Non-genetic Diseases Research Articles

Relationship between the effect of panic attack and physiological parameters in some patients and animals lab

The effects of a panic attack were studied in some patients who do not have hereditary diseases "sudden onset" as well as using laboratory animal "rats" to examine the types of effects on some physiological parameters. compared with control. These attacks affect daily life and result from a complex interaction between environmental, neurological, and psychological factors. Venous blood samples were collected from people suffering from non-genetic diseases. Blood samples were also collected from experimental animals exposed to fear at intervals of 0, 3, 7, and 28 days to detect the relationship between environmental factors and some physiological factors. Statistical analysis was performed using the SPSS program. The results indicated an increase in the level of cholesterol, glucose, and C-reactive protein in people with non-genetic diseases compared to their decrease in the control group, in addition to an increase in the level of cholesterol and glucose and no effect on C-reactive protein in rats exposed to the impact of fear and low body weight. The results also show a significant increase in heart and breathing rates and a significant decrease in oxygen levels.

The translational gap for gene therapies in low- and middle-income countries.

Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.

People with genetic kidney diseases on kidney replacement therapy have different clinical outcomes compared to people with other kidney diseases

Despite increasing awareness of genetic kidney disease prevalence, there is limited population-level information about long term outcomes of people with genetic kidney disease receiving kidney replacement therapy. This analysis included people who commenced kidney replacement therapy between 1989 and 2020 as recorded in the Australian and New Zealand Dialysis and Transplant registry. Genetic kidney diseases were subclassified as majority and minority monogenic. Non-genetic kidney diseases were included as the comparator group. Primary outcome measures were 10-year mortality and 10-year graft failure. Cox proportional hazard regression were used to calculate unadjusted and adjusted hazard ratios (AHRs) for primary outcomes. There were 59,231 people in the dialysis subgroup and 21,860 people in the transplant subgroup. People on dialysis with genetic kidney diseases had reduced 10-year mortality risk (majority monogenic AHR: 0.70, 95% CI 0.66–0.76; minority monogenic AHR 0.86, 95% CI 0.80–0.92). This reduced 10-year mortality risk continued after kidney transplantation (majority monogenic AHR: 0.82, 95% CI 0.71–0.93; minority monogenic AHR 0.80, 95% CI 0.68–0.95). Majority monogenic genetic kidney diseases were associated with reduced 10-year graft failure compared to minority monogenic genetic kidney diseases and other kidney diseases (majority monogenic AHR 0.69, 95% CI 0.59–0.79). This binational registry analysis identified that people with genetic kidney disease have different mortality and graft failure risks compared to people with other kidney diseases.

Angiotensinogen: in-silico insight to mutations, protein-protein interactions and evolution

In this era of rapidly evolving genetic and non-genetic diseases, in-silico analysis of disease related proteins has proven beneficial in identification and characterization of potential therapeutic targets. In present study, angiotensinogen (AGT) was studied for its sequence based ortholog and paralogs, structural characterization, mutational analysis, protein interactions and evolutionary changes. Sequence studies identified 194 orthologs and 36 paralogs of AGT. Functional analysis AGT polymorphisms revealed the association of M235T with increased AGT stability. Protein-protein interaction analysis exposed the involvement of AGT in metabolic diseases. So, this study provided base for the experimentally proven association of M235T polymorphism with metabolic diseases. Moreover, it presents AGT as strong therapeutic target for the control of these diseases.

Advances in transposable elements: from mechanisms to applications in mammalian genomics

It has been 70 years since Barbara McClintock discovered transposable elements (TE), and the mechanistic studies and functional applications of transposable elements have been at the forefront of life science research. As an essential part of the genome, TEs have been discovered in most species of prokaryotes and eukaryotes, and the relative proportion of the total genetic sequence they comprise gradually increases with the expansion of the genome. In humans, TEs account for about 40% of the genome and are deeply involved in gene regulation, chromosome structure maintenance, inflammatory response, and the etiology of genetic and non-genetic diseases. In-depth functional studies of TEs in mammalian cells and the human body have led to a greater understanding of these fundamental biological processes. At the same time, as a potent mutagen and efficient genome editing tool, TEs have been transformed into biological tools critical for developing new techniques. By controlling the random insertion of TEs into the genome to change the phenotype in cells and model organisms, critical proteins of many diseases have been systematically identified. Exploiting the TE’s highly efficient in vitro insertion activity has driven the development of cutting-edge sequencing technologies. Recently, a new technology combining CRISPR with TEs was reported, which provides a novel targeted insertion system to both academia and industry. We suggest that interrogating biological processes that generally depend on the actions of TEs with TEs-derived genetic tools is a very efficient strategy. For example, excessive activation of TEs is an essential factor in the occurrence of cancer in humans. As potent mutagens, TEs have also been used to unravel the key regulatory elements and mechanisms of carcinogenesis. Through this review, we aim to effectively combine the traditional views of TEs with recent research progress, systematically link the mechanistic discoveries of TEs with the technological developments of TE-based tools, and provide a comprehensive approach and understanding for researchers in different fields.

Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice

BackgroundGene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia.ResultsIn this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2–4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment.ConclusionsThese results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective.

Clustered randomly interspaced short palindromic repeats (CRISPRs) and its associated endonuclease protein, i.e., Cas9, have been discovered as an immune system in bacteria and archaea; nevertheless, they are now being adopted as mainstream biotechnological/molecular scissors that can modulate ample genetic and nongenetic diseases via insertion/deletion, epigenome editing, messenger RNA editing, CRISPR interference, etc. Many Food and Drug Administration-approved and ongoing clinical trials on CRISPR adopt ex vivo strategies, wherein the gene editing is performed ex vivo, followed by reimplantation to the patients. However, the in vivo delivery of the CRISPR components is still under preclinical surveillance. This review has summarized the nonviral nanodelivery strategies for gene editing using CRISPR/Cas9 and its recent advancements, strategic points of view, challenges, and future aspects for tissue-specific in vivo delivery of CRISPR/Cas9 components using nanomaterials.

Genetic architecture of brain age and its causal relations with brain and mental disorders

The difference between chronological age and the apparent age of the brain estimated from brain imaging data—the brain age gap (BAG)—is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and nongenetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3–95 years). A genome-wide association analysis across 28,104 individuals (40–84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p < 5 × 10−8) implicating neurological, metabolic, and immunological pathways – among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson’s disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p = 7.9 × 10−4) and bipolar disorder (p = 1.35 × 10−2) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.

Promises and challenges of cardiac organoids.

Cardiovascular diseases are currently the main cause of death. The study of the pathogenesis and treatment of these diseases is still a major challenge. Traditional 2D cultured cells and animal models have certain limitations. Heart organoids as models can simulate the structure and function of the body, providing a new research strategy. This paper mainly discusses the development of organoids and their application in the study of the cardiac developmental process, drug screening and treatment of genetic and non-genetic diseases, concluding with their strengths and weaknesses.

Off-target effects in CRISPR/Cas9 gene editing.

Gene editing stands for the methods to precisely make changes to a specific nucleic acid sequence. With the recent development of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system, gene editing has become efficient, convenient and programmable, leading to promising translational studies and clinical trials for both genetic and non-genetic diseases. A major concern in the applications of the CRISPR/Cas9 system is about its off-target effects, namely the deposition of unexpected, unwanted, or even adverse alterations to the genome. To date, many methods have been developed to nominate or detect the off-target sites of CRISPR/Cas9, which laid the basis for the successful upgrades of CRISPR/Cas9 derivatives with enhanced precision. In this review, we summarize these technological advancements and discuss about the current challenges in the management of off-target effects for future gene therapy.

The Expanding Spectrum of Autoinflammatory Diseases

Autoinflammatory diseases are systemic disorders caused by genetic or acquired abnormalities in certain signaling pathways of the innate immune system. Dysregulated activation of the inflammasome, i.e. molecular platforms responsible for the activation of caspase-1 and production of interleukin-1β, causes autoinflammation. Familial Mediterranean fever (FMF), the most common genetic autoinflammatory disease, is characterized by a periodic fever and serositis. The complex and heterogeneous genetic background of Japanese FMF patients, accompanied by potential overlap with other rheumatic diseases, suggests crosstalk between genetic and environmental factors. Recently, FMF has been recognized as being part of a spectrum of autoinflammatory syndromes named pyrin-associated autoinflammatory diseases. The discovery of a new monogenic autoinflammatory disease, A20 haploinsufficiency, may provide novel insights into early-onset Behçet's-like diseases. In contrast, adult-onset Still's disease and Schnitzler's syndrome are acquired autoinflammatory diseases without a monogenic abnormality. Although the concept of autoinflammatory diseases originally applied to monogenic hereditary recurrent fevers, it has been expanded to include non-genetic complex autoinflammatory diseases. Information concerning monogenic autoinflammatory diseases may prove useful for elucidating the molecular mechanisms underlying non-genetic autoinflammatory diseases.

Melanocytotoxic chemicals and their toxic mechanisms.

Melanocyte cell death can lead to various melanocyte-related skin diseases including vitiligo and leukoderma. Melanocytotoxic chemicals are one of the most well-known causes of nongenetic melanocyte-related diseases, which induce melanocyte cell death through apoptosis. Various chemicals used in cosmetics, medicine, industry and food additives are known to induce melanocyte cell death, which poses a significant risk to the health of consumers and industrial workers. This review summarizes recently reported melanocytotoxic chemicals and their mechanisms of toxicity in an effort to provide insight into the development of safer chemicals.

Rationally designed nanoparticle delivery of Cas9 ribonucleoprotein for effective gene editing

Programmable endonucleases such as CRISPR/Cas9 system emerge as a promising tool to treat genetic and non-genetic diseases such as hypercholesterolemia, Duchenne muscular dystrophy, and cancer. However, the lack of safe and efficient vehicles that enable intracellular delivery of CRISPR/Cas9 endonuclease is a big hurdle for its therapeutic applications. Here, we employed porous nanoparticle for the Cas9 ribonucleoprotein (RNP) delivery and achieved efficient knockout of target genes in vitro and in vivo. The porous nanoparticle, called ‘BALL’, enabled safe and direct intracellular Cas9 RNP delivery by improving bioavailability and serum stability. The BALL-mediated delivery of Cas9 RNP showed superior indel efficiency of about 40% in vitro and 20% in vivo in a model system employing green fluorescent protein (GFP). More importantly, intramuscular injection of the Cas9 RNP-BALL complex targeting the myostatin (MSTN) gene which is known to suppress muscle growth achieved successful knockout of the MSTN gene, resulting in the increase of muscle and the improved motor functions. Thus, we believe that the BALL is a promising delivery system for CRISPR-based genome editing technology, which can be applied to the treatment of various genetic diseases.

Cystic renal diseases: role of ultrasound. Part II, genetic cystic renal diseases.

Kidney cysts are quite common in adults. Though small simple renal cysts in an adult over 30-40 years of age are not too unusual, however, if the same cysts are seen in a child, and especially if there are additional findings, then several diagnostic possibilities may come to mind. The role of ultrasound, together with the help of intravenous contrast agents and Doppler mode, are very critical in describing the morphologic features and follow-up of the complex or multiple and bilateral renal cysts. These sonographic signs are occasionally specific for diagnosis, but in many cases sonographic clues should be evaluated together with the other genetic and clinical data to reach diagnosis.The first part of this pictorial essay included the introduction into the subject and the classification of non-genetic cystic renal diseases. The key features for the non-genetic cystic renal diseases are illustrated. In the second part, eye-catching features of genetic cystic renal diseases are demonstrated.

The Expanding Spectrum of Autoinflammatory Diseases.

Autoinflammatory diseases are systemic disorders caused by genetic or acquired abnormalities in certain signaling pathways of the innate immune system. Dysregulated activation of the inflammasome, i.e. molecular platforms responsible for the activation of caspase-1 and production of interleukin-1β, causes autoinflammation. Familial Mediterranean fever (FMF), the most common genetic autoinflammatory disease, is characterized by a periodic fever and serositis. The complex and heterogeneous genetic background of Japanese FMF patients, accompanied by potential overlap with other rheumatic diseases, suggests crosstalk between genetic and environmental factors. Recently, FMF has been recognized as being part of a spectrum of autoinflammatory syndromes named pyrin-associated autoinflammatory diseases. The discovery of a new monogenic autoinflammatory disease, A20 haploinsufficiency, may provide novel insights into early-onset Behçet's-like diseases. In contrast, adult-onset Still's disease and Schnitzler's syndrome are acquired autoinflammatory diseases without a monogenic abnormality. Although the concept of autoinflammatory diseases originally applied to monogenic hereditary recurrent fevers, it has been expanded to include non-genetic complex autoinflammatory diseases. Information concerning monogenic autoinflammatory diseases may prove useful for elucidating the molecular mechanisms underlying non-genetic autoinflammatory diseases.

Correlation of dermatoglyphics patterns with skeletal malocclusion

Dermatoglyphic Patterns and Skeletal Malocclusion: Dermatoglyphics is the study of the intricate dermal patterns found on the skin of the palmar and plantar surfaces of the hands and feet. The term dermatoglyphics means “skin carving.” He has proven to be of predictive value for both genetic and nongenetic diseases in the medical field. It has been noted that the period of embryonic development for oral and dermal tissues overlaps. Thus, any impact on the development of oral tissues during this period may also represent itself in the dermatoglyphic patterns. Aim: Keeping this in mind, the present study was designed to investigate the correlation between malocclusions and representation in dermatoglyphic patterns. Materials and Methodology: A total of 90 subjects were selected for the study. Thirty cases each of Class I, Class II, and Class III skeletal malocclusions were selected from the age group of 13–18 years of age with permanent molars present. Lateral cephalograms were taken and their dermatoglyphic patterns were recorded by rolling impression technique. The dermatoglyphic data were assessed for different finger ridge patterns and total ridge count (TRC). Results: On comparison of dermatoglyphic patterns between skeletal Class I, II, and III, the skeletal Class I group showed a markedly decreased number of loops and increased TRC. In the skeletal Class II group, we found markedly increased number of loops and markedly decreased TRC. In the skeletal Class III group, we observed a markedly decreased number of arches and increased TRC. Loops were found to be the most predominant pattern in the skeletal Class II and III groups. The mean TRC was found to be increased in the skeletal Class III group, followed by the Class I group and markedly decreased in the skeletal Class II group, which was statistically significant. Conclusion: It is concluded that dermatoglyphics can be used as a screening tool and for the early prediction of skeletal malocclusion at a younger age group. Dermatoglyphics have important practical and clinical implications which can be applied for preventive and interceptive orthodontics among pediatric patients and also for parent counseling.

Cystic renal diseases: role of ultrasound. Part I, non-genetic cystic renal diseases

Kidney cysts are quite common in adults. Though small simple renal cysts in an adult over 30-40 years of age are not too unusual, however, if the same cysts are seen in a child, and especially if there are additional findings, then several diagnostic possibilities may come to mind. The role of ultrasound, together with the help of intravenous contrast agents and Doppler mode, is very critical in describing the morphologic features and follow-up of the complex or multiple and bilateral renal cysts. Sonographic signs are occasionally specific for diagnosis, but in many cases they should be evaluated together with the other genetic and clinical data to reach a diagnosis.The first part of this pictorial essay includes "non-genetic cystic renal diseases" and the second part will include "genetic cystic renal diseases".

Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts.

Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog’s MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros’ O2k-technology and Agilent Seahorse XF technology.

Mesoscopic Optical Imaging of Whole Mouse Heart.

Both genetic and non-genetic cardiac diseases can cause severe remodeling processes in the heart. Structural remodeling, such as collagen deposition (fibrosis) and cellular misalignment, can affect electrical conduction, introduce electromechanical dysfunctions and, eventually, lead to arrhythmia. Current predictive models of these functional alterations are based on non-integrated and low-resolution structural information. Placing this framework on a different order of magnitude is challenging due to the inefficacy of standard imaging methods in performing high-resolution imaging in massive tissue. In this work, we describe a methodological framework that allows imaging of whole mouse hearts with micrometric resolution. The achievement of this goal has required a technological effort where advances in tissue transformation and imaging methods have been combined. First, we describe an optimized CLARITY protocol capable of transforming an intact heart into a nanoporous, hydrogel-hybridized, lipid-free form that allows high transparency and deep staining. Then, a fluorescence light-sheet microscope able to rapidly acquire images of a mesoscopic field of view (mm-scale) with the micron-scale resolution is described. Following the mesoSPIM project, the conceived microscope allows the reconstruction of the whole mouse heart with micrometric resolution in a single tomographic scan. We believe that this methodological framework will allow clarifying the involvement of the cytoarchitecture disarray in the electrical dysfunctions and pave the way for a comprehensive model that considers both the functional and structural data, thus enabling a unified investigation of the structural causes that lead to electrical and mechanical alterations after the tissue remodeling.

RARE ORPHAN DISEASES IN PATIENTS ON HOME ARTIFICIAL NUTRITION.

Rare genetic and non-genetic diseases are often associated with high risk of malnutrition[1]. The purpose of the study is to evaluated rare diseases among patients on Home Artificial Nutrition (HAN) and prescriptions registered at Local Health Care Unit Naples 3, Italy. Data were collected from 231 patients (M=131; F=100) recorded in 2019 (1st January-31st December). Oral Nutritional Supplements (ONS), Enteral Nutrition (HEN), Parenteral Nutrition (HPN) were included; complications of pregnancy and childbirth were excluded. Adults were 182 (78.8%), Pediatrics 49 (21.2% ). Rare diseases of the nervous system were 177 (76.7%), congenital anomalies 25 (10.8%) and inborn errors of metabolism 8 (3%). Respiratory, hematologic, immunologic, and skin diseases, primitive glomerulopathies and intestinal disorders, rare tumors were found in fewer cases (9.1%). Amyotrophic Lateral Sclerosis was the most frequent diagnosis (43.3%; 94 ALS and 6 ALS-Juvenile). Spinal Muscolar Atrophy (SMA) was found in 23.8% of pediatrics, Progressive Supranuclear Palsy (PSP) and Duchenne Muscular Dystrophy (DMD) in 8.4% and 4.5% of adult patients. ONS were 123, mainly prescribed to adults (87%); HEN were 100, administered through Percutaneous Endoscopy Gastrostomy (86%) and nasogastric tube feeding (14%), HPN were only 9 prescriptions. Nutritional impairment in patient with rare neurologic diseases is frequent. HAN could improve clinical management of symptoms worsening quality of life of patients. Further research is needed to evaluate the impact of nutritional intervention on individual clinical outcome[1].