bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival
Authors: Strauss Alexandra , Swann Peter , Kigar Stacey , Christou Rafailia , Yarkoni Natalia Savinykh , Murley Alexander , Chouliaras Leonidas , Savulich George , Bevan-Jones Richard , Surendranthan Ajenthan , O’Brien John , Rowe James , Malpetti Maura 
Published: January 2024

AbstractThe innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g. cerebral microglia), peripheral innate immune cells (e.g. blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells, in n=148 people with Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Corticobasal syndrome (CBS), Progressive Supranuclear Palsy (PSP), Lewy Body Disease (LBD) as compared to n=37 healthy controls. To compare groups, we used Principal Component Analysis and multivariate Dissimilarity analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals’ immune profile weighting, positively to TREM2+ and nonclassical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies.
Concerted Transport and Phosphorylation of Diacylglycerol at ER-PM Contacts Sites Regulates Phospholipid Dynamics During Stress
Authors: García-Hernández Selene , Haslam Richard , Moya-Cuevas José , Catalá Rafael , Michaelson Louise , Amorim-Silva Vitor , Marković Vedrana , Salinas Julio , Napier Johnathan , Jaillais Yvon , Ruiz-Lopez Noemí , Botella Miguel A. 
Published: January 2024

ABSTRACTA universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C (PLC) that hydrolyzes phosphatidylinositol phosphate (PIP) to produce soluble inositol phosphate (IP) and diacylglycerol (DAG). DAG produced in this way can be either phosphorylated by PM diacylglycerol kinases (DGKs) to produce the second messenger phosphatidic acid (PA) or transferred to the endoplasmic reticulum (ER) by the Synaptotagmin 1 (SYT1) protein at ER-PM Contact Sites (CS). In Arabidopsis, the clearance of DAG at the PM (avoiding deleterious accumulation) by the transfer activity of SYT is essential to maintain PM stability after stress. In this study we identify that DGK1 and DGK2 form a module with SYT1 at ER-PM CS through interaction of their C1 and C2 domains respectively. Global transcriptomic and metabolomic analyses confirms thatSYT1andDGK1/DGK2are functionally related and lipidomic analysis supports the hypothesis that DGK1 and DGK2 function at the ER by phosphorylating DAG transferred by SYT1 from the PM. DGK1 and DGK2 show structural similarity to human DGKε, the DGK isoform that function at ER-PM CS in the phosphoinositide (PI) cycle. Our data indicate that components of the PI cycle are conserved between animals and plants and provide a novel mechanism leading to an increase in the efficiency of the PI cycle by channeling the transport and hydrolysis of DAG at the ER-PM CS.
Single-Molecule Force Spectroscopy of Toehold-Mediated Strand Displacement
Authors: Walbrun Andreas , Wang Tianhe , Matthies Michael , Šulc Petr , Simmel Friedrich C. , Rief Matthias 
Published: January 2024

AbstractToehold-mediated strand displacement (TMSD) is extensively utilized in dynamic DNA nanotechnology and is the foundation for a wide range of DNA or RNA-based reaction circuits. Previous studies have typically relied on bulk fluorescence measurements to investigate the kinetics of TMSD, which only provide effective, bulk-averaged reaction rates and do not resolve the process on the level of individual molecules or even base pairs. In this work, we addressed this limitation by exploring the dynamics of strand displacement processes at the single-molecule level using single-molecule force spectroscopy (SMFS) with an optical trap supported by state-of-the-art coarse-grained simulations.By probing the ends of the hairpin of a toehold structure, we can trigger and observe TMSD in real time with microsecond and nanometer resolution. Using a microfluidic assay where we expose the hairpin to a solution of trigger strands, we find that under load, TMSD proceeds very rapidly, with single step times of 1 μs. Introducing mismatches into the invader sequence allows us to tune stability such that invasion and re-invasion occur in equilibrium, even under load. This allows us to study thousands of invasion/re-invasion events on a single molecule and analyze the kinetics of the invasion process. Extrapolating our findings to zero load, we find single step times for DNA invading DNA four times faster than for RNA invading RNA. Moreover, we used force to study the kinetics of DNA invading RNA, a process that in the absence of force would rarely occur. Our results reveal the importance of sequence effects for the TMSD process and have importance for a wide range of applications in nucleic acid nanotechnology and synthetic biology.
Ciliary length regulation by intraflagellar transport in zebrafish
Authors: Sun Yi , Chen Zhe , Jin Minjun , Xie Haibo , Zhao Chengtian 
Published: January 2024

ABSTRACTHow cells regulate the size of their organelles remains a fundamental question in cell biology. Cilia, with their simple structure and surface localization, provide an ideal model for investigating organelle size control. However, most studies on cilia length regulation are primarily performed on several single-celled organisms. In contrast, the mechanism of length regulation in cilia across diverse cell types within multicellular organisms remains a mystery. Similar to humans, zebrafish contain diverse types of cilia with variable lengths. Taking advantage of the transparency of zebrafish embryos, we conducted a comprehensive investigation into intraflagellar transport (IFT), an essential process for ciliogenesis. By generating a transgenic line carrying Ift88-GFP transgene, we observed IFT in multiple types of cilia with varying lengths. Remarkably, cilia exhibited variable IFT speeds in different cell types, with longer cilia exhibiting faster IFT speeds. This increased IFT speed in longer cilia is likely not due to changes in common factors that regulate IFT, such as motor selection, BBSome proteins, or tubulin modification. Interestingly, longer cilia in the ear cristae tend to form larger IFT compared to shorter spinal cord cilia. Reducing the size of IFT particles by knocking down Ift88 slowed IFT speed and resulted in the formation of shorter cilia. Our study proposes an intriguing model of cilia length regulation via controlling IFT speed through the modulation of the size of the IFT complex. This discovery may provide further insights into our understanding of how organelle size is regulated in higher vertebrates.
A pathogenic variant in RAB32 causes autosomal dominant Parkinson’s disease andactivates LRRK2 kinase
Authors: Gustavsson Emil K. , Follett Jordan , Trinh Joanne , Barodia Sandeep K. , Real Raquel , Liu Zhiyong , Grant-Peters Melissa , Fox Jesse D. , Appel-Cresswell Silke , Stoessl A. Jon , Rajput Alex , Rajput Ali H. , Auer Roland , Tilney Russel , Sturm Marc , Haack Tobias B. , Lesage Suzanne , Tesson Christelle , Brice Alexis , Vilariño-Güell Carles , Ryten Mina , Goldberg Matthew S. , West Andrew B. , Hu Michele T. , Morris Huw R. , Sharma Manu , Gan-Or Ziv , Samanci Bedia , Lis Pawel , Tocino Teresa , Amouri Rim , Sassi Samia Ben , Hentati Faycel ,   Global Parkinson’s Genetics Program (GP2), Tonelli Francesca , Alessi Dario R. , Farrer Matthew J. 
Published: January 2024

SummaryBackgroundParkinson’s disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.MethodsAffected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.FindingsWe foundRAB32c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families.RAB32Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably,RAB32Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.InterpretationOur study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.FundingNational Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson’s, the Michael J. Fox Foundation for Parkinson’s Research, and the UK Medical Research Council.
Lesions causing Alice in Wonderland Syndrome map to a common brain network linking body and size perception
Authors: Friedrich Maximilian U. , Baughan Elijah C. , Kletenik Isaiah , Younger Ellen , Zhao Charlie W. , Howard Calvin , Ferguson Michael A. , Chen Amalie , Zeller Daniel , Piervincenzi Claudia , Tommasin Silvia , Pantano Patrizia , Blanke Olaf , Prasad Sashank , Nielsen Jared A. , Fox Michael D. 
Published: January 2024

AbstractBackgroundIn Lewis Carroll’s 1865 novel “Alice’s Adventures in Wonderland”, the protagonist experiences distortions in the size of her body and those of others. This fiction becomes reality in neurological patients with Alice in Wonderland Syndrome (AIWS). Brain lesions causing AIWS may offer unique insights into the syndrome’s elusive neuroanatomy.MethodsA systematic literature search identified 37 cases of lesion-induced AIWS. Lesion locations were mapped onto a brain atlas and functional connectivity between each lesion location and other brain regions was estimated using resting-state fMRI data from 1000 healthy subjects. Connections common to AIWS lesions were identified and compared to connections from 1073 lesions associated with 25 other neuropsychiatric disorders. Alignment between this lesion-derived AIWS network and neuroimaging findings from patients with AIWS due to other etiologies was assessed.ResultsAlthough AIWS lesions occurred in many different brain locations, these lesions fell within a specific, functionally connected brain network. This network was defined by connectivity to the right extrastriate body area, a brain region selectively activated by viewing body parts, and the inferior parietal cortex, a brain region involved in processing of size and scale. This connectivity pattern was specific to AIWS when compared to lesions causing other neuropsychiatric disorders and aligned with neuroimaging findings in patients with AIWS from other etiologies.ConclusionLesions causing AIWS fall within a specific brain network defined by connectivity to two distinct brain regions, one region involved in body perception and another in processing of size and scale.
Alcohol septal ablation in hypertrophic obstructive cardiomyopathy: do sex, mitral valve leaflet length and septal thickness affect the outcome?
Authors: Mustafic Mesud , Jandér Rebecka , Marlevi David , Rickenlund Anette , Rück Andreas , Saleh Nawzad , Abdi Sam , Eriksson Maria J , Damlin Anna 
Published: January 2024

AbstractPurposeThis retrospective cohort study aimed to assess whether basal septal wall thickness (BSWT), anterior (AML) and posterior (PML) mitral leaflet length, or sex were associated with remaining left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing alcohol septal ablation (ASA).Methods154 patients that underwent ASA at the Karolinska University Hospital in Stockholm, Sweden, between 2009 and 2021, were retrospectively included. Anatomical and hemodynamic parameters were collected from invasive catheterization before and during ASA, and from echocardiography (ECHO) examinations before, during, and at one-year follow-up after ASA. Linear and logistic regression models were used to assess the association between sex, BSWT, AML, PML, and outcome defined as remaining LVOTO (>30 mmHg) after ASA.ResultsThe median follow-up was 364 days (IQR 334-385 days). BSWT>23 mm (n=13, 12%) was associated with remaining LVOTO at follow-up (p=0.004). Elongated MVLL (either AML or PML) was present in 125 (90%) of the patients. Elongated AML (>24 mm) was present in 67 (44%) of the patients, although AML length was not associated with remaining LVOTO at follow-up. Elongated PML (>14 mm) was present in 114 (74%) and not associated with remaining LVOTO at follow-up. No significant sex differences were observed regarding remaining LVOTO.ConclusionECHO measurement of BSWT can be used effectively for patient selection for successful ASA and for identification of patients with a risk of incomplete resolution of LVOTO after ASA.
The Seasonal Influenza Vaccine Cannot Trigger a Titer Increase Among Some Elderly Individuals
Authors: Ge Yang , Cao Wangnan , Sun Shengzhi , Ross Ted M. , Shen Ye 
Published: January 2024

AbstractMany elderlies exhibited absent responses to influenza vaccines. Our exploration of this heterogeneity revealed associations with vaccine dose (HD vs. SD, OR: 0.59 (95%CrI, 0.4 to 0.87)), pre-vaccination titer levels (OR: 1.57 (95%CrI, 1.38 to 1.8), and gender (Male vs. Female OR: 2.12 (95%CrI, 1.38 to 3.25)).
Intrasubject variability in Potential Early Markers of Sensorineural Hearing Damage
Authors: De Poortere Nele , Keshishzadeh Sarineh , Keppler Hannah , Dhooge Ingeborg , Verhulst Sarah 
Published: January 2024

ABSTRACTThe quest for noninvasive early markers for sensorineural hearing loss (SNHL) has yielded diverse measures of interest. However, comprehensive studies evaluating the test-retest reliability of multiple measures and stimuli within a single study are scarce, and a standardized clinical protocol for robust early markers of SNHL remains elusive. To address these gaps, this study explores the intra-subject variability of various potential EEG-biomarkers for cochlear synaptopathy (CS) and other SNHL-markers in the same individuals. Fifteen normal-hearing young adults underwent repeated measures of (extended high-frequency) pure-tone audiometry, speech-in-noise intelligibility, distortion-product otoacoustic emissions (DPOAEs), and auditory evoked potentials; comprising envelope following responses (EFR) and auditory brainstem responses (ABR). Results confirm high reliability in pure-tone audiometry, whereas the matrix sentence-test exhibited a significant learning effect. The reliability of DPOAEs varied across three evaluation methods, each employing distinct SNR-based criteria for DPOAE-datapoints. EFRs exhibited superior test-retest reliability compared to ABR-amplitudes. Our findings emphasize the need for careful interpretation of presumed noninvasive SNHL measures. While tonal-audiometry’s robustness was corroborated, we observed a confounding learning effect in longitudinal speech audiometry. The variability in DPOAEs highlights the importance of consistent ear probe replacement and meticulous measurement techniques, indicating that DPOAE test-retest reliability is significantly compromised under less-than-ideal conditions. As potential EEG-biomarkers of CS, EFRs are preferred over ABR-amplitudes based on the current study results.
In vivo delivery of functional Cas:DNA nucleoprotein complexes into recipient bacteria through a Type IV Secretion System
Authors: Guzmán-Herrador Dolores L. , Fernández-Gómez Andrea , Depardieu Florence , Bikard David , Llosa Matxalen 
Published: January 2024

AbstractCRISPR-associated (Cas) endonucleases and their derivatives are widespread tools for the targeted genetic modification of both prokaryotic and eukaryotic genomes. A critical step of all CRISPR-Cas technologies is the delivery of the Cas endonuclease to the target cell. Here, we investigate the possibility of using bacterial conjugation to translocate Cas proteins into recipient bacteria. Conjugative relaxases are translocated through a Type IV Secretion System (T4SS) into the recipient cell, covalently attached to the transferred DNA strand. We fused relaxase R388-TrwC with the class 2 Cas endonuclease Cas12a and confirmed that it can be transported through a T4SS. The fusion protein maintained its activity upon translocation by conjugation into the recipient cell, as evidenced by the induction of the SOS signal resulting from the cuts produced by the endonuclease in the recipient cell, and the detection of mutations at the target position. We further show how a template DNA provided on the transferred DNA can be used to introduce specific mutations. The gRNA can also be encoded by the transferred DNA, enabling its production in the recipient cells where it can form a complex with the Cas nuclease transferred as a protein. This self-contained setup enables to target wild type bacterial cells. Finally, we extended this strategy to the delivery of relaxases fused to base editors. Using both TrwC and MobA relaxases as drivers, we achieved precise editing of transconjugants. Thus, conjugation provides anin vivodelivery system for Cas-derived editing tools, bypassing the need to deliver and express acasgene in the target cells.Significance StatementWe have developed a novel approach for introducing CRISPR-Cas genetic tools into bacteria. During bacterial conjugation, the relaxase protein is transferred through the secretion system covalently attached to the transferred DNA. By fusing the Cas protein with the conjugative relaxase, we have observed functional Cas activity in the recipient cells, eliminating the need for nuclease expression in these cells. The covalently attached DNA molecule can supply gRNA and donor DNA, enabling seamless genetic modifications through recombination. We have also successfully translocated fusions of relaxases to base editors which are active in recipient cells. This method can be applied to any potential recipient cells, making it particularly interesting for wild type bacterial strains that lack available genetic tools. Furthermore, this method has the potential to be extended to eukaryotic cells.
Multi-segmental heating of facing vertical walls in porous systems filled with hybrid nanofluid in a constant-strength magnetic environment
Authors: Pandit Sobhan , Mondal Milan K. , Sanyal Dipankar , Manna Nirmal K. , Biswas Nirmalendu , Mandal Dipak Kumar 
Published: January 2024

Purpose
This study aims to undertake a comprehensive examination of heat transfer by convection in porous systems with top and bottom walls insulated and differently heated vertical walls under a magnetic field. For a specific nanofluid, the study aims to bring out the effects of different segmental heating arrangements.

Design/methodology/approach
An existing in-house code based on the finite volume method has provided the numerical solution of the coupled nondimensional transport equations. Following a validation study, different explorations include the variations of Darcy–Rayleigh number (Ram = 10–104), Darcy number (Da = 10–5–10–1) segmented arrangements of heaters of identical total length, porosity index (ε = 0.1–1) and aspect ratio of the cavity (AR = 0.25–2) under Hartmann number (Ha = 10–70) and volume fraction of φ = 0.1% for the nanoparticles. In the analysis, there are major roles of the streamlines, isotherms and heatlines on the vertical mid-plane of the cavity and the profiles of the flow velocity and temperature on the central line of the section.

Findings
The finding of a monotonic rise in the heat transfer rate with an increase in Ram from 10 to 104 has prompted a further comparison of the rate at Ram equal to 104 with the total length of the heaters kept constant in all the cases. With respect to uniform heating of one entire wall, the study reveals a significant advantage of 246% rate enhancement from two equal heater segments placed centrally on opposite walls. This rate has emerged higher by 82% and 249%, respectively, with both the segments placed at the top and one at the bottom and one at the top. An increase in the number of centrally arranged heaters on each wall from one to five has yielded 286% rate enhancement. Changes in the ratio of the cavity height-to-length from 1.0 to 0.2 and 2 cause the rate to decrease by 50% and increase by 21%, respectively.

Research limitations/implications
Further research with additional parameters, geometries and configurations will consolidate the understanding. Experimental validation can complement the numerical simulations presented in this study.

Originality/value
This research contributes to the field by integrating segmented heating, magnetic fields and hybrid nanofluid in a porous flow domain, addressing existing research gaps. The findings provide valuable insights for enhancing thermal performance, and controlling heat transfer locally, and have implications for medical treatments, thermal management systems and related fields. The research opens up new possibilities for precise thermal management and offers directions for future investigations.