Opportunities For Discovery Research Articles

What Next for the ‘Text’? Popular Culture and Literature Today

Literary studies have evolved over the past few decades to include popular culture fields as text. Proponents of this inclusion argue that songs, memes, tweets, local dialects, and slogans say as much about people and cultures as traditional texts – perhaps even more. The opinion is that, by over-relying on traditional text for literary fodder, scholars shut themselves off from current and relevant information about the rapidly evolving literary and cultural landscape. The disregard for popular culture also turns away a younger audience that seems to prefer a more informal approach to art and literature. Thus, the reading of popular cultures as text is forcing the literary field to re-evaluate the fundamental principles that define its work. Literary scholars have to rethink their traditional ideals of writing, reading, and teaching texts. Yet, there remains a reluctance to accept such informal forms of communication as memes and tweets as legitimate literature. Popular culture is not well regarded in literary studies and some stakeholders fear its classification as text could dilute the impact of the field. This paper investigates this trepidation by analyzing how reading popular culture fields as text impacts the identity of text in literary studies. Based on selected tenets of Literary and Cultural Studies (LCS) Research, particularly cultural literacy, this paper examines the legitimacy of different popular culture formats to determine if they hold enough value to warrant literary analysis. The author argues that many forms of popular culture deserve a closer look, especially through a literary lens, because they reveal the cultures, beliefs, and practices of their audience. He suggests that the incorporation of popular culture into literary studies offers many opportunities for growth and discovery but only if implemented diligently. Finally, this paper investigates why the literary field is reluctant to read popular cultures as text and how scholars can navigate this inclusion to create a more cohesive definition of text.

Late-stage meta-C-H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step.

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)-H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C-H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

Leionema paulii (Rutaceae), a new, range-restricted endemic species from south-eastern New South Wales, Australia

Leionema paulii G.P.Phillips (Rutaceae), a newly recognised species of restricted distribution from montane south-eastern New South Wales is here described. It is compared with the morphologically similar L. phylicifolium (F.Muell.) Paul G.Wilson, L. ceratogynum N.G.Walsh and L. lachnaeoides (A.Cunn.) Paul G.Wilson. The distribution, habitat and proposed conservation status for the new taxon are presented, and a modified key to the species of Leionema found in New South Wales is also included. Leionema paulii was previously recorded as a disjunct population of L. phylicifolium that was previously not represented by any herbarium specimens. This highlights the opportunity for further taxonomic discovery through the collection and analysis of specimens from more disjunct and discrete populations in genera that contain large numbers of narrow-range endemics.

The Impact of the Digital Capability of College Students’ New Enterprises on Business Model Innovation Driven by the Digital Economy: The Mediating Effect of Digital Opportunity Discovery

Based on the theoretical frameworks on dynamic capabilities and business model innovation, we conducted a comprehensive survey and analysis involving 451 Chinese university student enterprises. The primary objective was to investigate the synergistic mechanism between these two factors, assessing their impact on business model innovation and tracing the evolutionary path. The study revealed the following key findings: (1) positive correlations exist between digital capabilities and business model innovation; (2) entrepreneurial passion serves as a mediator in the positive relationship between digital capabilities and the discovery of digital opportunities; (3) digital opportunity discovery acts as a mediator in the relationship between digital capabilities and business model innovation; (4) under the mediation of dynamic capabilities, digital opportunity discovery significantly promotes business model innovation. Our research contributes to the empirical exploration of digitization in enterprises, shedding light on the collaborative influence of digital capabilities and digital opportunity discovery on business model innovation. Importantly, it elucidates the contextual boundaries that influence business model innovation through diverse pathways, enhancing our comprehensive understanding of the dynamic landscape in the evolution of digital business transformations.

Distributed Architectures for Big Data Analytics in Cloud Computing: A Review of Data-Intensive Computing Paradigm

Big Data challenges are prevalent in various fields, including economics, business, public administration, national security, and scientific research. While it offers opportunities for productivity and scientific breakthroughs, it also presents challenges in data capture, storage, analysis, and visualization. This paper provides a comprehensive overview of Big Data applications, opportunities, challenges, and current techniques and technologies to address these issues. This study presents a system for managing big data resources using cloud for the development of data-intensive applications. It addresses even the challenges related to technologies that combine cloud computing with other allied technologies and devices. In addition, the increasing volume, velocity, and variety of data in the era of Big Data necessitate advanced methods for data processing and management. This study delves into the intricacies of data scalability, real-time processing, and the integration of diverse data types. Furthermore, it explores the role of machine learning algorithms and artificial intelligence in extracting meaningful insights from massive datasets.

An inside out journey: biogenesis, ultrastructure and proteomic characterisation of the ectoparasitic flatworm Sparicotyle chrysophrii extracellular vesicles

BackgroundHelminth extracellular vesicles (EVs) are known to have a three-way communication function among parasitic helminths, their host and the host-associated microbiota. They are considered biological containers that may carry virulence factors, being therefore appealing as therapeutic and prophylactic target candidates. This study aims to describe and characterise EVs secreted by Sparicotyle chrysophrii (Polyopisthocotyla: Microcotylidae), a blood-feeding gill parasite of gilthead seabream (Sparus aurata), causing significant economic losses in Mediterranean aquaculture.MethodsTo identify proteins involved in extracellular vesicle biogenesis, genomic datasets from S. chrysophrii were mined in silico using known protein sequences from Clonorchis spp., Echinococcus spp., Fasciola spp., Fasciolopsis spp., Opisthorchis spp., Paragonimus spp. and Schistosoma spp. The location and ultrastructure of EVs were visualised by transmission electron microscopy after fixing adult S. chrysophrii specimens by high-pressure freezing and freeze substitution. EVs were isolated and purified from adult S. chrysophrii (n = 200) using a newly developed ultracentrifugation-size-exclusion chromatography protocol for Polyopisthocotyla, and EVs were characterised via nanoparticle tracking analysis and tandem mass spectrometry.ResultsFifty-nine proteins involved in EV biogenesis were identified in S. chrysophrii, and EVs compatible with ectosomes were observed in the syncytial layer of the haptoral region lining the clamps. The isolated and purified nanoparticles had a mean size of 251.8 nm and yielded 1.71 × 108 particles · mL−1. The protein composition analysis identified proteins related to peptide hydrolases, GTPases, EF-hand domain proteins, aerobic energy metabolism, anticoagulant/lipid-binding, haem detoxification, iron transport, EV biogenesis-related, vesicle-trafficking and other cytoskeletal-related proteins. Several identified proteins, such as leucyl and alanyl aminopeptidases, calpain, ferritin, dynein light chain, 14–3–3, heat shock protein 70, annexin, tubulin, glutathione S-transferase, superoxide dismutase, enolase and fructose-bisphosphate aldolase, have already been proposed as target candidates for therapeutic or prophylactic purposes.ConclusionsWe have unambiguously demonstrated for the first time to our knowledge the secretion of EVs by an ectoparasitic flatworm, inferring their biogenesis machinery at a genomic and transcriptomic level, and by identifying their location and protein composition. The identification of multiple therapeutic targets among EVs' protein repertoire provides opportunities for target-based drug discovery and vaccine development for the first time in Polyopisthocotyla (sensu Monogenea), and in a fish-ectoparasite model.Graphical

How do research participants with age-related vision loss talk about their experiences? A secondary discourse analysis of published qualitative extracts

Abstract Age-related macular degeneration (AMD) is a chronic, progressive eye condition that can affect individuals in later life and lead to loss of central visual function. In this analysis, we aimed to explore the discursive landscape of talk about AMD, drawing on extracts published in peer-reviewed qualitative studies on AMD. Drawing on procedures of qualitative meta-synthesis, we compiled a corpus of raw data extracts from 25 qualitative studies on AMD published in English, largely carried out in high-income countries. Extracts were analysed to identify dominant discourses and key interpretative repertoires (such as recurring metaphors, tropes and figures of speech). We adopted a Foucauldian discourse analytic approach, to consider the implications of dominant discourses, and their associated subject positions, for the subjective experience of living with AMD. Our analysis identified five distinct ways in which AMD was constructed in research participants' talk about experiences of AMD. They included: AMD as a mysterious affliction, linked to biological ageing; AMD as a total loss of independence; AMD as grievous loss; AMD as a condition to be stoically accepted; and – to a more limited extent – AMD as an opportunity for discovery. Drawing on theory from critical disability studies and gerontology, we suggest that the constructions identified are underpinned by broader societal discourses which construct ageing and disability in largely negative, medicalised and individualistic terms. Taking up subject positions within such discourses may compound feelings of isolation, hopelessness and powerlessness. We suggest there may be value in exploring talk about experiences of living with AMD within a broader range of everyday social, relational and environmental contexts.

Science as exploration in a knowledge landscape: tracing hotspots or seeking opportunity?

The selection of research topics by scientists can be viewed as an exploration process conducted by individuals with cognitive limitations traversing a complex cognitive landscape influenced by both individual and social factors. While existing theoretical investigations have provided valuable insights, the intricate and multifaceted nature of modern science hinders the implementation of empirical experiments. This study leverages advancements in Geographic Information System (GIS) techniques to investigate the patterns and dynamic mechanisms of topic-transition among scientists. By constructing the knowledge space across 6 large-scale disciplines, we depict the trajectories of scientists’ topic transitions within this space, measuring the flow and distance of research regions across different sub-spaces. Our findings reveal a predominantly conservative pattern of topic transition at the individual level, with scientists primarily exploring local knowledge spaces. Furthermore, simulation modeling analysis identifies research intensity, driven by the concentration of scientists within a specific region, as the key facilitator of topic transition. Conversely, the knowledge distance between fields serves as a significant barrier to exploration. Notably, despite potential opportunities for breakthrough discoveries at the intersection of subfields, empirical evidence suggests that these opportunities do not exert a strong pull on scientists, leading them to favor familiar research areas. Our study provides valuable insights into the exploration dynamics of scientific knowledge production, highlighting the influence of individual cognition, social factors, and the intrinsic structure of the knowledge landscape itself. These findings offer a framework for understanding and potentially shaping the course of scientific progress.

318 Profiling Long RNA Transcriptome From Circulating Extracellular Vesicles in Subarachnoid Hemorrhage for Biomarker Discovery

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with a high mortality rate and permanent neurological deficits following acute brain injury. Previous studies have aimed at investigating CNS specific biomarkers that can predict the outcomes following aSAH. Liquid biopsy represents a promising minimally invasive approach for biomarker discovery using biofluids (plasma, CSF). METHODS: CSF was collected from patients (n = 10) during in-hospital stay at multiple time points via the external ventricular drain and EV RNA was sequenced using Oxford Nanopore Technologies. RESULTS: We detected different biotypes in EV RNA with minimal rRNA contamination (protein coding; 58.4%, pseudogene; 23.1%, LncRNA; 10%, rRNA; 1.7%). This is the first study reporting presence of long (>500 bp) RNA transcripts in CSF derived EVs. Approximately, 80% of the sequenced reads were up to 500 bp long and 20% reads 500-10,000 bp long. Principal Component Analysis demonstrated distinct clustering of samples based on location (anterior vs. posterior circulation) and type of aneurysm (saccular, dissecting, bilobed). A set of protein coding genes (S100A9, EEF1A1, SCARNA1, DMTN) were found to be differentially enriched in patients who developed cerebral vasospasm (n = 6). Furthermore, for each patient there was a unique population of biomarkers upregulated in acute (HBB, COX2) vs. chronic (SEPTIN7, PDK4) immune response following aSAH. Preliminary findings reveal potential candidate biomarkers providing insight into the pathogenesis and prognosis. CONCLUSIONS: There is an unmet need for inclusion of diagnostic and predictive biomarkers in clinical management of aSAH to decrease the overall mortality. In this study, we overcame challenges of analyzing low input RNA using a sensitive and optimized sequencing platform. Validation and testing in a larger study population offers new opportunities for biomarker discovery.

Alpha-amylase and Alpha-glucosidase Inhibitory Activities of Philippine Indigenous Medicinal Plants

In the Philippines, medicinal plants still provide the first line of therapeutic remedies and their reported efficacy in traditional treatments provides an opportunity for drug discovery and development. The study aimed to evaluate in vitro commonly used Philippine medicinal plants for their alpha-amylase and alpha-glucosidase inhibitory activities as potential sources of antidiabetic agents. The study emphasised the inhibitory activities of 54 medicinal plants against α-amylase and α-glucosidase enzymes. The findings revealed 7 medicinal plants with the highest alpha-glucosidase inhibitory activity of ≥ 50% and 3 with alpha-amylase inhibitory activity of ≥ 20%. Ethyl acetate extract of Cycas sp. exhibited the highest α-glucosidase inhibitory activity with 83.87% ± 1.52 followed by the aqueous extract of cf. Calyptranthera sp. With 82.07% ± 0.14 with Acarbose as the reference standard (99.71% ± 0.63) at 10µg/mL (w/v) concentration. For the alpha-amylase inhibitory assay, the highest bioactivity was observed in ethyl acetate extract of Curcuma longa L. (39.44% ± 1.56) with Acarbose as the reference standard (51.59% ± 0.98) at 10µg/mL (w/v) concentration. These findings suggest the potential of the above-mentioned plants as sources of alpha-amylase and alpha-glucosidase inhibitors that may be used as antidiabetic agents.

Autonomous closed-loop mechanistic investigation of molecular electrochemistry via automation

Electrochemical research often requires stringent combinations of experimental parameters that are demanding to manually locate. Recent advances in automated instrumentation and machine-learning algorithms unlock the possibility for accelerated studies of electrochemical fundamentals via high-throughput, online decision-making. Here we report an autonomous electrochemical platform that implements an adaptive, closed-loop workflow for mechanistic investigation of molecular electrochemistry. As a proof-of-concept, this platform autonomously identifies and investigates an EC mechanism, an interfacial electron transfer (E step) followed by a solution reaction (C step), for cobalt tetraphenylporphyrin exposed to a library of organohalide electrophiles. The generally applicable workflow accurately discerns the EC mechanism’s presence amid negative controls and outliers, adaptively designs desired experimental conditions, and quantitatively extracts kinetic information of the C step spanning over 7 orders of magnitude, from which mechanistic insights into oxidative addition pathways are gained. This work opens opportunities for autonomous mechanistic discoveries in self-driving electrochemistry laboratories without manual intervention.

Internationalisation Process of A Coffee Producer: Born Global and Effectuation Logic

The entrepreneurial process of young exporters in the coffee industry in Indonesia lacks investigation. This study examines how a young company in the coffee industry is able to enter international markets early and rapidly since its inception called a born global company. Effectuation theory was employed to understand how entrepreneurs in the coffee industry made decisions and behaved in pursuing international opportunities. Data was collected through an exploratory case study of a born global firm in the coffee industry in Aceh, Sumatra, Indonesia by doing a semi-structured interview with the CEO of a co-operative. The study's findings revealed that a born global company applied the effectuation logic both in the new venture creation and in the early stage of the internationalisation process. According to the effectuation theory, the entrepreneur's network of domestic partners and prior experience allowed the business to quickly join the international market. The results showed that serendipity discovery was a key factor that enabled early internationalisation to occur. Moreover, serendipity discovery played a role as a base of a cognitive source of opportunity discovery and entrepreneurial acquisition of knowledge of international opportunities.

FORECASTOR. I. Finding Optics Requirements and Exposure Times for the Cosmological Advanced Survey Telescope for Optical and UV Research Mission

The Cosmological Advanced Survey Telescope for Optical and ultraviolet Research (CASTOR) is a proposed Canadian-led 1 m class space telescope that will carry out ultraviolet and blue optical wide-field imaging, spectroscopy, and photometry. CASTOR will provide an essential bridge in the post-Hubble era, preventing a protracted UV-optical gap in space astronomy and enabling an enormous range of discovery opportunities from the solar system to the nature of the cosmos, in conjunction with the other great wide-field observatories of the next decade (e.g., Euclid, Roman, Vera Rubin). FORECASTOR (Finding Optics Requirements and Exposure times for CASTOR) will supply a coordinated suite of mission-planning tools that will serve as the one-stop shop for proposal preparation, data reduction, and analysis for the CASTOR mission. We present the first of these tools: a pixel-based, user-friendly, extensible, multi-mission exposure time calculator built in Python, including a modern browser-based graphical user interface that updates in real time. We then provide several illustrative examples of FORECASTOR’s use that advance the design of planned legacy surveys for the CASTOR mission: a search for the most massive white dwarfs in the Magellanic Clouds, a study of the frequency of flaring activity in M stars and their distribution and impacts on habitability of exoplanets, mapping the proper motions of faint stars in the Milky Way, wide and deep galaxy surveys, and time-domain studies of active galactic nuclei.

Metabolism and physiology of pathogenic bacterial obligate intracellular parasites.

Bacterial obligate intracellular parasites (BOIPs) represent an exclusive group of bacterial pathogens that all depend on invasion of a eukaryotic host cell to reproduce. BOIPs are characterized by extensive adaptation to their respective replication niches, regardless of whether they replicate within the host cell cytoplasm or within specialized replication vacuoles. Genome reduction is also a hallmark of BOIPs that likely reflects streamlining of metabolic processes to reduce the need for de novo biosynthesis of energetically costly metabolic intermediates. Despite shared characteristics in lifestyle, BOIPs show considerable diversity in nutrient requirements, metabolic capabilities, and general physiology. In this review, we compare metabolic and physiological processes of prominent pathogenic BOIPs with special emphasis on carbon, energy, and amino acid metabolism. Recent advances are discussed in the context of historical views and opportunities for discovery.

Abstract 6765: A patient-derived hepatocellular carcinoma multicellular spheroid platform harnessing autologous patient serum to model the tumor microenvironment and treatment response

Abstract Hepatocellular carcinoma (HCC) is the third leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC is hampered by the absence of authentic tractable systems recapitulating the heterogeneity of patient HCC tumors and the tumor microenvironment (TME). Here, we established a novel, simple and robust patient-derived multicellular tumorspheroid model based on clinical HCC tumor tissues combined with the autologous patient serum. The model was robust and reproducible independently from cancer etiology and grade recapitulating key functional features of original tissue. We show that the use of autologous patient serum was essential for the TME function. The tumorspheroids comprised the main cell compartments including epithelial cancer cells as well as all major cell populations of the TME (cancer-associated fibroblasts, macrophages and T cells). Cell type proportions were variable between tumorspheroids reflecting HCC heterogeneity. Moreover, we observed differential responses to FDA HCC approved drugs (including tyrosine kinase and checkpoint inhibitors as well as VEGF-targeting agents) between donors as in patients. This patient HCC serum-tumorspheroid model provides novel opportunities for drug discovery and development as well mechanism of action studies including compounds targeting the TME. In conclusion, this HCC serum-tumorspheroid platform will contribute to improve the dismal outcome of patients with HCC. Citation Format: Emilie Crouchet, Nuno Almeida, Sarah C. Durand, Marie Parnot, Marine A. Oudot, Fabio Giannone, Cloé Gadenne, Sara Cherradi, Natascha Roehlen, Antonio Saviano, Emanuele Emanuele Felli, Patrick Pessaux, Kazuaki Chayama, Hong Tuan F. Duong, Thomas F. Baumert, Catherine Schuster. A patient-derived hepatocellular carcinoma multicellular spheroid platform harnessing autologous patient serum to model the tumor microenvironment and treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6765.

FUTURE RESEARCH DIRECTIONS IN THE PARTIAL OXIDATION OF METHANE TO METHANOL OVER COPPER‐CONTAINING ZEOLITES

The direct partial oxidation of methane to methanol is a potentially transformative approach to upgrading methane to higher value molecules. Copper‐exchanged zeolites show potential to achieve this aim and have been extensively reported and reviewed in the open literature. This concept paper highlights selected works that point to knowledge gaps in this space, which opens opportunities for further breakthroughs. Specifically, these literature reports highlight the need for 1) additional research exploring how reactor operating conditions (space velocity, feed composition, temperature) can be optimized to improve methanol selectivity, 2) developing a better understanding of how the zeolite topology impacts the reactivity of methane, and 3) how different methods of loading copper into the zeolite impact reactivity.

An economical, high-throughput protein-protein interaction modulator drug screening technique based on surface-enhanced Raman scattering

Increasing identification of protein-protein interaction (PPI) targets creates opportunities for drug discovery. However, the current drug screening strategies are costly and reagent-consuming, which hinders the progress in PPI modulator drug discovery. The primary obstacle lies in the inability to achieve molecular fishing with existing technology. Herein, we present a novel high-throughput, homogeneous-phase screening assay for PPI modulator discovery called “SERScreen”, based on a magnetic field-amplified surface-enhanced Raman spectroscopy (SERS). Two high-affinity proteins are fixed respectively on the magnetic beads (MBs) and the SERS tags, and the cross-linking of two nanoprobes induced by PPI enables strong SERS signals. Candidate modulators interfere with the PPI according to higher affinity toward one protein, resulting in a significant reduction in SERS intensity above the MBs. We established a potential drug screening platform for PD-1/PD-L1, and demonstrated its feasiblility not only with known inhibitors (Durvalumab and BMS-202), but also with a small-molecule combinatorial library, successfully identifying two new candidate inhibitors via the molecular fishing of SERScreen. Furthermore, the anticancer mechanism of two candidates was discussed. As an ultrasensitive, low reagent consumption (2 µL sample solution), high-throughput screening technique in the PPI modulator discovery, SERScreen offers an effective solution for molecular fishing from complex samples and displays high compatibility with automatic measurement equipment.

An overview of aptamer: Design strategy, prominent applications, and potential challenge in plants

Aptamers, serving as highly efficient molecular recognition and biotechnology tools, have garnered increasing interest in the realm of plant science in recent years. Aptamers are synthetic single-stranded short nucleotides or peptides, that bind targets with high specificity and affinity, triggering precise biological responses. As an alternative to antibodies, aptamers present promising avenues for advancement in biological researches. Aptamers function in a range of fields, encompassing cell signaling, drug development, biosensor technology, as well as botany, agricultural and forestry sciences. In this review, we introduce classifications and screening methods of aptamers, as well as aptamer-based technologies, highlighting their significant contributions to recent advancements. With their powerful functionality and ability to bind targets with high specificity and affinity, aptamers offer promising opportunities for breakthroughs in plant research.

Breast and bowel cancers diagnosed in people 'too young to have cancer': A blueprint for research using family and twin studies.

Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID(Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

Identification of gene regulatory networks affected across drug-resistant epilepsies

Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies). This systematic comparison characterized the global molecular signature of epilepsies, elucidating the key underlying mechanisms of disease pathology including neurotransmission and synaptic plasticity, brain extracellular matrix and energy metabolism. In addition, specific dysregulations in neuroinflammation and oligodendrocyte function were observed in TLE-HS and mTORopathies, respectively. The aforementioned mechanisms are proposed as molecular hallmarks of DRE with the identified upstream regulators offering opportunities for drug-target discovery and development.