bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale Rare Variant Burden Testing in Parkinson’s Disease Identifies Novel Associations with Genes Involved in Neuro-inflammation
Authors: Makarious Mary B. , Lake Julie , Pitz Vanessa , Fu Allen Ye , Guidubaldi Joseph L. , Solsberg Caroline Warly , Bandres-Ciga Sara , Leonard Hampton L. , Kim Jonggeol Jeffrey , Billingsley Kimberley J. , Grenn Francis P. , Jerez Pilar Alvarez , Alvarado Chelsea , Iwaki Hirotaka , Ta Michael , Vitale Dan , Hernandez Dena , Torkamani Ali , Ryten Mina , Hardy John ,   UK Brain Expression Consortium (UKBEC), Scholz Sonja W. , Traynor Bryan J. , Dalgard Clifton L. , Ehrlich Debra J. , Tanaka Toshiko , Ferrucci Luigi , Beach Thomas G. , Serrano Geidy E. , Real Raquel , Morris Huw R. , Ding Jinhui , Gibbs J. Raphael , Singleton Andrew B. , Nalls Mike A. , Bhangale Tushar , Blauwendraat Cornelis 
Published: November 2022

AbstractParkinson’s disease (PD) has a large heritable component and genome-wide association studies to date have identified over 90 variants associated with PD, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for PD. To address this gap, we investigated the rare genetic component of PD at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7,184 PD cases, 6,701 proxy-cases, and 51,650 healthy controls from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank, and Genentech. We performed burden tests meta-analyses on protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. While two of these genes,GBAandLRRK2, have been previously implicated as risk factors for PD, we identify potential novel associations forB3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10, andTREML1. Of these,B3GNT3andTREML1provide new evidence for the role of neuroinflammation in PD. To date, this is the largest analysis of rare genetic variation in PD.
Astrocytic Gapjinc (TMEM43) modulates gap junction networks by facilitating transjunctional potentials
Authors: Jang Minwoo Wendy , Kim Ki Jung , Lim Jiwoon , Kim Daeun , Park Yongmin Mason , Kim Tai Young , Roh Woo Suk , Han Young-Eun , Won Joungha , Lee Jae-Hun , Shin Eunjin , Han Ah-reum , Kim Ho Min , Han Kyung-Seok , Lee C. Justin 
Published: November 2022

AbstractTheTMEM43gene has been reported to play supportive but critical roles in human diseases including cancer, arrhythmogenic right ventricular cardiomyopathy (ARVC), and auditory neuropathy spectrum disorder (ANSD). However, direct characterization of the TMEM43 protein itself and its role in the brain remain unexplored. In this study, we demonstrated that TMEM43 confers ion channel activities via the lipid bilayer reconstitution of purified TMEM43 protein and further characterized TMEM43 as a pH-sensing cation channel in the heterologous expression system. TMEM43 was shown to conduct transjunctional potentials between adjacent cells, further facilitating electrical couplings of the gap junctions. In the hippocampus of TMEM43 knockout (KO) mice, we observed a decrease in astrocytic dye diffusion and potassium buffering, an increase in neuronal excitability, and alterations in AMPA/NMDA ratio and LTP. The electrophysiological changes in the KO mice led to a disturbance in memory retrieval which was rescued with TMEM43 overexpression. These results indicate that TMEM43 actively participates in gap junction networks of the hippocampus to prevent neurons from hyperexcitability, which is critical for memory retrieval. Together, our study elucidates the molecular and functional identities of TMEM43 and underscores its role in memory retrieval.
Progress in elementary school reading linked to growth of cortical responses to familiar letter combinations within visual word forms
Authors: Wang Fang , Kaneshiro Blair , Toomarian Elizabeth Y. , Gosavi Radhika S. , Hasak Lindsey R. , Moron Suanna , Nguyen Quynh Trang H. , Norcia Anthony M. , McCandliss Bruce D. 
Published: November 2022

AbstractLearning to read depends on the ability to extract precise details of letter combinations, which convey critical information that distinguishes tens of thousands of visual word forms. To support fluent reading skill, one crucial neural developmental process is one’s brain sensitivity to statistical constraints inherent in combining letters into visual word forms. To test this idea in early readers, we tracked the impact of two years of schooling on within-subject longitudinal changes in cortical responses to different properties of words (coarse tuning for print, and fine tuning to visual word forms and whole word representations) and their growth in reading skill. Three stimulus contrasts—words versus pseudofonts, words versus pseudowords, pseudowords versus nonwords—were presented while high-density EEG Steady-State Visual Evoked Potentials (SSVEPs, n=31) were recorded. Internalization of abstract visual word form structures over two years of reading experience resulted in a near doubling of SSVEP amplitude, with increasing left lateralization. Longitudinal changes in brain responses to such word form structural information were linked to the growth in reading, especially in rapid automatic naming for letters. No such changes were observed for whole word representation processing and coarse tuning for print. Collectively, these findings indicate that sensitivity to visual word form structure develops rapidly through exposure to print and is linked to growth in reading skill.Research HighlightsLongitudinal changes in cognitive responses to coarse print tuning, visual word from structure, and whole word representation were examined in early readers.Visual word form structure processing demonstrated striking patterns of growth with nearly doubled in EEG amplitude and increased left lateralization.Longitudinal changes in brain responses to visual word form structural information were linked to the growth in rapid automatic naming for letters.No longitudinal changes were observed for whole word representation processing and coarse tuning for print.
Callose deposition at plasmodesmata suggests a role in viral movement restriction in transgenic tobacco plants during recovery fromTobacco etch virusinfection
Authors: Vargas-Mejía Pablo , Olguín-Lamas Alejandro , Fernandez-Valverde Selene L. , Flores-García Carmen M. , Lund Gertrud , Vielle-Calzada Jean-Philippe , Silva-Rosales Laura 
Published: November 2022

AbstractViruses are amongst the most prevalent pathogens that threaten plants. Plants have evolved a sequence-specific defense mechanism against viruses to ensure survival, known as RNA silencing, which includes transcriptional and post-transcriptional gene silencing. After a viral infection, some plants undergo recovery and become further resistant to viral infection. To identify additional mechanisms underlying disease recovery besides the known RNA silencing, we analyzed transgenic tobacco plants expressing a transcript derived from the Nuclear Inclusion “a” protein (NIa) cistron of thetobacco etch virus(TEV), which had recovered from infection three weeks following viral inoculation. Usingin situhybridizations and qRT-PCR, we detected the viral RNA and the transgene-derived transcript in stem sections adjacent to the recovered leaves. To further characterize the silenced and non-silenced conditions, we undertook tissue-specific RNA-Seq and small RNA-Seq analyses in leaf and stem. We found more differentially expressed genes (DEGs) in the recovered leaf, primarily related to defense, silencing, and hormone signaling responses. Finally, we observed differences in plasmodesmata callose deposition and callose-related genes. Overall, our findings suggest that cell-to-cell viral restriction movement also participates in the recovery of TEV infection in transgenic tobacco plants, besides the key function of RNA silencing.
Event-Related Desynchronization induced by Tactile Imagery: an EEG Study
Authors: Yakovlev Lev , Syrov Nikolay , Miroshnikov Andrei , Lebedev Mikhail , Kaplan Alexander 
Published: November 2022

ABSTRACTIt is well known that both the movement of the hand itself and the mental representation of it lead to event-related desynchronization (ERD) of EEG recorded over the corresponding motor areas of the cerebral cortex. Similarly, in somatosensory cortical areas, ERD occurs upon tactile stimulation of the hand, but whether this effect is caused by mental representation of sensations from tactile stimulation remains poorly understood. In the present study, the effects on the EEG of imaginary vibrotactile sensations on the right hand were compared with the effects of real vibrotactile stimulation. Both actual vibrotactile stimulation and mental representation of it have been found to elicit contralateral ERD patterns, particularly prominent in theμ-band and most pronounced in the C3 region. The paper discusses tactile imagery as a part of the complex sensorimotor mental image and its prospects for using EEG patterns of imagery-induced tactile sensations as control signals in BCI circuits independently and when combined with ERD based on movement imagination to improve the efficiency of neurointerface technologies in rehabilitation medicine, in particular, to restore movements after a stroke and neurotrauma.
Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits
Authors: Zhang Jilin , Zhang Ming , Wang Qinrui , Wen Han , Liu Zheyi , Wang Fangjun , Wang Yuhang , Yao Fenyong , Song Nan , Kou Zengwei , Li Yang , Guo Fei , Zhu Shujia 
Published: November 2022

AbstractN-Methyl-D-Aspartate (NMDA) receptors are essential for many brain functions. These receptors are heterotetramers typically comprising two GluN1 subunits and two GluN2 subunits. The latter could alternate among four subtypes (N2A-N2D) and determine the functional diversity of NMDA receptors1, 2. For example, receptors containing N2C or N2D exhibit 50-fold lower channel open probability (Po) than those containing N2A (ref.3–5). Structures of N2A- and N2B-containing receptors have been extensively characterized, providing molecular basis for understanding NMDA receptor function6–14. Here we report the cryo-EM structures of N1-N2D and N1-N2C di-heterotetramers (di-receptors), and N1-N2A-N2C tri-heterotetramer (tri-receptor) at a resolution up to 3.0 Å. Structural analysis showed that the bilobate N-terminal domain (NTD) in N2D adopted an intrinsic closed conformation, leading to a compact NTD tetramer in N1-N2D receptor. Functional studies further demonstrated that, in di-receptors containing N2D but not N2A or N2B, crosslinking NTD at the tetrameric interface had no effect on channel activity, while crosslinking ligand-binding domain (LBD) of two N1 protomers significantly elevated Po. Surprisingly, we found that the N1-N2C di-receptors spontaneously oscillated between symmetric and asymmetric conformation. The later one occupied a predominant population, whereby two N2C protomers exhibited distinct conformation. This asymmetry, which was also found to a lesser extent in N1-N2A di-receptor10, was further locked by the binding of an N2C-specific allosteric potentiator PYD-106 to a unique binding pocket between NTD and LBD in only one N2C protomer. Finally, N2A and N2C in the N1-N2A-N2C tri-receptor displayed the conformation close to that found in one protomer of N1-N2A and N1-N2C di-receptors, respectively. These findings provide a comprehensive structural understanding of diverse functional properties of major NMDA receptor subtypes.
Differential requirement for IRGM proteins during tuberculosis infection in mice
Authors: Wilburn Kaley M. , Meade Rachel K. , Heckenberg Emma M. , Dockterman Jacob , Coers Jörn , Sassetti Christopher M. , Olive Andrew J. , Smith Clare M. 
Published: November 2022

ABSTRACTMycobacterium tuberculosis(Mtb) is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection againstMtbinfection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins. Polymorphisms in humanIRGMassociate with altered susceptibility to mycobacterial disease, and human IRGM promotes the delivery ofMtbinto degradative autolysosomes. Among the three murine IRGM orthologs,Irgm1has been singled out as essential for host protection duringMtbinfections in cultured macrophages andin vivo. However, whether the paralogous murineIrgmgenes,Irgm2andIrgm3, play roles in host defense againstMtbor exhibit functional relationships withIrgm1duringMtbinfection remains undetermined. Here, we report thatIrgm1-/-mice are indeed acutely susceptible to aerosol infection withMtb, yet the additional deletion of the paralogousIrgm3gene restores protective immunity toMtbinfections inIrgm1-deficient animals. Mice lacking all threeIrgmgenes (panIrgm-/-) are characterized by shifted lung cytokine profiles at 4 and 24 weeks post infection, but control disease until the very late stages of the infection, when panIrgm-/-mice display increased mortality compared to wild type mice. Collectively, our data demonstrate that disruptions in the balance betweenIrgmisoforms is more detrimental to theMtb-infected host than total loss ofIrgm-mediated host defense, a concept that also needs to be considered in the context of humanMtbsusceptibility linked toIRGMpolymorphisms.
Pluripotent, germ cell competent adult stem cells underlie cnidarian plant-like life history
Authors: Varley Áine , Horkan Helen R , McMahon Emma T , Krasovec Gabriel , Frank Uri 
Published: November 2022

AbstractIn most animals, pluripotency is irreversibly lost post-gastrulation. By this stage, all embryonic cells have already committed either to one of the somatic lineages (ectoderm, endoderm, mesoderm) or to the germline. The lack of pluripotent cells in adult life may be linked to organismal aging. Cnidarians (corals, and jellyfish) are an early branch of animals that do not succumb to age, but the developmental potential of their adult stem cells remains unclear. Here, we show that adult stem cells in the cnidarianHydractinia symbiolongicarpus(known as i-cells) are pluripotent. We transplanted single i-cells from transgenic fluorescent donors to wild type recipients and followed themin vivoin the translucent animals. Single engrafted i-cells self-renewed and contributed to all somatic lineages and to gamete production, co-existing with and eventually displacing the allogeneic recipient’s cells. Hence, a fully functional, sexually competent individual can originate from a single adult i-cell. Given that some of their cells remain pluripotent beyond embryogenesis and throughout life, we conclude thatHydractiniaembryos never complete gastrulation. Pluripotent i-cells underlie a regenerative, plant-like life history in these animals.
Expanding the molecular and morphological diversity of Apusomonadida, a deep-branching group of gliding bacterivorous protists
Authors: Torruella Guifré , Galindo Luis Javier , Moreira David , Ciobanu Maria , Heiss Aaron A. , Yubuki Naoji , Kim Eunsoo , López-García Purificación 
Published: November 2022

AbstractApusomonads are cosmopolitan bacterivorous biflagellate protists usually gliding on freshwater and marine sediment or wet soils. These nanoflagellates form a sister lineage to opisthokonts and may have retained ancestral features helpful to understanding the early evolution of this large supergroup. Although molecular environmental analyses indicate that apusomonads are genetically diverse, few species have been described. Here, we morphologically characterize eleven new apusomonad strains. Based on molecular phylogenetic analyses of the rRNA gene operon, we describe four new strains of the known speciesMultimonas media, Podomonas capensis, Apusomonas proboscideaandApusomonas australiensis, and renameThecamonas oxoniensisasMylnikovia oxoniensisn. gen., n. comb. Additionally, we describe four new genera and six new species:Catacumbia lutetiensisn. gen. n. sp.,Cavaliersmithia chaoaen. gen. n. sp.,Singekia montserratensisn. gen. n. sp.,Singekia franciliensisn. gen. n. sp.,Karpovia croatican. gen. n. sp. andChelonemonas dolanin. sp. Our comparative analysis suggests that apusomonad ancestor was a fusiform biflagellate with a dorsal pellicle, a plastic ventral surface and a sleeve covering the anterior flagellum, that thrived in marine, possibly oxygen-poor, environments. It likely had a complex cell cycle with dormant and multiple fission stages, and sex. Our results extend known apusomonad diversity, allow updating their taxonomy, and provide elements to understand early eukaryotic evolution.
The C-terminal acid phosphatase module of the RNase HI enzyme RnhC controls rifampicin sensitivity and light-dependent colony pigmentation ofMycobacterium smegmatis
Authors: Dupuy Pierre , Glickman Michael S 
Published: November 2022

ABSTRACTRNase H enzymes participate in various processes that require processing of RNA:DNA hybrids, including DNA replication, transcription, and ribonucleotide excision from DNA. Mycobacteria encode multiple RNase H enzymes and prior data indicates that RNase HI activity is essential for mycobacterial viability. However, the additional roles of mycobacterial RNase Hs are unknown, including whether RNase HII (RnhB and RnhD) excises chromosomal ribonucleotides misincorporated during DNA replication and whether individual RNase HI enzymes (RnhA and RnhC) mediate additional phenotypes. We find that loss of RNase HII activity inM. smegmatis(through combined deletion ofrnhB/rnhD) or individual RNase HI enzymes, does not affect growth, hydroxyurea sensitivity, or mutagenesis, whereas overexpression of either RNase HII severely compromises bacterial viability. We also show that deletion ofrnhC, which encodes a protein with an N terminal RNase HI domain and a C terminal acid phosphatase domain, confers sensitivity to rifampicin and oxidative stress as well as loss of light induced carotenoid pigmentation. These phenotypes are due to loss of the activity of the C terminal acid phosphatase domain rather than the RNase HI activity, suggesting that the acid phosphatase activity may confer rifampicin resistance through the antioxidant properties of carotenoid pigment production.
Radical pair based magnetic field effects in cells: the importance of photoexcitation conditions and single cell measurements
Authors: Woodward Jonathan R. , Ikeya Noboru 
Published: November 2022

AbstractA recent publication1on the bioRxiv preprint server aims to replicate our observation of magnetic field effects on the autofluorescence of HeLa cells2, but is unable to reproduce the effects described in our original work. Here we examine this new study and demonstrate, based on a model of the reaction photocycle, why the differences in the measurement conditions used render the experiment unlikely to be able to observe the originally reported effect. In addition, we highlight substantial problems in the quality of the data in the replicate study and reiterate the advantages of the direct modulation, single cell measurement approach presented in the original work over a more standard statistical approach.
ConstrastivePose: A contrastive learning approach for self-supervised feature engineering for pose estimation and behavorial classification of interacting animals
Authors: Zhou Tianxun , Hoe Cheah Calvin Chee , Mun Chin Eunice Wei , Chen Jie , Farm Hui Jia , Keow Goh Eyleen Lay , Chiam Keng Hwee 
Published: November 2022

AbstractIn recent years, supervised machine learning models trained on videos of animals with pose estimation data and behavior labels have been used for automated behavior classification. Applications include, for example, automated detection of neurological diseases in animal models. However, there are two problems with these supervised learning models. First, such models require a large amount of labeled data but the labeling of behaviors frame by frame is a laborious manual process that is not easily scalable. Second, such methods rely on handcrafted features obtained from pose estimation data that are usually designed empirically. In this paper, we propose to overcome these two problems using contrastive learning for self-supervised feature engineering on pose estimation data. Our approach allows the use of unlabeled videos to learn feature representations and reduce the need for handcrafting of higher-level features from pose positions. We show that this approach to feature representation can achieve better classification performance compared to handcrafted features alone, and that the performance improvement is due to contrastive learning on unlabeled data rather than the neural network architecture.Author SummaryAnimal models are widely used in medicine to study diseases. For example, the study of social interactions between animals such as mice are used to investigate changes in social behaviors in neurological diseases. The process of manually annotating animal behaviors from videos is slow and tedious. To solve this problem, machine learning approaches to automate the video annotation process have become more popular. Many of the recent machine learning approaches are built on the advances in pose-estimation technology which enables accurate localization of key points of the animals. However, manual labeling of behaviors frame by frame for the training set is still a bottleneck that is not scalable. Also, existing methods rely on handcrafted feature engineering from pose estimation data. In this study, we propose ConstrastivePose, an approach using contrastive learning to learn feature representation from unlabeled data. We demonstrate the improved performance using the features learnt by our method versus handcrafted features for supervised learning. This approach can be helpful for work seeking to build supervised behavior classification models where behavior labelled videos are scarce.
A phloem-localized Arabidopsis metacaspase (AtMC3) improves drought tolerance
Authors: Pitsili Eugenia , Rodriguez-Trevino Ricardo , Ruiz-Solani Nerea , Demir Fatih , Kastanaki Elizabeth , Dambire Charlene , de Pedro Roger , Vercammen Dominique , Salguero-Linares Jose , Hall Hardy , Mantz Melissa , Schuler Martin , Tuominen Hannele , Breusegem Frank Van , Valls Marc , Munné-Bosch Sergi , Holdsworth Michael J. , Huesgen Pitter F. , Rodriguez-Villalon Antia , Coll Nuria S. 
Published: November 2022

AbstractIncreasing drought phenomena pose a serious threat to agricultural productivity. Although plants have multiple ways to respond to the complexity of drought stress, the underlying mechanisms of stress sensing and signalling remain unclear. The role of the vasculature, in particular the phloem, in facilitating inter-organ communication is critical. Here, we investigated the role of AtMC3, a phloem-specific member of the metacaspase family, in osmotic stress responses inArabidopsis thaliana. Overexpression ofAtMC3conferred drought tolerance by enhancing the differentiation of the metaphloem sieve elements and maintaining higher levels of vascular-mediated transportation, whilst plants lacking the protein showed an impaired response to drought and inability to respond effectively to the hormone abscisic acid. Analyses of the proteome in plants with altered AtMC3 levels revealed differential abundance of proteins related to osmotic stress. Overall, our data highlight the importance of AtMC3 and vascular plasticity in fine-tuning early drought responses at the whole plant level without affecting growth or yield.