bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking Enlarged Choroid Plexus with Plasma Analyte and Structural Phenotypes in Clinical High Risk for Psychosis: A Multisite Neuroimaging Study
Authors: Bannai Deepthi , Reuter Martin , Hegde Rachal , Hoang Dung , Adhan Iniya , Gandu Swetha , Pong Sovannarath , Raymond Nick , Zeng Victor , Chung Yoonho , He George , Sun Daqiang , van Erp Theo G.M. , Addington Jean , Bearden Carrie E. , Cadenhead Kristin , Cornblatt Barbara , Mathalon Daniel H. , McGlashan Thomas , Jeffries Clark , Stone William , Tsuang Ming , Walker Elaine , Woods Scott W. , Cannon Tyrone D. , Perkins Diana , Keshavan Matcheri , Lizano Paulo 
Published: October 2022

AbstractBackgroundChoroid plexus (ChP) enlargement exists in first-episode and chronic psychosis, but whether enlargement occurs before psychosis onset is unknown. This study investigated whether ChP volume is enlarged in individuals with clinical high-risk (CHR) for psychosis and whether these changes are related to clinical, neuroanatomical, and plasma analytes.MethodsClinical and neuroimaging data from the North American Prodrome Longitudinal Study 2 (NAPLS2) was used for analysis. 509 participants (169 controls, 340 CHR) were recruited. Conversion status was determined after 2-years of follow-up, with 36 psychosis converters. The lateral ventricle ChP was manually segmented from baseline scans. A subsample of 31 controls and 53 CHR had plasma analyte and neuroimaging data.ResultsCompared to controls, CHR (d=0.23, p=0.017) and non-converters(d=0.22, p=0.03)demonstrated higher ChP volumes, but not in converters. In CHR, greater ChP volume correlated with lower cortical(r=-0.22, p<0.001), subcortical gray matter(r=-0.21, p<0.001), and total white matter volume(r=-0.28,p<0.001), as well as larger lateral ventricle volume(r=0.63,p<0.001). Greater ChP volume correlated with makers functionally associated with the lateral ventricle ChP in CHR [CCL1(r=-0.30, p=0.035), ICAM1(r=0.33, p=0.02)], converters [IL1β(r=0.66, p=0.004)], and non-converters [BMP6(r=-0.96, p<0.001), CALB1(r=-0.98, p<0.001), ICAM1(r=0.80, p=0.003), SELE(r=0.59, p=0.026), SHBG(r=0.99, p<0.001), TNFRSF10C(r=0.78, p=0.001)].ConclusionsCHR and non-converters demonstrated significantly larger ChP volumes compared to controls. Enlarged ChP was associated with neuroanatomical alterations and analyte markers functionally associated with the ChP. These findings suggest that the ChP may be a key explanatory biomarker in CHR for psychosis.
Synaptic mechanisms for associative learning in the cerebellar nuclei
Authors: Broersen Robin , Albergaria Catarina , Carulli Daniela , Carey Megan R. , Canto Cathrin B. , De Zeeuw Chris I. 
Published: October 2022

AbstractAssociative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not of climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.
Age-specific activation of microglial genes in a mouse model of AD
Authors: Zhou Haoyang , Yu Yizhou 
Published: October 2022

ABSTRACTAlzheimer’s disease (AD) is a neurodegenerative disease that increases its prevalence with age. AD is characterized by a progressive loss of cognitive function, leading to dementia. The conventional pathological hallmarks of AD include deposition of amyloid plaque, aggregation of neurofibrillary tangles, and sustained inflammation. Recent studies have confirmed that immune responses play an important role in AD progression. Single-cell RNA-sequencing (RNA-seq) studies of the AD mouse model identified the disease-associated microglia (DAM) population during AD progression, where the pro-inflammatory activity was mediated by Trem2. However, the time points and nature of DAM activation remain largely unknown. Here, we compared the time-result bulk sequencing andsingle nuclei RNA sequencing data in a mouse model of AD. We identified an age-dependent activation of Trem2 targeted immune-related genes. We showed that Trem2 affected DAM activation at an early stage (4-8 months) rather than the late stage (12-16 months). Our results highlight an age-dependent change in the Trem2-linked immune response in AD.
Mining impactful discoveries from the biomedical literature
Authors: Moreau Erwan , Hardiman Orla , Heverin Mark , O’Sullivan Declan 
Published: October 2022

AbstractMotivationLiterature-Based Discovery (LBD) aims to help researchers to identify relations between concepts which are worthy of further investigation by text-mining the biomedical literature. While the LBD literature is rich and the field is considered mature, standard practice in the evaluation of LBD methods is methodologically poor and has not progressed on par with the domain. The lack of properly designed and decent-sized benchmark dataset hinders the progress of the field and its development into applications usable by biomedical experts.ResultsThis work presents a method for mining past discoveries from the biomedical literature. It leverages the impact made by a discovery, using descriptive statistics to detect surges in the prevalence of a relation across time. This method allows the collection of a large amount of time-stamped discoveries which can be used for LBD evaluation or other applications. The validity of the method is tested against a baseline representing the state of the art “time sliced” method.AvailabilityThe source data used in this article are publicly available. The implementation and the resulting data are published under open-source license:https://github.com/erwanm/medline-discoveries(code)https://zenodo.org/record/5888572(datasets). An online exploration tool is also provided athttps://brainmend.adaptcentre.ie/.Contacterwan.moreau@adaptcentre.ie
PNPO-PLP Axis Senses Prolonged Hypoxia by Regulating Lysosomal Activity
Authors: Sekine Hiroki , Takeda Haruna , Kishino Akihiro , Anzawa Hayato , Isagawa Takayuki , Ohta Nao , Kato Nobufumi , Kimura Shu , Liu Zun , Kato Koichiro , Katsuoka Fumiki , Yamamoto Masayuki , Miura Fumihito , Ito Takashi , Takahashi Masatomo , Izumi Yoshihiro , Fujita Hiroyuki , Yamagata Hitoshi , Takeda Norihiko , Bamba Takeshi , Suzuki Norio , Kinoshita Kengo , Motohashi Hozumi 
Published: October 2022

AbstractOxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen sensing systems inducing acute hypoxic response, including HIF pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here, we show that pyridoxine 5’-phosphate oxidase (PNPO) that catalyzes bioactivation of vitamin B6 serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decline of PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5’-phosphate (PLP), and inhibited lysosomal activity, leading to the augmentation of inflammatory response of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing, which gradually turns down and up the PLP-dependent metabolism according to prolonged changes in oxygen availability.
Formation and three-dimensional architecture ofLeishmaniaadhesion in the sand fly vector
Authors: Yanase Ryuji , Moreira-Leite Flávia , Rea Edward , Wilburn Lauren , Sádlová Jovana , Vojtkova Barbora , Pružinová Katerina , Taniguchi Atsushi , Nonaka Shigenori , Volf Petr , Sunter Jack D. 
Published: October 2022

AbstractAttachment to a substrate to maintain position in a specific ecological niche is a common strategy across biology, especially for eukaryotic parasites. During development in the sand fly vector, the eukaryotic parasiteLeishmaniaadheres to the stomodeal valve, as the specialised haptomonad form. Dissection of haptomonad adhesion is a critical step for understanding parasite transmission. Nevertheless, haptomonad studies are limited, as this is a technically challenging life cycle form to investigate. Here, we have combined three-dimensional electron microscopy approaches, including serial block face scanning electron microscopy (SBFSEM) and serial tomography to dissect the organisation and architecture of haptomonads in the sand fly. We showed that the attachment plaque contains distinct structural elements. Using time-lapse light microscopy, we identified five stages of haptomonad differentiation, and showed that calcium is necessary for haptomonad adhesion to the surface. This study provides the structural and regulatory foundations of the haptomonad form, which are critical for a holistic understanding ofLeishmaniatransmission.
Prophage taming by the adherent-invasiveEscherichia coliLF82 upon macrophage infection
Authors: Misson Pauline , Bruder Emma , Cornuault Jeffrey K. , Paepe Marianne De , Demarre Gaëlle , Petit Marie-Agnès , Espeli Olivier , Lecointe François 
Published: October 2022

ABSTRACTAdherent-invasiveEscherichia coli(AIEC) strains are frequently recovered from stools of patients with dysbiotic microbiota. They have remarkable properties of adherence to the intestinal epithelium, and survive better than otherE. coliin macrophages. The best studied of these AIEC is probably strain LF82, which was isolated from a Crohn’s disease patient. This strain contains five complete prophages, which have not been studied until now. We undertook their analysis, bothin vitroand inside macrophages, and show that all of them form virions. The Gally prophage is by far the most active, generating spontaneously over 108viral particles per mL of culture supernatantsin vitro, more than 100-fold higher than the other phages. Gally is over-induced after a genotoxic stress generated by ciprofloxacin and trimethoprim. However, upon macrophage infection, Gally virion production is decreased by more than 20-fold, and the transcription profile of the prophage indicates that part of the structural module is specifically repressed while the replication module is overexpressed compared to unstressed culture conditions. We conclude that strain LF82 has evolved an efficient way to “tame” its most active prophage upon macrophage infection, which may participate to its good survival in macrophages. The results are discussed in light of the active lysogeny process.AUTHOR SUMMARYProphages are bacterial viruses stably integrated into their host, to which they can provide new functions, thus increasing their fitness in the environment. Thereby, they can participate to the virulence of bacterial pathogens. However, prophages are double-edged swords that can be awakened in response to genotoxic stresses, resulting in the death of their bacterial host. This raises the question of the effect of this type of stress in the natural environments where their bacterial hosts exert their virulence. In this study, we characterized the five active prophages present inEscherichia coliLF82, a strain belonging to the intestinal microbiota and suspected to be involved in Crohn’s disease via its ability to invade macrophages, a highly genotoxic environment. We show that LF82 inhibits the awakening of its prophages in macrophages, allowing it to survive there. Moreover, deletion of its most active prophage does not affect the viability of LF82 in this environment. These results show that LF82 has tamed its prophages in macrophages and also suggest that if they convey fitness advantages, they probably do so in environments differing from macrophages, and which remain to be discovered.
Bacterial chemoreceptor signaling complexes control kinase activity by stabilizing the catalytic domain of CheA
Authors: Tran Thomas , Karunanayake Mudiyanselage Aruni P. K. K. , Eyles Stephen J. , Thompson Lynmarie K. 
Published: October 2022

AbstractMotile bacteria have a chemotaxis system that enables them to sense their environment and direct their swimming towards favorable conditions. Chemotaxis involves a signaling process in which ligand binding to the extracellular domain of the chemoreceptor alters the activity of the histidine kinase, CheA, bound ∼300 Å away to the distal cytoplasmic tip of the receptor, to initiate a phosphorylation cascade that controls flagellar rotation. The cytoplasmic domain of the receptor is thought to propagate this signal via changes in dynamics and/or stability, but it is unclear how these changes modulate the kinase activity of CheA. To address this question, we have used hydrogen deuterium exchange mass spectrometry to probe the structure and dynamics of CheA within functional signaling complexes of theE. coliaspartate receptor cytoplasmic fragment, CheA, and CheW. Our results reveal that stabilization of the P4 catalytic domain of CheA correlates with kinase activation. Furthermore, differences in activation of the kinase that occur during sensory adaptation depend on receptor destabilization of the P3 dimerization domain of CheA. Finally, hydrogen exchange properties of the P1 domain that bears the phosphorylated histidine identify the dimer interface of P1/P1’ in the CheA dimer and support an ordered sequential binding mechanism of catalysis, in which dimeric P1/P1’ has productive interactions with P4 only upon nucleotide binding. Thus stabilization/destabilization of domains is a key element of the mechanism of modulating CheA kinase activity in chemotaxis, and may play a role in the control of other kinases.
Spatiotemporal coordination of stem cell behavior following alveolar injury
Authors: Chioccioli Maurizio , Magruder Sumner , McDonough John E. , Nouws Jessica , Yang Tao , Gonzalez David , Borriello Lucia , Traub Brian , Ye Xianjun , Hendry Caroline E. , Entenberg David , Krishnaswamy Smita , Kaminski Naftali , Sauler Maor 
Published: October 2022

SUMMARYTissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 (AT2) cells act as stem cells and can replace both themselves and alveolar type 1 cells (AT1); however, the complex orchestration of AT2 stem cell activity following lung injury is poorly understood owing to the inability of tracking individual stem cells and their dynamic behavior over time. Here, we apply live time lapse imaging to ex vivo mouse precision cut lung slice (PCLS) culture and in vivo mouse lung to track individual GFP-labeled AT2 cells following induction of alveolar injury by bleomycin. We observe highly dynamic movement of AT2 cells, including migration within and between alveoli. To map the dynamic evolution of AT2 cell behavior, we introduce Live Cell Encoder (LCE-PHATE), a novel method for converting static snapshots from time lapse imaging into single points representative of entire, dynamic cellular trajectories. Applying LCE-PHATE, we observe the emergence of at least three distinct morphokinetic AT2 cell states associated with AT2 stem cell injury response. Finally, small molecule-based inhibition of Rho-associated protein kinase (ROCK) pathway significantly reduced motility of AT2 stem cells following injury and reduced expression of Krt8, a marker of intermediate progenitor cells. Together, our results uncover motility of alveolar stem cells as a new injury response mechanism in the lung and reveal properties of stem cell motility at high cellular resolution.
Mapping the “missing” pathways of the anterior cingulate cortex in the human brain
Authors: Tang Wei , Guaje Javier , Fadnavis Shreyas , Garyfallidis Eleftherios 
Published: October 2022

AbstractThe anterior cingulate cortex (ACC) is functionally closely related with the insula and the ventral lateral prefrontal cortex (vlPFC). Extensive work on their functional relationships has led to the salience network theory and advanced understanding of value-based learning and decision making. However, the anatomical connections between the ACC and the two regions remain unknown in the human brain. Despite the anatomical ground truth established by nonhuman primate (NHP) tract-tracing, diffusion magnetic resonance imaging (dMRI) has not seen success identifying homologous pathways in humans. In this study we show that the negative finding does not reflect a cross-species discrepancy but rather a technical issue. We used NHP dMRI as a bridge to compare the ground-truth pathways in NHPs and dMRI-derived pathways in humans. The insight from NHP data helped pinpoint a bias in fiber orientation distribution functions (fODFs) caused by the disproportion of anterior-posterior vs. medial-lateral fibers in the human brain. Guided by this information, we successfully recovered the ACC-insula and ACC-vlPFC pathways that followed the same trajectories as in the NHP dMRI and tract-tracing data. Our findings provide an anatomical basis for the functional interactions among the ACC, the insula and the vlPFC.
Development of a soil inoculation method coupled with blocker-mediated 16S rRNA gene amplicon sequencing reveals the effect of antibacterial T6SS on agrobacteria tumorigenesis and gallobiome composition
Authors: Wang Si-Chong , Chen Ai-Ping , Chou Shu-Jen , Kuo Chih-Horng , Lai Erh-Min 
Published: October 2022

ABSTRACTThe type VI secretion system (T6SS) is deployed by many proteobacteria to secrete effector proteins into bacterial competitors for competition or eukaryotic cells for pathogenesis. Agrobacteria, a group of soil-borne phytopathogens causing crown gall disease on various plant species, deploys the T6SS to attack closely- and distantly-related bacterial speciesin vitroandin planta. Current evidence suggests that the T6SS is not essential for pathogenesis under direct inoculation but it remains unknown whether the T6SS influences natural disease incidence or the microbial community within crown galls (i.e., gallobiome). To address these two key questions, we established a soil inoculation method on wounded tomato seedlings that mimics natural infections and developed a bacterial 16S rRNA gene amplicon enrichment sequencing platform. By comparing theAgrobacteriumwild-type strain C58 with two T6SS mutants, we demonstrate that the T6SS influences both disease occurrence and gallobiome composition. Based on multiple inoculation trials across seasons, all three strains could induce tumors but the mutants had significantly lower disease incidences. The season of inoculation played a more important role than the T6SS in shaping the gallobiome. The influence of T6SS was evident in summer, in which twoSphingomonasspecies and the family Burkhoderiaceae were enriched in the gallobiome induced by the mutants. Furtherin vitrocompetition and colonization assay demonstrated the T6SS-mediated antagonism to aSphingomonassp. R1 strain isolated from tomato rhizosphere in this study. In conclusion, this work demonstrates that theAgrobacteriumT6SS promotes tumorigenesis in infection process and provides competitive advantages in gall-associated microbiota.IMPORTANCEThe T6SS is widespread among Proteobacteria and used for interbacterial competition by agrobacteria, which are soil inhabitants and opportunistic bacterial pathogens causing crown gall disease in a wide range of plants. Current evidence indicates that the T6SS is not required for gall formation when agrobacteria are inoculated directly on plant wounding sites. However, in natural settings, agrobacteria may need to compete with other bacteria in bulk soil to gain access to plant wounds and influence microbial community inside crown galls. The role of the T6SS in these critical aspects of disease ecology have remained largely unknown. In this study, we successfully developed aSoilInoculation method coupled withBlocker-mediated enrichment ofBacterial 16S rRNA gene AmpliconSequencing, named as SI-BBacSeq, to address these two important questions. We provided evidence that the T6SS promotes disease occurrence and influences crown gall microbiota composition by interbacterial competition.
Expanding the epitranscriptomic RNA sequencing and modification mapping mass spectrometry toolbox with field asymmetric waveform ion mobility and electrochemical elution liquid chromatography
Authors: Lauman Richard , Kim Hee Jong , Pino Lindsay K. , Scacchetti Alessandro , Bonasio Roberto , Garcia Benjamin A. 
Published: October 2022

AbstractPost-transcriptional modifications of RNA strongly influence RNA structure and function. Recent advances in RNA sequencing and mass spectrometry (MS) methods have identified over 140 of these modifications on a wide variety of RNA species. Most next-generation sequencing approaches can only map one RNA modification at a time, and while MS can assign multiple modifications simultaneously in an unbiased manner, MS cannot accurately catalog and assign RNA modifications in complex biological samples due to limitations in fragment length and coverage depth. Thus, a facile method to identify novel RNA modifications while simultaneously locating them in the context of their RNA sequences is still lacking. We combined two orthogonal modes of RNA ion separation before mass-spectrometry identification: high-field asymmetric ion mobility separation (FAIMS) and electrochemically modulated liquid chromatography (EMLC). FAIMS RNA-MS increases both coverage and throughput, while the EMLC LC-MS orthogonally separates RNA of different length and charge. The combination of the two methods offers a broadly applicable platform to improve length and depth of MS-based RNA sequencing while providing contextual access to the analysis of RNA modifications.
Tuned Fitness Landscapes for Benchmarking Model-Guided Protein Design
Authors: Thomas Neil , Agarwala Atish , Belanger David , Song Yun S. , Colwell Lucy J. 
Published: October 2022

AbstractAdvancements in DNA synthesis and sequencing technologies have enabled a novel paradigm of protein design where machine learning (ML) models trained on experimental data are used to guide exploration of a protein fitness landscape. ML-guided directed evolution (MLDE) builds on the success of traditional directed evolution and unlocks strategies which make more efficient use of experimental data. Building an MLDE pipeline involves many design choices across the design-build-test-learn loop ranging from data collection strategies to modeling, each of which has a large impact on the success of designed sequences. The cost of collecting experimental data makes benchmarking every component of these pipelines on real data prohibitively difficult, necessitating the development ofsyntheticlandscapes where MLDE strategies can be tested. In this work, we develop a framework called SLIP (“Synthetic Landscape Inference for Proteins”) for constructing biologically-motivated synthetic landscapes with tunable difficulty based on Potts models. This framework can be extended to any protein family for which there is a sequence alignment. We show that without tuning, Potts models are easy to optimize. In contrast, our tuning framework provides landscapes sufficiently challenging to benchmark MLDE pipelines. SLIP is open-source and is available athttps://github.com/google-research/slip.