bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic map of regional sulcal morphology in the human brain
Authors: Sun Benjamin B. , Loomis Stephanie J. , Pizzagalli Fabrizio , Shatokhina Natalia , Painter Jodie N. , Foley Christopher N. , Team Biogen Biobank , Jensen Megan E. , McLaren Donald G. , Chintapalli Sai Spandana , Zhu Alyssa H. , Dixon Daniel , Islam Tasfiya , Gari Iyad Ba , Runz Heiko , Medland Sarah E. , Thompson Paul M. , Jahanshad Neda , Whelan Christopher D. 
Published: October 2021

AbstractThe human brain is a complex organ underlying many cognitive and physiological processes, affected by a wide range of diseases. Genetic associations with macroscopic brain structure are emerging, providing insights into genetic sources of brain variability and risk for functional impairments and disease. However, specific associations with measures of local brain folding, associated with both brain development and decline, remain under-explored. Here we carried out detailed large-scale genome-wide associations of regional brain cortical sulcal measures derived from magnetic resonance imaging data of 40,169 individuals in the UK Biobank. Combining both genotyping and whole-exome sequencing data (∼12 million variants), we discovered 388 regional brain folding associations across 77 genetic loci at p<5×10−8, which replicated at p<0.05. We found genes in associated loci to be independently enriched for expression in the cerebral cortex, neuronal development processes and differential regulation in early brain development. We integrated coding associations and brain eQTLs to refine genes for various loci and demonstrated shared signal in the pleiotropic KCNK2 locus with a cortex-specific KCNK2 eQTL. Genetic correlations with neuropsychiatric conditions highlighted emerging patterns across distinct sulcal parameters and related phenotypes. We provide an interactive 3D visualisation of our summary associations, making complex association patterns easier to interpret, and emphasising the added resolution of regional brain analyses compared to global brain measures. Our results offer new insights into the genetic architecture underpinning brain folding and provide a resource to the wider scientific community for studies of pathways driving brain folding and their role in health and disease.
Dual polarity voltage imaging reveals subthreshold dynamics and concurrent spiking patterns of multiple neuron-types
Authors: Kannan Madhuvanthi , Vasan Ganesh , Haziza Simon , Huang Cheng , Chrapkiewicz Radek , Luo Junjie , Cardin Jessica A. , Schnitzer Mark J. , Pieribone Vincent A. 
Published: October 2021

AbstractGenetically encoded fluorescent voltage indicators are ideally suited to reveal the millisecond-scale interactions among and between distinct, targeted cell populations. However, current indicator families lack the requisite sensitivity forin vivomultipopulation imaging. We describe high-performance green and red sensors, Ace-mNeon2 and VARNAM2, and their reverse response-polarity variants, pAce and pAceR. Our indicators enable 0.4-1 kHz voltage recordings from >50 neurons per field-of-view in awake mice and ∼30-min continuous imaging in flies. Using dual-polarity multiplexed imaging, we uncovered behavioral state-dependent interactions between distinct neocortical subclasses, as well as contributions to hippocampal field potentials from non-overlapping projection neuronal ensembles. By combining three mutually compatible indicators, we demonstrate concurrent triple-population voltage imaging. Our approach will empower investigations of the dynamic interplay between neuronal subclasses at single-spike resolution.One Sentence SummaryA new suite of voltage sensors enables simultaneous cellular-resolution activity imaging from multiple, targeted neuron-types in awake animals.
Time-tagged ticker tapes for intracellular recordings
Authors: Lin Dingchang , Li Xiuyuan (Ted) , Park Pojeong , Tang Benjamin , Shen Hao , Grimm Jonathan B. , Falco Natalie , Baker David , Lavis Luke D. , Cohen Adam E. 
Published: October 2021

AbstractA core taken in a tree today can reveal climate events from centuries past. Here we adapt this idea to record histories of neural activation. We engineered slowly growing intracellular protein fibers which can incorporate diverse fluorescent marks during growth to store linear ticker tape-like histories. An embedded HaloTag reporter incorporated user-supplied HaloTag-ligand dyes, leading to colored stripes whose boundaries mapped fiber growth to wall-clock time. A co-expressed eGFP tag driven by the cFos immediate early gene promoter recorded the history of neural activity. High-resolution multispectral imaging on fixed samples read the cellular histories. We demonstrated recordings of cFos activation in ensembles of cultured neurons with a single-cell absolute accuracy of approximately 39 min over a 12-hour interval. Protein-based ticker tapes have the potential to achieve massively parallel single-cell recordings of multiple physiological modalities.
A KARRIKIN INSENSITIVE2 paralog in lettuce mediates highly sensitive germination responses to karrikinolide
Authors: Martinez Stephanie E. , Conn Caitlin E. , Guercio Angelica M. , Sepulveda Claudia , Fiscus Christopher J. , Koenig Daniel , Shabek Nitzan , Nelson David C. 
Published: October 2021

ABSTRACTKarrikins (KARs) are chemicals in smoke that can enhance germination of many plants. Lactuca sativa cv. Grand Rapids (lettuce), germinates in the presence of nanomolar karrikinolide (KAR1). We found that lettuce is much less responsive to KAR2 or a mixture of synthetic strigolactone analogs, rac-GR24. We investigated the molecular basis of selective and sensitive KAR1 perception in lettuce. The lettuce genome contains two copies of KARRIKIN INSENSITIVE2 (KAI2), a receptor that is required for KAR responses in Arabidopsis thaliana. LsKAI2b is more highly expressed than LsKAI2a in dry achenes and during early stages of seed imbibition. Through cross-species complementation assays in Arabidopsis we found that LsKAI2b confers robust responses to KAR1, but LsKAI2a does not. Therefore, LsKAI2b likely mediates KAR1 responses in lettuce. We compared homology models of the ligand-binding pockets of KAI2 proteins from lettuce and a fire follower, Emmenanthe penduliflora. This identified pocket residues 96, 124, 139, and 161 as candidates that influence the ligand-specificity of KAI2. Further support for the significance of these residues was found through a broader comparison of pocket residue conservation among 324 asterid KAI2 proteins. We tested the effects of substitutions at these four positions in Arabidopsis thaliana KAI2 and found that a broad array of responses to KAR1, KAR2, and rac-GR24 could be achieved.
ALLOPURINOL BLOCKS AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME VIA REDUCING AORTIC OXIDATIVE STRESS
Authors: Rodríguez-Rovira Isaac , Arce Cristina , De Rycke Karo , Pérez Belén , Carretero Aitor , Arbonés Marc , Teixidò-Turà Gisela , Gómez-Cabrera Mari Carmen , Campuzano Victoria , Jiménez-Altayó Francesc , Egea Gustavo 
Published: October 2021

ABSTRACTBackgroundIncreasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy.Methods and ResultsIn aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, fibrotic collagen remodeling, nuclear translocation of pNRF2 and increased 3’-nitrotyrosine levels all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression.ConclusionsAllopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.HIGHLIGHTSXanthine oxidoreductase (XOR) is upregulated in the aortic aneurysm of Marfan syndrome (MFS) both in patients and young mice.Allopurinol halts the formation and progression of aortic aneurysm in MFS miceAllopurinol reduces a variety of oxidative stress-associated molecular reactions.Allopurinol prevents MFS endothelial-dependent vasodilator dysfunction.The antioxidant action of allopurinol suggests its repositioning for pharmacological use in MFS aortopathy.GRAPHICAL ABSTRACT
Weak representation of awake/sleep states by local field potentials in aged mice
Authors: Konno Daichi , Ikegaya Yuji , Sasaki Takuya 
Published: October 2021

AbstractSenescence affects various aspects of sleep, and it remains unclear how sleep-related neuronal network activity is altered by senescence. Here, we recorded local field potential signals from multiple brain regions covering the forebrain in young (10-week-old) and aged (2-year-old) mice. Interregional LFP correlations across these brain regions showed smaller differences between awake and sleep states in aged mice. Multivariate analyses with machine learning algorithms with uniform manifold approximation and projection (UMAP) and robust continuous clustering (RCC) demonstrated that these LFP correlational patterns in aged mice less represented awake/sleep states than those in young mice. By housing aged mice in an enriched environment, the LFP patterns were restored to those observed in young mice. Our results demonstrate senescence-induced changes in neuronal activity at the network level and provide insight into the prevention of pathological symptoms associated with sleep disturbance in senescence.
Detecting Cd adaptation footprint in C. riparius with a multi-genomic approach
Authors: Doria Halina Binde , Hannapel Pauline , Pfenninger Markus 
Published: October 2021

AbstractEvolutionary processes and acquired tolerance to toxicants are important factors governing how animals respond to chemical exposure. Evidence for increased tolerance to cadmium (Cd), a widely distributed toxic metal in aquatic environments, inChironomus ripariusis conflicting and still questioned if it happens through phenotypic plasticity or genetic adaptation. The present study considered the relevance of directional environmental changes by increasing contaminant concentration in a multigenerational selection experiment. Evaluation of measurable life-cycle traits, transcriptomic responses and quantitative genetics from an evolve and resequencing (E&R) experiment were integrated to assess the potential ofC. ripariusto adapt to Cd. Survival tests revealed some adaptation to Cd exposure. Genomic analyses showed a strong, genome-wide selective response in all replicates, emphasizing that even control laboratory conditions continually exert selective pressure. The integration of transcriptomic and genomic data could isolate the genes related to Cd acquired resistance. Those genes could be linked to an efflux of metals. Therefore, it is possible to conclude thatC. ripariuscan endure long-term Cd exposure also through genetic adaptation.
Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism
Authors: Tzanoulinou Stamatina , Musardo Stefano , Contestabile Alessandro , Bariselli Sebastiano , Casarotto Giulia , Magrinelli Elia , Jiang Yong-hui , Jabaudon Denis , Bellone Camilla 
Published: October 2021

AbstractAutism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.
Disentangling choice value and choice conflict in sequential decisions under risk
Authors: Fontanesi Laura , Shenhav Amitai , Gluth Sebastian 
Published: October 2021

AbstractRecent years have witnessed a surge of interest in understanding the neural and cognitive dynamics that drive sequential decision making in general and foraging behavior in particular. Due to the intrinsic properties of most sequential decision-making paradigms, however, previous research in this area has suffered from the difficulty to disentangle properties of the decision related to (a) the value of switching to a new patch versus (b) the conflict experienced between choosing to stay or leave. Here, we show how the same problems arise in studies of sequential decision-making under risk, and how they can be overcome, taking as a specific example recent research on the ‘pig’ dice game. In each round of the ‘pig’ dice game, people roll a die and accumulate rewards until they either decide to proceed to the next round or lose all rewards. By combining simulation-based dissections of the task structure with two experiments, we show how an extension of the standard paradigm, together with cognitive modeling of decision-making processes, disentangles value-from conflict-related choice properties. Our study elucidates the cognitive mechanisms of sequential decision making and underscores the importance of avoiding potential pitfalls of paradigms that are commonly used in this research area.
Single-cell analysis of hepatoblastoma identifies distinct tumor cell signatures that predict susceptibility to chemotherapy using patient-specific tumor spheroids
Authors: Song Hanbing , Bucher Simon , Rosenberg Katherine , Tsui Margaret , Burhan Deviana , Cho Soo-Jin , Rangaswami Arun , Huang Franklin W. , Nijagal Amar , Wang Bruce 
Published: October 2021

ABSTRACTPediatric hepatoblastoma (HB) is the most common primary liver cancer in infants and children. Studies of HB that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, HB tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we used single-cell genomic techniques to analyze resected human pediatric HB specimens. This study establishes that tumor heterogeneity can be defined by the relative proportions of five distinct subtypes of tumor cells. Notably, patient-derived HB spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. Collectively, these results define HB tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.
Parkinsonian gait effects with DBS are associated with pallido-peduncular axis activation
Authors: Goftari Mojgan , Lu Chiahao , Schmidt Megan , Patriat Remi , Palnitkar Tara , Kim Jiwon , Harel Noam , Johnson Matthew D. , Cooper Scott E. 
Published: October 2021

AbstractBackgroundDeep brain stimulation (DBS) targeting the subthalamic nucleus (STN) often shows variable outcomes on treating gait dysfunction in Parkinson’s disease (PD). Such variability may stem from which specific neuronal pathways are modulated by DBS and the extent to which those pathways are modulated relative to one another.ObjectiveLeveraging ultra-high-field (7T) imaging data and subject-specific computational models, this study investigated how activation of seven distinct pathways in and around STN, including the pallidopeduncular and pedunculopallidal pathways, affect step length at clinically-optimized STN-DBS settings.MethodsPersonalized computational models were developed for 10 subjects with a clinical diagnosis of PD and with bilateral STN-DBS implants.ResultsThe subject-specific pathway activation models showed a significant positive association between activation of the pedunculopallidal pathway and increased step length, and negative association on step length with pallidopeduncular pathway and hyperdirect pathway activation.ConclusionsThe STN region includes multiple pathways, including fibers of passage to and from the mesencephalic locomotor area. Future clinical optimization of STN-DBS should consider these fibers of passage in the context of treating parkinsonian gait.
PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation
Authors: Lewis Brandon W. , Amici Stephanie A. , Kim Hye-Young , Shalosky Emily , Khan Aiman , Walum Joshua , Gowdy Kymberly M. , Englert Joshua A. , Porter Ned A. , Grayson Mitchell H. , Britt Rodney D. , Guerau-de-Arellano Mireia 
Published: October 2021

AbstractSevere asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding in mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in asthmatic lungs. Here, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, ROR-γt and Th17 responses, with PRMT5-dependent increases in ROR-γt’s agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.
Reservoir-based Tracking (TRAKR) For One-shot Classification Of Neural Time-series Patterns
Authors: Afzal Muhammad Furqan , Márton Christian David , Rich Erin L. , Mayberg Helen , Rajan Kanaka 
Published: October 2021

AbstractDistinguishing between complex nonlinear neural time-series patterns is a challenging problem in neuroscience. Accurately classifying different patterns could be useful for a wide variety of applications, e.g. detecting seizures in epilepsy and optimizing control spaces for brain-machine interfaces. It remains challenging to correctly distinguish nonlinear time-series patterns because of the high intrinsic dimensionality of such data, making accurate inference of state changes (for intervention or control) difficult. On the one hand, simple distance metrics, which can be computed quickly, often do not yield accurate classifications; on the other hand, ensembles or deep supervised approaches offer high accuracy but are training data intensive. We introduce a reservoir-based tool, state tracker (TRAKR), which provides the high accuracy of ensembles or deep supervised methods while preserving the benefits of simple distance metrics in being applicable to single examples of training data (one-shot classification). We show that TRAKR instantaneously detects deviations in dynamics as they occur through time, and can distinguish between up to 40 patterns from different chaotic data recurrent neural networks (RNNs) with above-chance accuracy. We apply TRAKR to a benchmark time-series dataset – permuted sequential MNIST – and show that it achieves high accuracy, performing on par with deep supervised networks and outperforming other distance-metric based approaches. We also apply TRAKR to electrocorticography (ECoG) data from the macaque orbitofrontal cortex (OFC) and, similarly, find that TRAKR performs on par with deep supervised networks, and more accurately than commonly used approaches such as Dynamic Time Warping (DTW). Altogether, TRAKR allows for high accuracy classification of time-series patterns from a range of different biological and non-biological datasets based on single training examples. These results demonstrate that TRAKR could be a viable alternative in the analysis of time-series data, offering the potential to generate new insights into the information encoded in neural circuits from single-trial data.
Structural rearrangement of the intracellular gate of the serotonin transporter induced by Thr276 phosphorylation
Authors: Chan Matthew C. , Procko Erik , Shukla Diwakar 
Published: October 2021

AbstractThe reuptake of the neurotransmitter serotonin from the synaptic cleft by the serotonin transporter, SERT, is essential for proper neurological signaling. Biochemical studies have shown Thr276 of transmembrane helix 5 is a site of PKG-mediated SERT phosphorylation, which has been proposed to shifts the SERT conformational equlibira to promote inward-facing states, thus enhancing 5HT transport. Recent structural and simulation studies have provided insights into the conformation transitions during substrate transport but have not shed light on SERT regulation via post-translational modifications. Using molecular dynamics simulations and Markov state models, we investigate how Thr276 phosphorylation impacts the SERT mechanism and its role in enhancing transporter stability and function. Our simulations show that Thr276 phosphorylation alters the hydrogen-bonding network involving residues on transmembrane helix 5. This in turn decreases the free energy barriers for SERT to transition to the inward-facing state, thus facilitating 5HT transport. The results provide atomistic insights into in vivo SERT regulation and can be extended to other pharmacologically important transporters in the solute carrier superfamily.