bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient expression of an adenine base editor corrects the Hutchinson-Gilford progeria syndrome mutation and improves the skin phenotype in mice
Authors: Whisenant Daniel , Lim Kayeong , Revêchon Gwladys , Yao Haidong , Bergo Martin O. , Machtel Piotr , Kim Jin-Soo , Eriksson Maria 
Published: June 2022

AbstractHutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder caused by a point mutation in the LMNA gene (LMNA c.1824 C > T), resulting in the production of a detrimental protein called progerin. Adenine base editors recently emerged with a promising potential for HGPS gene therapy. However adeno-associated viral vector systems currently used in gene editing raise concerns, and the long-term effects of heterogeneous mutation correction in highly proliferative tissues like the skin are unknown. Here we use a non-integrative transient lentiviral vector system, expressing an adenine base editor to correct the HGPS mutation in the skin of HGPS mice. Transient adenine base editor expression corrected the mutation in 20.8-24.1% of the skin cells. Four weeks post delivery, the HGPS skin phenotype was improved and clusters of progerin-negative keratinocytes were detected, indicating that the mutation was corrected in both progenitor and differentiated skin cells. These results demonstrate that transient non-integrative viral vector mediated adenine base editor expression is a plausible approach for future gene-editing therapies.
Aseismic slip and recent ruptures of persistent asperities along the Alaska-Aleutian subduction zone
Authors: Zhao Bin , Bürgmann Roland , Wang Dongzhen , Zhang Jian , Yu Jiansheng , Li Qi 
Published: June 2022

AbstractThe frictional properties and slip behaviors of subduction thrusts play a key role in seismic and tsunami hazard assessment, especially in weakly coupled “seismic gaps”. Here, we rely on GPS observations in the Shumagin Gap of the Aleutian subduction zone to derive the slip distribution of the 2020 Mw 7.8 Simeonof Island, Alaska earthquake and of the subsequent afterslip during the first 87-day period. Our modeling results show that the mainshock ruptured at depths of ∼30–40 km beneath Simeonof Island. Kinematic and stress-driven models indicate that the afterslip occurred both updip and downdip of the mainshock rupture. Physically plausible locking models derived from interseismic GPS velocities suggest that the 2020 Simeonof and 2021 Mw 8.2 Chignik earthquakes ruptured persistent asperities on the subduction thrust. We infer that there are several additional persistent asperities at depths of 20–50 km west ∼157°W. However, it is still uncertain whether there are additional locked asperities at shallow depths because of the current lack of geodetic observations close to the trench.
Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar
Authors: Chemaitelly Hiam , Ayoub Houssein H. , AlMukdad Sawsan , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J. 
Published: June 2022

AbstractSARS-CoV-2 Omicron BA.1 and BA.2 subvariants are genetically divergent. We conducted a matched, test-negative, case-control study to estimate duration of protection of the second and third/booster doses of mRNA COVID-19 vaccines against BA.1 and BA.2 infections in Qatar. BNT162b2 effectiveness was highest at 46.6% (95% CI: 33.4–57.2%) against symptomatic BA.1 and at 51.7% (95% CI: 43.2–58.9%) against symptomatic BA.2 infections in the first three months after the second dose, but declined to ~10% or below thereafter. Effectiveness rebounded to 59.9% (95% CI: 51.2–67.0%) and 43.7% (95% CI: 36.5–50.0%), respectively, in the first month after the booster dose, before declining again. Effectiveness against COVID-19 hospitalization and death was 70–80% after the second dose and >90% after the booster dose. mRNA-1273 vaccine protection showed similar patterns. mRNA vaccines provide comparable, moderate, and short-lived protection against symptomatic BA.1 and BA.2 Omicron infections, but strong and durable protection against COVID-19 hospitalization and death.
Quantitative detection of α-Synuclein and Tau oligomers and other aggregates by digital single particle counting
Authors: Blömeke Lara , Pils Marlene , Kraemer-Schulien Victoria , Dybala Alexandra , Schaffrath Anja , Kulawik Andreas , Rehn Fabian , Cousin Anneliese , Nischwitz Volker , Willbold Johannes , Zack Rebecca , Tropea Thomas F. , Bujnicki Tuyen , Tamgüney Gültekin , Weintraub Daniel , Irwin David , Grossman Murray , Wolk David A. , Trojanowski John Q. , Bannach Oliver , Chen-Plotkin Alice , Willbold Dieter 
Published: June 2022

AbstractThe pathological hallmark of neurodegenerative diseases is the formation of toxic oligomers by proteins such as alpha-synuclein (aSyn) or microtubule-associated protein tau (Tau). Consequently, such oligomers are promising biomarker candidates for diagnostics as well as drug development. However, measuring oligomers and other aggregates in human biofluids is still challenging as extreme sensitivity and specificity are required. We previously developed surface-based fluorescence intensity distribution analysis (sFIDA) featuring single-particle sensitivity and absolute specificity for aggregates. In this work, we measured aSyn and Tau aggregate concentrations of 237 cerebrospinal fluid (CSF) samples from five cohorts: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and a neurologically-normal control group. aSyn aggregate concentration discriminates PD and DLB patients from normal controls (sensitivity 73%, specificity 65%, area under the receiver operating curve (AUC) 0.68). Tau aggregates were significantly elevated in PSP patients compared to all other groups (sensitivity 87%, specificity 70%, AUC 0.76). Further, we found a tight correlation between aSyn and Tau aggregate titers among all patient cohorts (Pearson coefficient of correlation r = 0.81). Our results demonstrate that aSyn and Tau aggregate concentrations measured by sFIDA differentiate neurodegenerative disease diagnostic groups. Moreover, sFIDA-based Tau aggregate measurements might be particularly useful in distinguishing PSP from other parkinsonisms. Finally, our findings suggest that sFIDA can improve pre-clinical and clinical studies by identifying those individuals that will most likely respond to compounds designed to eliminate specific oligomers or to prevent their formation.
Validation of the PD home diary for assessment of motor fluctuations in advanced Parkinson’s disease
Authors: Löhle Matthias , Bremer Alexander , Gandor Florin , Timpka Jonathan , Odin Per , Ebersbach Georg , Storch Alexander 
Published: June 2022

AbstractThe Parkinson’s disease (PD) home diary is frequently used in clinical trials to measure efficacy of medical treatments for motor fluctuations in advanced PD. This prospective study in fluctuating PD patients examines the validity of the diary for quantification of motor states in comparison to direct clinical observation. 51 patients (median age: 65 years, disease duration: 11 years) completed the diary half-hourly for two consecutive days and were simultaneously rated by an experienced observer, who independently evaluated motor states half-hourly throughout daytime. Overall agreement (Cohen’s kappa) between patient and observer diary entries was 59.8% (0.387). Patients documented more On without dyskinesia (52.3% vs. 38.9%, P < 0.001) and less On with dyskinesia (21.5% vs. 34.2%, P < 0.001), whereas proportions for Off intervals were not different between patient and observer diaries (26.2% vs. 27.0%, P = 0.97). Temporal agreement between diary ratings was unsatisfactory, particularly for On with dyskinesia. Taken together, our study suggests that the PD home diary only inadequately reflects actual motor states compared to direct clinical observation.
TR12 centers in diamond as a room temperature atomic scale vector magnetometer
Authors: Foglszinger Jonas , Denisenko Andrej , Kornher Thomas , Schreck Matthias , Knolle Wolfgang , Yavkin Boris , Kolesov Roman , Wrachtrup Jörg 
Published: June 2022

AbstractThe family of room temperature atomic scale magnetometers is currently limited to nitrogen-vacancy centers in diamond. However, nitrogen-vacancy centers are insensitive to strong off-axis magnetic fields. In this work, we show that the well-known TR12 radiative defect in diamond, exhibits strong optically detected magnetic resonance (ODMR) signal under optical saturation. We also demonstrate that the spin system responsible for the magnetic resonance is an excited triplet state that can be coherently controlled at room temperature on a single defect level. The high optically detected magnetic resonance contrast, which is maintained even for strong off-axis magnetic fields, suggests that TR12 centers can be used for vector magnetometry even at high field.
METALIC reveals interorganelle lipid flux in live cells by enzymatic mass tagging
Authors: John Peter Arun T. , Petrungaro Carmelina , Peter Matthias , Kornmann Benoît 
Published: June 2022

AbstractThe distinct activities of organelles depend on the proper function of their membranes. Coordinated membrane biogenesis of different organelles necessitates lipid transport from their site of synthesis to their destination. Several factors have been proposed to participate in lipid distribution, but despite its basic importance, in vivo evidence linking the absence of putative transport pathways to specific transport defects remains scarce. A reason for this scarcity is the near absence of in vivo lipid trafficking assays. Here we introduce a versatile method named METALIC (Mass tagging-Enabled TrAcking of Lipids In Cells) to track interorganelle lipid flux inside cells. In this strategy, two enzymes, one directed to a ‘donor’ and the other to an ‘acceptor’ organelle, add two distinct mass tags to lipids. Mass-spectrometry-based detection of lipids bearing the two mass tags is then used to quantify exchange between the two organelles. By applying this approach, we show that the ERMES and Vps13–Mcp1 complexes have transport activity in vivo, and unravel their relative contributions to endoplasmic reticulum–mitochondria lipid exchange.
Genetic correlates of phenotypic heterogeneity in autism
Authors: Warrier Varun , Zhang Xinhe , Reed Patrick , Havdahl Alexandra , Moore Tyler M. , Cliquet Freddy , Leblond Claire S. , Rolland Thomas , Rosengren Anders ,   EU-AIMS LEAP, Caceres Antonia San Jose , Hayward Hannah , Crawley Daisy , Faulkner Jessica , Sabet Jessica , Ellis Claire , Oakley Bethany , Loth Eva , Charman Tony , Murphy Declan , Holt Rosemary , Waldman Jack , Upadhyay Jessica , Gunby Nicola , Lai Meng-Chuan , Renouf Gwilym , Ruigrok Amber , Taylor Emily , Ziauddeen Hisham , Deakin Julia , di Bruttopilo Sara Ambrosino , van Dijk Sarai , Rijks Yvonne , Koops Tabitha , Douma Miriam , Spaan Alyssia , Selten Iris , Steffers Maarten , van Themaat Anna Ver Loren , Bast Nico , Baumeister Sarah , O’Dwyer Larry , Bours Carsten , Rausch Annika , von Rhein Daniel , Cornelissen Ineke , de Bruin Yvette , Graauwmans Maartje , Kostrzewa Elzbieta , Cauvet Elodie , Tammimies Kristiina , Sitnikow Rouslan , Dumas Guillaume , Kim Yang-Min , Bourgeron Thomas ,   iPSYCH-Autism Working Group, Hougaard David M. , Bybjerg-Grauholm Jonas , Werge Thomas , Mortensen Preben Bo , Mors Ole , Nordentoft Merete ,   Spectrum 10K and APEX Consortia, Adhya Dwaipayan , Alamanza Armandina , Allison Carrie , Garvey Isabelle , Parsons Tracey , Smith Paula , Tsompanidis Alex , Burton Graham J. , Heazell Alexander E. P. , Gabis Lidia V. , Biron-Shental Tal , Lancaster Madeline A. , Srivastava Deepak P. , Mill Jonathan , Rowitch David H. , Hurles Matthew E. , Geschwind Daniel H. , Børglum Anders D. , Robinson Elise B. , Grove Jakob , Martin Hilary C. , Bourgeron Thomas , Baron-Cohen Simon 
Published: June 2022

AbstractThe substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.
Transferability of genetic risk scores in African populations
Authors: Kamiza Abram B. , Toure Sounkou M. , Vujkovic Marijana , Machipisa Tafadzwa , Soremekun Opeyemi S. , Kintu Christopher , Corpas Manuel , Pirie Fraser , Young Elizabeth , Gill Dipender , Sandhu Manjinder S. , Kaleebu Pontiano , Nyirenda Moffat , Motala Ayesha A. , Chikowore Tinashe , Fatumo Segun 
Published: June 2022

AbstractThe poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.
Dental macrowear reveals ecological diversity of Gorilla spp.
Authors: Harty Teagan , Berthaume Michael A. , Bortolini Eugenio , Evans Alistair R. , Galbany Jordi , Guy Franck , Kullmer Ottmar , Lazzari Vincent , Romero Alejandro , Fiorenza Luca 
Published: June 2022

AbstractSize and shape variation of molar crowns in primates plays an important role in understanding how species adapted to their environment. Gorillas are commonly considered to be folivorous primates because they possess sharp cusped molars which are adapted to process fibrous leafy foods. However, the proportion of fruit in their diet can vary significantly depending on their habitats. While tooth morphology can tell us what a tooth is capable of processing, tooth wear can help us to understand how teeth have been used during mastication. The objective of this study is to explore if differences in diet at the subspecies level can be detected by the analysis of molar macrowear. We analysed a large sample of second lower molars of Grauer’s, mountain and western lowland gorilla by combining the Occlusal Fingerprint Analysis method with other dental measurements. We found that Grauer’s and western lowland gorillas are characterised by a macrowear pattern indicating a larger intake of fruit in their diet, while mountain gorilla’s macrowear is associated with the consumption of more folivorous foods. We also found that the consumption of herbaceous foods is generally associated with an increase in dentine and enamel wear, confirming the results of previous studies.
A computational model of stem cells’ decision-making mechanism to maintain tissue homeostasis and organization in the presence of stochasticity
Authors: Khorasani Najme , Sadeghi Mehdi 
Published: June 2022

AbstractThe maintenance of multi-cellular developed tissue depends on the proper cell production rate to replace the cells destroyed by the programmed process of cell death. The stem cell is the main source of producing cells in a developed normal tissue. It makes the stem cell the lead role in the scene of a fully formed developed tissue to fulfill its proper functionality. By focusing on the impact of stochasticity, here, we propose a computational model to reveal the internal mechanism of a stem cell, which generates the right proportion of different types of specialized cells, distribute them into their right position, and in the presence of intercellular reactions, maintain the organized structure in a homeostatic state. The result demonstrates that the spatial pattern could be harassed by the population geometries. Besides, it clearly shows that our model with progenitor cells able to recover the stem cell presence could retrieve the initial pattern appropriately in the case of injury. One of the fascinating outcomes of this project is demonstrating the contradictory roles of stochasticity. It breaks the proper boundaries of the initial spatial pattern in the population. While, on the flip side of the coin, it is the exact factor that provides the demanded non-genetic diversity in the tissue. The remarkable characteristic of the introduced model as the stem cells’ internal mechanism is that it could control the overall behavior of the population without need for any external factors.
Measurement of circulating CD21−CD27− B lymphocytes in SLE patients is associated with disease activity independently of conventional serological biomarkers
Authors: Horisberger Alice , Humbel Morgane , Fluder Natalia , Bellanger Florence , Fenwick Craig , Ribi Camillo , Comte Denis 
Published: June 2022

AbstractDetermining disease activity in systemic lupus erythematosus (SLE) patients is challenging and limited by the lack of reliable biomarkers. Abnormally activated B cells play a key role in the pathogenesis of SLE, but their measure in clinical practice is currently not recommended. Here, we studied peripheral B cells to identify a valid biomarker. We analyzed peripheral B cells in a discovery cohort of 30 SLE patients compared to 30 healthy controls (HC) using mass cytometry and unsupervised clustering analysis. The relevant B cell populations were subsequently studied by flow cytometry in a validation cohort of 63 SLE patients, 28 autoimmune diseases controls and 39 HC. Our data show an increased frequency of B cell populations with activated phenotype in SLE compared to healthy and autoimmune diseases controls. These cells uniformly lacked the expression of CD21 and CD27. Measurement of CD21−CD27− B cells in the blood identified patients with active disease and their frequency correlated with disease severity. Interestingly, we did not observe an increase in the frequency of CD21−CD27− B cells in patients with clinically inactive disease but with elevated conventional biomarkers (anti-dsDNA and complement levels). Accordingly, measurement of CD21−CD27− B cells represents a robust and easily accessible biomarker to assess the activity of the disease in SLE patients.
Complex effects on CaV2.1 channel gating caused by a CACNA1A variant associated with a severe neurodevelopmental disorder
Authors: Grosso Benjamin J. , Kramer Audra A. , Tyagi Sidharth , Bennett Daniel F. , Tifft Cynthia J. , D’Souza Precilla , Wangler Michael F. , Macnamara Ellen F. , Meza Ulises , Bannister Roger A. 
Published: June 2022

AbstractP/Q-type Ca2+ currents mediated by CaV2.1 channels are essential for active neurotransmitter release at neuromuscular junctions and many central synapses. Mutations in CACNA1A, the gene encoding the principal CaV2.1 α1A subunit, cause a broad spectrum of neurological disorders. Typically, gain-of-function (GOF) mutations are associated with migraine and epilepsy while loss-of-function (LOF) mutations are causative for episodic and congenital ataxias. However, a cluster of severe CaV2.1 channelopathies have overlapping presentations which suggests that channel dysfunction in these disorders cannot always be defined bimodally as GOF or LOF. In particular, the R1667P mutation causes focal seizures, generalized hypotonia, dysarthria, congenital ataxia and, in one case, cerebral edema leading ultimately to death. Here, we demonstrate that the R1667P mutation causes both channel GOF (hyperpolarizing voltage-dependence of activation, slowed deactivation) and LOF (slowed activation kinetics) when expressed heterologously in tsA-201 cells. We also observed a substantial reduction in Ca2+ current density in this heterologous system. These changes in channel gating and availability/expression manifested in diminished Ca2+ flux during action potential-like stimuli. However, the integrated Ca2+ fluxes were no different when normalized to tail current amplitude measured upon repolarization from the reversal potential. In summary, our findings indicate a complex functional effect of R1667P and support the idea that pathological missense mutations in CaV2.1 may not represent exclusively GOF or LOF.
Similarity matrix-based anomaly detection for clinical intervention
Authors: D’Mello Ryan , Melcher Jennifer , Torous John 
Published: June 2022

AbstractThe use of digital phenotyping methods in clinical care has allowed for improved investigation of spatiotemporal behaviors of patients. Moreover, detecting abnormalities in mobile sensor data patterns can be instrumental in identifying potential changes in symptomology. We propose a method that temporally aligns sensor data in order to achieve interpretable measures of similarity between time points. These computed measures can then be used for anomaly detection, baseline routine computation, and trajectory clustering. In addition, we apply this method on a study of 695 college participants, as well as on a patient with worsening anxiety and depression. With varying temporal constraints, we find mild correlations between changes in routine and clinical scores. Furthermore, in our experiment on an individual with elevated depression and anxiety, we are able to cluster GPS trajectories, allowing for improved understanding and visualization of routines with respect to symptomology. In the future, we aim to apply this method on individuals that undergo data collection for longer periods of time, thus allowing for a better understanding of long-term routines and signals for clinical intervention.