bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topography of speech-related acoustic and phonological feature encoding throughout the human core and parabelt auditory cortex
Authors: Hamilton Liberty S. , Oganian Yulia , Chang Edward F. 
Published: June 2020

AbstractSpeech perception involves the extraction of acoustic and phonological features from the speech signal. How those features map out across the human auditory cortex is unknown. Complementary to noninvasive imaging, the high spatial and temporal resolution of intracranial recordings has greatly contributed to recent advances in our understanding. However, these approaches are typically limited by piecemeal sampling of the expansive human temporal lobe auditory cortex. Here, we present a functional characterization of local cortical encoding throughout all major regions of the primary and non-primary human auditory cortex. We overcame previous limitations by using rare direct recordings from the surface of the temporal plane after surgical microdissection of the deep Sylvian fissure between the frontal and temporal lobes. We recorded neural responses using simultaneous high-density direct recordings over the left temporal plane and the lateral superior temporal gyrus, while participants listened to natural speech sentences and pure tone stimuli. We found an anatomical separation of simple spectral feature tuning, including tuning for pure tones and absolute pitch, on the superior surface of the temporal plane, and complex tuning for phonological features, relative pitch and speech amplitude modulations on lateral STG. Broadband onset responses are unique to posterior STG and not found elsewhere in auditory cortices. This onset region is functionally distinct from the rest of STG, with latencies similar to primary auditory areas. These findings reveal a new, detailed functional organization of response selectivity to acoustic and phonological features in speech throughout the human auditory cortex.
Population density modeling of mixed polymorphic phenotypes: an application of spatial mark-resight models
Authors: Harihar Abishek , Lahkar Dipankar , Singh Aparajita , Das Sunit Kumar , Ahmed M Firoz , Begum Ramie H 
Published: June 2020

AbstractMelanism is a form of pigmentation polymorphism where individuals have darker colouration than what is considered the “wild” phenotype. In the case of leopards,Panthera pardus, melanism occurs at higher frequencies amongst populations in tropical and subtropical moist forests of south and southeast Asia, presenting a unique challenge in estimating and monitoring these populations. Unlike the wild phenotype that is readily recognizable by its rosette patterns, melanism results in individuals being unidentifiable or ‘unmarked’ through photographic captures obtained using white flash cameras. Spatial mark-resight (SMR) models that require only a subset of the population to be ‘marked’ offer the opportunity to estimate population density. In this study, we present an application of SMR models to estimate leopard densities using camera trap survey data from three sampling years at Manas National Park (MNP), India. By using an SMR model that allowed us to include captures of unidentified sightings of marked individuals, we were also able to incorporate captures where identity was either not confirmed or only known from a single flank. Following 18,674 trap-days of sampling across three years, we obtained 728 leopard photo-captures, of which 22.6% (165) were melanistic. We estimated leopard densities of 4.33, 2.61 and 3.37 individuals/100km2across the three years. To our best knowledge, these represent the first known estimates of leopard densities from populations comprising both melanistic and wild phenotypes. Finally, we highlight that SMR models present an opportunity to revisit past camera trap survey data for leopards and other species such as Jaguars,P. onca, that exhibit phenotypic polymorphism towards generating valuable information on populations.
Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia
Authors: Pasetto Laura , Grassano Maurizio , Pozzi Silvia , Luotti Silvia , Sammali Eliana , Migazzi Alice , Basso Manuela , Spagnolli Giovanni , Biasini Emiliano , Micotti Edoardo , Cerovic Milica , Carli Mirjana , Forloni Gianluigi , Marco Giovanni De , Manera Umberto , Moglia Cristina , Mora Gabriele , Traynor Bryan J. , Chiò Adriano , Calvo Andrea , Bonetto Valentina 
Published: June 2020

AbstractAggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolylcis-transisomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of ALS. Here we characterizedPPIAknock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of FTD, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces aggregation of the GTP-binding nuclear protein Ran, a PPIA substrate required for TDP-43 nucleocytoplasmic trafficking. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several ALS and ALS-FTD patients and identified a PPIA loss-of-function mutation in a sporadic ALS patient. The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.
PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus
Authors: Park Pojeong , Georgiou John , Sanderson Thomas M. , Ko Kwang-Hee , Kang Heather , Kim Ji-il , Bradley Clarrisa A. , Bortolotto Zuner A. , Zhuo Min , Kaang Bong-Kiun , Collingridge Graham L. 
Published: June 2020

ABSTRACTLong-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involved purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA was activated, resulted in LTP that was associated with a transient increase in γ (LTPγ). This γ increase was due to the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII was necessary and sufficient for LTPNwhilst PKA was additionally required for LTPγ. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.
Effects of Sequence Composition and Patterning on the Structure and Dynamics of Intrinsically Disordered Proteins
Authors: Vovk Andrei , Zilman Anton 
Published: June 2020

AbstractUnlike the well defined structures of classical natively folded proteins, Intrinsically Disordered Proteins (IDP) and Intrinsically Disordered Regions (IDR) dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures, dynamics, and function. Multiple experimental and theoretical evidence points in many cases to the overall importance of the general properties of the amino acid sequence of the IPDs rather than their precise atomistic details. However, while different experimental techniques can probe aspects of the IDP conformations, often different techniques or conditions offer seemingly contradictory results. Using coarse-grained polymer models informed by experimental observations, we investigate the effects of several key variables on the dimensions and the dynamics of IDPs. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence specific. We identify the conditions that allow mapping of highly heterogeneous sequences of IDPs onto averaged minimal polymer models. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for further development of appropriate mesoscopic models of IDPs.
Endogenous Rab29 does not impact basal or nigericin and monensin stimulated LRRK2 pathway activity
Authors: Kalogeropulou Alexia F. , Freemantle Jordana B. , Lis Pawel , Vides Edmundo G. , Polinski Nicole K. , Alessi Dario R. 
Published: June 2020

AbstractMutations that enhance LRRK2 protein kinase activity cause inherited Parkinson’s disease. LRRK2 phosphorylates a group of Rab GTPase proteins, including Rab10 and Rab12, within the effector-binding switch-II motif. Previous work has indicated that the PARK16 locus, which harbors the gene encoding for Rab29, is involved in Parkinson’s, and that Rab29 operates in a common pathway with LRRK2. Co-expression of Rab29 and LRRK2 stimulates LRRK2 activity by recruiting LRRK2 to the surface of the trans Golgi network. Here we report that knock-out of Rab29 does not influence endogenous LRRK2 activity, based on assessment of Rab10 and Rab12 phosphorylation, in wildtype LRRK2, LRRK2[R1441C] or VPS35[D620N] knock-in mouse tissues and primary cell lines, including brain extracts and embryonic fibroblasts. We find that in brain extracts, Rab12 phosphorylation is more robustly impacted by LRRK2 inhibitors and pathogenic mutations than Rab10 phosphorylation. Transgenic overexpression of Rab29 in a mouse model was also insufficient to stimulate basal LRRK2 activity. We observed that monovalent cation ionophore antibiotics nigericin and monensin enhance LRRK2-mediated Rab10 and Rab12 phosphorylation 4 to 9-fold, in a manner that is independent from Rab29. Moderate stimulation of Rab10 and Rab12 induced by lysosome stressors chloroquine and LLOMe was also not regulated by Rab29. Our findings indicate that basal, pathogenic, as well as nigericin and monensin stimulated LRRK2 pathway activity is not controlled by Rab29. Further work is required to establish how LRRK2 activity is regulated, and whether other Rab proteins can control LRRK2 by targeting it to diverse membranes.
Reconciling Conformational Heterogeneity and Substrate Recognition in Cytochrome P450
Authors: Dandekar B. , Ahalawat N. , Mondal J. 
Published: June 2020

ABSTRACTCytochrome P450, the ubiquitous metalloenzyme involved in detoxification of foreign components, has remained one of the most popular systems for substrate-recognition process. However, despite being known for its high substrate specificity, the mechanistic basis of substrate-binding by archetypal system cytochrome P450cam has remained at odds with the contrasting reports of multiple diverse crystallographic structures of its substrate-free form. Here we address this issue by elucidating the probability of mutual dynamical transition to the other crystallographic pose of cytochrome P450cam and vice versa via unbiased all-atom computer simulation. A robust Markov state model (MSM), constructed using adaptively sampled 84 microsecond-long Molecular dynamics simulation trajectories, maps the broad and heterogenous P450cam conformational landscape into five key sub-states. In particular, the MSM identifies an intermediate-assisted dynamic equilibrium between a pair of conformations of P450cam, in which the substrate-recognition sites remain ‘closed’ and ‘open’ respectively. However, the estimate of a significantly high stationary population of closed conformation, coupled with faster rate of open → closed transition than its reverse process, dictates that the net conformational equilibrium would be swayed in favour of ‘closed’ conformation. Together, the investigation quantitatively infers that while a potential substrate of cytochrome P450cam would in principle explore a diverse array of conformations of substrate-free protein, it would mostly encounter a ‘closed’ or solvent-occluded conformation and hence would follow an induced-fit based recognition process. Overall, the work reconciles multiple precedent crystallographic, spectroscopic investigations and establishes how a statistical elucidation of conformational heterogeneity in protein would provide crucial insights in the mechanism of potential substrate-recognition process.STATEMENT OF SIGNIFICANCEConformational heterogeneity plays an important role in defining the structural and functional dynamics of the enzymes. While the static three-dimensional crystallographic structures of enzymes solved in different conditions and/or environments are crucial to provide the conformational sub-states of enzymes, these are not sufficient to understand the kinetics and thermodynamics of these sub-states and their role in substrate recognition process. Cytochrome P450cam, the archtypal metalloenzyme, presents such a complex scenario due to prevalent reports of contrasting crystallographic structures of its substrate-free form. This work quantifies the conformational heterogeneity of substrate-free P450cam by exploring the possibility of mutual transition among the crystallographic poses at an atomic resolution and in the process elucidates its possible substrate-recognition mechanism.
Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis
Authors: Sterkel Marcos , Haines Lee R. , Casas-Sánchez Aitor , Adung’a Vincent Owino , Vionette-Amaral Raquel J. , Quek Shannon , Rose Clair , dos Santos Mariana Silva , Escude Natalia Garcia , Ismael Hanafy , Paine Mark I. , Barribeau Seth M. , Wagstaff Simon , MacRae James I. , Masiga Daniel , Yakob Laith , Oliveira Pedro L. , Acosta-Serrano Álvaro 
Published: June 2020

AbstractTsetse transmit African trypanosomiasis, which is a disease fatal to both humans and animals. A vaccine to protect against this disease does not exist so transmission control relies on eliminating tsetse populations. Although neurotoxic insecticides are the gold standard for insect control, they negatively impact the environment and reduce insect pollinator species. Here we present a promising, environment-friendly alternative that targets insect tyrosine metabolism pathway. A bloodmeal contains high levels of tyrosine, which is toxic to haematophagous insects if it is not degraded. RNAi silencing of either the first two enzymes in the tyrosine degradation pathway (TAT and HPPD) was lethal to tsetse. Furthermore, nitisinone (NTBC), an FDA-approved tyrosine catabolism inhibitor, killed tsetse regardless if the drug was orally or topically applied. However, it did not affect bumblebee survival. A mathematical model shows that NTBC could reduce the transmission of African trypanosomiasis in sub-Saharan Africa, thus accelerating current elimination programmes.
Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia
Authors: Wan Hongbin , Selvaggio Gianluca , Pearlstein Robert A. 
Published: June 2020

AbstractThe human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of:Diffusion of a single fully solvated blocker copy into a large cavity lined by the intracellular cyclic nucleotide binding homology domain (the initial capture step). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.Translocation of the captured blocker along the channel axis (the IKrdisruption step), such that:The head group, consisting of a quasi-linear moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface.One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost).Blockers containing a highly planar moiety that projects into a putative constriction zone within theclosedchannel become trapped upon closing, as do blockers terminating prior to this region.A single captured blocker molecule may associate and dissociate from the pore many times before exiting the CNBHD cavity.Lastly, we highlight possible flaws in the current hERG safety index (SI) and propose an alternatein vivo-relevantstrategy factoring in:Benefit/risk.The predicted arrhythmogenic fractional hERG occupancy (based on action potential simulations of theundiseasedhuman ventricular cardiomyocyte).Alteration of the safety threshold due to underlying disease.Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.
A consensus-based ensemble approach to improve transcriptome assembly
Authors: Voshall Adam , Behera Sairam , Li Xiangjun , Yu Xiao-Hong , Kapil Kushagra , Deogun Jitender S. , Shanklin John , Cahoon Edgar B. , Moriyama Etsuko N. 
Published: June 2020

AbstractBackgroundSystems-level analyses, such as differential gene expression analysis, co-expression analysis, and metabolic pathway reconstruction, depend on the accuracy of the transcriptome. Multiple tools exist to perform transcriptome assembly from RNAseq data. However, assembling high quality transcriptomes is still not a trivial problem. This is especially the case for non-model organisms where adequate reference genomes are often not available. Different methods produce different transcriptome models and there is no easy way to determine which are more accurate. Furthermore, having alternative-splicing events exacerbates such difficult assembly problems. While benchmarking transcriptome assemblies is critical, this is also not trivial due to the general lack of true reference transcriptomes.ResultsIn this study, we first provide a pipeline to generate a set of the benchmark transcriptome and corresponding RNAseq data. Using the simulated benchmarking datasets, we compared the performance of various transcriptome assembly approaches including bothde novoand genome-guided methods. The results showed that the assembly performance deteriorates significantly when alternative transcripts (isoforms) exist or for genome-guided methods when the reference is not available from the same genome. To improve the transcriptome assembly performance, leveraging the overlapping predictions between different assemblies, we present a new consensus-based ensemble transcriptome assembly approach, ConSemble.ConclusionsWithout using a reference genome, ConSemble using fourde novoassemblers achieved an accuracy up to twice as high as anyde novoassemblers we compared. When a reference genome is available, ConSemble using four genome-guided assemblies removed many incorrectly assembled contigs with minimal impact on correctly assembled contigs, achieving higher precision and accuracy than individual genome-guided methods. Furthermore, ConSemble usingde novoassemblers matched or exceeded the best performing genome-guided assemblers even when the transcriptomes included isoforms. We thus demonstrated that the ConSemble consensus strategy both forde novoand genome-guided assemblers can improve transcriptome assembly. The RNAseq simulation pipeline, the benchmark transcriptome datasets, and the script to perform the ConSemble assembly are all freely available from:http://bioinfolab.unl.edu/emlab/consemble/.
miR-218 in adolescence predicts and mediates vulnerability to stress
Authors: Torres-Berrío Angélica , Morgunova Alice , Giroux Michel , Cuesta Santiago , Nestler Eric J. , Flores Cecilia 
Published: June 2020

ABSTRACTAdolescence is a period of increased vulnerability to psychiatric disorders including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor geneDcc(Deleted incolorectalcancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulatesDccexpression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively withDcclevels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions.