-
Advanced Materials (Deerfield Beach,... Jun 2024Proteins with multiple domains play pivotal roles in various biological processes, necessitating a thorough understanding of their structural stability and functional...
Proteins with multiple domains play pivotal roles in various biological processes, necessitating a thorough understanding of their structural stability and functional interplay. Here, a structure-guided protein engineering approach is proposed to develop thermostable Cas9 (CRISPR-associated protein 9) variant for CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) interference applications. By employing thermodynamic analysis, combining distance mapping and molecular dynamics simulations, deletable domains are identified to enhance stability while preserving the DNA recognition function of Cas9. The resulting engineered Cas9, termed small and dead form Cas9, exhibits improved thermostability and maintains target DNA recognition function. Cryo-electron microscopy analysis reveals structural integrity with reduced atomic density in the deleted domain. Fusion with functional elements enables intracellular delivery and nuclear localization, demonstrating efficient gene suppression in diverse cell types. Direct delivery in the mouse brain shows enhanced knockdown efficiency, highlighting the potential of structure-guided engineering to develop functional CRISPR systems tailored for specific applications. This study underscores the significance of integrating computational and experimental approaches for protein engineering, offering insights into designing tailored molecular tools for precise biological interventions.
PubMed: 38944889
DOI: 10.1002/adma.202404680 -
Journal of Gastrointestinal and Liver... Jun 2024Recent research has shown that Western-style diets have been associated with an increased risk of inflammatory bowel diseases (IBD). Our aim was to examine the link...
BACKGROUND AND AIMS
Recent research has shown that Western-style diets have been associated with an increased risk of inflammatory bowel diseases (IBD). Our aim was to examine the link between an anti-inflammatory diet and the maintenance of IBD remission, as well as to assess the potential therapeutic advantages of this dietary approach in preserving IBD remission.
METHODS
The inclusion and exclusion criteria were applied to a total of 189 individuals with IBD, with 21 individuals not meeting the criteria. Therefore, 168 eligible patients were enrolled in the study and allocated to either an anti-inflammatory diet or a regular diet, based on their personal preference.
RESULTS
A cohort of 168 IBD adult patients was recruited for the study: 88 patients with ulcerative colitis and 80 with Crohn's disease. The intervention group received an anti-inflammatory diet consisting of the removal of red and processed meat, fried foods, high-lactose foods, fast food, white bread, sugar, and vegetable oils rich in omega-6 for a period of 1 year. The clinical response was maintained in 80 patients (95.2%) in the intervention group and in 72 patients (85.7%) in the control group (p-value=0.036). Although not statistically significant, fecal calprotectin was higher in the control group than in the intervention group at follow-up.
CONCLUSIONS
Patients who adhered to an anti-inflammatory diet exhibited a higher rate of maintenance of clinical remission. Furthermore, improvement in inflammation tests was observed in the intervention group, reinforcing the proposition that IBD is a lifestyle-related disease.
Topics: Humans; Female; Male; Adult; Prospective Studies; Crohn Disease; Colitis, Ulcerative; Biomarkers; Recurrence; Middle Aged; Feces; Remission Induction; Leukocyte L1 Antigen Complex; Treatment Outcome; Young Adult; Time Factors; Inflammation Mediators; Diet, Healthy
PubMed: 38944867
DOI: 10.15403/jgld-5482 -
Advances in Gerontology = Uspekhi... 2024The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in...
The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in comparison with young and middle-aged patients. A total of 81 patients with chronic pyelonephritis in the exacerbation phase were examined. All patients were divided into three age groups according to WHO recommendations: the 1st - 42patients of young age (18-44 years); the 2nd - 17 patients of middle age (45-59 years); the 3rd - 22 elderly patients (60-74 years). Computer morphometry of lymphocytes was performed in all examined patients. In elderly patients with chronic pyelonephritis the size and сytoplasmic-nuclear ratio of lymphocytes increase. This indicates the preservation of lymphocyte defense responses at this age. In male patients with chronic pyelonephritis in the 1st and 2nd age groups the size of lymphocytes increases, and in female patients - decreases. The сytoplasmic-nuclear ratio increases in males of these age groups, while it remains unchanged or decreases in females. Indirect indications of reduced immunity in young and middle-aged women with chronic inflammation in the kidneys have been obtained.
Topics: Humans; Pyelonephritis; Middle Aged; Female; Male; Lymphocytes; Aged; Adult; Chronic Disease; Age Factors
PubMed: 38944771
DOI: No ID Found -
The FEBS Journal Jun 2024Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the...
Iron overload (IO) is known to contribute to metabolic dysfunctions such as type 2 diabetes and insulin resistance. Using L6 skeletal muscle cells overexpressing the CDGSH iron-sulfur domain-containing protein 1 (CISD1, also known as mitoNEET) (mitoN) protein, we examined the potential role of MitoN in preventing IO-induced insulin resistance. In L6 control cells, IO resulted in insulin resistance which could be prevented by MitoN as demonstrated by western blot of p-Akt and Akt biosensor cells. Mechanistically, IO increased; mitochondrial iron accumulation, mitochondrial reactive oxygen species (ROS), Fis1-dependent mitochondrial fission, mitophagy, FUN14 domain-containing protein 1 (FUNDC1) expression, and decreased Parkin. MitoN overexpression was able to reduce increases in mitochondrial iron accumulation, mitochondrial ROS, mitochondrial fission, mitophagy and FUNDC1 upregulation due to IO. MitoN did not have any effect on the IO-induced downregulation of Parkin. MitoN alone also upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) protein levels, a master regulator of mitochondrial biogenesis. The use of mitochondrial antioxidant, Skq1, or fission inhibitor, Mdivi-1, prevented IO-induced insulin resistance implying both mitochondrial ROS and fission play a causal role in the development of insulin resistance. Taken together, MitoN is able to confer protection against IO-induced insulin resistance in L6 skeletal muscle cells through regulation of mitochondrial iron content, mitochondrial ROS, and mitochondrial fission.
PubMed: 38944692
DOI: 10.1111/febs.17214 -
American Journal of Surgery Jun 2024Experimental work suggested that resuscitative Endovascular Balloon Occlusion of the aorta (REBOA) preserves cerebral circulation in animal models of traumatic brain...
BACKGROUND
Experimental work suggested that resuscitative Endovascular Balloon Occlusion of the aorta (REBOA) preserves cerebral circulation in animal models of traumatic brain injury. No clinical work has evaluated the role of REBOA in the presence of associated severe traumatic brain injury (TBI). We investigated the impacts of REBOA on neurological and survival outcomes.
METHODS
Propensity-score matched study, using the American College of Surgeons Trauma Quality Improvement Program database. Patients with severe TBI patients (Abbreviated Injury Scale ≥3) receiving REBOA within 4 h from arrival were matched with similar patients not receiving REBOA. Neurological matching included head AIS, pupils, and midline shift. Clinical outcomes were compared between the two groups.
RESULTS
434 REBOA patients were matched with 859 patients without REBOA. Patients in the REBOA group had higher rates of in-hospital mortality (63.6 % vs 44.2 %, p < 0.001), severe sepsis (4.4 % vs 2.2 %, p = 0.029), acute kidney injury (10.1 % vs 6.6 %, p = 0.029), and withdrawal of life support (25.4 % vs 19.6 %, p = 0.020) despite of lower craniectomy/craniotomy rate (7.1 % vs 12.7 %, p < 0.002).
CONCLUSION
In patients with severe TBI, REBOA use is associated with an increased risk of in-hospital mortality, AKI, and infectious complications.
PubMed: 38944625
DOI: 10.1016/j.amjsurg.2024.115798 -
Obesity Research & Clinical Practice Jun 2024Transit bipartition (TB) emerges as a bariatric surgery alternative to Duodenal Switch (DS), emphasizing complete intestinal access and reduced malabsorption. By...
Transit bipartition (TB) emerges as a bariatric surgery alternative to Duodenal Switch (DS), emphasizing complete intestinal access and reduced malabsorption. By directly stimulating the distal ileum, TB promotes weight loss while preserving endoscopic duodenal access. This technique enhances anorexigenic hormones, aiding in satiety and weight loss, with lower malnutrition risks than DS. TB shows favorable short-term outcomes in weight management and comorbidity reduction, serving as a simpler, less malabsorptive option than DS. Nonetheless, long-term studies are essential for comprehensive efficacy assessment.
PubMed: 38944551
DOI: 10.1016/j.orcp.2024.06.002 -
Thoracic Surgery Clinics Aug 2024Cardiothoracic surgeons work in high-intensity environments starting in surgical training and throughout their careers. They deal with critical patients. Their routine... (Review)
Review
Cardiothoracic surgeons work in high-intensity environments starting in surgical training and throughout their careers. They deal with critical patients. Their routine procedures are delicate, require extensive attention to detail, and can have detrimental effects on patients' lives. Cardiothoracic surgeons are required to perform at their best capacity incessantly. To do this, they must safeguard their mental and physical well-being. Preserving health through sleep, nutrition, exercise, and routine medical checkups ensures a cardiothoracic surgeon's well-being. Great personal effort and discipline is required to maintain health in a busy schedule. We offer our best recommendations from expert peers in the field.
Topics: Humans; Sleep; Nutritional Status; Cardiac Surgical Procedures; Thoracic Surgical Procedures; Thoracic Surgery; Exercise
PubMed: 38944448
DOI: 10.1016/j.thorsurg.2024.04.004 -
International Journal of Cardiology Jun 2024Heart failure is an important cause of mortality and morbidity worldwide. Heart failure with preserved ejection fraction (HFpEF) incidence and prevalence is increasing,... (Review)
Review
Heart failure is an important cause of mortality and morbidity worldwide. Heart failure with preserved ejection fraction (HFpEF) incidence and prevalence is increasing, and the phenotype associated with obesity is the most frequent. Epicardial adipose tissue (EAT) is directly associated with systemic obesity and several previous studies have shown a clear link between EAT and HFpEF. Moreover, the restriction induced by the pericardium is also linked to HFpEF. In this review we will describe the epidemiological association between the pericardium, EAT and HFpEF, how to quantify EAT, what are the pathophysiological mechanism to explain theses association and how can the pericardium and EAT be a treatment target in patients with HFpEF.
PubMed: 38944349
DOI: 10.1016/j.ijcard.2024.132303 -
International Journal of Cardiology Jun 2024The prevalence of HF with preserved ejection raction (HFpEF, with EF ≥50%) is increasing across all populations with high rates of hospitalization and mortality,... (Review)
Review
The prevalence of HF with preserved ejection raction (HFpEF, with EF ≥50%) is increasing across all populations with high rates of hospitalization and mortality, reaching up to 80% and 50%, respectively, within a 5-year timeframe. Comorbidity-driven systemic inflammation is thought to cause coronary microvascular dysfunction and increased epicardial adipose tissue, leading to downstream friborsis and molecular changes in the cardiomyocyte, leading to increased stiffness and diastolic dynsfunction. HFpEF poses unique challenges in terms of diagnosis due to its complex and diverse nature. The diagnosis of HFpEF relies on a combination of clinical assessment, imaging studies, and biomarkers. An additional important step in diagnosing HFpEF involves excluding certain cardiac diagnoses that may be specific underlying causes of HFpEF or may be masquerading as HFpEF and require specific alternative treatment approaches. In addition to administering sodium-glucose cotransporter 2 inhibitors to all patients, the most effective approach to enhance clinical outcomes may involve tailored therapy based on each patient's unique clinical profile. Exercise should be recommended for all patients to improve the quality of life. Glucagon-like peptide-1 1 agonists are a promising treatment option in obese HFpEF patients. Novel approaches targeting inflammation are also in early phase trials.
PubMed: 38944348
DOI: 10.1016/j.ijcard.2024.132304 -
The Science of the Total Environment Jun 2024Microplastics (MPs) are particles with sizes of ≤5 mm formed when plastic materials break down. These contaminants are often found in marine environments, making it... (Review)
Review
Microplastics (MPs) are particles with sizes of ≤5 mm formed when plastic materials break down. These contaminants are often found in marine environments, making it easy for sea turtles to ingest them and for their microbiome to be exposed. MPs can disrupt microbiome balance, leading to dysbiosis and making organisms more susceptible to diseases. Owing to the significance of these processes, it is crucial to dedicate research to studying the metabolic and genetic analysis of the gut microbiome in sea turtles. The objective of this study was to describe the effects of exposure to MPs on the gut microbiome of sea turtles, based on current knowledge. This review also aimed to explore the potential link between MP exposure and disease susceptibility in these animals. We show that the metabolites produced by the gut microbiome, such as short-chain fatty acids (SCFAs), polyamines, and polysaccharide A, can regulate the expression of host genes. Regulation occurs through various mechanisms, including histone acetylation, DNA methylation, and the modulation of cytokine gene expression. These processes are essential for preserving the integrity of the gut mucosa and enhancing the functionality of immune cells. Exposure to MPs disrupts the gut microbiome and alters gene expression, leading to immune system disturbances in sea turtles. This vulnerability makes turtles more susceptible to opportunistic microorganisms such as chelonid alphaherpesvirus 5 (ChAHV5), which is linked to the development of fibropapillomatosis (FP). Additionally, targeted dietary interventions or the use of live microorganisms such as probiotics can help restore microbial biodiversity and recover lost metabolic pathways. The goal of these interventions is to restore the functionality of the immune system in sea turtles undergoing rehabilitation at specialized centers. The gut microbiome plays a crucial role in sea turtle health, sparking discussions and investigations that can potentially lead to promising treatments for these animals.
PubMed: 38944299
DOI: 10.1016/j.scitotenv.2024.174298