Multi-omics analysis reveals drivers of loss of ß-cell function after newly diagnosed autoimmune type 1 diabetes: An INNODIA multicenter study.

AIMS: Heterogeneity in the rate of ß-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis. METHODS: We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in ß-cell mass measured as fasting C-peptide. RESULTS: Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in ß-cell function. The second signature was related to translation and viral infection was inversely associated with change in ß-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid ß-cell decline. CONCLUSIONS: Features that differ between individuals with slow and rapid decline in ß-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.

Lipid levels in a cohort of healthy Danish schoolchildren ages 5 to 17 years.

It is internationally recognized to use clinical decision limits (CDL) when interpreting the lipid levels in both adults and children, even though the evidence for children is scarce. The purpose of this study is to describe how lipid levels progress in healthy Danish children ages 5 to 17 years. This study is based on the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS-study DK) consisting of 1456 observations of schoolchildren aged 5 to 17 years. Participants have been tested for blood levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and remnant cholesterol levels are calculated. Finally, sex-specific percentile reference curves are presented. Percentile reference curves stratified by sex were generated for all cholesterols and showed that the total cholesterol level peaks at 4.32 mmol/l in 10-year-old boys and 4.46 mmol/l in nine-year-old girls. HDL levels in boys peak at 1.72 mmol/l in nine-year-old boys. HDL levels in girls and LDL levels in both sexes are nearly constant. Triglycerides kept rising to the age of 17 years in both sexes and remnant cholesterol decreased from age 5 to 17 years in both sexes. BMI z-score adjustment revealed no significant association with total cholesterol in both sexes but a significant association between HDL, LDL, triglycerides, and remnant cholesterol. This study is the first to generate percentile reference curves for blood levels of total cholesterol, LDL, HDL, triglycerides, and remnant cholesterol in a cohort of healthy Danish children aged 5 to 17 years.

Electrostatic Correlations Lead to High Capacitance in Zwitterion-Containing Thin Films.

A novel zwitterion composed of an imidazolium tethered to an anionic sulfonyl(trifluoromethane sulfonyl)imide group was prepared as an alternative dielectric material to traditional ionic liquids. The zwitterion not only melted below 100 °C but also proved to be nonhygroscopic. High-capacitance organic dielectric materials were obtained by blending this compound with poly(methyl methacrylate) over a range of concentrations and thicknesses. Above a specific temperature and concentration, films exhibit a capacitance nearly equivalent to that of an electrostatic double layer, approximately 10 µF/cm2, regardless of their thickness. Grazing-incidence wide-angle X-ray scattering experiments suggest that the zwitterions adopt a lamellar ordering at their surface above a critical concentration. The observed ordering is correlated with a 1000-fold increase in capacitance. The behavior suggests that the zwitterions exhibit strong electrostatic correlations throughout the film bulk, pointing the way toward a novel class of organic dielectric materials.

Prediction of progression to type 1 diabetes with dynamic biomarkers and risk scores.

Identifying biomarkers of functional ß-cell loss is an important step in the risk stratification of type 1 diabetes. Genetic risk scores (GRS), generated by profiling an array of single nucleotide polymorphisms, are a widely used type 1 diabetes risk-prediction tool. Type 1 diabetes screening studies have relied on a combination of biochemical (autoantibody) and GRS screening methodologies for identifying individuals at high-risk of type 1 diabetes. A limitation of these screening tools is that the presence of autoantibodies marks the initiation of ß-cell loss, and is therefore not the best biomarker of progression to early-stage type 1 diabetes. GRS, on the other hand, represents a static biomarker offering a single risk score over an individual's lifetime. In this Personal View, we explore the challenges and opportunities of static and dynamic biomarkers in the prediction of progression to type 1 diabetes. We discuss future directions wherein newer dynamic risk scores could be used to predict type 1 diabetes risk, assess the efficacy of new and emerging drugs to retard, or prevent type 1 diabetes, and possibly replace or further enhance the predictive ability offered by static biomarkers, such as GRS.

Nucleic acids based integrated macromolecular complexes for SiRNA delivery: Recent advancements.

The therapeutic potential of small interfering RNA (siRNA) is monumental, offering a pathway to silence disease-causing genes with precision. However, the delivery of siRNA to target cells in-vivo remains a formidable challenge, owing to degradation by nucleases, poor cellular uptake and immunogenicity. This overview examines recent advancements in the design and application of nucleic acid-based integrated macromolecular complexes for the efficient delivery of siRNA. We dissect the innovative delivery vectors developed in recent years, including lipid-based nanoparticles, polymeric carriers, dendrimer complexes and hybrid systems that incorporate stimuli-responsive elements for targeted and controlled release. Advancements in bioconjugation techniques, active targeting strategies and nanotechnology-enabled delivery platforms are evaluated for their contribution to enhancing siRNA delivery. It also addresses the complex interplay between delivery system design and biological barriers, highlighting the dynamic progress and remaining hurdles in translating siRNA therapies from bench to bedside. By offering a comprehensive overview of current strategies and emerging technologies, we underscore the future directions and potential impact of siRNA delivery systems in personalized medicine.

Noninvasive neuromodulatory effect on cognition in individuals with traumatic brain injury: A single-blinded, two-arm parallel randomized clinical trial.

Objectives: The study aimed to compare the effect of cranial electrical stimulation (CES) and transcranial direct current stimulation (tDCS) in improving cognition among individuals with mild traumatic brain injury. Patients and methods: The pretest-posttest randomized controlled study was conducted between November 2020 and March 2022. Seventy-two patients (64 males, 8 females; mean age: 40.5±9.5 years; range, 18 to 45 years) experiencing cognitive impairment within three months of traumatic brain injury were recruited. Participants were randomly assigned into two groups: Group 1 (CES with cognitive training, n=36) and Group 2 (tDCS with cognitive training, n=36). Participants were blinded in the study. Both groups received 30-min sessions of neuromodulation along with 30 min of cognitive training five days a week for four weeks. The patients were assessed at baseline and at the end of two and four weeks of intervention. The primary outcome measure was the Montreal Cognition Assessment (MoCA), and the secondary outcome measure was the Galveston Orientation Amnesia Test (GOAT). Results: Demographic and baseline characteristics depicted normal distribution for both groups (p>0.05). Within group analyses of both groups demonstrated significant differences for both outcome measures (MoCA: p=0.001; GOAT: p=0.001). Between group analyses of MoCA showed significant improvement with p-value of 0.001 while GOAT exhibited p-value of 0.002 showing significant difference between the two groups. Time group interaction effect and covariance analyses depicted significant improvement with p-value of 0.001 for both outcome measures with excellent effect size >0.80. Conclusion: Cranial electrical stimulation was a more effective noninvasive neuromodulatory device than tDCS in improving cognition among individuals with traumatic brain injury.

Production of Alginate Oligosaccharides (AOSs) Using Enhanced Physicochemical Properties of Immobilized Alginate Lyase for Industrial Application.

Alginate lyase (AL) is a polysaccharide-degrading enzyme that can degrade alginate by hydrolyzing glycosidic bonds and produces unsaturated alginate oligosaccharides (AOSs). These AOSs have wide therapeutic and nutraceutical applications. However, to produce alginate oligosaccharides in a cost-effective manner is challenging due to the low availability and high cost of this degrading enzyme. Immobilization of the enzyme facilitates industrial applications owing to its stability, reusability, and cost-effectiveness. This study was focused on the enhancement of the properties of alginate lyase and improvement of the production of AOS. Alginate lyase was immobilized on magnetic nanoparticles (NPs) using glutaraldehyde as the crosslinker. The study showed that the maximum binding achieved between NPs and protein in the enzyme was 71% at a ratio of 1:150 NP:protein. As a result of immobilization, the optimum activity of free enzyme which was obtained at 37 °C and pH 7.4 changed to 45 °C and pH 9. Furthermore, the enzyme was thermostable at 45 °C for 3 h with up to 50% reusability for six consecutive cycles. Storage stability after 15 days showed ~67% relative hydrolysis of alginate. The free alginate lyase (25 IU) showed 76% raw biomass (seaweed) hydrolysis which is higher compared to 63% provided by the immobilized enzyme. As a result of efficient hydrolysis, AOSs with molecular weight profile of 370-1040 kDa were produced and detected using HPLC.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Group tele-rehabilitation improves quality of life among subjects with Parkinson's disease: A two arm non-parallel non-randomized clinical trial.

INTRODUCTION: Tele-rehabilitation has lately emerged as a promising medium for increasing patient adherence with significant positive results. One of the most prevalent neurological diseases affecting movement is Parkinson's disease (PD), which causes a variety of motor and non-motor symptoms among patients. Consequentially, the study was designed to compare the efficacy of group tele-rehabilitation with individual tele-rehabilitation in improving quality of life (QoL) among subjects with PD. METHOD: A two-group pretest-posttest, non-randomized clinical study recruited 68 subjects and classified them into two groups, i.e., Group A (group therapy, n = 36) and Group B (individual therapy, n = 32). Groups A and B received a supervised protocol consisting of a 40-min session on alternate days/week for twelve weeks via the WhatsApp Messenger application through group and individual therapy, respectively. The Parkinson's disease questionnaire (PDQ-39), mental and physical components of the Short Form Survey (SF-12) were used as primary outcome variables, while the Satisfaction questionnaire was used as a secondary outcome variable. RESULT: The p-values related to within-group analyses were <0.05 except SF-12 PCS >0.05 in Group A and <0.05 in Group B. While the p-values related to between-group analyses were <0.05 except for pre-scores of SF-12 (MCS and PCS). The effect sizes for PDQ-39, SF-12 (MCS), and SF-12 (PCS) were -2.37, 3.36, and 0.66 in Group A and 1.95, 2.69, and 2.03 in Group B, respectively. CONCLUSION: The study concluded that group tele-rehabilitation is more effective in improving QoL among subjects with PD as compared to individual tele-rehabilitation. Clinical trial Registration NoCTRI/2022/04/041818.

The combined effect of neuro-modulation and neuro-stimulation on pain in patients with cervical radiculopathy - a double-blinded, two-arm parallel randomized controlled trial.

INTRODUCTION: Cervical radiculopathy is one of those disabling conditions which results in central and peripheral pain and thus affects the quality of life. Transcutaneous Electrical Nerve Stimulation (TENS) and exercises produce analgesic effect but their long-term effect has not been available to date. Transcranial Direct Current stimulation (tDCS) is known to produce promising effects on central pain by targeting cortical activity. PURPOSE: To determine the combined effect of tDCS and TENS with exercises on pain and quality of life in patients with cervical radiculopathy. METHOD: Forty four patients (male: female = 26:18) of the age group 18-50 years were recruited and randomly allocated into the experimental group and control group. The experimental group received active anodal tDCS for 20 min with an intensity of 2 mA, while the control group received sham anodal tDCS. TENS over the pain distribution area for 20 min with 5 Hz intensity and 80-150 ms pulse duration followed by neck-specific exercises were given in both groups. This protocol was given 5 days a week for 4 weeks. Pre and post-assessments were obtained through outcome measures that the Numeric Pain Rating Scale and Neck Disability Index for the measurement of pain, functional disability, and quality of life. RESULT: Paired t-test/Wilcoxon-Signed Rank test, and Index and Mann-Whitney U test were used to compare the demographic variables within and across the groups, respectively for Neck Disability for Numeric Pain Rating Scale, keeping the P-value < 0.05 as significant. One-way repeated-measures analysis of variance (ANOVA) was applied to determine the between-subject factor differences. Post hoc tests with Bonferroni correction for repeated analyses were performed. Results depicted a significant effect for NDI (P = 0.001 for both groups) and NPRS (P = 0.003 for the experimental group and 0.007 for the control group). Significant Interaction effect (time*group) was observed for NDI (F = 42, 5382.77) and NPRS (F = 42, 1844.57) with a P-value of 0.001 for both outcome measures. Clinical significance was observed for both outcome measures having a mean difference in 50.21 and 4.57 for NDI and NPRS, respectively compared with the established MCID of 13.2 and 2.2 scores for respective outcome measures. CONCLUSION: It was concluded that active tDCS along with TENS and exercise intervention was effective on pain, disability, and quality of life in patients with cervical radiculopathy.

A Short Appraisal of Magnetic Nanoparticles for Breast Cancer: In vitro and In vivo Research.

The increasing incidence of breast cancer and the associated morbidity due to higher metastasis created the urge to develop a nanocarrier that can be used as a potent therapeutic carrier with targeting efficacy. The use of superparamagnetic nanoparticles in breast cancer research and treatment has gained considerable attention in recent years. Magnetic nanoparticles (MNPs) can be used to construct nanocarriers since they possess superior properties such as superparamagnetism, easy surface functionalization to attach ligands, and non-immunogenic. MNPs are superior carriers that are used to target cancer cells without harming the normal cells in the body, which leads to therapeutic efficacy in the body. Along with their established anticancer potential and enhanced drug concentration at endosomal pH, the superparamagnetic property of MNPs was further exploited for their applications in reticuloendothelial uptake, drug delivery, medical imaging, and theranostics applications in breast cancer. Moreover, the clinical translational of MNPs, along with future prospects and key challenges in vivo, have been duly presented in the final review. The scientists preferred the ongoing research in MNPs due to their high biocompatibility and ease of targeting at molecular and cellular levels. The review highlighted the in vitro and in vivo research and patent supported data for potential use of MNPs for the treatment of breast cancer.

Scheuermann's Disease.

Scheuermann's disease is a rigid progressive kyphosis occurring in late childhood to adolescence. It is the most common cause of sagittal imbalance and angular progressive kyphosis in adolescents associated with back pain. The exact etiology of the disease is unclear, but it is characterized by defective growth of the end plate that may result from excessive mechanical stress on a weakened end plate during spinal growth. Several other theories have been proposed, and it is thought to be a multifactorial disease occurring as a result of the interplay of multiple factors. The radiographic features consist of anterior vertebral body wedging, irregular end plates, Schmorl's nodes, and intervertebral disk degeneration. The natural history and evolution of this disease is also unknown. Conservative management with physiotherapy, rehabilitation, and bracing is the first line of treatment. Mechanical bracing helps prevent further progression of the kyphotic deformity. Surgery is mostly indicated in patients with failure of conservative management, with neurologic compromise, and for cosmetic reasons.

A Critical Appraisal of Functionalized 2-Dimensional Carbon-Based Nanomaterials for Drug Delivery Applications.

The development of an efficient and innovative drug delivery system is essential to improve the pharmacological parameters of the medicinal compound or drug. The technique or manner used to improve the pharmacological parameters plays a crucial role in the delivery system. In the current scenario, various drug delivery systems are available where nanotechnology has firmly established itself in the field of drug delivery. One of the most prevalent elements is carbon with its allotropic modifications such as graphene-based nanomaterials, carbon nanotubes, carbon dots, and carbon fullerenes, these nanomaterials offer notable physiochemical and biochemical properties for the delivery applications due to their smaller size, surface area, and ability to interact with the cells or tissues. The exceptional physicochemical properties of carbon-based 2D nanomaterials, such as graphene and carbon nanotubes, make them attractive candidates for drug delivery systems. These nanomaterials offer a large surface area, high drug loading capacity, and tunable surface chemistry, enabling efficient encapsulation, controlled release, and targeted delivery of therapeutic agents. These properties of the nanomaterials can be exploited for drug delivery applications, like assisting the target delivery of drugs and aiding combination molecular imaging. This review emphasizes the drug delivery system and the role of carbon-based nanomaterials in drug delivery systems. Carbon-based 2D nanomaterials present a wealth of opportunities for advanced drug delivery systems. Their exceptional properties and versatility offers great potential in improving therapeutic efficacy, minimizing side effects, and enabling personalized medicine.

ß Cell and Autophagy: What Do We Know?

Pancreatic ß cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in ß cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in ß cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects ß cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect ß cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to ß cell failure.

Characterization of the functional and transcriptomic effects of pro-inflammatory cytokines on human EndoC-ßH5 beta cells.

Objective: EndoC-ßH5 is a newly established human beta-cell model which may be superior to previous model systems. Exposure of beta cells to pro-inflammatory cytokines is widely used when studying immune-mediated beta-cell failure in type 1 diabetes. We therefore performed an in-depth characterization of the effects of cytokines on EndoC-ßH5 cells. Methods: The sensitivity profile of EndoC-ßH5 cells to the toxic effects of interleukin-1ß (IL-1ß), interferon γ (IFNγ) and tumor necrosis factor-α (TNFα) was examined in titration and time-course experiments. Cell death was evaluated by caspase-3/7 activity, cytotoxicity, viability, TUNEL assay and immunoblotting. Activation of signaling pathways and major histocompatibility complex (MHC)-I expression were examined by immunoblotting, immunofluorescence, and real-time quantitative PCR (qPCR). Insulin and chemokine secretion were measured by ELISA and Meso Scale Discovery multiplexing electrochemiluminescence, respectively. Mitochondrial function was evaluated by extracellular flux technology. Global gene expression was characterized by stranded RNA sequencing. Results: Cytokines increased caspase-3/7 activity and cytotoxicity in EndoC-ßH5 cells in a time- and dose-dependent manner. The proapoptotic effect of cytokines was primarily driven by IFNγ signal transduction. Cytokine exposure induced MHC-I expression and chemokine production and secretion. Further, cytokines caused impaired mitochondrial function and diminished glucose-stimulated insulin secretion. Finally, we report significant changes to the EndoC-ßH5 transcriptome including upregulation of the human leukocyte antigen (HLA) genes, endoplasmic reticulum stress markers, and non-coding RNAs, in response to cytokines. Among the differentially expressed genes were several type 1 diabetes risk genes. Conclusion: Our study provides detailed insight into the functional and transcriptomic effects of cytokines on EndoC-ßH5 cells. This information should be useful for future studies using this novel beta-cell model.

Aberrant protein glycosylation: Implications on diagnosis and Immunotherapy.

Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and cell-to-cell interaction. Alterations in the N-linked or O-linked glycosylation pattern of regulatory proteins like transcription factors or cellular receptors lead to many diseases, including cancer. These alterations give rise to micro- and macro-heterogeneity in tumor cells. Here, we review the role of O- and N-linked glycosylation and its regulatory function in autoimmunity and aberrant glycosylation in cancer. The change in cellular glycome could result from a change in the expression of glycosidases or glycosyltransferases like N-acetyl-glucosaminyl transferase V, FUT8, ST6Gal-I, DPAGT1, etc., impact the glycosylation of target proteins leading to transformation. Moreover, the mutations in glycogenes affect glycosylation patterns on immune cells leading to other related manifestations like pro- or anti-inflammatory effects. In recent years, understanding the glycome to cancer indicates that it can be utilized for both diagnosis/prognosis as well as immunotherapy. Studies involving mass spectrometry of proteome, site- and structure-specific glycoproteomics, or transcriptomics/genomics of patient samples and cancer models revealed the importance of glycosylation homeostasis in cancer biology. The development of emerging technologies, such as the lectin microarray, has facilitated research on the structure and function of glycans and glycosylation. Newly developed devices allow for high-throughput, high-speed, and precise research on aberrant glycosylation. This paper also discusses emerging technologies and clinical applications of glycosylation.

A Sojourn on Liposomal Delivery System: Recent Advances and Future Prospects.

Liposomes are unique novel drug delivery carriers that favor the effective transportation of pharmaceuticals. These vesicles acquire one or more phospholipid bilayer membranes, and an inner aqueous core can carry both aqueous and lipid drugs. While hydrophilic molecules can be confined in the aqueous core, hydrophobic molecules are injected into the bilayer membrane. Liposomes have many benefits as a drug delivery method, including biocompatibility, the capacity to carry large drug payloads, and a variety of physicochemical and biological parameters that can be altered to influence their biological characteristics. In addition, being a size of 10-100 nm range can have numerous additional benefits, including enhanced pharmacokinetics, clever escape from the reticuloendothelial system, greater in vivo stability, longer and site-specific administration, and increased internalization in tumor tissue (enhanced permeability and retention impact). The current review focuses on the structural composition of liposomes, formulation technologies, and suitable case studies for optimizing biopharmaceutical performance. Moreover, clinical trials and marketed formulations of liposomes have been also stated in the prior art.