Interconnected Pathways Research Articles

Flexible 3D‐Printed Cellulosic Constructs for EMI Shielding and Piezoresistive Sensing

AbstractAdvances in materials science and sustainability have positioned cellulose nanofibers (CNFs) as an important nanomaterial for creating complex 3D architectures through 3D printing techniques. However, the inherent limitations of 3D‐printed CNF‐based materials, such as poor electrical conductivity and restricted mechanical flexibility, pose barriers to their application in next‐generation electronics. The research addresses these challenges by integrating CNF‐based 3D printed frameworks with a conductive polymer via a process known as “cold chemical vapor polymerization” (CCVP). The procedure initiates with the direct ink writing (DIW) of the CNF hydrogel, which then undergoes saturation with Fe3+ ions and freeze‐drying to produce ion‐embedded CNF frameworks. Subsequently, interconnected conductive pathways of poly(3,4‐ethylenedioxythiophene) (PEDOT) are generated within these structures using CCVP. This methodology allows for precise customization of electrical conductivity, resulting in the production of highly conductive (546 S m−1) and mechanically flexible (70% compressible) patterned constructs. This advancement is highlighted by the development of grid‐based structures designed for electromagnetic interference (EMI) shields. These innovative shields demonstrate an absorbance of 0.71 and a specific EMI shielding effectiveness of 3406.45 dB cm2 g−1. Furthermore, these aerogels function as highly sensitive piezoresistive sensors, demonstrating the versatility of this sustainable approach for advancing wearable electronics and multifunctional technologies.

Multifaceted Actions of Neurosteroids.

Neurosteroids modulate neuronal function and are promising therapeutic agents for neuropsychiatric disorders. Neurosteroid analogues are approved for treating postpartum depression and are of interest in other disorders. GABA-A receptors are well characterized targets of natural neurosteroids, but other biological pathways are likely relevant to therapeutic mechanisms and/or to off-target effects. We performed hypothesis-generating in silico analyses and broad in vitro biological screens to assess the range of actions of neurosteroids analogues of varying structural attributes. We employed in silico molecular similarity analysis and network pharmacology to elucidate likely targets. This analysis confirmed likely targets beyond GABA-A receptors. We then functionally screened 19 distinct neurosteroid structures across 78 targets representing interconnected signaling pathways, complemented with a limited screen of kinase activation. Results revealed unanticipated modulation of targets by neurosteroids with some structural selectivity. Many compounds-initiated androgen receptor translocation with little or no enantioselectivity. Modulation of multiple G-protein receptors was also unexpected. Neurosteroids are ascendant treatments in neuropsychiatry, but their full spectrum of actions remains unclear. This virtual and biological screening discovery approach opens new vistas for exploring mechanism of neurosteroids analogues. The multifaceted approach provides an unbiased, holistic exploration of the potential effects of neurosteroids across various molecular targets and provides a platform for future validation studies to aid drug discovery.

Cu‐Driven Active Cu2Se@MXene Heterointerface Reconstruction and Co Electron Reservoir Toward Superior Sodium Storage

AbstractHeterostructure engineering and active component reconstruction are effective strategies for efficient and rapid charge storage in advanced sodium‐ion batteries (SIBs). Herein, sandwich‐type CoSe2@MXene composites are used as a model to reconstruct new active Cu2Se@MXene heterostructures by in situ electrochemical driving. The MXene core provides interconnected pathways for electron and ion conduction, while also buffering volumetric expansion to stabilize the structure. This reconstructed Cu2Se@MXene heterointerface features abundant sodium storage active sites, enhanced Na+ adsorption, and diffusion kinetics, thus increasing sodium storage capacity. Moreover, the elevated Co valence state during the discharge process allows it to act as an electron reservoir to provide additional electron supply for Cu2Se conversion and accelerate the sodium storage kinetics. When employed as an anode in SIBs, the CoSe2@MXene electrode exhibits high capacity (694 mAh g−1 at 0.1 A g−1), excellent rate performance (425 mAh g−1 at 20 A g−1), and exceptional durability (437 mAh g−1 after 10 000 cycles at 5 A g−1 with a 0.0014% capacity decay per cycle). The electrochemical reconstruction and sodium storage mechanism of Cu2Se@MXene anode is further revealed through ex situ characterization and theoretical calculations. This work provides a new approach for designing advanced conversion‐type anodes for SIBs.

Unraveling the molecular complexity of bicuspid aortopathy: Lessons from comparative proteomics.

Molecular markers and pathways involved in the etiology and pathophysiology of bicuspid aortopathy are poorly understood. The aim here is to delve into the molecular and cellular mechanisms of the disease and identify potential predictive molecular markers using a well-established isogenic hamster model (T-strain) of bicuspid aortic valve (BAV) and thoracic aortic dilatation (TAD). We carried out comparative quantitative proteomics combined with western blot and morpho-molecular analyses in the ascending aorta of tricuspid aortic valve (TAV) and BAV animals from the T-strain, and TAV animals from a control strain. This strategy allows discriminating between genetic and hemodynamic factors in genetically homogeneous populations. The major molecular alteration in the aorta of genetically homogeneous BAV individuals is PI3K/AKT overactivation caused by changes in the EGF, ANGII and TGF-β pathways. PI3K/AKT affects downstream eNOS, MAP2K1/2, NF-κB, mTOR and WNT pathways. Most of these alterations are seen in independent patient studies with different clinical presentations, but not in TAV hamsters from T-strain that mainly exhibit WNT pathway downregulation. Therefore, we identify a combination of defective interconnected molecular pathways, directly linked to the central PI3K/AKT pathway, common to both BAV-associated TAD patients and hamsters. The defects indicate smooth muscle cell shift towards the synthetic phenotype induced by endothelial-to-mesenchymal transition, oxidative stress and inflammation. WNT signaling represent one genetic factor that may cause structural aortic abnormalities and aneurysm predisposition, whereas hemodynamics is the main trigger of molecular alterations, probably determining aortopathy progression. We identify twenty-seven novel potential biomarkers with a high predictive value.

Quantitative analysis of the polar cod (Boreogadus saida) hepatic proteome highlights interconnected responses in cellular adaptation and defence mechanisms after dietary benzo[a]pyrene exposure.

Increased industrial offshore activities in northern waters raise the question of impact of polycyclic aromatic hydrocarbons (PAHs) on key Arctic marine species. One of these is the ecologically important polar cod (Boreogadus saida), which is the primary food source for Arctic marine mammals and seabirds. In the present work, we have conducted the first comprehensive proteomics study with this species by exploring the effects of dietary PAH exposure on the hepatic proteome, using benzo[a]pyrene (BaP) as a PAH model-compound. Functional annotation and pathway analyses of the proteins affected by BaP revealed a concerted cellular response for handling and adopting to its exposure, involving numerous interconnected signalling pathways and metabolic processes. In accordance with BaP being a strong aryl hydrocarbon receptor (Ahr) agonist, a prominent activation of the canonical Ahr signalling pathway was observed, including upregulation of Ahr target proteins like cytochrome P450 enzymes and microsomal glutathione transferase. Furthermore, cellular pathways for handling oxidative stress, protein misfolding and degradation, as well as endoplasmic reticulum stress and calcium homeostasis, were also activated by BaP, possibly as a result of the formation of harmful and redox reactive BaP metabolites via phase I metabolism. Activation of proteins that participate in the acute-phase response was also observed, suggesting prevalent tissue- and cellular damage that triggers the immune system and inflammatory responses. Our results at the protein level aligns well with previous analyses on the effects of BaP on the polar cod liver transcriptome and support that exposure to BaP and structural similar PAHs can cause adverse effects on polar cod physiology. Although more data is required for demonstrating how these molecular responses propagate to higher levels of biological organisation, increased knowledge about the initial cellular and molecular mechanisms that induce toxicity is a key-step towards a mechanistically informed impact assessment of PAH pollutants in the Arctic.

Elusive modes of Foxp3 activity in versatile regulatory T cells.

Foxp3-expressing CD4 regulatory T (Treg) cells play a crucial role in suppressing autoimmunity, tolerating food antigens and commensal microbiota, and maintaining tissue integrity. These multifaceted functions are guided by environmental cues through interconnected signaling pathways. Traditionally, Treg fate and function were believed to be statically determined by the forkhead box protein Foxp3 that directly binds to DNA. However, this model has not been rigorously tested in physiological and pathological conditions where Treg cells adapt their function in response to environmental cues, raising questions about the contribution of Foxp3-dependent gene regulation to their versatility. Recent research indicates that Foxp3 primarily functions as a transcriptional cofactor, whose chromatin interaction is influenced by other DNA-binding proteins that respond to cell activation, stimulation, or differentiation. This new perspective offers an opportunity to reevaluate Foxp3's activity modes in diverse biological contexts. By exploring this paradigm, we aim to unravel the fundamental principles of Treg cell biology.

Recent Advances in the Mechanisms of Postoperative Neurocognitive Dysfunction: A Narrative Review.

Postoperative neurocognitive dysfunction (PND) is a prevalent and debilitating complication in elderly surgical patients, characterized by persistent cognitive decline that negatively affects recovery and quality of life. As the aging population grows, the rising number of elderly surgical patients has made PND an urgent clinical challenge. Despite increasing research efforts, the pathophysiological mechanisms underlying PND remain inadequately characterized, underscoring the need for a more integrated framework to guide targeted interventions. To better understand the molecular mechanisms and therapeutic targets of PND, this narrative review synthesized evidence from peer-reviewed studies, identified through comprehensive searches of PubMed, Embase, Cochrane Library, and Web of Science. Key findings highlight neuroinflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalances, microvascular changes, and white matter lesions as central to PND pathophysiology, with particular parallels to encephalocele- and sepsis-associated cognitive impairments. Among these, neuroinflammation, mediated by pathways such as the NLRP3 inflammasome and blood-brain barrier disruption, emerges as a pivotal driver, triggering cascades that exacerbate neuronal injury. Oxidative stress and mitochondrial dysfunction synergistically amplify these effects, while neurotransmitter imbalances and microvascular alterations, including white matter lesions, contribute to synaptic dysfunction and cognitive decline. Anesthetic agents modulate these interconnected pathways, exhibiting both protective and detrimental effects. Propofol and dexmedetomidine demonstrate neuroprotective properties by suppressing neuroinflammation and microglial activation, whereas inhalational anesthetics like sevoflurane intensify oxidative stress and inflammatory responses. Ketamine, with its anti-inflammatory potential, offers promise but requires further evaluation to determine its long-term safety and efficacy. By bridging molecular insights with clinical practice, this review highlights the critical role of personalized anesthetic strategies in mitigating PND and improving cognitive recovery in elderly surgical patients. It aims to inform future research and clinical decision-making to address this multifaceted challenge.

Ferroptosis and PANoptosis under hypoxia pivoting on the crosstalk between DHODH and GPX4 in corneal epithelium.

Cell death under stress conditions like hypoxia, involves multiple interconnected pathways. In this study, a stable dihydroorotate dehydrogenase (DHODH) knockdown human corneal epithelial cell line was established to explore the regulation of hypoxic cell death, which was mitigated by various cell death inhibitors, particularly by a lipid peroxyl radical scavenger liproxstatin-1 (Lip-1), suggesting that hypoxic cell death involves crosstalk of ferroptosis and PANoptosis. We discovered that both DHODH and Glutathione peroxidase 4 (GPX4) protected cells from hypoxic death by inhibiting lipid peroxidation, mitochondrial reactive oxygen species (ROS) and maintaining mitochondrial membrane potential. However, upregulation of DHODH suppressed GPX4 upstream, exhibiting a trade-off in the expression levels between DHODH and GPX4 under hypoxia, with DHODH exerting a more decisive impact on cell survival. DHODH knockdown under hypoxia did not significantly alter lipid peroxidation levels, demonstrating the balance between DHODH and GPX4 expression finely regulated cellular ferroptosis homeostasis. This study highlights the complex interplay between ferroptosis and PANoptosis in hypoxic cell death, particularly the dual role of DHODH in regulating both pathways. DHODH is not merely maintaining the quantity of mitochondria but is promoting the selection of mitochondria favorable to cell survival. These findings not only deepen our understanding of cell death but also suggest potential therapeutic strategies for diseases involving oxidative stress and mitochondrial dysfunction.

Multi-omics profiling reveals altered mitochondrial metabolism in adipose tissue from patients with metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH. We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n=100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples. Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC=0.919, 95% CI 0.840-0.979) for screening MASH. Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses. The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

Energy transition and bioeconomy: an integrated review of interconnected pathways to sustainable development

This review examines the pivotal interaction between the energy transition and the bioeconomy, underscoring their pivotal role in mitigating climate change, resource limitations, and socioeconomic disparities. The study aims to map the evolution of ETBE research, identifying key themes, regions, and scholarly contributions driving progress in these fields. Using a bibliometric and systematic elements review approach, the study analyzes trends, collaborations, and thematic clusters from 2000 to 2023. The findings reveal exponential growth in ETBE research, with distinct thematic focuses on policy, technology, socio-economic impacts, and sustainability. Four major thematic clusters are identified: policy and economy, societal and environmental implications of energy transitions, energy systems and technologies, market dynamics, and strategic planning. The analysis underscores the global collaboration between leading nations like the United States, China, and Germany, which play pivotal roles in advancing ETBE research and innovation. While energy transition dominates the discourse, the integration with bioeconomy still needs to be explored, accounting for only 14% of the reviewed studies. This highlights the need for greater synergy between renewable energy technologies and bio-based solutions to achieve holistic sustainability goals. The review concludes that fostering inclusive collaborations, prioritizing equity, and aligning renewable energy with bioeconomic strategies are essential for achieving a low-carbon, sustainable future. The study provides a roadmap for future research and policy, emphasizing the critical importance of interdisciplinary and international efforts in shaping the global energy transition and bioeconomy landscape.

To be or not to be manipulated by our bacteria?

The gut microbiota has become a central focus of research since its intricate connection with the brain was identified. Notably, the gut microbiota can influence mental health, opening new prospects for improving the management of psychiatric disorders. Understanding the bidirectional interactions between the brain, gut, and microbiome is crucial for evaluating the true impact of gut microbiota on mental health and its subsequent implications for psychiatry. Currently, the brain-gut-microbiome axis communicates through five interconnected pathways: the immune system, the vagus nerve, the enteric nervous system, the neuroendocrine system, and the circulatory system. The development of microbiota-based therapeutics signals significant changes in current clinical practices. Furthermore, microbiome-based therapeutics are expected to undergo substantial regulatory transformations in Europe in the coming years. This mini-review aims to explore these aspects to evaluate the potential of gut bacteria to shape mental health interventions.

Expression of LncRNAs in anterior capsule of lens in patients with pathologic myopia complicated with cataract.

To explore the expressions and functions of lncRNAs in the pathogenesis of pathologic myopia complicated with cataract (PMC). The anterior capsular tissues were collected from patients with age-related cataract (ARC) and PMC. One group of the samples was used to detected by whole-transcriptome sequencing (LC-Bio, Hangzhou, China) and investigated by GO and KEGG enrichment analysis. We selected the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), predicted the miRNAs with gene binding sites to it and the downstream mRNAs with gene binding sites to miRNAs through the Starbase and Targetscan websites. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the other group to further preliminarily validate the prediction. A total of 471 lncRNAs were significantly differential expressed in PMC group compared with ARC group, in which 231 lncRNAs were up-regulated, including MALAT1, and 240 lncRNAs were down-regulated. GO and KEGG enrichment analysis showed that lncRNAs targeted differential mRNAs were involved in various biological functions, cell components, molecular functions and signaling pathways. Taking MALAT1 as an example, we predicted that it had binding sites with 113 miRNAs such as hsa-miR-20a-5p, has-miR-20b-5p, hsa-miR-26a-5p, has-miR-106-5p and hsa-miR-204-5p, which were lower in PMC group than these in ARC group. Inversely, the downstream mRNAs of the above miRNAs, such as MMP9, TNF-α, TGF-β2, NF-KB, IL6 and Smad4 were higher. The differentially expressed lncRNAs, especially MALAT1, may act as ceRNA via sponging miRNAs and to regulate the targeting downstream mRNAs in development of PMC and participate in numerous biological processes through interconnected signaling pathways.

Unmasking the Invisible Threat: Biological Impacts and Mechanisms of Polystyrene Nanoplastics on Cells

Polystyrene nanoplastics (PS-NPs), a pervasive component of plastic pollution, have emerged as a significant environmental and health threat due to their microscopic size and bioaccumulative properties. This review systematically explores the biological effects and mechanisms of PS-NPs on cellular systems, encompassing oxidative stress, mitochondrial dysfunction, DNA damage, inflammation, and disruptions in autophagy. Notably, PS-NPs induce multiple forms of cell death, including apoptosis, ferroptosis, necroptosis, and pyroptosis, mediated through distinct yet interconnected molecular pathways. The review also highlights various factors that influence the cytotoxicity of PS-NPs, such as particle size, surface modifications, co-exposure with other pollutants, and protein corona formation. These complex interactions underscore the extensive and potentially hazardous impacts of PS-NPs on cellular health. The findings presented here emphasize the need for continued research on the mechanisms underlying PS-NP toxicity and the development of effective strategies for mitigating their effects, thereby informing regulatory frameworks aimed at minimizing environmental and biological risks.

Preparation of liquid metal/thermoplastic polyurethane composites with enhanced thermal conductivity via rolling regulation

Abstract This work reports a method for preparing liquid metal/thermoplastic polyurethane (LM/TPU) elastic composite materials through melt blending, and enhancing the thermal conductivity of the composites using a rolling regulation process. Through observation of the microstructure of the composite material, it is found that the vane mixer can effectively disperse LM uniformly, which leads to a significant enhancement in thermal conductivity from 0.21 W m−1 K−1 of pure TPU to 2.12 W m−1 K−1 for composite with 50 vol % LM. After rolling regulation, SEM images reveal the formation of interconnected thermal conduction pathways within the composites. The thermal conductivity of the composite material with 30 vol % LM increases from 1.74 W m−1 K−1 to 2.50 W m−1 K−1, which is higher than the pre-regulation thermal conductivity of the composite with 50 vol % LM. Moreover, the thermal conductivity of the composite material with 50 vol % LM increases even further to 3.16 W m−1 K−1. The rheological behavior of the composite further substantiates the establishment of a network configuration after the rolling regulation that facilitates heat transfer. This implies that the melt blending-rolling regulation process can achieve the fabrication of composite materials with high thermal conductivity, offering a reliable strategy for industrial development of flexible thermal conductive materials.

Pathophysiology, Diagnosis, and Management of Coronary Artery Disease inthe Setting of Atrial Fibrillation.

Atrial fibrillation (AF) and coronary artery disease are frequently associated and, when so, lead to a grim prognosis. Recent studies suggest the presence of interconnected pathophysiological pathways between the 2 conditions that can promote and aggravate each other, igniting a vicious cycle. Notwithstanding, in contrast with the attention dedicated to the management of antithrombotic treatment, research on other aspects of coronary artery disease in AF is only recently gaining traction. The clinical impact of correct assessment of coronary artery stenosis in AF is especially high, due to the antithrombotic therapy imposed by both AF and coronary stenting. Until recently, an in-depth characterization of coronary microcirculation in AF was lacking. However, contemporary studies indicate that coronary microvascular dysfunction is a frequent encounter in AF, possibly explaining the ischemic symptoms even in the absence of obstructive coronary artery disease and interfering with the use of pressure-based indices to evaluate the hemodynamic significance of coronary artery stenosis. This comprehensive review addresses our current knowledge on coronary physiology in AF and its repercussion on the invasive management of coronary artery disease in this setting.

Differential tumor protein expression at follicular lymphoma diagnosis reveals dysregulation of key molecular pathways associated with histological transformation

Follicular lymphoma (FL) is the most common low-grade lymphoma. Despite its indolent nature, FL carries an inherent risk of histological transformation (HT) to a more aggressive lymphoma. Existing biomarkers are insufficient to predict HT, indicating the need for more robust biological predictors. Previously, we used mass spectrometry-based proteomics to identify differentially expressed proteins in diagnostic FLs with and without subsequent HT. This study sought to further investigate identified proteins in transformation of FL, generally acting in important cellular pathways such as (i) apoptosis (BID), (ii) cell cycle (CDC26, CDK6, SRSF1, SRSF2), (iii) GTPase signaling (IQGAP2, MEK1), (iv) cytoskeletal rearrangement and cellular migration (ACTB, CD11a, MMP9, SEPT6), and (v) immune processes (CD81, IgG, MPO, PIK3AP1). We analyzed pre-therapeutic samples from 48 FL patients, either non-transforming FL (nt-FL, n = 30) or subsequently-transforming FL (st-FL, n = 18), the latter with histologically-confirmed transformation after their initial FL diagnosis. Paired high-grade lymphomas (tFL, n = 18) from the time of transformation were also analyzed. We used immunohistochemistry and digital image analysis to quantify protein levels. In all five pathway classes, several proteins were differentially expressed between either the diagnostic nt-FL and st-FL samples, or between the paired st-FL and tFL samples (p < 0.05). Interestingly, we found correlation between expression levels of several proteins, indicating a complex involvement between several pathways. Differential expression of most proteins was also associated with shorter transformation-free survival (p < 0.05). These findings emphasize underlying differences in FL biology predictive of subsequent transformation, highlighting deregulation of important interconnected cellular pathways.

Obesity and Depression: Common Link and Possible Targets.

Depression is among the main causes of disability, and its protracted manifestations could make it even harder to treat metabolic diseases. Obesity is linked to episodes of depression, which is closely correlated to abdominal adiposity and impaired food quality. The present review is aimed at studying possible links between obesity and depression along with targets to disrupt it. Research output in Pubmed and Scopus were referred for writing this manuscript. Obesity and depression are related, with the greater propensity of depressed people to gain weight, resulting in poor dietary decisions and a sedentary lifestyle. Adipokines, which include adiponectin, resistin, and leptin are secretory products of the adipose tissue. These adipokines are now being studied to learn more about the connection underlying obesity and depression. Ghrelin, a gut hormone, controls both obesity and depression. Additionally, elevated ghrelin levels result in anxiolytic and antidepressant-like effects. The gut microbiota influences the metabolic functionalities of a person, like caloric processing from indigestible nutritional compounds and storage in fatty tissue, that exposes an individual to obesity, and gut microorganisms might connect to the CNS through interconnecting pathways, including neurological, endocrine, and immunological signalling systems. The alteration of brain activity caused by gut bacteria has been related to depressive episodes. Monoamines, including dopamine, serotonin, and norepinephrine, have been widely believed to have a function in emotions and appetite control. Emotional signals stimulate arcuate neurons in the hypothalamus that are directly implicated in mood regulation and eating. The peptide hormone GLP-1(glucagon-like peptide- 1) seems to have a beneficial role as a medical regulator of defective neuroinflammation, neurogenesis, synaptic dysfunction, and neurotransmitter secretion discrepancy in the depressive brain. The gut microbiota might have its action in mood and cognition regulation, in addition to its traditional involvement in GI function regulation. This review addressed the concept that obesity-related low-grade mild inflammation in the brain contributes to chronic depression and cognitive impairments.

A Comprehensive Review of Pathophysiological Link Between Non-alcoholic Fatty Liver Disease, Insulin Resistance, and Metabolic Syndrome.

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition characterized by hepatic steatosis in the absence of significant alcohol consumption and is increasingly recognized as the hepatic manifestation of metabolic syndrome (MetS). This review aims to explore the molecular mechanisms underlying the interaction between NAFLD, insulin resistance (IR), and MetS, with a focus on identifying therapeutic targets. A comprehensive review of existing literature on NAFLD, IR, and MetS was conducted. The review indicates that IR contributes to hepatic lipid accumulation through increased lipolysis, elevated free fatty acid flux, and impaired fatty acid oxidation, while MetS exacerbates the condition by promoting visceral adiposity, chronic inflammation, and impaired lipid metabolism. Additionally, dysbiosis and increased intestinal permeability in the gut-liver axis worsen IR, leading to a vicious cycle of metabolic dysfunction. In conclusion, addressing these interconnected pathways could enhance therapeutic strategies and reduce the burden of NAFLD-related complications.

White Matter Integrity of Age‐Related Hearing Loss and Cognitive Impairment

AbstractBackgroundEmerging research, underscored by the UK National Institute of Health and Care Excellence and the US National Institutes of Health, suggests that age‐related hearing loss (ARHL) is linked to the development of dementias such as Alzheimer's disease (AD). In this study, we aim to investigate the neural correlates of ARHL and cognitive impairments based on the changes in white matter (WM) microstructures in a population of non‐demented adults.Method129 participants (94 female) aged between 20‐79 years old (Mean = 51.35 ± 20.65) were recruited as part of the Aging Brain Cohort at the University of South Carolina (ABC@UofSC). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Hearing ability was evaluated by measuring pure‐tone thresholds (PTT) and words‐in‐noise (WIN) thresholds. Structural T1 weighted and diffusion tensor imaging (DTI) scans were administered, and data preprocessing was performed with our nii_preprocess automated pipeline, available for public use. Changes in the WM integrity were measured using fractional anisotropy (FA) and mean diffusivity (MD). Finally, we examined the relationship between DTI metrics (FA and MD) and hearing and cognitive performance using region‐of‐interest‐based regression analysis.ResultOur investigation identified a constellation of brain regions where lower FA and higher MD were significantly associated with both poorer auditory and cognitive processing. Specifically, poorer cognitive performance, as reflected by lower MoCA total scores, was associated with lower FA and higher MD values across major interconnecting pathways, including superior longitudinal fasciculus, fornix, corona radiata, and splenium of corpus callosum. Individuals with poorer hearing sensitivity and difficulty in words‐in‐noise recognition showed reduced FA and increased MD in fornix, superior longitudinal fasciculus, optic tract, and corona radiata (anterior and posterior sections).ConclusionOur findings reveal that the integrity of the white matter tracts across multiple brain regions is correlated with both auditory and cognitive performance, suggesting that these tracts may underlie a shared neural substrate for hearing and cognitive processes. The identified brain regions offer promising neural targets for the early detection of ARHL and cognitive impairments, as well as potential neural substrates for applying effective intervention strategies aimed at reducing the risk of dementia.

Expanding the genetic landscape of endometriosis: Integrative -omics analyses uncover key pathways from a multi-ancestry study of over 900,000 women.

We report the findings of a genome-wide association study (GWAS) meta-analysis of endometriosis consisting of a large portion (31%) of non-European samples across 14 biobanks worldwide as part of the Global Biobank Meta-Analysis Initiative (GBMI). We identified 45 significant loci using a wide phenotype definition, seven of which are previously unreported and detected first genome-wide significant locus ( POLR2M ) among only African-ancestry. Our narrow phenotypes and surgically confirmed case definitions for endometriosis analyses replicated the known loci near CDC42 , SKAP1 , and GREB1 . Through this large ancestry stratified analyses, we document heritability estimates in range of 10-12% for all ancestral groups. Thirty-eight loci had at least one variant in the credible set after fine-mapping. An imputed transcriptome-wide association study (TWAS) identified 11 associated genes (two previously unreported), while the proteome-wide association study (PWAS) suggests significant association of R-spondin 3 (RSPO3) with wide endometriosis, which plays a crucial role in modulating the Wnt signaling pathway. Our diverse, comprehensive GWAS, coupled with integrative -omics analysis, identifies critical roles of immunopathogenesis, Wnt signaling, and balance between proliferation, differentiation, and migration of endometrial cells as hallmarks for endometriosis. These interconnected pathways and risk factors underscore a complex, multi-faceted etiology of endometriosis, suggesting multiple targets for precise and effective therapeutic interventions.