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  1. Article ; Online: Graphs and the idiographic brain.

    Elmalem, Michael S / Nachev, Parashkev / Jha, Ashwani

    Brain : a journal of neurology

    2024  Volume 147, Issue 3, Page(s) 752–754

    MeSH term(s) Humans ; Connectome ; Brain
    Language English
    Publishing date 2024-02-12
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awae044
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  2. Article ; Online: Digital Biomarkers in Parkinson's Disease: Missing the Forest for the Trees?

    Jha, Ashwani / Espay, Alberto J / Lees, Andrew J

    Movement disorders clinical practice

    2023  Volume 10, Issue Suppl 2, Page(s) S68–S72

    Language English
    Publishing date 2023-05-17
    Publishing country United States
    Document type Journal Article
    ISSN 2330-1619
    ISSN (online) 2330-1619
    DOI 10.1002/mdc3.13746
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  3. Article ; Online: Widespread alteration of protein autoinhibition in human cancers.

    Holguin-Cruz, Jorge A / Bui, Jennifer M / Jha, Ashwani / Na, Dokyun / Gsponer, Jörg

    Cell systems

    2024  Volume 15, Issue 3, Page(s) 246–263.e7

    Abstract: Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we ...

    Abstract Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.
    MeSH term(s) Humans ; Calcineurin/genetics ; Neoplasms/genetics ; Mutation/genetics ; Carcinogenesis ; Mutation, Missense/genetics
    Chemical Substances Calcineurin (EC 3.1.3.16)
    Language English
    Publishing date 2024-02-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2854138-8
    ISSN 2405-4720 ; 2405-4712
    ISSN (online) 2405-4720
    ISSN 2405-4712
    DOI 10.1016/j.cels.2024.01.009
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  4. Article ; Online: Neurodevelopmental Disorders: Sensing Tourette's Tics Away.

    Jha, Ashwani / Nachev, Parashkev

    Current biology : CB

    2020  Volume 30, Issue 12, Page(s) R698–R700

    Abstract: Though still shrouded in mystery, Gilles de la Tourette's syndrome is widely regarded as an archetypal neurodevelopmental disorder of central, motor control. New evidence that its cardinal manifestation - prominent tics - may be ameliorated by a ... ...

    Abstract Though still shrouded in mystery, Gilles de la Tourette's syndrome is widely regarded as an archetypal neurodevelopmental disorder of central, motor control. New evidence that its cardinal manifestation - prominent tics - may be ameliorated by a peripheral, sensory intervention compels us to revise not only our conception of the syndrome, but of the motor system itself.
    MeSH term(s) Brain ; Humans ; Movement ; Tics ; Tourette Syndrome
    Language English
    Publishing date 2020-06-22
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2020.04.079
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  5. Article ; Online: Generating truth from error: insights from neurodevelopmental disorders.

    Jha, Ashwani / Nachev, Parashkev

    Brain : a journal of neurology

    2018  Volume 142, Issue 1, Page(s) 11–14

    MeSH term(s) Humans ; Neurodevelopmental Disorders ; Problem Solving ; Tourette Syndrome ; Young Adult
    Language English
    Publishing date 2018-12-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awy311
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  6. Article ; Online: Generative model-enhanced human motion prediction.

    Bourached, Anthony / Griffiths, Ryan-Rhys / Gray, Robert / Jha, Ashwani / Nachev, Parashkev

    Applied AI letters

    2022  Volume 3, Issue 2, Page(s) e63

    Abstract: The task of predicting human motion is complicated by the natural heterogeneity and compositionality of actions, necessitating robustness to distributional shifts as far as out-of-distribution (OoD). Here, we formulate a new OoD benchmark based on the ... ...

    Abstract The task of predicting human motion is complicated by the natural heterogeneity and compositionality of actions, necessitating robustness to distributional shifts as far as out-of-distribution (OoD). Here, we formulate a new OoD benchmark based on the Human3.6M and Carnegie Mellon University (CMU) motion capture datasets, and introduce a hybrid framework for hardening discriminative architectures to OoD failure by augmenting them with a generative model. When applied to current state-of-the-art discriminative models, we show that the proposed approach improves OoD robustness without sacrificing in-distribution performance, and can theoretically facilitate model interpretability. We suggest human motion predictors ought to be constructed with OoD challenges in mind, and provide an extensible general framework for hardening diverse discriminative architectures to extreme distributional shift. The code is available at: https://github.com/bouracha/OoDMotion.
    Language English
    Publishing date 2022-03-23
    Publishing country United States
    Document type Journal Article
    ISSN 2689-5595
    ISSN (online) 2689-5595
    DOI 10.1002/ail2.63
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  7. Article ; Online: A framework for focal and connectomic mapping of transiently disrupted brain function.

    Elmalem, Michael S / Moody, Hanna / Ruffle, James K / de Schotten, Michel Thiebaut / Haggard, Patrick / Diehl, Beate / Nachev, Parashkev / Jha, Ashwani

    Communications biology

    2023  Volume 6, Issue 1, Page(s) 430

    Abstract: The distributed nature of the neural substrate, and the difficulty of establishing necessity from correlative data, combine to render the mapping of brain function a far harder task than it seems. Methods capable of combining connective anatomical ... ...

    Abstract The distributed nature of the neural substrate, and the difficulty of establishing necessity from correlative data, combine to render the mapping of brain function a far harder task than it seems. Methods capable of combining connective anatomical information with focal disruption of function are needed to disambiguate local from global neural dependence, and critical from merely coincidental activity. Here we present a comprehensive framework for focal and connective spatial inference based on sparse disruptive data, and demonstrate its application in the context of transient direct electrical stimulation of the human medial frontal wall during the pre-surgical evaluation of patients with focal epilepsy. Our framework formalizes voxel-wise mass-univariate inference on sparsely sampled data within the statistical parametric mapping framework, encompassing the analysis of distributed maps defined by any criterion of connectivity. Applied to the medial frontal wall, this transient dysconnectome approach reveals marked discrepancies between local and distributed associations of major categories of motor and sensory behaviour, revealing differentiation by remote connectivity to which purely local analysis is blind. Our framework enables disruptive mapping of the human brain based on sparsely sampled data with minimal spatial assumptions, good statistical efficiency, flexible model formulation, and explicit comparison of local and distributed effects.
    MeSH term(s) Humans ; Connectome ; Magnetic Resonance Imaging/methods ; Brain/physiology ; Epilepsies, Partial ; Electric Stimulation
    Language English
    Publishing date 2023-04-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-023-04787-1
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  8. Article ; Online: GeoSPM: Geostatistical parametric mapping for medicine.

    Engleitner, Holger / Jha, Ashwani / Pinilla, Marta Suarez / Nelson, Amy / Herron, Daniel / Rees, Geraint / Friston, Karl / Rossor, Martin / Nachev, Parashkev

    Patterns (New York, N.Y.)

    2022  Volume 3, Issue 12, Page(s) 100656

    Abstract: The characteristics and determinants of health and disease are often organized in space, reflecting our spatially extended nature. Understanding the influence of such factors requires models capable of capturing spatial relations. Drawing on statistical ... ...

    Abstract The characteristics and determinants of health and disease are often organized in space, reflecting our spatially extended nature. Understanding the influence of such factors requires models capable of capturing spatial relations. Drawing on statistical parametric mapping, a framework for topological inference well established in the realm of neuroimaging, we propose and validate an approach to the spatial analysis of diverse clinical data-GeoSPM-based on differential geometry and random field theory. We evaluate GeoSPM across an extensive array of synthetic simulations encompassing diverse spatial relationships, sampling, and corruption by noise, and demonstrate its application on large-scale data from UK Biobank. GeoSPM is readily interpretable, can be implemented with ease by non-specialists, enables flexible modeling of complex spatial relations, exhibits robustness to noise and under-sampling, offers principled criteria of statistical significance, and is through computational efficiency readily scalable to large datasets. We provide a complete, open-source software implementation.
    Language English
    Publishing date 2022-12-09
    Publishing country United States
    Document type Journal Article
    ISSN 2666-3899
    ISSN (online) 2666-3899
    DOI 10.1016/j.patter.2022.100656
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  9. Article ; Online: Orienting to fear under transient focal disruption of the human amygdala.

    Jha, Ashwani / Diehl, Beate / Strange, Bryan / Miserocchi, Anna / Chowdhury, Fahmida / McEvoy, Andrew W / Nachev, Parashkev

    Brain : a journal of neurology

    2022  Volume 146, Issue 1, Page(s) 135–148

    Abstract: Responding to threat is under strong survival pressure, promoting the evolution of systems highly optimized for the task. Though the amygdala is implicated in 'detecting' threat, its role in the action that immediately follows-'orienting'-remains unclear. ...

    Abstract Responding to threat is under strong survival pressure, promoting the evolution of systems highly optimized for the task. Though the amygdala is implicated in 'detecting' threat, its role in the action that immediately follows-'orienting'-remains unclear. Critical to mounting a targeted response, such early action requires speed, accuracy, and resilience optimally achieved through conserved, parsimonious, dedicated systems, insured against neural loss by a parallelized functional organization. These characteristics tend to conceal the underlying substrate not only from correlative methods but also from focal disruption over time scales long enough for compensatory adaptation to take place. In a study of six patients with intracranial electrodes temporarily implanted for the clinical evaluation of focal epilepsy, we investigated gaze orienting to fear during focal, transient, unilateral direct electrical disruption of the amygdala. We showed that the amygdala is necessary for rapid gaze shifts towards faces presented in the contralateral hemifield regardless of their emotional expression, establishing its functional lateralization. Behaviourally dissociating the location of presented fear from the direction of the response, we implicated the amygdala not only in detecting contralateral faces, but also in automatically orienting specifically towards fearful ones. This salience-specific role was demonstrated within a drift-diffusion model of action to manifest as an orientation bias towards the location of potential threat. Pixel-wise analysis of target facial morphology revealed scleral exposure as its primary driver, and induced gamma oscillations-obtained from intracranial local field potentials-as its time-locked electrophysiological correlate. The amygdala is here reconceptualized as a functionally lateralized instrument of early action, reconciling previous conflicting accounts confined to detection, and revealing a neural organisation analogous to the superior colliculus, with which it is phylogenetically kin. Greater clarity on its role has the potential to guide therapeutic resection, still frequently complicated by impairments of cognition and behaviour related to threat, and inform novel focal stimulation techniques for the management of neuropsychiatric conditions.
    MeSH term(s) Humans ; Fear/physiology ; Fear/psychology ; Amygdala ; Cognition ; Facial Expression ; Magnetic Resonance Imaging ; Photic Stimulation
    Language English
    Publishing date 2022-02-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awac032
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  10. Article ; Online: MiRNAting control of DNA methylation.

    Jha, Ashwani / Shankar, Ravi

    Journal of biosciences

    2014  Volume 39, Issue 3, Page(s) 365–380

    Abstract: DNA methylation is a type of epigenetic modification where a methyl group is added to the cytosine or adenine residue of a given DNA sequence. It has been observed that DNA methylation is achieved by some collaborative agglomeration of certain proteins ... ...

    Abstract DNA methylation is a type of epigenetic modification where a methyl group is added to the cytosine or adenine residue of a given DNA sequence. It has been observed that DNA methylation is achieved by some collaborative agglomeration of certain proteins and non-coding RNAs. The assembly of IDN2 and its homologous proteins with siRNAs recruits the enzyme DRM2, which adds a methyl group at certain cytosine residues within the DNA sequence. In this study, it was found that de novo DNA methylation might be regulated by miRNAs through systematic targeting of the genes involved in DNA methylation. A comprehensive genome-wide and system-level study of miRNA targeting, transcription factors, DNA-methylation-causing genes and their target genes has provided a clear picture of an interconnected relationship of all these factors which regulate DNA methylation in Arabidopsis. The study has identified a DNA methylation system that is controlled by four different genes: IDN2, IDNl1, IDNl2 and DRM2. These four genes along with various critical transcription factors appear to be controlled by five different miRNAs. Altogether, DNA methylation appears to be a finely tuned process of opposite control systems of DNAmethylation- causing genes and certain miRNAs pitted against each other.
    MeSH term(s) Arabidopsis/genetics ; Arabidopsis Proteins/genetics ; Arabidopsis Proteins/metabolism ; Arabidopsis Proteins/physiology ; Computational Biology ; DNA Methylation ; Epigenesis, Genetic ; Gene Regulatory Networks ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Methyltransferases/physiology ; MicroRNAs/physiology ; Models, Genetic ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; RNA-Binding Proteins/physiology ; Transcription Factors/physiology
    Chemical Substances Arabidopsis Proteins ; FDM1 protein, Arabidopsis ; FDM2 protein, Arabidopsis ; IDN2 protein, Arabidopsis ; MicroRNAs ; RNA-Binding Proteins ; Transcription Factors ; Methyltransferases (EC 2.1.1.-) ; DRM2 protein, Arabidopsis (EC 2.1.1.37)
    Language English
    Publishing date 2014-04-06
    Publishing country India
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 756157-x
    ISSN 0973-7138 ; 0250-5991
    ISSN (online) 0973-7138
    ISSN 0250-5991
    DOI 10.1007/s12038-014-9437-9
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