bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Endosome Capture Proteomics and its Application to Amyloid Precursor Protein Intramembrane Processing by β and γ-Secretases
Authors: Park Hankum , Yu Qing , Hundley Frances V. , Overmyer Katherine , Serrano Lia , Paulo Joao A. , Paoli Julia C. , Swarup Sharan , Coon Joshua J. , Gygi Steven P. , Harper J. Wade 
Published: April 2022

SUMMARYDegradation and recycling of plasma membrane-localized proteins occurs via the endolysosomal system, wherein endosomes bud into the cytosol from the plasma membrane and subsequently mature into degradative lysosomal compartments. The endolysosomal system also participates in intracellular membrane protein trafficking, signaling, and protein degradation via autophagy. Our understanding of the endolysosomal system has been significantly advanced through the development of methods for selective capture of lysosomes (termed Lyso-IP), but methods for analogous isolation of early intermediates in the endolysosomal system are lacking. Here, we develop an approach for rapid isolation of early/sorting endosomes through affinity capture of the early endosome-associated protein EEA1 (Endo-IP) and provide proteomic and lipidomic snapshots of early endosomes in action. In addition to resident endosomal components, we identify numerous recycling, regulatory and membrane fusion complexes as well as candidate cargo, providing a proteomic landscape of early/sorting endosomes that we distinguished from lysosomes via comparative proteomics. The approach allows capture of internalized transferrin within minutes of its addition to cells, indicating the utility of the approach for dynamic analysis of early/sorting endosomes. Among the endocytic cargo identified by Endo-IP was the amyloid precursor protein (APP) genetically linked with Alzheimer’s disease. Processing of APP to amyloidogenic Aβ peptides by β- and γ-Secretases can occur within the endolysosomal system among other compartments, but methods for spatial quantification of Aβ products in individual organelles are lacking. We combined Endo- and Lyso-IP with targeted proteomics to provide a spatial digital snapshot of Aβ products. This analysis revealed that products of Aβ processing by β- and γ-Secretases, and alterations in the specificity of cleavage by small molecule γ-Secretase modulators, can be quantified in both early/sorting endosomes and lysosomes. We anticipate that the Endo-IP approach will facilitate systematic interrogation of the many processes that are coordinated on early endosomes.
Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2
Authors: Shak Caroline , Vuolo Laura , Uddin Borhan , Katoh Yohei , Brown Tom , Mukhopadhyay Aakash G. , Heesom Kate , Roberts Anthony J. , Stevenson Nicola , Nakayama Kazuhisa , Stephens David J. 
Published: April 2022

AbstractThe primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. Motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport respectively in the cilium. WDR34, a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome or asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34 knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, IFT-B protein localization, transition zone (TZ) integrity, and Hedgehog signalling were also affected.Summary statementDisease-associated mutations in WDR34 are found to have diverse impacts on ciliogenesis and cilia function following stable expression in a WDR34 knockout cell model.
Recurrent but short-lived duplications of centromeric proteins in holocentricCaenorhabditisspecies
Authors: Caro Lews , Raman Pravrutha , Steiner Florian A. , Ailion Michael , Malik Harmit S. 
Published: April 2022

AbstractCentromeric histones (CenH3s) are essential for chromosome inheritance during cell division in most eukaryotes.CenH3genes have rapidly evolved and undergone repeated gene duplications and diversification in many plant and animal species. InCaenorhabditis,two independent duplications ofCenH3(namedhcp-3forHoloCentric chromosome-bindingProtein 3) have been previously identified: inC. elegansandC. remanei. Here, using phylogenomic analyses inCaenorhabditis,we find strict retention of the ancestralhcp-3gene and eight additional independenthcp-3duplications, most of which are only found in one or two species.hcp-3L(hcp-3-like) paralogs are expressed in both sexes (males and females/ hermaphrodites) and have a conserved histone fold domain. We identified novel N-terminal protein motifs, including putative kinetochore protein-interacting motifs and a potential separase cleavage site, which are well-conserved acrossCaenorhabditisHCP-3 proteins. Other N-terminal motifs vary in their retention across paralogs or species, revealing potential sub-functionalization or functional loss following duplication.C. afraencodes an unprecedented protein fusion, where thehcp-3paralog fused to duplicated segments fromhcp-4(nematode CENP-C). Extending our analyses beyond CenH3, we found gene duplications of six inner and outer kinetochore genes inCaenorhabditis, including co-retention of different kinetochore protein paralogs in a few species. Our findings suggest that centromeric protein duplications occur frequently inCaenorhabditisnematodes, are selectively retained under purifying selection but only for short evolutionary periods, then degenerate or are lost entirely. We hypothesize that unique challenges associated with holocentricity inCaenorhabditismay lead to this rapid ‘revolving door’ of kinetochore protein paralogs.
Performance comparison of systemic activity correction in functional near-infrared spectroscopy for methods with and without short distance channels
Authors: Klein Franziska , Lührs Michael , Benitez-Andonegui Amaia , Roehn Pauline , Kranczioch Cornelia 
Published: April 2022

AbstractSignificanceFunctional near-infrared spectroscopy (fNIRS) is a promising tool for neurofeedback (NFB) or brain–computer interfaces (BCIs). However, fNIRS signals are typically highly contaminated by systemic activity (SA) artifacts, and, if not properly corrected, NFB or BCIs run the risk of being based on noise instead of brain activity. This risk can likely be reduced by correcting for SA, in particular when short-distance channels (SDCs) are available. Literature comparing correction methods with and without SDCs is still sparse, specifically comparisons considering single trials are lacking.AimThis study aimed at comparing the performance of SA correction methods with and without SDCs.ApproachSemisimulated and real motor task data of healthy older adults were used. Correction methods without SDCs included a simple and a more advanced spatial filter. Correction methods with SDCs included a regression approach considering only the closest SDC and two GLM-based methods, one including all eight SDCs and one using only twoa prioriselected SDCs as regressors. All methods were compared with data uncorrected for SA and correction performance was assessed with quality measures quantifying signal improvement and spatial specificity at single trial level.ResultsAll correction methods were found to improve signal quality and enhance spatial specificity as compared with the uncorrected data. Methods with SDCs usually outperformed methods without SDCs. Correction methods without SDCs tended to overcorrect the data. However, the exact pattern of results and the degree of differences observable between correction methods varied between semisimulated and real data, and also between quality measures.ConclusionsOverall, results confirmed that both Δ[HbO] and Δ[HbR] are affected by SA and that correction methods with SDCs outperform methods without SDCs. Nonetheless, improvements in signal quality can also be achieved without SDCs and should therefore be given priority over not correcting for SA.
Conformational flexibility, lipid binding, and regulatory domains in CelTOS
Authors: Kumar Hirdesh , Jimah John R. , Ntumngia Francis B. , Misal Santosh A. , Barnes Samantha J. , Fried Michal , Adams John H. , Schlesinger Paul H. , Tolia Niraj H. 
Published: April 2022

AbstractCelTOS is an essential Plasmodium traversal protein and conserved in apicomplexan parasites. We showed that CelTOS forms pores in cell membranes to enable traversal of parasites through cells (Jimah et al., 2016). Here, we establish roles for the distinct regions of CelTOS, examine the mechanism of pore formation and evaluate the immunogenicity of engineered CelTOS variants. CelTOS dimer dissociation is required for pore formation as disulfide bridging between monomers inhibits pore formation and this inhibition is rescued by disulfide-bridge reduction. A helix destabilizing Pro127 allows CelTOS to undergo significant conformational changes to assemble into pores. The flexible C-terminus of CelTOS is a negative regulator that limits pore formation. Lipid binding is a pre-requisite for pore assembly as mutation of a phospholipid binding site in CelTOS resulted in loss of lipid binding and abrogated pore formation. The disulfide-locked and N-terminal deletion mutants showed improved immunogenicity relative to wild-type CelTOS in mice. These findings have implications for pore-forming proteins that are essential for diverse functions, identify critical regions in CelTOS, and will guide the design of effective CelTOS-targeting vaccines to combat infection and transmission of malaria and apicomplexan parasites.
Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors
Authors: Kang Minsu , Na Hee Young , Ahn Soomin , Kim Ji-Won , Lee Sejoon , Ahn Soyeon , Lee Ju Hyun , Youk Jeonghwan , Kim Haesook T. , Kim Kui-Jin , Suh Koung Jin , Lee Jun Suh , Kim Se Hyun , Kim Jin Won , Kim Yu Jung , Lee Keun-Wook , Yoon Yoo-Seok , Kim Jee Hyun , Chung Jin-Haeng , Han Ho-Seong , Lee Jong Seok 
Published: April 2022

AbstractWe aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient, and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 (54.5%), followed by TP53 (45.5%), and FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia, BilIN), but some of them were subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. In combined analysis with metastatic tumors (n=11), branching evolution was identified in 9 (81.8%) patients. Of these, 8 patients (88.9%) had a total of 11 subclones expanded at least 7-fold during metastasis. These subclones harbored putative metastasis-driving mutations in tumor suppressor genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, 6 mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and the clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.
The role of clearance in neurodegenerative diseases
Authors: Brennan Georgia S. , Thompson Travis B. , Oliveri Hadrien , Rognes Marie E. , Goriely Alain 
Published: April 2022

AbstractAlzheimer’s disease, the most common form of dementia, is a systemic neurological disorder associated with the formation of toxic, pathological aggregates of proteins within the brain that lead to severe cognitive decline, and eventually, death. In normal physiological conditions, the brain rids itself of toxic proteins using various clearance mechanisms. The efficacy of brain clearance can be adversely affected by the presence of toxic proteins and is also known to decline with age. Motivated by recent findings, such as the connection between brain cerebrospinal fluid clearance and sleep, we propose a mathematical model coupling the progression of toxic proteins over the brain’s structural network and protein clearance. The model is used to study the interplay between clearance in the brain, toxic seeding, brain network connectivity, aging, and progression in neurodegenerative diseases such as Alzheimer’s disease. Our findings provide a theoretical framework for the growing body of medical research showing that clearance plays an important role in the etiology, progression and treatment of Alzheimer’s disease.
Sensitive detection and structural characterisation of UV-induced cross-links in protein-RNA complexes using CLIR-MS
Authors: Sarnowski Chris P. , Knörlein Anna , de Vries Tebbe , Götze Michael , Beusch Irene , Aebersold Ruedi , Allain Frédéric H.-T. , Hall Jonathan , Leitner Alexander 
Published: April 2022

AbstractCross-linking coupled with mass spectrometry is an increasingly popular methodology for elucidating structural information from biological complexes. Whilst protein-protein cross-linking workflows are widely used and well characterised, adoption of protein-RNA cross-linking workflows for structural studies is less widespread, and data produced from such experiments remains less well understood. The cross-linking of stable isotope labelled RNA coupled to mass spectrometry (CLIR-MS) workflow uses isotope labelled RNA to simultaneously confirm that peptides are cross-linked to RNA and aid cross-link localisation in an RNA sequence. For broader application of CLIR-MS as part of the structural analysis of ribonucleoproteins, the method must be sensitive, robust, and its reaction products need to be well characterised. We enhanced our previously published workflow, improving coverage and sensitivity. We used it to infer common properties of protein-RNA cross-links such as cross-linking distance, and to assess the impact of substitution of uracil with 4-thio-uracil in structural proteomics experiments. We profiled the compositional diversity of RNA-derived peptide modifications, and subsequently defined a more inclusive data analysis approach which more than doubles the number of cross-link spectrum matches compared with our past work. We defined distance restraints from these cross-links, and with the aid of visualisation software, demonstrated that on their own they provide sufficient information to localise an RNA chain to the correct position on the surface of a protein. We applied our enhanced workflow and understanding to characterise the binding interface of several protein-RNA complexes containing classical and uncommon RNA binding domains. The enhanced sensitivity and understanding demonstrated here underpin a wider adoption of protein-RNA cross-linking in structural biology.
High predation risk decimates survival during the reproduction season
Authors: Smolinský Radovan , Hiadlovská Zuzana , Maršala Štěpán , Škrabánek Pavel , Škrobánek Michal , Martínková Natália 
Published: April 2022

AbstractPredators attack conspicuous prey phenotypes that are present in the environment. Male display behaviour of conspicuous nuptial colouration becomes risky in the presence of a predator, and adult males face higher predation risk. High predation risk in one sex will lead to low survival and sex ratio bias in adult cohorts, unless the increased predation risk is compensated by higher escape rate.Here, we tested the hypothesis that sand lizards (Lacerta agilis) have sex-specific predation risk and escape rate. We expected the differences to manifest in changes in sex ratio with age, differences in frequency of tail autotomy, and in sex-specific survival rate.We developed a statistical model to estimate predation risk and escape rate, combining the observed sex ratio and frequency of tail autotomy with likelihood-based survival rate. Using Bayesian framework, we estimated the model parameters. We projected the date of the tail autotomy events from growth rates derived from capturerecapture data measurements.We found statistically stable sex ratio in age groups, equal frequency of tail regenerates between sexes, and similar survival rate. Predation risk is similar between sexes, and escape rate increases survival by about 5%. We found low survival rate and a low number of tail autotomy events in females during months when sand lizards mate and lay eggs, indicating high predator pressure throughout reproduction. Our data show that gravid females fail to escape predation.The risks of reproduction season in an ectotherm are a convolution of morphological changes (conspicuous colouration in males, body allometry changes in gravid females), behaviour (nuptial displays), and environmental conditions which challenge lizard thermal performance. Performance of endotherm predators in cold spring months endangers gravid females more than displaying males in bright nuptial colouration.
EEG-representational geometries and psychometric distortions in approximate numerical judgment
Authors: Appelhoff Stefan , Hertwig Ralph , Spitzer Bernhard 
Published: April 2022

AbstractWhen judging the average value of sample stimuli (e.g., numbers) people tend to either over- or underweight extreme sample values, depending on task context. In a context of overweighting, recent work has shown that extreme sample values were overly represented also in neural signals, in terms of an anti-compressed geometry of number samples in multivariate electroencephalography (EEG) patterns. Here, we asked whether neural representational geometries may also reflect underweighting of extreme values (i.e., compression) which has been observed behaviorally in a great variety of tasks. We used a simple experimental manipulation (instructions to average a single-stream or to compare dual-streams of samples) to induce compression or anti-compression in behavior when participants judged rapid number sequences. Model-based representational similarity analysis (RSA) replicated the previous finding of neural anti-compression in the dual-stream task, but failed to provide evidence for neural compression in the single-stream task, despite the evidence for compression in behavior. Instead, the results suggested enhanced neural processing of extreme values in either task, regardless of whether extremes were over- or underweighted in subsequent behavioral choice. We further observed more general differences in the neural representation of the sample information between the two tasks. The results suggest enhanced processing of extreme values as the brain’s default. Such a default raises new questions about the origin of common psychometric distortions, such as diminishing sensitivity for larger values.
MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size
Authors: Lafferty Michael J. , Aygün Nil , Patel Niyanta K. , Krupa Oleh , Liang Dan , Wolter Justin M. , Geschwind Daniel H. , de la Torre-Ubieta Luis , Stein Jason L. 
Published: April 2022

AbstractExpression quantitative trait loci (eQTL) data have proven important for linking non-coding loci to protein-coding genes. But eQTL studies rarely measure microRNAs (miRNAs), small non-coding RNAs known to play a role in human brain development and neurogenesis. Here, we performed small-RNA sequencing across 212 mid-gestation human neocortical tissue samples, measured 907 expressed miRNAs, discovering 111 of which were novel, and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707-3p expression with educational attainment and brain size phenotypes, where the miRNA expression increasing allele was associated with decreased brain size. Exogenous expression of miR-4707-3p in primary human neural progenitor cells decreased expression of predicted targets and increased cell proliferation, indicating miR-4707-3p modulates progenitor gene regulation and cell fate decisions. Integrating miRNA-eQTLs with existing GWAS yielded evidence of a miRNA that may influence human brain size and function via modulation of neocortical brain development.
Unraveling the functional attributes of the language connectome: crucial subnetworks, flexibility and variability
Authors: Roger E. , Rodrigues De Almeida L. , Lœvenbruck H. , Perrone-Bertolotti M. , Cousin E. , Schwartz JL. , Perrier P. , Dohen M. , Vilain A. , Baraduc P. , Achard S. , Baciu M. 
Published: April 2022

AbstractLanguage processing is a highly integrative function, intertwining linguistic operations (processing the language code intentionally used for communication) and extra-linguistic processes (e.g., attention monitoring, predictive inference, long-term memory). This synergetic cognitive architecture requires a distributed and specialized neural substrate. Brain systems have mostly been examined at rest. However, task-related functional connectivity provides additional and valuable information about how information is processed when various cognitive states are involved. We gathered thirteen language fMRI tasks in a unique database of one hundred and fifty neurotypical adults (InLang database). The tasks were designed to assess a wide range of linguistic processes and subprocesses. From this database, we applied network theory as a computational tool to model the task-related functional connectome of language (LANG). The organization of this data-driven neurocognitive atlas of language is examined at multiple levels, uncovering its major components (orcrucial subnetworks) and its anatomical and functional correlates. Furthermore, we estimate its reconfiguration as a function of linguistic demand (flexibility), or several factors such as age or gender (variability). By accounting for the multifaceted nature of language and modulating factors, this study can contribute to enrich and refine existing neurocognitive models of language. The LANG atlas can also be considered as a reference for comparative or clinical studies, involving a variety of patients and conditions.