Candidate Mechanism Research Articles

Slow oscillation-spindle coupling predicts sequence-based language learning.

Sentence comprehension involves the rapid decoding of both semantic and grammatical information, a process fundamental to communication. As with other complex cognitive processes, language comprehension relies, in part, on long-term memory. However, the electrophysiological mechanisms underpinning the initial encoding and generalisation of higher-order linguistic knowledge remain elusive, particularly from a sleep-based consolidation perspective. One candidate mechanism that may support the consolidation of higher-order language is the temporal coordination of slow oscillations (SO) and sleep spindles during non-rapid eye movement sleep (NREM). To examine this hypothesis, we analysed electroencephalographic (EEG) data recorded from 35 participants (Mage = 25.4, SD = 7.10; 16 males) during an artificial language learning task, contrasting performance between individuals who were given an 8hr nocturnal sleep period or an equivalent period of wake. We found that sleep relative to wake was associated with superior performance for rules that followed a sequence-based word order. Post-sleep sequence-based word order processing was further associated with less task-related theta desynchronisation, an electrophysiological signature of successful memory consolidation, as well as cognitive control and working memory. Frontal NREM SO-spindle coupling was also positively associated with behavioural sensitivity to sequence-based word order rules, as well as with task-related theta power. As such, theta activity during retrieval of previously learned information correlates with SO-spindle coupling, thus linking neural activity in the sleeping and waking brain. Taken together, this study presents converging behavioral and neurophysiological evidence for a role of NREM SO-spindle coupling and task-related theta activity as signatures of successful memory consolidation and retrieval in the context of higher-order language learning.Significance statement The endogenous temporal coordination of neural oscillations supports information processing during both wake and sleep states. Here we demonstrate that slow oscillation-spindle coupling during non-rapid eye movement sleep predicts the consolidation of complex grammatical rules and modulates task-related oscillatory dynamics previously implicated in sentence processing. We show that increases in theta power predict enhanced sensitivity to grammatical violations after a period of sleep and strong slow oscillation-spindle coupling modulates subsequent task-related theta activity to influence behaviour. Our findings reveal a complex interaction between both wake- and sleep-related oscillatory dynamics during the early stages of language learning beyond the single word level.

Choice and motor impulsivity in Veterans with mild traumatic brain injury with and without history of suicide attempt

Traumatic brain injury is associated with increased risk for suicide, but the underlying mechanisms remain poorly understood. One candidate mechanism is impulsivity, which includes both choice impulsivity (e.g., preference for smaller, immediate rewards) and motor impulsivity (inability to inhibit prepotent motor responding). We evaluated these facets of impulsivity in Veterans classified according to their history of mild TBI (mTBI) and/or prior suicide attempt. 99 Veterans were classified as having no mTBI or suicide attempt (control, n = 35), mTBI but no suicide attempt (mTBI, n = 42), or mTBI and prior attempt (mTBI+SA, n = 22). A computerized temporal discounting task (Monetary Choice Questionnaire) assessed choice impulsivity and a Go/No-go task assessed motor impulsivity. On temporal discounting, the control group showed less choice impulsivity than the mTBI group. Temporal discounting was not associated with suicide attempt history. However, among the mTBI+SA group, those with high-lethality suicide attempts showed less choice impulsivity than those with low-lethality attempts. No group differences emerged on the Go/No-go task. The findings are consistent with choice impulsivity as a potential pathway by which mTBI affects risk for suicide. The finding that high-lethality attempts were associated with greater willingness to wait for reward supports the emerging view of heterogeneous underlying pathways to suicide risk, with distinct phenotypes that implicate different therapeutic options.

Abstract A027: Acceleration of drug metabolism mediated by CYP3A4 enzyme activation provides a bona fide environmental resistance mechanism to targeted therapies

Abstract Background: Targeted therapies against oncogenic signaling addictions, including one resulting from EML4-ALK fusions, can induce strong and durable clinical responses. However, these therapies are not curative in advanced cancers, as a subset of tumor cells avoid elimination, and these persisting populations evolve resistance that drives tumor relapse. Using a drug screen, we found that the evolving ALK inhibitor (ALKi) persisters display exquisite sensitivity to the histone demethylase inhibitor, JIB04 in vitro. Paradoxically, validation studies in mice revealed that instead of enhancing tumor sensitivity, JIB04 desensitizes tumors to ALKi, alectinib and lorlatinib, suggesting that it activates an unknown environmental modifier. While JIB04 is not used in the clinics, we reasoned that deciphering the underlying mechanism could uncover environment-mediated resistance to ALKi that might be triggered by clinically relevant factors. Results: We found that the resistance-promoting effect of JIB04 in mice is mediated by reducing systemic ALKi concentrations. This reduction is attributable to accelerated pharmacokinetics, due to the hyperactivation of the P450 family member, CYP3A4. Higher CYP3A4 activity leads to faster drug clearance and reduced drug exposure to tumors. Importantly, JIB04 triggers a similar resistance to other clinically relevant CYP3A4 substrates, the frontline EGFR inhibitor, osimertinib and the recently introduced KRASG12C inhibitor, sotorasib. Finally, the resistance- promoting effects of JIB04 could be phenocopied by chemically unrelated activators of CYP3A4, indicating a wide generalizability of this macro-environmental therapy resistance mechanism. Conclusions: Our study uncovered that acceleration of drug metabolism, triggered by CYP3A4 enzyme activators is a bona fide environmental resistance mechanism. Since P450 family liver detoxifying enzymes mediate the metabolism of many drugs, this resistance mechanism is likely to be relevant to a broad range of therapeutic contexts. Significance: While the importance of pharmacokinetic considerations is widely appreciated, modulation of drug metabolism is not typically considered as a candidate mechanism when therapy resistance is encountered in research and clinical settings. Multiple dietary, pharmacological and genetic modifiers are known to modulate P450 family enzymes. Moreover, substantial variability in drug plasma concentrations was documented in patients treated with identical doses of targeted therapies, and this variability strongly correlated with variability in clinical responses. While the direct link between variability in CYP3A4 activity and clinical outcomes in human patients has yet to be established, the mechanism uncovered in our study might represent a substantial but entirely overlooked contributor to resistance. Consequently, consideration of this mechanism and monitoring of CYP3A4 activity and systemic drug levels might improve our understanding of the biology of therapy resistance and enable an actionable path to improve clinical outcomes. Citation Format: Pragya Kumar, Robert Vander Velde, Malgorzata Weh, Andriy Marusyk. Acceleration of drug metabolism mediated by CYP3A4 enzyme activation provides a bona fide environmental resistance mechanism to targeted therapies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A027.

Abstract A038: A targetable tumor-induced wound-healing response is essential for osteosarcoma lung metastasis

Abstract Lung metastasis is responsible for nearly all deaths in children and teenagers affected by osteosarcoma, the most common pediatric sarcoma. The mechanisms by which malignant bone cells manipulate the lung microenvironment to promote the colonization and growth of metastatic tumor cells remain unclear but represent a potential therapeutic opportunity for preventing and treating metastasis. In this study, we sought to understand how osteosarcoma cells educate the lung microenvironment during metastatic progression. To address this gap, we generated several time series datasets of niche-labeled, single-cell RNA-seq of developing metastatic lesions and then used these to characterize the changes occurring in tumor and tumor-associated stromal cells during colonization. After identifying candidate mechanisms, we tested several therapeutic interventions to evaluate their effects on metastasis development in vitro using a tumor-on-lung co-culture system and in vivo using our animal models. Osteosarcoma cells induced acute epithelial injury upon lung dissemination. Shortly after dissemination, a paracrine loop established between a hyper-secretory, hypo-proliferative subpopulation of tumor cells and alveolar epithelial cells triggers the adoption of a chronic, non-resolving wound phenotype within the surrounding tissues that culminates in extensive tissue fibrosis with persistent extracellular matrix deposition, especially fibronectin. Cellular changes observed during this process include the proliferation of type 2 alveolar epithelial cells, the accumulation of highly fibrogenic epithelial intermediates (analogous to those observed in pulmonary fibrosis), and the emergence of a large population of scar-promoting macrophages. The formation of this matrix seems essential for lesion formation—disruption of the matrix-tumor cell interaction eliminated pseudonodules in vivo. Inhibition of pro-fibrotic pathways using nintedanib, an FDA- approved drug used to treat pulmonary fibrosis, or of tumor-epithelial paracrine signals with anakinra, an antagonist of IL1 signaling, effectively blocked metastatic lesion growth in both murine and human xenograft models, showing evidence of microenvironment reprogramming in the single cell data. Combining these therapies, which target primarily the hyper-secretory, hypo-proliferative “anchor” cells, with conventional therapies, which target proliferating tumor cells, proved highly effective in eliminating established metastatic lesions. Our work demonstrates that disseminated osteosarcoma cells trigger an aberrant, non-resolving wound-healing response in tumor-associated lung tissues, similar to that observed in non-malignant pulmonary fibrosis, and that this pathologic wound-healing response promotes metastatic growth. Therapeutic disruption of fibrosis-associated signaling prevents metastasis and treats established metastatic disease in multiple osteosarcoma models. Citation Format: James B. Reinecke, Leyre Jimenez Garcia, Amy C. Gross, Matthew V. Cannon, Yogesh Budhathoki, Ryan D. Roberts. A targetable tumor-induced wound-healing response is essential for osteosarcoma lung metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A038.

Enhanced Gαq Signaling in TSC2-deficient Cells Is Required for Their Neoplastic Behavior.

Inherited or sporadic loss of the TSC2 gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage ('LAM cells'). Their aberrant growth is attributed to increased activity of 'mechanistic target of rapamycin complex 1' (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM, but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G-protein coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in TSC2-deficient cells remained unknown. Using a human pluripotent stem cell-derived in vitro model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and pro-neoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking TSC2 demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared to wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in TSC2-deleted cells was independent of mTOR activity, and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent pro-neoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.

Identifying cognitive, affective, and developmental mechanisms linking threat and deprivation with adolescent psychopathology.

The mechanisms linking early-life adversity with psychopathology over the life-course are complex. In this prospective study, we collectively examined cognitive, affective, and developmental mediators previously found to individually link childhood threat and deprivation experiences to adolescent psychopathology to identify the most potent mechanisms. Data came from a community sample of 227 children (mean child age 11.5 ± 0.5 years, 48.5% female) from the Seattle metro area with recruitment designed to reflect diversity in family income. Candidate mechanisms included self-rated pubertal development and task-measured attention bias to threat, emotion regulation, theory of mind, fear learning, inhibitory control, language ability, reasoning, and reward sensitivity. Using a high-dimensional mediation approach, we determined which mediating pathways linking threat and deprivation to psychopathology persisted after controlling for all candidate mechanisms associated with psychopathology. Models additionally controlled for the child's age, sex, early-childhood emotional and behavioral symptoms, poverty, and maternal depression. Blunted reward sensitivity mediated the prospective relationship between threat and internalizing psychopathology, explaining 17.25% (95% CI 1.08%, 69.96%) of this association. Advanced pubertal development was associated with increases in internalizing and externalizing symptoms (standardized associations of 0.16 (95% CI 0.03, 0.29) and 0.17 (95% CI 0.05, 0.29), respectively), but not with adversity. Although deprivation was strongly related to psychopathology, no mechanisms were empirically identified. In a well-characterized community sample, we isolated reward sensitivity as a robust mediator of the prospective association between early-life threat and adolescent internalizing psychopathology. Interventions aimed at bolstering reward sensitivity may mitigate the impact of early-life threat experiences on internalizing problems.

Regulation of BCR-dependent germinal center B-cell formation by HGAL and insight into its emerging myeloid ortholog, C1ORF150.

The specificity of cytokine and immunoreceptor signaling frequently depends upon receptor recruitment of select adaptor proteins and specifically engaged effectors. This review focuses on the orthologous adaptor proteins, HGAL and C1ORF150, and aims to provide insight into their respective modulation of lymphoid and myeloid cell signaling, formation, and function. HGAL acts predominantly within germinal center B cells as an important BCR signal transducer. Effects on BCR signalosome assembly involve HGAL's localization to the plasma membrane via its lipidation, initial interactions with SYK, the pY-phosphorylation of HGAL including its recruitment of GRB2, and HGAL engagement of PDZ-RhoGEF and RhoA signaling. At ligated BCRs, this includes HGAL(-GRB2) stimulation of SYK kinase, attenuation of calcium flux-dependent and NF-κB expression, promotion of cSMAC formation, and cytoskeletal remodeling associated with HGAL-attenuated cell migration. HGAL and partnered effectors also impact on DLBCL pathogenesis, and studies are summarized on HGAL's actions (using DLBCL and Burkitt lymphoma B cells) including cell migration effects, HGAL modulation of cytoskeletal components, and insightful HGAL transgenic mouse and xenograft models. For C1ORF150, its HGAL-homologous subdomains are considered, together with studies that demonstrate C1OR150's FcϵRI- and KIT-mediated expression and phosphorylation in primary human mast cells. Intriguingly, recent GWAS studies have identified a C1ORF150 in-frame splice variant that is strongly associated with urticaria. Candidate mechanisms via which the encoded "C1ORF150-Δexon2" isoform affects mast cell degranulation are considered, including FcϵR1 and/or KIT receptor connections, and candidate "myristoylation switch" mechanisms.

Correction to “cross-cultural differences in memory specificity: Investigation of candidate mechanisms” by Leger and Gutchess (2021).

Correction to “cross-cultural differences in memory specificity: Investigation of candidate mechanisms” by Leger and Gutchess (2021).

Modeling magnetic field amplification in supernova remnants driven by laser

Abstract The origin of magnetic fields and their amplification have always been hot topics in fields such as astrophysics and high-energy-density physics. Among them, the turbulent dynamo effect is an important candidate mechanism, and the interaction between supernova remnants (SNRs) is an important carrier for studying the amplification effect of turbulent magnetic fields. In this paper, we use the radiation magnetohydrodynamic simulation program to carry out a scaling simulation study on the amplification effect of turbulent magnetic fields in the interaction of SNRs driven by powerful lasers. We investigate and compare the evolution of turbulence under different laser driving methods, different directions, and different intensities of initial external environmental magnetic fields. Here, we carefully identify the contributions of Biermann self-generated magnetic fields and environmental magnetic fields in the process of magnetic field amplification, present magnetic energy spectra, and magnetic field amplification factors, and analyze the influence of radiative cooling effect on turbulence and magnetic field evolution. The results show that the collision direction component of the environmental magnetic field dominates the process of magnetic field amplification, and the frequency spectrum of turbulence is consistent with Kolmogorov’s law. The research results are necessary for sorting out and elucidating the physical mechanism of magnetic field amplification in SNRs, and have reference significance for regulating turbulence in strong magnetic fields in the future.

Recording morphogen signals reveals mechanisms underlying gastruloid symmetry breaking.

Aggregates of stem cells can break symmetry and self-organize into embryo-like structures with complex morphologies and gene expression patterns. Mechanisms including reaction-diffusion Turing patterns and cell sorting have been proposed to explain symmetry breaking but distinguishing between these candidate mechanisms of self-organization requires identifying which early asymmetries evolve into subsequent tissue patterns and cell fates. Here we use synthetic 'signal-recording' gene circuits to trace the evolution of signalling patterns in gastruloids, three-dimensional stem cell aggregates that form an anterior-posterior axis and structures resembling the mammalian primitive streak and tailbud. We find that cell sorting rearranges patchy domains of Wnt activity into a single pole that defines the gastruloid anterior-posterior axis. We also trace the emergence of Wnt domains to earlier heterogeneity in Nodal activity even before Wnt activity is detectable. Our study defines a mechanism through which aggregates of stem cells can form a patterning axis even in the absence of external spatial cues.

Hybrid-Vlasov Modelling of Ion Velocity Distribution Functions Associated with the Kelvin–Helmholtz Instability with a Density and Temperature Asymmetry

The Kelvin–Helmholtz instability (KHI), characterized by vortices forming at a perturbed velocity shear layer, is a prominent candidate mechanism for mass, momentum, and energy transport across boundaries with velocity shear in various space plasma environments. It is of particular interest at the flanks of Earth’s magnetopause, which separates the plasma of the magnetosphere from the adjacent shocked solar wind flow in the magnetosheath. In the present study, we use local hybrid-Vlasov simulations to investigate the ion velocity distribution functions (VDFs) associated with KHI in a magnetopause-like, transverse velocity shear layer setting (magnetic field perpendicular to the shear plane). We look for signatures of ion finite Larmor radius (FLR) effects, which could be utilized in spacecraft measurements to recognize when such effects are active, influencing KHI evolution and driving plasma mixing. We show that when a density/temperature asymmetry exists across the shear layer, FLR effects produce a heat flux along the vortex edges. With a magnitude (≳0.1 mW m−2) that is a significant fraction of the total magnetosheath energy flux, the heat flux provides a distinct signature that could be measured with a single spacecraft. During the late nonlinear stage of KHI, mixed non-Maxwellian ion VDFs are additionally found within the vortices. Our results are also valid in the presence of a small magnetic shear across the magnetopause.

Stability Conditions and Stiffness Variability of General Tensegrity Systems with Kinematic Joints

Abstract Tensegrity systems represent promising candidate mechanisms with in-situ stiffness variability through changing the cables' prestress levels. However, prestress-based stiffness behaviors of tensegrity systems with arbitrary kinematic joints have not been analyzed systematically. This paper adopts the natural absolute coordinates for static modeling of tensegrity systems consisting of rigid members and tension elements. Then, a generic stiffness analysis method is developed to formulate the reduced-basis tangent stiffness matrix, which is found to include three parts: positive semi-definite material and geometric stiffness matrices, and an indefinite constraint stiffness matrix. Based on these findings, a systematic stability-checking procedure is derived to determine prestress and super stability, which are qualitative indicators of the softening and stiffening effects in different tensegrity systems. Then, we proceed to quantify the range of prestress-based stiffness variability by formulating semidefinite programming problems that numerically pinpoint the maximum and zero stiffness points. Furthermore, this paper reveals the composable nature of multiple self-stress states, enabling the composability of stiffness properties in mechanism designs. Several numerical examples verify the efficacy and versatility of the proposed method and demonstrate interesting stiffness behaviors of tensegrity systems with kinematic joints.

Pre- and Postsynaptic MEF2C Promotes Experience-Dependent, Input-Specific Development of Cortical Layer 4 to Layer 2/3 Excitatory Synapses and Regulates Activity-Dependent Expression of Synaptic Cell Adhesion Molecules.

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.

Nonthermal Observations of a Flare Loop-top Using IRIS Fe xxi: Implications for Turbulence and Electron Acceleration

The excess broadening of high-temperature spectral lines, long observed near the tops of flare arcades, is widely considered to result from magnetohydrodynamic turbulence. According to different theories, plasma turbulence is also believed to be a candidate mechanism for particle acceleration during solar flares. However, the degree to which this broadening is connected to the acceleration of nonthermal electrons remains largely unexplored outside of recent work, and many observations have been limited by limited spatial resolution and cadence. Using the Interface Region Imaging Spectrometer, we present spatially resolved observations of loop-top (LT) broadenings using hot (≈11 MK) Fe xxi 1354.1 Å line emission at ≈9 s cadence during the 2022 March 30 X1.3 flare. We find nonthermal velocities upward of 65 km s−1 that decay linearly with time, indicating the presence and subsequent dissipation of plasma turbulence. Moreover, the initial Fe xxi signal was found to be cospatial and cotemporal with microwave emission measured by the Expanded Owens Valley Solar Array, placing a population of nonthermal electrons in the same region as the LT turbulence. Evidence of electron acceleration at this time is further supported by hard X-ray measurements from the Spectrometer/Telescope for Imaging X-rays on board Solar Orbiter. Using the decay of nonthermal broadenings as a proxy for turbulent dissipation, we found the rate of energy dissipation to be consistent with the power of nonthermal electrons deposited into the chromosphere, suggesting a possible connection between turbulence and electron acceleration.

Opening the Black Box: The Underlying Working Mechanisms in Virtual-Reality Exposure Therapy for Anxiety Disorders

Although research on virtual-reality (VR) exposure therapy (VRET) in anxiety disorders has primarily focused on effectiveness and acceptability, the underlying working mechanisms have received scant attention. To fill this knowledge gap, we discuss potential theoretical underpinnings of VRET based on three dominant theoretical accounts on exposure: inhibitory-learning theory (expectancy violation), emotional-processing theory (habituation), and self-efficacy theory. Whereas theoretically speaking, habituation and self-efficacy seem plausible candidate mechanisms to explain the effects of VRET, the role of expectancy violation is less straightforward. Because of the simulated nature of VR, some feared outcomes cannot occur, and therefore, possibilities to violate expectancies about their occurrence may be compromised. Empirical evidence on the working mechanisms of VRET is scarce and has important limitations. Avenues for future research are provided. Insights into the mechanisms of VRET not only are of theoretical importance but also can provide theory-based directions to optimize the application of VRET.

Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions.

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease.

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

Attentional dynamics of evidence accumulation explain why more numerate people make better decisions under risk

In decisions under risk, more numerate people are typically more likely to choose the option with the highest expected value (EV) than less numerate ones. Prior research indicates that this finding cannot be explained by differences in the reliance on explicit EV calculation. The current work uses the attentional Drift Diffusion Model as a unified computational framework to formalize three candidate mechanisms of pre-decisional information search and processing—namely, attention allocation, amount of deliberation, and distorted processing of value—which may differ between more and less numerate people and explain differences in decision quality. Computational modeling of an eye-tracking experiment on risky choice demonstrates that numeracy is linked to how people allocate their attention across the options, how much evidence they require before committing to a choice, and also how strongly they distort currently non-attended information during preference formation. Together, especially the latter two mechanisms largely mediate the effect of numeracy on decision quality. Overall, the current work disentangles and quantifies latent aspects of the dynamics of preference formation, explicates how their interplay may give rise to manifest differences in decision quality, and thereby provides a fully formalized, mechanistic explanation for the link between numeracy and decision quality in risky choice.

Impact of cognitive behavioural therapy on neural, inflammatory, & autonomic markers in a sample with PTSD and cardiovascular risk: protocol for a pilot randomised controlled trial

ABSTRACT Background: Individuals with posttraumatic stress disorder (PTSD) are at heightened risk for cardiovascular disease (CVD) compared to the general population. Inflammation and autonomic dysfunction are candidate mechanisms of CVD risk in PTSD; however, these mechanisms have not been well-characterised in the PTSD-CVD link. Further, these mechanisms may operate through altered stress-related neural activity (SNA). Yet, it remains unknown if changes in PTSD are associated with changes in CVD risk mechanisms. Objective: This manuscript describes the design and procedures of a pilot randomised controlled trial to assess the impact of a first-line treatment for PTSD (Cognitive Processing Therapy; CPT) versus waitlist control on mechanisms of CVD risk. Further, this study will test the hypothesis that CPT reduces CVD risk through its effects on inflammation and autonomic function and that these changes are driven by changes in SNA. Methods: Adults with PTSD and CVD risk (N = 30) will be randomised to CPT or waitlist control. Participants complete two laboratory visits (baseline and post-treatment) that include surveys, brain and peripheral imaging via 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and resting measures of autonomic function. Primary outcomes include arterial inflammation and heart rate variability. Secondary outcomes include leukopoiesis (bone marrow uptake), heart rate, and blood pressure. The indirect effects of PTSD treatment on changes in inflammation and autonomic function through SNA will also be examined. Conclusions: This study seeks to characterise candidate neuroimmune mechanisms of the PTSD-CVD link to identify treatment targets and develop personalised interventions to reduce CVD events in PTSD populations. Trial registration: ClinicalTrials.gov identifier: NCT06429293..

Achieving Occam's razor: Deep learning for optimal model reduction.

All fields of science depend on mathematical models. Occam's razor refers to the principle that good models should exclude parameters beyond those minimally required to describe the systems they represent. This is because redundancy can lead to incorrect estimates of model parameters from data, and thus inaccurate or ambiguous conclusions. Here, we show how deep learning can be powerfully leveraged to apply Occam's razor to model parameters. Our method, FixFit, uses a feedforward deep neural network with a bottleneck layer to characterize and predict the behavior of a given model from its input parameters. FixFit has three major benefits. First, it provides a metric to quantify the original model's degree of complexity. Second, it allows for the unique fitting of data. Third, it provides an unbiased way to discriminate between experimental hypotheses that add value versus those that do not. In three use cases, we demonstrate the broad applicability of this method across scientific domains. To validate the method using a known system, we apply FixFit to recover known composite parameters for the Kepler orbit model and a dynamic model of blood glucose regulation. In the latter, we demonstrate the ability to fit the latent parameters to real data. To illustrate how the method can be applied to less well-established fields, we use it to identify parameters for a multi-scale brain model and reduce the search space for viable candidate mechanisms.