Complex Disease Research Articles

The genetic and molecular basis of a connexin-linked skin disease.

Erythrokeratodermia variabilis et progressiva (EKVP) is a rare hereditary skin disorder characterized by hyperkeratotic plaques and erythematous patches that progressively worsen with age. This disorder has been associated with variants in three connexin encoding genes (GJA1, GJB3, GJB4) and four unrelated genes (KRT83, KDSR, TRPM4, PERP). Most cases of connexin-linked EKVP exhibit an autosomal dominant mode of inheritance, with rare autosomal recessive cases. Collectively, evidence suggests that connexin variants associated with EKVP elicit a plethora of molecular defects including impaired gap junction (GJ) formation, dysregulated hemichannel and/or GJ channel function, cytotoxicity, dominant disruption of co-expressed connexins, and/or altered turnover kinetics. Here, we review the progress made in understanding the genetic and molecular basis of EKVP associated with connexin gene variants. We also discuss the landscape of treatment options used for this disorder and the future directions for research into this rare condition.

Exploring the Molecular Interaction Between NR2E3 and NR1D1 in Retinitis Pigmentosa: A Docking and Molecular Dynamics Study

ABSTRACTBackground and AimsRetinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina.MethodsTwenty‐five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole‐exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein–protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants.ResultsOphthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co‐segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In‐depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes.ConclusionExploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP.

MS brain health quality standards: a survey on the reality in clinical practice in Germany

Abstract Background The quality of treatment is especially critical in the context of complex and chronic diseases such as multiple sclerosis (MS). The Brain Health Initiative, an independent international consortium of neurologists, reached a consensus on time-based quality standards prioritizing brain health-focused care for people with MS. Objectives To gain deeper insights into the transferability of these quality standards to a specific area, we conducted a survey among MS experts across various MS centers in Germany. Methods Participants were asked about time frames considered high standards and those currently being implemented in daily routine based on their experience. Results The results reveal a large gap between ideal conceptions and their adaptation in the real world, mostly due to a lack of resources. Conclusions Nevertheless, these guidelines and recommendations can be aspired to as ideals. Consensual and inclusive clinical pathways complemented by measurable quality indicators are needed to improve care and approach these ideals. Neither exists in the current management of MS.

Gain of bipolar disorder-related lncRNA AP1AR-DT in mice induces depressive and anxiety-like behaviors by reducing Negr1-mediated excitatory synaptic transmission

Abstract Background Bipolar disorder is a complex polygenic disorder that is characterized by recurrent episodes of depression and mania, the heterogeneity of which is likely complicated by epigenetic modifications that remain to be elucidated. Methods We performed transcriptomic analysis of peripheral blood RNA from monozygotic (MZ) twins discordant for bipolar disorder to identify disease-associated differentially expressed long noncoding RNAs (DE-lncRNAs), which were further validated in the PsychENCODE brain RNA-seq dataset. We then performed behavioral tests, electrophysiological assays, chromatin immunoprecipitation, and PCR to investigate the function of DE-lncRNAs in the mouse and cell models. Statistical analyses were performed using GraphPad Prism 9.0 or SPSS. Results We identified a bipolar disorder-associated upregulated long non-coding RNA (lncRNA), AP1AR-DT. We observed that overexpression of AP1AR-DT in the mouse medial prefrontal cortex (mPFC) resulted in a reduction of both the total spine density and the spontaneous excitatory postsynaptic current (sEPSC) frequency of mPFC neurons as well as depressive and anxiety-like behaviors. A combination of the results of brain transcriptome analysis of AP1AR-DT overexpressing mice brains with the known genes associated with bipolar disorder revealed that NEGR1, which encodes neuronal growth regulator 1, is one of the AP1AR-DT targets and is reduced in vivo upon gain of AP1AR-DT in mice. We further demonstrated that overexpression of recombinant Negr1 in the mPFC neurons of AP1AR-DTOE mice ameliorates depressive and anxiety-like behaviors and normalizes the reduced excitatory synaptic transmission induced by the gain of AP1AR-DT. We finally identified that AP1AR-DT reduces NEGR1 expression by competing for the transcriptional activator NRF1 in the overlapping binding site of the NEGR1 promoter region. Conclusions The epigenetic and pathophysiological mechanism linking AP1AR-DT to the modulation of depressive and anxiety-like behaviors and excitatory synaptic function provides etiological implications for bipolar disorder.

Parallel Analyses by Mass Spectrometry (MS) and Reverse Phase Protein Array (RPPA) Reveal Complementary Proteomic Profiles in Triple-Negative Breast Cancer (TNBC) Patient Tissues and Cell Cultures.

High-plex proteomic technologies have made substantial contributions to mechanism studies and biomarker discovery in complex diseases, particularly cancer. Despite technological advancements, inherent limitations in individual proteomic approaches persist, impeding the achievement of comprehensive quantitative insights into the proteome. In this study, we employed two widely used proteomic technologies, mass spectrometry (MS) and reverse phase protein array (RPPA) to analyze identical samples, aiming to systematically assess the outcomes and performance of the different technologies. Additionally, we sought to establish an integrated workflow by combining these two proteomic approaches to augment the coverage of protein targets for discovery purposes. We used 14 fresh frozen tissue samples from triple-negative breast cancer (TNBC: seven tumors versus seven adjacent non-cancerous tissues) and cell line samples to evaluate both technologies and implement this dual-proteomic strategy. Using a single-step protein denaturation and extraction protocol, protein samples were subjected to reverse-phase liquid chromatography (LC) followed by electrospray ionization (ESI)-mediated MS/MS for proteomic profiling. Concurrently, identical sample aliquots were analyzed by RPPA for profiling of over 300 proteins and phosphoproteins that are in key signaling pathways or druggable targets in cancer. Both proteomic methods demonstrated the expected ability to differentiate samples by groups, revealing distinct proteomic patterns under various experimental conditions, albeit with minimal overlap in identified targets. Mechanism-based analysis uncovered divergent biological processes identified with the two proteomic technologies, capitalizing on their complementary exploratory potential.

Detection of BRCA-1 gene mutations in epithelial ovarian tumors at tertiary care hospital Karachi

ABSTRACT Background: Ovarian cancer is the most common and lethal gynecological malignancy. Ovarian malignancy is the 3rd most common cancer in Pakistan. More than 90% ovarian cancers are of epithelial cell origin, about 24-40% such cancers have hereditary or sporadic mutation in the BRCA-1 or BRCA-2 genes. The present study was designed to detect BRCA-1 gene mutations in different histological sub-types of epithelial origin of benign, borderline and malignant ovarian tumors. Methods: This cross-sectional study was based on the analysis of BRCA-1 gene mutations in the epithelial origin of benign, borderline and malignant ovarian tumors received at the department of Pathology, Basic Medical Sciences Institute, Jinnah Post graduate Medical Centre, from 01-01-2011 to 31-12-2015. A total of 80 diagnosed cases were selected and analyzed for PCR. Results: BRCA-1 gene mutations were detected in 22 (27.5%) cases out of the 80 randomly selected epithelial ovarian tumors. Serous cyst adenocarcinoma was the commonest including 63% cases. BRCA-1 gene mutations were also positive in other epithelial ovarian tumors, including Mucinous cyst adenocarcinoma (13.6%), Endometroid adenocarcinoma and Mixed Mullerian tumor (4.5% each). In addition mutations were also detected in borderline tumors including Mucinous borderline tumor (9.09%) and Seromucinous borderline tumors (4.5%).The observations and results of the study were elaborated with the assistance of tables, figures and photomicrographs. Conclusion: BRCA-1 gene mutations manifestations were identified in a large number of serous malignant ovarian tumor cases. Small percentages of borderline and malignant mucinous tumors, endometroid adenocarcinoma and mixed mullerian tumor were also positive for BRCA-1 gene mutations.

Environmental public health research at the U.S. Environmental Protection Agency: A blueprint for exposure science in a connected world.

Exposure science plays an essential role in the U.S. Environmental Protection Agency's (U.S. EPA) mission to protect human health and the environment. The U.S. EPA's Center for Public Health and Environmental Assessment (CPHEA) within the Office of Research and Development (ORD) provides the exposure science needed to characterize the multifaceted relationships between people and their surroundings in support of national, regional, local and individual-level actions. Furthermore, exposure science research must position its enterprise to tackle the most pressing public health challenges in an ever-changing environment. These challenges include understanding and confronting complex human disease etiologies, disparities in the social environment, and system-level changes in the physical environment. Solutions will sustainably balance and optimize the health of people, animals, and ecosystems. Our objectives for this paper are to review the role of CPHEA exposure science research in various recent decision-making contexts, to present current challenges facing U.S. EPA and the larger exposure science field, and to provide illustrative case examples where CPHEA exposure science is demonstrating the latest methodologies at the intersection of these two motivations. This blueprint provides a foundation for applying exposomic tools and approaches to holistically understand real-world exposures so optimal environmental public health protective actions can be realized within the broader context of a One Health framework. IMPACT STATEMENT: The U.S. EPA's Center for Public Health and Environmental Assessment exposure research priorities reside at the intersection of environmental decision contexts and broad public health challenges. The blueprint provides a foundation for advancing the tools and approaches to holistically understand real-world exposures so optimal environmental protection actions can be realized. A One Health lens can help shape exposure research for maximum impact to support solutions that are transdisciplinary and must engage multiple sectors.

Effects of Short-Term Treatment with α-Lipoic Acid on Neuropathic Pain and Biomarkers of DNA Damage in Patients with Diabetes Mellitus

Background/Objectives: Diabetes mellitus (DM) is a complex and heterogenous disease classified as a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. It leads to various complications, some of which are macrovascular or microvascular complications, like diabetic polyneuropathy (DPN), having a profound impact on patients’ quality of life. Oxidative stress (OS) is one of the significant mechanisms in the development and progression of DPN. Thus, targeting OS pathways by antioxidants, such as α-lipoic acid (ALA), could represent a promising therapeutic strategy for alleviating neuropathic symptoms. The aim of our study was to evaluate whether short-term (from 4 to 9 days) intravenous administration of ALA could cause any measurable improvement in subjects with DM. Methods: Sixteen subjects with DM (six type 1 and ten type 2) and sixteen nondiabetic subjects matched by sex and age were recruited to this study. Only subjects with DM received treatment with ALA (600 mg daily). Pain intensity and biomarkers of DNA damage including plasma concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG), frequency of micronucleated lymphocytes (MN), and frequency of sister-chromatid exchanges (SCEs), were measured before and after the treatment with ALA. Results: Pain intensity and 8-OHdG levels were significantly lower in DM subjects after the ALA treatment than before the treatment. However, no changes in the frequency of SCEs and MN were observed. Conclusions: Our results show some evidence that even a short-term intravenous treatment with ALA could be beneficial for diabetic subjects, reducing pain intensity and concentration of 8-OHdG in blood plasma.

Non-invasive prenatal detection of dominant single-gene disorders in fetal structural abnormalities: a clinical feasibility study.

This study evaluated the accuracy of non-invasive prenatal testing (NIPT-SGDs) for dominant monogenic genetic diseases associated with fetal structural abnormalities and to assess the feasibility of clinical application. Pregnant women requiring prenatal diagnosis due to fetal structural abnormalities were enrolled. Maternal peripheral blood was analyzed for cell-free DNA (cfDNA) using coordinative allele-aware target enrichment sequencing (COATE-seq). This assessed fetal allele depth distribution, fraction and variation ratio. The variation's origin was then determined to obtain fetal variation information. Finally, NIPT-SGDs results were confirmed via invasive prenatal diagnosis (IPD). Upon examination of 113 samples using NIPT-SGDs, COATE-seq successfully analyzed 112 for fetal variation, excluding one due to hemolysis. The study detected six positive cases, yielding a 5.36% detection rate. These disorders included tuberous sclerosis complex (TSC1 and TSC2 being its causative genes), Noonan syndrome (PTPN11), polycystic kidney disease (PKD1), and Kabuki syndrome (KMT2D), occurring twice each, except for Noonan and polycystic kidney disease. Two false positives were due to the mother being a genetic mosaicism. Compared to invasive whole-exome sequencing (WES), NIPT-SGDs did not detect nine positive cases of IPD dominant monogenic diseases, accurately identifying 90.18% (101/112) of the actual positive and negative cases. Our findings demonstrate the clinical utility of NIPT-SGDs using COATE-seq in effectively identifying fetuses with dominant single-gene disorders. Furthermore, this method can be applied to all fetuses.

Uncovering disease-related multicellular pathway modules on large-scale single-cell transcriptomes with scPAFA.

Pathway analysis is a crucial analytical phase in disease research on single-cell RNA sequencing (scRNA-seq) data, offering biological interpretations based on prior knowledge. However, currently available tools for generating cell-level pathway activity scores (PAS) exhibit computational inefficacy in large-scale scRNA-seq datasets. Additionally, disease-related pathways are often identified through cross-condition comparisons within specific cell types, overlooking potential patterns that involve multiple cell types. Here, we present single-cell pathway activity factor analysis (scPAFA), a Python library designed for large-scale single-cell datasets allowing rapid PAS computation and uncovering biologically interpretable disease-related multicellular pathway modules, which are low-dimensional representations of disease-related PAS alterations in multiple cell types. Application on colorectal cancer (CRC) datasets and large-scale lupus atlas over 1.2 million cells demonstrated that scPAFA can achieve over 40-fold reductions in the runtime of PAS computation and further identified reliable and interpretable multicellular pathway modules that capture the heterogeneity of CRC and transcriptional abnormalities in lupus patients, respectively. Overall, scPAFA presents a valuable addition to existing research tools in disease research, with the potential to reveal complex disease mechanisms and support biomarker discovery at the pathway level.

Partial response to treatment with ALK inhibitor in a patient with SQSTM1-ALK fusion positive lung adenocarcinoma

Introduction: Lung cancer is the second most common cancer worldwide and the leading cause of cancer deaths; non-small cell lung cancer (NSCLC) constitutes about 85% of lung cancer cases, with ALK fusions representing 3–6% of them. The SQSTM1-ALK fusion is a rare finding in NSCLC, accounting for only 1.1% of ALK rearrangements. We present a case of lung adenocarcinoma with documentation of SQSTM1-ALK fusion that showed a partial response to alectinib. Case description: This case details the clinical course of a 71-year-old, non-smoking woman with no significant medical history who presented with confusion, aphasia and multiple cerebral lesions detected on imaging. Further investigations revealed a stage IV lung adenocarcinoma with metastases to the brain and adrenal gland. Molecular profiling identified a rare SQSTM1-ALK fusion mutation alongside other genetic abnormalities, including low programmed death-ligand 1 expression and ROS1 kinase protein presence. Treatment with alectinib, initiated based on the identified ALK fusion, resulted in significant tumour regression in the lungs and complete resolution of the adrenal mass, as evidenced by follow-up imaging and clinical assessments. Conclusion: This case highlights the efficacy of alectinib in treating rare ALK fusion variants in and underscores the importance of comprehensive molecular profiling in guiding targeted therapy decisions.

The Notable Role of Telomere Length Maintenance in Complex Diseases

Telomere length function serves as a critical biomarker for biological aging and overall health. Its maintenance is linked to cancer, neurodegenerative conditions, and reproductive health. This review mainly examines genetic variations and environmental influences on telomere dynamics, highlighting key regulatory genes and mechanisms. Advances in telomere measurement methodologies are also reviewed, underscoring the importance of precise telomere assessment for disease prevention and treatment. Telomerase activation offers potential for cellular lifespan extension and anti-aging effects, whereas its inhibition emerges as a promising therapeutic approach for cancer. Regulatory mechanisms of tumor suppressor genes on telomerase activity are analyzed, with a comprehensive overview of the current state and future potential of telomerase inhibitors. In addition, the association between telomeres and neurodegenerative diseases is discussed, detailing how telomere attrition heightens disease risk and outlining multiple pathways by which telomerase protects neurons from damage and apoptosis.

The dopamine hypothesis for ADHD: An evaluation of evidence accumulated from human studies and animal models

Multiple lines of evidence indicate that altered dopamine signaling may be involved in neuropsychiatric disorders and common behavioral traits. Here we critically review evidence collected during the past 40-plus years supporting the role of dopamine dysfunction in attention deficit hyperactivity disorder (ADHD). We recapitulate the basic components of dopaminergic signaling in the central nervous system, focusing on core enzymes, transporters and receptors involved in monoaminergic functions, particularly in striatal and cortical regions. We summarize key human brain imaging and genetic studies reporting associations between dopaminergic neurotransmission and behavioral traits, with an emphasis on ADHD. We also consider ADHD in the context of animal models and single gene, metabolic, and neurological disorders with established dysfunction of the dopaminergic system. Examining the evidence in this way leads us to conclude that there is evidence for the involvement of dopamine but limited evidence for a hypo-dopaminergic state per se as a key component of ADHD. We propose a path forward to increase our understanding of dopamine signaling in human behavioral traits and disorders that should particularly focus on its role in clinical subgroups, during brain development and how it interacts with other neurotransmitter systems.

Recurrent Early Pregnancy Loss and Congenital Thrombophilia: A Prospective Study

Background/Objectives: This study aims to investigate the role of congenital single nucleotide thrombophilia in young females with early recurrent pregnancy loss (RPL). Methods: We studied 120 pregnant females with RPL and 80 matched females as a control with no RPL. Females were aged ≤ 35 years, had at least two consecutive first-trimester RPLs, and the acquired cause of RPL was excluded. A matched control group of 80 pregnant women with no RPL was studied. Coagulation tests included prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), a Factor XIII functional assay, and detecting IgM and IgG anti-beta2-Glycoprotein I (β2GPI) antibodies by an ELISA. The DNA samples were tested for Factor V Leiden, Factor II G20210A, Methylenetetrahydrofolate reductase (MTHFR C677T, A1298C), FXIII V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G, endothelial protein C receptor (EPCR) A4600G, and endothelial protein C receptor (EPCR) G4678C. Results: Of the single nucleotide gene mutations investigated, the most relevant mutations were MTHFR C677T, MTHFR A1298C, heterozygous FXIII Val34Leu, and heterozygous FXIII 1694 C>T. Each of them conferred a statistically significant effect. There was a statistically significant protective role for the endothelial protein C receptor (EPCR) A2/A2, wild FXIII Val34Leu, and heterozygousFXIII1694 C>T. Conclusions: Our findings suggest the important role of congenital single nucleotide thrombophilia mutations in young Middle Eastern women with early RPL, particularly MTHFR mutations and FXIII Val34Leu. We found a protective effect of EPCR A2/A2, wild FXIIIVal34Leu, and heterozygous FXIII1694 C>T. We recommend additional studies to explore detrimental factors and protective factors.

Double-Layered Microneedle Patch Integrated with Multifunctional Nanoparticles and Live Bacteria for Long-Term Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a complex and prevalent chronic inflammatory skin disease that impacts a significant portion of the global population. Conventional treatments often focus on a singular pathogenic factor or suffer from limited skin penetration, resulting in unsatisfactory outcomes. Here, a multifunctional double-layered microneedle (MN) patch is proposed for long-term and effective treatment of AD by integrating therapeutic nanoparticles (NPs) and live bacteria. In the design, the MN tips are loaded with Prussian blue NPs encapsulating cetirizine hydrochloride (CET@PB NPs), while the patch backing incorporates Bacillus subtilis (B. subtilis). Upon skin insertion, the MN patch efficiently delivers CET@PB NPs into the skin and deposits live B. subtilis on the skin surface after fast dissolution. The delivered NPs not only scavenge reactive oxygen species (ROS) and improve oxidative stress microenvironments in the AD lesions, but also provide sustained release of the antihistamine CET in the skin for alleviating AD symptoms. Furthermore, B. subtilis survives on the skin for over 9 days and effectively inhibits the growth of the harmful bacteria Staphylococcus aureus. These features highlight the superior efficacy of the MN patch in long-term treatment of AD, offering a promising alternative for the management of skin disorders in clinics.

Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review

Cancer is a complex disease characterized by specific “mission-critical” events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways—such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and—allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

Marginal interaction test for detecting interactions between genetic marker sets and environment in genome-wide studies.

As human complex diseases are influenced by the interaction between genetics and the environment, identifying gene-environment interactions (G × E) is crucial for understanding disease mechanisms and predicting risk. Developing robust quantitative tools for G × E analysis can enhance the study of complex diseases. However, many existing methods that explore G × E focus on the interplay between an environmental factor and genetic variants, exclusively for common or rare variants. In this study, we developed MAGEIT_RAN and MAGEIT_FIX to identify interactions between an environmental factor and a set of genetic markers, including both rare and common variants, based on the MinQue for Summary statistics. The genetic main effects in MAGEIT_RAN and MAGEIT_FIX are modeled as random and fixed effects, respectively. Simulation studies showed that both tests had type I error under control, with MAGEIT_RAN being the most powerful test. Applying MAGEIT to a genome-wide analysis of gene-alcohol interactions on hypertension and seated systolic blood pressure in the Multi-Ethnic Study of Atherosclerosis revealed genes like EIF2AK2, CCNDBP1 and EPB42 influencing blood pressure through alcohol interaction. Pathway analysis identified one apoptosis and survival pathway involving PKR and two signal transduction pathways associated with hypertension and alcohol intake, demonstrating MAGEIT_RAN's ability to detect biologically relevant gene-environment interactions.

Machine learning-driven discovery of novel therapeutic targets in diabetic foot ulcers.

To utilize machine learning for identifying treatment response genes in diabetic foot ulcers (DFU). Transcriptome data from patients with DFU were collected and subjected to comprehensive analysis. Initially, differential expression analysis was conducted to identify genes with significant changes in expression levels between DFU patients and healthy controls. Following this, enrichment analyses were performed to uncover biological pathways and processes associated with these differentially expressed genes. Machine learning algorithms, including feature selection and classification techniques, were then applied to the data to pinpoint key genes that play crucial roles in the pathogenesis of DFU. An independent transcriptome dataset was used to validate the key genes identified in our study. Further analysis of single-cell datasets was conducted to investigate changes in key genes at the single-cell level. Through this integrated approach, SCUBE1 and RNF103-CHMP3 were identified as key genes significantly associated with DFU. SCUBE1 was found to be involved in immune regulation, playing a role in the body's response to inflammation and infection, which are common in DFU. RNF103-CHMP3 was linked to extracellular interactions, suggesting its involvement in cellular communication and tissue repair mechanisms essential for wound healing. The reliability of our analysis results was confirmed in the independent transcriptome dataset. Additionally, the expression of SCUBE1 and RNF103-CHMP3 was examined in single-cell transcriptome data, showing that these genes were significantly downregulated in the cured DFU patient group, particularly in NK cells and macrophages. The identification of SCUBE1 and RNF103-CHMP3 as potential biomarkers for DFU marks a significant step forward in understanding the molecular basis of the disease. These genes offer new directions for both diagnosis and treatment, with the potential for developing targeted therapies that could enhance patient outcomes. This study underscores the value of integrating computational methods with biological data to uncover novel insights into complex diseases like DFU. Future research should focus on validating these findings in larger cohorts and exploring the therapeutic potential of targeting SCUBE1 and RNF103-CHMP3 in clinical settings.

High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes.

The availability and integration of electrophysiological and molecular data from the living brain is critical to understand and diagnose complex human disease. Intracranial stereo electroencephalography (SEEG) electrodes used for identifying the seizure focus on epilepsy patients could enable the integration of such multimodal data. Here, we report MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes), a method that recovers extensive protein-coding transcripts, including cell-type markers, DNA methylation and short variant profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function. We find gene expression gradients that correspond with the neurophysiology-assigned epileptogenicity index but also outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states and SEEG-adherent differentially expressed and methylated genes not previously associated with epilepsy. Together, these findings validate that RNA profiles and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. The MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.

Epicardial Lead Performance Trends in Pediatric and Congenital Heart Disease.

Background: Epicardial pacing systems, rather than transvenous systems, are utilized in pediatric patients who are too small to undergo transvenous access and/or have complex congenital heart disease (CHD) anatomically precluding a transvenous system. Longitudinal performance studies indicate that epicardial leads have higher failure rates when compared with transvenous leads but there are limited data on lead measurement changes in the acute phase after implantation. The objective of this study was to assess epicardial lead performance in the acute postimplant period and at one-year follow-up. Methods: This is a retrospective single center study of children and adult patients with CHD undergoing epicardial bipolar pacing lead and generator implantation between January 2012 and June 2022. We empirically selected 2 V as a critical lead threshold. Results: There were 256 leads implanted in 127 patients (mean age 6.1 ± 9.8 years), including 201/256 (79%) leads in patients with CHD. At the time of implant, 47/256 leads (18%) had a lead threshold of ≥2 V. Of those, 42 of 47 (89%) had recorded threshold values on postoperative day 1 (POD1) and 37 of 42 (88%) had decreased to a more acceptable threshold that was <2 V. For patients with an implant threshold of ≥2 V; impedance >1000 ohms, presence of CHD, perioperative or acute postop status, and location of the lead (atrial vs ventricular) did not significantly impact the odds of having a persistently high threshold (≥2 V) on POD1. Conclusion: Epicardial pacing lead thresholds generally improve in the immediate postop period and in our experience most leads with a high implant threshold improved to <2 V by POD1.