB cases and prevent 88% and 70% of deaths among undernourished HHCs and persons with HIV, respectively. Augmented rations resulted in 10-fold higher resolution of undernutrition and were highly cost-effective with (incremental cost-effectiveness ratio [ICER] of $470/DALY averted). ICER was lower for HHCs ($360/DALY averted) and the HIV population ($250/DALY averted).

Conclusions
A robust nutritional intervention would be highly cost-effective in reducing TB incidence and mortality while reducing chronic undernutrition in India.
Randomized clinical study to evaluate the effect of personalized therapy on patients with immunoglobulin A nephropathy
Authors: Schena Francesco P , Tripepi Giovanni , Rossini Michele , Abbrescia Daniela I , Manno Carlo 
Published: December 2021

ABSTRACT

Background
Randomized controlled trials (RCTs) have been conducted, stratifying idiopathic immunoglobulin A nephropathy (IgAN) patients based on the laboratory findings [serum creatinine, estimated glomerular filtration rate (eGFR) and daily proteinuria]. In contrast, data from kidney biopsy have been used only for clinical diagnosis. Therefore, IgAN patients with active or chronic renal lesions have been receiving the same therapy in experimental and control arms of randomized clinical trials (RCTs).

Methods
Our clinical study of IgAN (CLIgAN) is a multicentre, prospective, controlled and open-label RCT based on patients’ stratification at the time of their kidney biopsy. We will consider, first, the type of renal lesions, followed by serum creatinine values, eGFR and proteinuria. Primary and secondary endpoints will be monitored. Then, we will determine whether personalized therapy can slow the decline of renal function and delay end-stage kidney disease.

Results
We will enrol 132 IgAN patients with active renal lesions (66 patients per arm) in the first RCT (ACIgAN). They will receive corticosteroids combined with renin–angiotensin system blockers (RASBs) or only RASBs. A total of 294 IgAN patients with chronic or moderate renal lesions at high or very high risk of chronic kidney disease (147 patients per arm) will be enrolled in the second RCT (CHRONIgAN), in which they will receive dapagliflozin, a sodium–glucose cotransporter 2 inhibitor, combined with RASBs, or RASBs alone.

Conclusion
Using this approach, we hypothesize that patients could receive personalized therapy based on renal lesions to ensure that the right drug gets to the right patient at the right time.
The year in cardiovascular medicine 2021: diabetes and metabolic disorders
Authors: Cosentino Francesco , Bhatt Deepak L. , Marx Nikolaus , Verma Subodh 
Published: December 2021

Abstract
In the current paper, we review recently published studies that are helping us to understand how the treatment landscape for glucagon-like peptiide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors is moving forward. We have also included relevant articles related to cardiovascular disease prevention in the setting of obesity, atherogenic dyslipidaemia and chronic kidney disease.
Measurement of obesity in primary care practice: chronic conditions matter
Authors: Lindeman Cliff , Jones Allyson , Klein Doug , Prado Carla M , Pham Anh N Q , Spence John C , Drummond Neil 
Published: December 2021

Lay Summary
Primary care providers can deliver tailored advice and support to patients who are overweight or have obesity. The 2020 Canadian Adult Obesity Practice Guideline for primary care providers recommended that patients’ waist circumference (WC) be measured if their height and weight place them in the overweight or Class I obesity category. The guideline does not recommend how often providers should measure WC nor describe how often this is measured in current practice. We reviewed electronic medical records (EMRs) of 707,819 Canadian adult patients aged 40 and older. Among them, 48.7% had 1 or more body mass index (BMI) recorded; 11.5% had at least 1 waist measurement recorded. Of those with a BMI classified as overweight or having Class I obesity, 23.7% had at least 1 WC measurement recorded, which differed by chronic disease. WC was documented in more patients who had diabetes mellitus (36.8%) than hypertension (26.1%), or osteoarthritis (24.3%). This difference may be reflective of more specific advice in diabetes guidelines. To our knowledge, this is the first study to describe documentation of WC measurement for patients who are overweight or have Class I obesity in Canadian primary care EMRs across obesity-related conditions.
Efficient ancestry and mutation simulation with msprime 1.0
Authors: Baumdicker Franz , Bisschop Gertjan , Goldstein Daniel , Gower Graham , Ragsdale Aaron P , Tsambos Georgia , Zhu Sha , Eldon Bjarki , Ellerman E Castedo , Galloway Jared G , Gladstein Ariella L , Gorjanc Gregor , Guo Bing , Jeffery Ben , Kretzschumar Warren W , Lohse Konrad , Matschiner Michael , Nelson Dominic , Pope Nathaniel S , Quinto-Cortés Consuelo D , Rodrigues Murillo F , Saunack Kumar , Sellinger Thibaut , Thornton Kevin , van Kemenade Hugo , Wohns Anthony W , Wong Yan , Gravel Simon , Kern Andrew D , Koskela Jere , Ralph Peter L , Kelleher Jerome 
Published: December 2021

Abstract
Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime’s many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.
N-glycan profiles of acute myocardial infarction patients reveal potential biomarkers for diagnosis, severity assessment and treatment monitoring
Authors: Lim Si Ying , Hendra Christopher , Yeo Xin Hao , Tan Xin Yi , Ng Bao Hui , Laserna Anna Karen Carrasco , Tan Sock Hwee , Chan Mark Y , Khan Shaheer H , Chen Shiaw-Min , Li Sam Fong Yau 
Published: December 2021

Abstract
Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity worldwide. Diagnostic challenges remain in this highly time-sensitive condition. Using capillary electrophoresis-laser-induced fluorescence, we analyzed the blood plasma N-glycan profile in a cohort study comprising 103 patients with AMI and 69 controls. Subsequently, the data generated was subjected to classification modeling to identify potential AMI biomarkers. An area under the Receiving Operating Characteristic curve (AUCROC) of 0.81 was obtained when discriminating AMI vs. non-MI patients. We postulate that the glycan profile involves a switch from a pro- to an anti-inflammatory state in the AMI pathophysiology. This was supported by significantly decreased levels in galactosylation, alongside increased levels in sialylation, afucosylation and GlcNAc bisection levels in the blood plasma of AMI patients. By substantiating the glycomics analysis with immunoglobulin G (IgG) protein measurements, robustness of the glycan-based classifiers was demonstrated. Changes in AMI-related IgG activities were also confirmed to be associated with alterations at the glycosylation level. Additionally, a glycan-biomarker panel derived from glycan features and current clinical biomarkers performed remarkably (AUCROC = 0.90, sensitivity = 0.579 at 5% false positive rate) when discriminating between patients with ST-segment elevation MI (n = 84) and non-ST-segment elevation MI (n = 19). Moreover, by applying the model trained using glycomics information, AMI and controls can still be discriminated at 1 and 6 months after baseline. Thus, glycomics biomarkers could potentially serve as a valuable complementary test to current diagnostic biomarkers. Additional research on their utility and associated biomechanisms via a large-scale study is recommended.
Mammalian sialyltransferases allow efficient Escherichia coli-based production of mucin-type O-glycoproteins but can also transfer Kdo
Authors: Sim Lyann , Thompson Nicole , Geissner Andreas , Withers Stephen G , Wakarchuk Warren W 
Published: December 2021

Abstract
The prospect of producing human-like glycoproteins in bacteria is becoming attractive as an alternative to already-established but costly mammalian cell expression systems. We previously described an Escherichia coli expression platform that uses a dual-plasmid approach to produce simple mucin type O-glycoproteins: one plasmid encoding the target protein and another O-glycosylation machinery. Here, we expand the capabilities of our platform to carry out sialylation and demonstrate the high-yielding production of human interferon α2b and human growth hormone bearing mono- and disialylated T-antigen glycans. This is achieved through engineering an E. coli strain to produce CMP-Neu5Ac and introducing various α-2,3- and α-2,6 mammalian or bacterial sialyltransferases into our O-glycosylation operons. We further demonstrate that mammalian sialyltransferases, including porcine ST3Gal1, human ST6GalNAc2 and human ST6GalNAc4, are very effective in vivo and outperform some of the bacterial sialyltransferases tested, including Campylobacter jejuni Cst-I and Cst-II. In the process, we came upon a way of modifying T-Antigen with Kdo, using a previously uncharacterised Kdo-transferase activity of porcine ST3Gal1. Ultimately, the heterologous expression of mammalian sialyltransferases in E. coli shows promise for the further development of bacterial systems in therapeutic glycoprotein production.
Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia
Authors: Chekuri Anil , Logan Emily M , Krauson Aram J , Salani Monica , Ackerman Sophie , Kirchner Emily G , Bolduc Jessica M , Wang Xia , Dietrich Paula , Dragatsis Ioannis , Vandenberghe Luk H , Slaugenhaupt Susan A , Morini Elisabetta 
Published: December 2021

Abstract
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease caused by a splicing mutation in the gene encoding Elongator complex protein 1 (ELP1, also known as IKBKAP). This mutation results in tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, predominantly in the central and peripheral nervous system. Although FD patients have a complex neurological phenotype caused by continuous depletion of sensory and autonomic neurons, progressive visual decline leading to blindness is one of the most problematic aspects of the disease, as it severely affects their quality of life. To better understand the disease mechanism as well as to test the in vivo efficacy of targeted therapies for FD, we have recently generated a novel phenotypic mouse model, TgFD9; IkbkapΔ20/flox. This mouse exhibits most of the clinical features of the disease and accurately recapitulates the tissue-specific splicing defect observed in FD patients. Driven by the dire need to develop therapies targeting retinal degeneration in FD, herein, we comprehensively characterized the progression of the retinal phenotype in this mouse, and we demonstrated that it is possible to correct ELP1 splicing defect in the retina using the splicing modulator compound (SMC) BPN-15477.