bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-Diagnostic Cognitive and Functional Impairment in Multiple Sporadic Neurodegenerative Diseases
Authors: Swaddiwudhipong Nol , Whiteside David J. , Hezemans Frank H. , Street Duncan , Rowe James B. , Rittman Timothy 
Published: April 2022

AbstractINTRODUCTIONThe pathophysiological processes of neurodegenerative diseases begin years before diagnosis. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease.METHODSUK Biobank data was extracted. Cognitive and functional measures in individuals who subsequently developed Alzheimer’s Disease, Parkinson’s Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, or Multiple System Atrophy, were compared against those without neurodegenerative diagnoses. The same measures were regressed against time to diagnosis, after adjusting for the effects of age.RESULTSThere was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in Alzheimer’s. Pre-diagnostic functional impairment and decline was observed in multiple diseases.DISCUSSIONThe scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials.Research in ContextSystematic reviewStudies of genetic dementia cohorts provide evidence for pre-diagnostic changes in disease biomarkers and cognitive function in several genetic neurode-generative diseases. The pre-diagnostic phase of sporadic neurodegenerative disease has been less well-studied. It is unclear whether early functional or cognitive changes are detectable in sporadic neurodegenerative disease.InterpretationWe have established an approach to identify cognitive and functional pre-diagnostic markers of neurodegenerative disease years before diagnosis. We found disease-relevant patterns of pre-diagnostic cognitive and functional impairment, and observed a pre-diagnostic linear decline in a number of cognitive and functional measures.Future DirectionsOur approach can form the basis for pre-diagnostic cognitive and functional screening to recruit into trials of disease prevention and disease modifying therapies for neurodegenerative diseases. A screening panel based on cognition and function could be followed by disease-specific biomarkers to further improve risk stratification.
SARS-CoV-2 Omicron sublineage BA.2 replaces BA.1.1: genomic surveillance in Japan from September 2021 to March 2022
Authors: Hirotsu Yosuke , Maejima Makoto , Shibusawa Masahiro , Natori Yume , Nagakubo Yuki , Hosaka Kazuhiro , Sueki Hitomi , Mochizuki Hitoshi , Tsutsui Toshiharu , Kakizaki Yumiko , Miyashita Yoshihiro , Omata Masao 
Published: April 2022

AbstractObjectiveThe new emerging Omicron strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently spreading worldwide. We aimed to analyze the genomic evolution of the shifting Omicron virus subtypes.MethodsThe study included 1,297 individuals diagnosed as SARS-CoV-2 positive by PCR test or antigen quantification test from September 2021 to March 2022. Samples were analyzed by whole genome sequencing analysis (n=489) or TaqMan assay (n=808).ResultsAfter the outbreak of the SARS-CoV-2 Delta strain, the Omicron strain spread rapidly in Yamanashi, Japan. BA.1.1 was the predominant sublineage of the Omicron strain from January to mid-February 2022, but the number of cases of sublineage BA.2 began to increase after mid-February, and this sublineage was shown to have replaced BA.1.1 by the end of March 2022. We observed higher viral and antigen levels of sublineage BA.2 than of sublineage BA.1.1 in nasopharyngeal swab samples. However, no difference in viral load by patient age was apparent between sublineages BA.1.1 and BA.2.ConclusionsA transition from sublineage BA.1.1 to sublineage BA.2 was clearly observed over approximately one month. Omicron sublineage BA.2 was found to be more transmissible owing to its higher viral load regardless of patient age.
Impact of energy limitations on function and resilience in long-wavelength Photosystem II
Authors: Viola Stefania , Roseby William , Santabarabara Stefano , Nürnberg Dennis , Assunção Ricardo , Dau Holger , Sellés Julien , Boussac Alain , Fantuzzi Andrea , Rutherford A William 
Published: April 2022

AbstractPhotosystem II (PSII) uses the energy from red light to split water and reduce quinone, an energy-demanding process based on chlorophyll a (Chl-a) photochemistry. Two kinds of cyanobacterial PSII can use Chl-d and Chl-f to perform the same reactions using lower energy, far-red light. PSII from Acaryochloris marina has Chl-d replacing all but one of its 35 Chl-a, while PSII from Chroococcidiopsis thermalis, a facultative far-red species, has just 4 Chl-f and 1 Chl-d and 30 Chl-a. From bioenergetic considerations, the far-red PSII were predicted to lose photochemical efficiency and/or resilience to photodamage. Here, we compare enzyme turnover efficiency, forward electron transfer, back-reactions and photodamage in Chl-f-PSII, Chl-d-PSII and Chl-a-PSII. We show that: i) all types of PSII have a comparable efficiency in enzyme turnover; ii) the modified energy gaps on the acceptor side of Chl-d-PSII favor recombination via PD1+Phe- repopulation, leading to increased singlet oxygen production and greater sensitivity to high-light damage compared to Chl-a-PSII and Chl-f-PSII; ii) the acceptor-side energy gaps in Chl-f-PSII are tuned to avoid harmful back reactions, favoring resilience to photodamage over efficiency of light usage. The results are explained by the differences in the redox tuning of the electron transfer cofactors Phe and QA and in the number and layout of the chlorophylls that share the excitation energy with the primary electron donor. PSII has adapted to lower energy in two distinct ways, each appropriate for its specific environment but with different functional penalties.
Intraspecific diversity based on low temperature induced arrhythmia in embryonic heart of medaka (Oryzias latipes)
Authors: Yoshimura Wataru , Oda Shoji , Katsumura Takafumi , Mitani Hiroshi , Watanabe-Asaka Tomomi 
Published: April 2022

AbstractBackgroundCold tolerance during embryonic development, especially blood circulation is important for growth in poikilothermic animals. Medaka (Oryzias latipes), has cold tolerance and is distributed in the highest latitudes occupied by the genus Oryzias. Regarding cold tolerance in embryogenesis, Hd-rR strain belonging to the southern Japanese (S.JPN) group showed arrhythmia when the embryo was exposed to 15 °C in the heartbeat initiation period (st. 24), whereas the embryo of Odate medaka, which belongs to the northern Japanese (N.JPN) group, showed stable heartbeats.ResultsIn this study, to verify the sensitivity to low temperature in the medaka wild populations, heartbeat intervals of st. 24 embryos derived from three N.JPN, eight S.JPN, and two western Korean/Chinese (W.KOR) populations were investigated at an arbitrary temperature range of 12–15 °C. There was no significant difference in the mean values of the heart rates and the coefficient of variation (CV) of interbeat intervals in the N.JPN, S.JPN, and W.KOR groups. A temperature dependency of the CV within 12–15 °C was observed only in five S.JPN specimens, whereas three S.JPN, the N.JPN and the W.KOR specimens showed no alteration in CV with temperature. Temperature dependency of the heart rate was also varied in the S.JPN specimens.ConclusionsThese results suggest that the temperature dependency of the CV under 12–15 °C during the heartbeat initiation period is a variation within the S.JPN after the divergence from the N.JPN.
Deep Local Analysis evaluates protein docking conformations with Locally oriented Cubes
Authors: Behbahani Yasser Mohseni , Crouzet Simon , Laine Elodie , Carbone Alessandra 
Published: April 2022

AbstractWith the recent advances in protein 3D structure prediction, protein interactions are becoming more central than ever before. Here, we address the problem of determining how proteins interact with one another. More specifically, we investigate the possibility of discriminating near-native protein complex conformations from incorrect ones by exploiting local environments around interfacial residues. Deep Local Analysis (DLA)-Ranker is a deep learning framework applying 3D convolutions to a set of locally oriented cubes representing the protein interface. It explicitly considers the local geometry of the interfacial residues along with their neighboring atoms and the regions of the interface with different solvent accessibility. We assessed its performance on three docking benchmarks made of half a million acceptable and incorrect conformations. We show that DLA-Ranker successfully identifies near-native conformations from ensembles generated by molecular docking. It surpasses or competes with other deep learning-based scoring functions. We also showcase its usefulness to discover alternative interfaces.Availabilityhttp://gitlab.lcqb.upmc.fr/dla-ranker/DLA-Ranker.git
Auditory Language Comprehension During Saccadic Eye Movements: An Investigation Using the N400 Event-Related Brain Potential
Authors: Dimigen Olaf , Schild Ulrike , Hohlfeld Annette , Sommer Werner 
Published: April 2022

AbstractIn many situations of everyday life, it is important to quickly understand a spoken message despite distraction by an already ongoing activity. Previous dual-task studies recording the N400 component of the event-related potential (ERP) have shown that auditory language comprehension can be strongly delayed by temporally overlapping additional tasks. In the current study, we investigated whether this interference is aggravated by the need for saccadic eye movements and visuospatial attention shifts in the overlapping task. In two dual-task experiments, a synonymy judgment task for spoken words was combined with a visual discrimination task at different stimulus onset asynchronies. In half of the trials, the primary visual task required a 10° exogenous saccade towards a peripheral stimulus. The timing of semantic processing in the secondary task was assessed by recording the N400. We replicated that with increasing temporal overlap between the tasks, the N400 component was strongly delayed. However, additional saccade-related processes in the primary task had no detrimental effects on concurrent spoken language processing on their own. Unexpectedly, we also observed that a preceding saccade consistently facilitated subsequent motoric processing in the visual task (as indexed by manual reaction times and the lateralized readiness potential), suggesting that saccade execution as such can significantly enhance subsequent processing.
Novel Bruton’s Tyrosine Kinase (BTK) substrates for time-resolved luminescence assays
Authors: Widstrom Naomi E. , Perez Minervo , Pratt Erica D. , Heier Jason L. , Blankenhorn John F. , Breidenbach Lindsay , Peterson Hannah , Parker Laurie L. 
Published: April 2022

ABSTRACTBruton’s tyrosine kinase (BTK) is a well-documented target for cancer therapeutics due to its role in B-cell signaling pathways. However, inhibitor design is hindered by lack of tools to assess kinase activity. We used in vitro phosphoproteomics to determine BTK’s substrate preferences and applied this information to our updated data processing pipeline, KINATEST-ID 2.1.0. This pipeline generates a position-specific scoring matrix for BTK and a list of candidate synthetic substrates, each given a score. Characterization of selected synthetic substrates demonstrated a correlation between KINATEST-ID 2.1.0 score and biochemical performance in in vitro kinase assays. Additionally, by incorporating a known terbium-chelation motif, we adapted synthetic substrates for use in an antibody-free time-resolved terbium luminescence assay. This assay has applications in high-throughput inhibitor screening.
Introducing CELLBLOKS®: a novel organ-on-a-chip platform allowing a plug-and-play approach towards building organotypic models
Authors: Llabjani Valon , Siddique M.R. , Makos Anaïs , Abozoid Afaf , Hoti Valmira , Martin Francis L , Patel Imran I. , Raza Ahtasham 
Published: April 2022

AbstractHuman organs are structurally and functionally complex systems. Their function is driven by interactions between many specialised cell types, which is difficult to unravel on a standard petri-dish format. Conventional “petri-dish” approaches to culturing cells are static and self-limiting. However, current organ-on-a-chip technologies are difficult to use, have a limited throughput and lack compatibility with standard workflow conditions. We developed CELLBLOKS® as a novel “plug & play” organ-on-a-chip platform that enables straightforward creation of multiple-cell type organ specific microenvironments and demonstrate its advantages by building a liver model representative of live tissue function. CELLBLOKS® allows one to systematically test and identify various cell combinations that replicate optimal hepatic relevance. The combined interactions of fibroblasts, endothelial cells and hepatocytes were analysed using hepatic biochemistry (CYP3A4 and urea), cellular proliferation and transporter activities (albumin). The results demonstrate that optimal liver functional can be achieved in cross talk co-culture combinations compared to conventional mono-culture. The optimised CELLBLOKS® liver model was tested to analyse drug-induced liver toxicity using tamoxifen. The data suggests that our CELLBLOKS® liver model is highly sensitive to toxic insult compared to mono-culture liver model. In summary, CELLBLOKS® provides a novel cell culture technology for creating human relevant organotypic models that are easy and straightforward to establish in laboratory settings.
Sexual dimorphism and biomechanical loading in occipital bone morphological variation
Authors: Hoover Kara C. , Thomas Geoffrey P. 
Published: April 2022

AbstractWe explore the contribution of biological sex and biomechanical activity from subsistence to occipital bone variation. Previous studies have used occipital bone traits to determine biological sex and identify ancestry to differing degrees of success. Biomechanical stress from variation in subsistence and gender-based divisions of labor could perhaps explain some of the noise in the signal for these grouping variables. To explore this possibility, we used metric (foramen magnum length and breadth, external occipital protuberance depth, lambda-inion length, bicondylar breadth) and nonmetric traits (general occipital form, presence of a nuchal crest, and nuchal line count). We collected original data and mined published data for our analysis using skeletal collections of Native American hunter-gatherers and horticulturalists, a historic military site, and contemporary study collections. We find that the foramen magnum area exhibits sexual dimorphism and is not influenced by subsistence but the accuracy of sex estimation is only 71%, suggesting the chance of being correct at slightly more than two-thirds. All traits exhibited sex-based variation but only bicondylar breadth and lambda-inion exhibited subsistence-based variation. Given the limited amount of variance explained by either sex or sex and subsistence, biomechanics may still play a role but not from the influence of subsistence practices. Additional data from a wider array of skeletal samples, perhaps with known occupation, is warranted if we are to understand how occipital variation is shaped.PRACTITIONER POINTSThe study examines the role of biological sex and biomechanical stress in shaping occipital morphology.We introduce an area variable to describe the foramen magnum and apply ectocranial metric and nonmetric states for the first time to sex estimation.We share methods and R code for cleaning data, testing assumptions, and analysis of research questions.
Transcriptional targets of senataxin and E2 promoter binding factors are associated with neuro-degenerative pathways during increased autophagic flux
Authors: Casey Aaron E. , Liu Wenjun , Hein Leanne K. , Sargeant Timothy J. , Pederson Stephen M. , Mäkinen Ville-Petteri 
Published: April 2022

AbstractAutophagy is an intracellular recycling process that degrades harmful molecules, maintains optimal composition of cellular organelles and enables survival during starvation. Previous studies have demonstrated how transcription factors (TFs) can increase autophagy with therapeutic potential (impaired autophagy in the ageing brain, in particular, may be an important risk factor for dementia). To investigate the transcriptional regulation of autophagy from a systems perspective, we induced autophagy by amino acid starvation and mTOR inhibition in HeLa, HEK 293 and SH-SY5Y cells and used RNA-seq to measure gene expression at three time points. We observed 453 differentially expressed (DE) genes due to starvation and 284 genes due to mTOR inhibition (PFDR < 0.05 in every cell line). Pathway analyses confirmed enrichment of genes implicated in Alzheimer’s (PFDR < 0.001 in SH-SY5Y and HeLa) and Parkinson’s (PFDR ≤ 0.024 in SH-SY5Y and HeLa) diseases and amyotrophic lateral sclerosis (ALS, PFDR < 0.05 in 4 of 6 experiments). We then integrated Signaling Pathway Impact Analysis and TF target enrichment testing to predict which TF target genes were contributing to pathway perturbation. Differential expression of the Senataxin (SETX) target gene set was predicted to activate multiple neurodegenerative pathways (PFDR ≤ 0.04). Notably, SETX is a causal gene for a rare form of ALS. In the SH-SY5Y cells of neuronal origin, the E2F transcription family was predicted to activate Alzheimer’s disease pathway (PFDR ≤ 0.0065). SETX and E2F may be important mediators of transcriptional regulation of autophagy and may provide new therapeutic opportunities for neuro-degenerative conditions.
A positive feedback loop controls Toxoplasma chronic differentiation
Authors: Licon M. Haley , Giuliano Christopher J. , Chakladar Sundeep , Shallberg Lindsey , Waldman Benjamin S. , Hunter Christopher A. , Lourido Sebastian 
Published: April 2022

SUMMARYSuccessful infection strategies must balance pathogen amplification and persistence. In Toxoplasma gondii, this is accomplished through differentiation into dedicated cyst-forming chronic stages that avoid clearance by the host immune system. The transcription factor BFD1 is both necessary and sufficient for stage conversion; however, its regulation is not understood. We examine five factors transcriptionally activated by BFD1. One of these is a cytosolic RNA-binding protein of the CCCH-type zinc finger family, which we name BFD2. Parasites lacking BFD2 fail to induce BFD1 and are consequently unable to fully differentiate in culture or in mice. BFD2 interacts with the BFD1 transcript in a stress-dependent manner. Deletion of BFD2 reduces BFD1 protein levels, but not mRNA abundance. The reciprocal effects on BFD2 transcription and BFD1 translation outline a positive feedback loop that enforces commitment to differentiation. BFD2 helps explain how parasites commit to the chronic gene-expression program and elucidates how the balance between proliferation and persistence is achieved over the course of infection.
The cytolethal distending toxin modulates cell differentiation and elicits epithelial to mesenchymal transition
Authors: Azzi-Martin Lamia , Touffait-Calvez Valentin , Everaert Maude , Jia Ruxue , Sifré Elodie , Seeneevassen Lornella , Varon Christine , Dubus Pierre , Ménard Armelle 
Published: April 2022

AbstractWe are frequently exposed to bacterial genotoxins, such as cytolethal distending toxin (CDT), a prevalent heterotrimeric toxin whose active moiety is its CdtB subunit. CdtB triggers potent DNA damage, predisposing factors in the development of cancers, in host cells. CDT fromHelicobacter hepaticus, a mouse pathogen, was shown to be directly involved in the development of murine hepatocarcinoma. Preliminary studies have shown that CDT induces certain phenotypes reminiscent of epithelial to mesenchymal transition (EMT), a process by which cells lose their epithelial characteristics in favor of mesenchymal ones, conducive to cell motility. In the present study, we investigated the different steps of EMT using liver tissues of mice infected withH. hepaticus, as well as human epithelial cell lines and xenograft mouse models followingH. hepaticusCdtB expression. Most of the different steps of the EMT process were reproduced throughout the studied models. Indeed, microarray data showed a CdtB- dependent regulation of EMT-related transcripts. The key transcriptional regulators of EMT (SNAIL1 and ZEB1) and EMT markers (Vimentin, Fibronectin and α5β1 integrin) were upregulated both at RNA and protein levels in response to CdtB. It also induced cell-cell junctions’ disassembly, causing individualization of cells and acquisition of a spindle-like morphology. CdtB activated the expression and activity of matrix metalloproteases and increased cell motility. This study demonstrated that CDT/CdtB elicits EMT process activation, supporting the idea that infection with genotoxin-producing bacteria can promote malignant transformation.Author SummaryWe are frequently exposed to infection with genotoxin--producing bacterial from the gut microbiota, such as cytolethal distending toxin (CDT). CDT,viaits active CdtB subunit, causes severe DNA damage in host cells, well-known risk factor of cancer development and progression. Chronic infection with CDT-producing bacteria is thus involved in cancer development. CDT is widespread among many bacteria and its impact in human cancer seems likely underestimated. Despite its major significance, CDT remains little studied. Here, we showed that cells exposed to CdtB are no longer cohesive, become individualized and acquire a spindle-shaped morphology known to be conducive to migration. These cells also express increased level of mesenchymal markers, as well as increased level of SNAIL1 and ZEB1, two key transcription factors orchestrating a crucial mechanism for cancer initiation and progression: epithelial to mesenchymal transition. These effects induced by CdtB were associated with increased matrix metalloproteinases degrading activity and emergence of cellular motility. Collectively, these data showed that CdB activates epithelial to mesenchymal transition, supporting the role of CDT in tumorigenesis.
Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site
Authors: Rennie ML , Arkinson C , Chaugule V , Walden H 
Published: April 2022

AbstractRepair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. USP1, a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase I clinical trials, have been established, their binding mode is unknown. Here we use cryo-Electron Microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5 Å resolution, we discover an unusual binding mode in which the inhibitor displaces part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1.One Sentence SummaryUSP1, a cancer target, is inhibited by ML323 displacing part of the protein fold, allosterically disrupting the active site.