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Biology subjects

Mahmoodi, A.

Publications and source records attributed to Mahmoodi, A..

9 recordsLinked to original sources

Causal necessity of human hippocampus for structure-based inference in learning

When meeting new individuals or encountering known individuals in new circumstances, we intuitively map out their relationships - not merely by direct experience, but by quickly inferring new connections based on prior relational knowledge. Using a novel task, we demonstrated that participants indeed employ knowledge of relational structures to facilitate learning of new relationships in a changing environment. Computational modelling revealed that participants leveraged relational knowledge to support inference, thus facilitating learning. Whole brain neuroimaging identified a uniquely robust representation of relational structure in the hippocampus. Neural networks trained on similar tasks demonstrated the emergence of relational structure representations, resembling those found in hippocampus. Lesioning network units sustaining such representations disrupted structure-based inference and predicted hippocampuss essential role. Transcranial ultrasound stimulation of human hippocampus, transiently modulating its activity without affecting overlying tissue, produced similar disruption effects, empirically confirming the causal necessity of hippocampal representations for structure-based inference in learning.

neuroscience↗

ACTIVITY IN HUMAN DORSAL RAPHE NUCLEUS SIGNALS CHANGES IN BEHAVIOURAL POLICY

The dorsal raphe nucleus (DRN) is an important source of serotonin to the human forebrain, however there is little consensus about its behavioural function. We build on recent results from animal models to demonstrate that activity in human DRN represents changes between general behavioural policies. We use a novel behavioural task to show that human participants change their policy to pursue or reject reward opportunities as a function of the average value of opportunities in the environment. Activity in DRN - but no other neuromodulatory nucleus - signalled such policy changes. Patterns of multivariate activity in dorsal anterior cingulate cortex (dACC) and anterior insular cortex (AI), meanwhile, tracked the relative value of reward opportunities given the average value of the environment. We therefore suggest that DRN, dACC and AI form a circuit in which dACC/AI compute the relative value of reward opportunities given the current context, and DRN implements changes in behavioural policy based on context-specific values.

neuroscience↗

DORSAL RAPHE NUCLEUS CONTROLS MOTIVATIONAL STATE TRANSITIONS IN MONKEYS

The dorsal raphe nucleus (DRN) is an important source of serotonin in the brain but fundamental aspects of its function remain elusive. Here, we present a combination of minimally invasive recording and disruption studies to show that DRN brings about changes in motivation states. We use recently developed methods for identifying temporal patterns in behaviour to show that monkeys change their motivation depending on the availability of rewards in the environment. Distinctive patterns of DRN activity occur when monkeys transition between a high motivation state occupied when rewards are abundant, to a low motivation state engendered by reward scarcity. Disrupting DRN diminishes sensitivity to the reward environment and perturbs transitions in motivational states.

neuroscience↗

Human hippocampus and dorsomedial prefrontal cortex infer and update latent causes during social interaction

When an important event occurs, the observer should identify which features of the environment might have caused it. This is the latent cause inference problem, and it must be solved if observers are to understand their environments. The problem is acute in social settings where individuals may not make equal contributions to the outcomes they achieve together. Here, we designed a novel task in which participants inferred which of two characters was the more likely to have been responsible for outcomes achieved by working together. Using computational modelling, univariate and multivariate analysis of human fMRI, and continuous theta burst stimulation we identified two brain regions that solved the task. Notably, as each outcome occurred, it was possible to decode inference of its cause (the responsible character) from activity in hippocampus. Activity in dorsomedial prefrontal cortex updated estimates of association between cause -- the responsible character - and the outcome.

neuroscience↗

SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species

BackgroundSQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492) demonstrating SQ3370s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity. MethodsTreatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors. ResultsSQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370s safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3+ and CD8+ T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment. ConclusionsSQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development. Trial registrationNCT04106492; 7 September 2019

pharmacology and toxicology↗

Social prediction modulates activity of macaque superior temporal cortex

The ability to attribute thoughts to others, also called theory of mind (TOM), has been extensively studied. Computationally, the basis of TOM in humans has been interpreted within the predictive coding framework and associated with activity in the temporo-parietal junction (TPJ). However, the evolutionary origins of these human mindreading abilities have been challenged since the concept was coined. Here we identify a brain region in the Rhesus macaque that shares computational properties with the human TPJ. We revealed, using a non-linguistic task and functional magnetic resonance imaging, that activity in a region of the macaque middle superior temporal cortex was specifically modulated by the predictability of social interactions. As in human TPJ, this region could be distinguished from other temporal regions involved in face processing. Our result suggests the existence of a precursor for the theory of mind ability in the last common ancestor of human and old-world monkeys.

neuroscience↗

SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions

While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic antitumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.

bioengineering↗

DrawAlignR: An interactive tool for across run chromatogram alignment visualization

Multi-run alignment is widely used in proteomics to establish analyte correspondence across runs. Generally alignment algorithms return a cumulative score, which may not be easily interpretable for each peptide. Here we present a novel tool, DrawAlignR, to visualize each chromatographic alignment for DIA/SWATH data. Furthermore, we have developed a novel C++ based implementation of raw chromatogram alignment which is 35 times faster than the previously published algorithm. This not only enables users to plot alignment interactively by DrawAlignR, but also allows other software platforms to use the algorithm. DrawAlignR is an open-source web application using R Shiny that can be hosted using the source-code available at https://github.com/Roestlab/DrawAlignR.

bioinformatics↗

Distributed neural replay of decision confidence mediates informational conformity

A change of mind in response to social influence could be driven by informational conformity to increase accuracy, or by normative conformity to comply with social norms such as reciprocity. Disentangling the behavioural, cognitive and neurobiological underpinnings of informational and normative conformity have proven elusive. Here, participants underwent fMRI while performing a perceptual task that involved both advice-taking and advice-giving to human and computer partners. The concurrent inclusion of two different social roles and two different social partners revealed distinct behavioural and neural markers for informational and normative conformity. dACC BOLD response tracked informational conformity towards both human and computer but tracked normative conformity only when interacting with human. A network of brain areas (dmPFC and TPJ) that tracked normative conformity increased their functional coupling with the dACC when interacting with humans. These findings enable differentiating the neural mechanisms by which different types of conformity shape social changes of mind.

neuroscience↗