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Siddiqui, R.

Publications and source records attributed to Siddiqui, R..

6 recordsLinked to original sources

Critical scaling of cortical ensembles without cooperative amplification

Cortical neurons are sparsely and weakly connected, motivating the long-standing idea that they must act collectively, as cell assemblies, to exert substantial influence on surrounding networks. Yet a few spikes in a single pyramidal neuron can recruit thousands of cortical neurons according to a power law with exponent ~0.285, consistent with a two-dimensional system near a critical percolation transition. Here we holographically stimulated ensembles of 1 to 16 layer 2/3 pyramidal neurons in visual cortex of awake mice while imaging hundreds of neighbouring neurons. Across two orders of magnitude in evoked spike count, network responses followed the same scaling law observed for single-neuron perturbations, with no detectable threshold at which co-activation produced additional amplification. Recruitment was sublinear, suppression increased with ensemble size, and ongoing scale-free avalanche dynamics remained stationary. Nevertheless, ensemble identity became increasingly decodable from surrounding activity. Thus, coordinated firing increases representational specificity without escaping the critical dynamics governing propagation: cortical ensembles convey identity without gaining disproportionate causal impact.

neuroscience↗

PCNA Inhibition Enhances the Antitumor Activity of KRAS-Targeted Therapies in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis. More than 90% of PDAC tumors harbor KRAS mutations, and several KRAS inhibitors, such as off-state, on-state, mutation-specific, and pan-RAS inhibitors, are being tested in preclinical and clinical settings. However, the response to these inhibitors as single agents is less than optimal, indicating the need to identify novel combination therapies to improve treatment outcomes. Proliferating cell nuclear antigen (PCNA) is a ring-shaped clamp protein that regulates DNA replication, repair, and resolution of transcription-replication conflict, which are critical processes for pancreatic cancer survival. AOH1996 is a first-in-class, selective PCNA inhibitor in Phase I trials. Here, we found that AOH1996 treatment is efficacious in various PDAC models in vitro. PCNA and KRAS are predicted to be synthetic lethal partners, and RNA sequencing of AOH1996-treated PDAC cells reveals enrichment of MAPK and PI3K signaling pathways. Combination of AOH1996 with KRAS inhibitors demonstrates strong synergy across KRAS G12C and G12D mutant models. Treatment with a combination of AOH1996 and KRAS inhibitors induces cell cycle arrest and apoptosis in PDAC cells. Robust antitumor activity of AOH1996 in combination with RMC-6236 was observed in PDAC tumoroids. In vivo, the combination of AOH1996 with sotorasib or MRTX1133 reduced tumor growth rates compared to single-agent therapy, with no impact on mouse body weight. Residual tumor analysis showed sustained pERK and Myc inhibition in the combination arm. In conclusion, combination of AOH1996 with KRAS inhibitors is a promising therapeutic strategy for KRAS-driven PDAC, warranting further clinical investigation.

cancer biology↗

Critical Scaling of Novelty in the Cortex

The ability to detect and transmit novel events is essential for adaptive behavior in uncertain environments. Here, we investigate how holographically triggered, unanticipated action potentials propagate through the primary visual cortex of resting mice, focusing on pyramidal neuron communication. We find that these novel spikes -- uncorrelated with ongoing activity -- exert a disproportionately large influence on neighboring neurons, whose response scales as a power law (exponent [~]0.2-0.3). Even a few such spikes can recruit a large fraction of the local network, enabling robust decoding of perturbation origin despite high trial-by-trial variability and ongoing activity dominated by large activity fluctuations in the form of scale-invariant, parabolic neuronal avalanches. Simulations confirm this scaling to small, local perturbations aligns with the high susceptibility of complex systems near criticality. These results suggest that critical dynamics facilitate efficient transmission of novel signals, revealing a fundamental mechanism for cortical novelty detection.

neuroscience↗

Olfactory basis for essential amino acid perception during foraging in Caenorhabditis elegans

Acquisition of essential nutrients through diet is crucial for the survival of animals. Dietary odors might enable animals to forage for nutrient-rich diets. We asked if Caenorhabditis elegans, a bacterivorous nematode, uses olfactory cues to forage for essential amino acid-rich (EAA) diets. Using the native microbiome of C. elegans, we show that worms rely on olfaction to select leucine (EAA)-enriched bacteria. Using gas chromatography, we find that leucine-enriched bacteria produce isoamyl alcohol (IAA) odor in the highest abundance. Prior adaptation of worms to IAA diminishes the diet preference of worms. Several wild isolates of C. elegans display robust responses to IAA emphasizing its ecological relevance. We find that foraging for a leucine-enriched diet is mediated via the AWC olfactory neurons. Finally, we identify SNIF-1 G protein-coupled receptor in AWC neurons as a receptor for IAA and a mediator of dietary decisions in worms. Our study identifies a receptor-ligand module underpinning foraging behavior in C. elegans.

animal behavior and cognition↗

Pyrrole produced by Pseudomonas aeruginosa influences olfactory food choice of Caenorhabditis elegans

Sense of smell can influence dietary choices in animals. So far, most of the research has focused on how animals respond to distinct odors when they are introduced individually. However, it remains unclear how animals evaluate foods that contain a bouquet of olfactory cues with contrasting effects. Here, we utilize Caenorhabditis elegans as a bacterivore to ask if odors produced by dietary bacteria can regulate worms food preferences. We show that the bacterium Pseudomonas aeruginosa produces a relatively small quantity of a new attractant for C. elegans. We identify the odor as a heterocyclic compound called pyrrole. We find that pyrrole contributes to the sensory decision-making of worms in diet preference assays. Using specific neuronal ablation lines and calcium response assays, we show that AWA odor sensory neurons of worms are necessary for sensing pyrrole. In all, we show that specific odors produced by bacteria can influence food choice behavior of animals.

animal behavior and cognition↗

Real-time analysis of the diphtheria outbreak in forcibly displaced Myanmar nationals in Bangladesh

BackgroundBetween August and December 2017, more than 625,000 Rohingya from Myanmar fled into Bangladesh, settling in informal makeshift camps in Coxs Bazar district, joining 212,000 Rohingya already present. In early November, a diphtheria outbreak was reported in the camps, with 440 cases being reported during the first month. A rise in cases during early December led to a collaboration between teams from Medecins sans Frontieres - who were running a provisional diphtheria treatment centre - and the London School of Hygiene & Tropical Medicine with the goal to use transmission dynamic models to forecast the potential scale of the outbreak and the resulting resource needs.\n\nMethodsWe first adjusted for delays between symptoms onset and case presentation using the observed distribution of reporting delays from previously reported cases. We then fit a compartmental transmission model to the adjusted incidence stratified by age-group and location. Model forecasts with a lead-time of two weeks were issued on 12th, 20th, 26th and 30th December and communicated to decision-makers.\n\nResultsThe first forecast estimated that the outbreak would peak on 16th December in Balukhali camp with 222 (95% prediction interval 126-409) cases and would continue to grow in Kutupalong camp, requiring a bed capacity of 200 (95% PI 142-301). On 16th December, a total of 70 cases were reported, lower than forecasted. Subsequent forecasts were more accurate: on 20th December we predicted a total of 701 cases (95% PI 477-901) and 105 (95% PI 72-135) hospitalizations until the end of the year, with 616 cases actually reported during this period.\n\nConclusionsReal-time modelling enabled feedback of key information about the potential scale of the epidemic, resource needs, and mechanisms of transmission to decision-makers at a time when this information was largely unknown. By December 20th, the model generated reliable forecasts and helped support decision-making on operational aspects of the outbreak response, such as hospital bed and staff needs, and with advocacy for control measures. Although modelling is only one component of the evidence base for decision-making in outbreak situations, suitable analysis and forecasting techniques can be used to gain insights into an ongoing outbreak.

epidemiology↗