Characteristic Structural Changes Research Articles

Establishment of closed 35S ribosomal RNA gene chromatin in stationary Saccharomyces cerevisiae cells.

As a first step in eukaryotic ribosome biogenesis RNA polymerase (Pol) I synthesizes a large ribosomal RNA (rRNA) precursor from multicopy rRNA gene loci. This process is essential for cellular growth and regulated in response to the cell's physiological state. rRNA gene transcription is downregulated upon growth to stationary phase in the yeast Saccharomyces cerevisiae. This reduction correlates with characteristic changes in rRNA gene chromatin structure from a transcriptionally active 'open' state to a non-transcribed 'closed' state. The conserved lysine deacetylase Rpd3 was shown to be required for this chromatin transition. We found that Rpd3 is needed for tight repression of Pol I transcription upon growth to stationary phase as a prerequisite for the establishment of the closed chromatin state. We provide evidence that Rpd3 regulates Pol I transcription by adjusting cellular levels of the Pol I preinitiation complex component core factor (CF). Importantly, our study identifies CF as the complex limiting the number of open rRNA genes in exponentially growing and stationary cells.

Brain network functional connectivity changes in long illness duration chronic schizophrenia.

Chronic schizophrenia has a course of 5 years or more and has a widespread abnormalities in brain functional connectivity. This study aimed to find characteristic functional and structural changes in a long illness duration chronic schizophrenia (10 years or more). Thirty-six patients with a long illness duration chronic schizophrenia and 38 healthy controls were analyzed by independent component analysis of brain network functional connectivity. Correlation analysis with clinical duration was performed on six resting state networks: auditory network, default mode network, dorsal attention network, fronto-parietal network, somatomotor network, and visual network. The differences in the resting state network between the two groups revealed that patients exhibited enhanced inter-network connections between default mode network and multiple brain networks, while the inter-network connections between somatomotor network, default mode network and visual network were reduced. In patients, functional connectivity of Cuneus_L was negatively correlated with illness duration. Furthermore, receiver operating characteristic curve of functional connectivity showed that changes in Thalamus_L, Rectus_L, Frontal_Mid_R, and Cerebelum_9_L may indicate a longer illness duration chronic schizophrenia. In our study, we also confirmed that the course of disease is significantly associated with specific brain regions, and the changes in specific brain regions may indicate that chronic schizophrenia has a course of 10 years or more.

Influence of milk phospholipids on microstructural changes in rat liver under tetracycline-induced hepatosis

The growing number of cases of adverse effects of medicines on the liver leads to hepatopathology and the development of complications such as cirrhosis, necrosis, liver failure, and liver carcinoma. Therefore, the purpose of this study was to determine the characteristic structural changes in the liver of rats with tetracycline damage and to find out the corrective effectiveness of milk phospholipids. The study performed histological examination of sections from different parts of the liver in experimental rats, which were stained with haematoxylin and eosin according to the conventional method. It was found that in case of artificial modelling of tetracycline-induced hepatosis in rats, the general architecture of the liver is preserved. At the same time, large-scale damage to hepatocytes and the development of fatty and granular dystrophy were recorded in the affected animals. Some of the damaged cells were destroyed, followed by lysis of fragments of the destroyed cells. The described microscopic changes were most pronounced in the areas of the liver under its capsule. As a result, there was partial or complete disorganisation of the liver lobes in all lobes of the organ. The use of milk phospholipids in the form of a biologically active additive “FLP-MD” as a corrective therapy in sick rats prevented the development of hepatocyte dyscomplexity, contributed to a substantial reduction in the count of destroyed cells in a state of dystrophy with isolated cases of disordered organisation of the liver laminae. This suggests a pronounced stimulatory effect of milk phospholipids on the processes of hepatocyte regeneration and repair in tetracycline-induced liver damage in rats. In case of separate administration of a milk phospholipid-based supplement to clinically healthy animals, the microscopic structure of liver samples did not differ from that of the control group. The findings of this study are of practical value for pathologists, clinicians, and therapists in case of development of drug-induced hepatopathology in animals, especially when using tetracycline antibiotics, and for determining the strategy in the treatment of such patients

Functional amyloid fibrils of biofilm-forming marine bacterium Pseudomonas aeruginosa PFL-P1 interact spontaneously with pyrene and augment the biodegradation

Bacteria thrive in biofilms embedding in the three-dimensional extracellular polymeric substances (EPS). Functional Amyloid in Pseudomonas (Fap), a protein in EPS, efficiently sequesters polycyclic aromatic hydrocarbons (PAHs). Present study reports the characterization of Fap fibrils from Pseudomonas aeruginosa PFL-P1 and describes the interaction with pyrene to assess the impact on pyrene degradation. Overexpression of fap in E. coli BL21(DE3) cells significantly enhances biofilm formation (p < 0.0001) and amyloid production (p = 0.0002), particularly with pyrene. Defibrillated Fap analysis reveals FapC monomers and increased fibrillation with pyrene. Circular Dichroism (CD), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray Diffraction (XRD) unveil characteristic amyloid peaks and structural changes in Fap fibrils upon pyrene exposure. 3D-EEM analysis identifies a protein-like fluorophore in Fap fibrils, exhibiting pyrene-induced fluorescence quenching. Binding constants range from 5.23 to 7.78 M−1, with ΔG of −5.10 kJ mol−1 at 298 K, indicating spontaneous and exothermic interaction driven by hydrophobic forces. Exogenous Fap fibrils substantially increased the biofilm growth and pyrene degradation by P. aeruginosa PFL-P1 from 46 % to 64 % within 7 days (p = 0.0236). GC–MS identifies diverse metabolites, implying phthalic acid pathway in pyrene degradation. This study deepens insights into structural dynamics of Fap fibrils when exposed to pyrene, offering potential application in environmental bioremediation.

Results of surgical treatment of hernias of the anterior abdominal wall in patients with connective tissue dysplasia syndrome

Relevance. The problem of surgical treatment of hernias of the anterior abdominal wall remains relevant. Despite the introduction of new technologies, the results of surgical interventions cannot be considered satisfactory. The development of hernias and their relapses is facilitated by connective tissue dysplasia syndrome, which manifests as phenotypic signs, disorders of the autonomic nervous system, and morphological changes in the structure of the connective tissue.Objective. To improve the results of surgical treatment of hernias of the anterior abdominal wall in patients with connective tissue dysplasia syndrome.Materials and methods. The study was based on clinical observations and studies of 497 patients with hernias of the anterior abdominal wall. Inguinal (29 %) and postoperative hernias (21 %) predominated. In the structure of recurrent hernias, postoperative (47 %) and inguinal (42 %) hernias were more often observed. Hernioautoplasty was performed in 31 %, plastic surgery using a mesh endoprosthesis — in 54 %, endoscopic hernioplasty — in 15 % of patients. The severity of the clinical, morphological, and metabolic signs of connective tissue dysplasia syndrome was assessed. The concentration of free hydroxyproline in the blood was determined as a marker of connective tissue metabolism. The state of the autonomic nervous system was assessed using variational pulsometry. To assess the state of collagen in connective tissue, a morphological study of the aponeuroses of the muscles of the anterior abdominal wall was performed in the clinic and experiment.Results. The overall incidence of dysplasia in hernias of the anterior abdominal wall was 48 %. The highest incidence of connective tissue dysplasia was detected in recurrent hernias (70 %). Studies of the level of free hydroxyproline in abdominal hernias have shown the dependence of this marker on the degree of connective tissue dysplasia. In cases of recurrent hernias, the highest intensity of collagen biodegradation was observed. A study of the functional state of the autonomic nervous system revealed a predominance of sympathetic activity in abdominal wall hernias with an increase in the tension index by more than 4 times. An increase in the severity of dysplasia is accompanied by an increase in sympathetic activity. Histological studies in patients with abdominal hernias revealed characteristic changes in the morphological structure of the connective tissue. The average thickness, specific area, brightness of staining, and orientation of collagen fibers in postoperative and recurrent hernias were significantly different compared to the group with primary hernias (p˂0.05). Additionally, an experiment was performed on 30 laboratory animals (white rats) to determine the optimal conditions for healing of the aponeurosis of the anterior abdominal wall. The activating effect of prozerin on the process of histogenesis in the wound was revealed. Based on the results of the study, the surgical treatment of hernias was assessed depending on the type of hernioplasty and the severity of connective tissue dysplasia. It has been established that with increasing severity of dysplasia, the frequency of relapses increases by 2.2–3.4 times. With the progression of dysplasia, the frequency of relapses increased by more than twice. The use of the endoscopic hernioplasty method reduced the risk of recurrent hernias by 9 times.Conclusion. In externally localized hernias, the incidence of connective tissue dysplasia ranges from 34 % to 70 %. In patients with connective tissue dysplasia syndrome after hernia autoplasty, the frequency of hernia recurrence is 3.4 times higher. Drug correction of sympathetic activity along with alloplasty increased collagen synthesis intensity by 36 %. The choice of hernia repair method should be determined by the type of hernia, the age of the patient, and the severity of connective tissue dysplasia.

Correlation between Structural and Functional Changes in Patients with Raised Intraocular Pressure Due to Graves' Orbitopathy.

This study explores the complication of secondary intraocular pressure (IOP) elevation and consequent glaucoma development in Graves' orbitopathy (GO), an autoimmune disorder associated with hyperthyroidism. Utilizing Octopus 900 visual field testing and optical coherence tomography (OCT), the research established correlations between functional and structural changes in optic nerve regions in patients with GO and patients with GO with elevated IOP (GO IOP) groups. A comparison with primary open-angle glaucoma (POAG) was conducted in a cohort of 182 subjects. The study identifies optic nerve head parameters that effectively differentiate changes in GO and GO IOP groups. In the GO group, the strongest correlation between structural and functional changes was observed in sector 7, while in the GO IOP group, it was in sectors 1 and 7. For POAG, correlation was found in six sectors. Elevated IOP in GO correlates with structural and functional impairments similarly to early glaucoma. Risk factors for GO-related elevated IOP included older age, longer duration of thyroid disease, and higher anti-thyroglobulin values. The study highlights the significance of regular IOP measurements, visual field assessments, and OCT examinations in GO patients. Early antiglaucoma intervention is warranted when characteristic structural and functional changes and/or risk factors are identified.

Right Ventricular Structure and Function in Adolescent Athletes: A 3D Echocardiographic Study.

The aim of this study was to characterize the right ventricular (RV) contraction pattern and its associations with exercise capacity in a large cohort of adolescent athletes using resting three-dimensional echocardiography (3DE). We enrolled 215 adolescent athletes (16±1 years, 169 males, 12±6 hours of training/week) and compared them to 38 age and sex-matched healthy, sedentary adolescents. We measured the 3DE-derived biventricular ejection fractions (EF). We also determined the relative contributions of longitudinal EF (LEF/RVEF) and radial EF (REF/RVEF) to the RVEF. Same-day cardiopulmonary exercise testing was performed to calculate VO2/kg. Both LV and RVEFs were significantly lower (athletes vs. controls; LVEF: 57±4 vs 61±3, RVEF: 55±5 vs 60±5%, p<0.001). Interestingly, while the relative contribution of radial shortening to the global RV EF was also reduced (REF/RVEF: 0.40±0.10 vs 0.49±0.06, p<0.001), the contribution of the longitudinal contraction was significantly higher in athletes (LEF/RVEF: 0.45±0.08 vs 0.40±0.07, p<0.01). The supernormal longitudinal shortening correlated weakly with a higher VO2/kg (r=0.138, P=0.044). Similarly to the adult athlete's heart, the cardiac adaptation of adolescent athletes comprises higher biventricular volumes and lower resting functional measures with supernormal RV longitudinal shortening. Characteristic exercise-induced structural and functional cardiac changes are already present in adolescence.

Structural Parameters of the Brain and Bone Structures of the Head and Neck in Patients with Various Types of Mucopolysaccharidoses According to Magnetic Resonance Imaging of the Brain

Background. Mucopolysaccharidoses are diseases from the group of lysosomal storage diseases that have a progressive course. CNS damage is one of the main factors in the development of severe, life-threatening complications. Aims — аssessment of structural changes in the brain and bones of the head and neck in patients with various types of mucopolysaccharidoses. Methods. The research included 136 children aged from 11 months to 17 years, 81 patients of which showed various types of mucopolysaccharidoses: MPS I — 15 people, MPS II — 37, MPS III A — 10, MPS IIIB — 4, MPS IIIC — 2, MPS IVA — 6, VI — 7 people. The control group included 56 children without neurological, psychiatric and severe somatic illnesses. Results. For mucopolysaccharidoses types I, II, III and VI, the most characteristic structural changes on the brain MRI were white matter lesions, mainly periventricular: expansion of the perivascular spaces (70%), atrophy of the cerebral hemispheres (42%), hippocampus, (31%), ventriculomegaly (6.2%), stenosis of the cervical spine (64%), hydrocephalus, expansion of the cerebrospinal fluid spaces of the posterior cranial fossa, arachnoid cysts. Conclusions. The results of the obtained data analysis made it possible to identify the macrostructural specifics of the brain disorders and cervical spine in various types of MPS, as well as their prognostic significance.

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Impulse oscillometry for the evaluation and management of pediatric asthma

Asthma is the most common chronic disease during childhood. While most of characteristic structural changes in asthma have been identified in the large airways, there is a growing recognition of peripheral airway dysfunction as a crucial factor in the development of asthma. This dysfunction is a defining feature in adults with persistent asthma. However, little is known about the contribution of small airway impairment in children with asthma due to the relatively low sensitivity of conventional lung function tests, such as spirometry. Recently, new diagnostic tools that are sensitive to both large and small airway function and inflammation have been introduced in clinical practice. The most widely studied of these tools in preschool and school-aged children is impulse oscillometry (IOS). This review addresses the latest findings on the usefulness of IOS in identifying small airway dysfunction, predicting the risk of uncontrolled asthma, and ultimately improving the diagnosis and management of asthma in children.

Study of Neutrophil–Lymphocyte Ratio, Interleukin-6 (IL-6) and Tumor Necrosis Factor-Alpha (TNF-α) in Type 2 Diabetes with Diabetic Nephropathy

Abstract Background Diabetic kidney disease is defined by characteristic structural and functional changes. The predominant structural changes include mesangial expansion, glomerular basement membrane thickening, podocyte injury, and, ultimately, glomerular sclerosis. The major clinical manifestations of diabetic nephropathy are albuminuria, hematuria (less often), and, in many patients, progressive chronic kidney disease, which can be slowed with optimal therapy. Objective to assess the Neutrophil-lymphocyte Ratio, Interleukin- 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in Type 2 Diabetes with Diabetic Nephropathy. Patients and Methods In Our study We collect 90 subjects with their ages ranging from 35-70, selected from Internal Medicine and Endocrinology outpatient clinics and the inpatient department at Ain Shams University Hospitals. Results As regards NLR, there were statistically significant and direct correlations between NLR and IL6, TNF, serum BUN, serum creatinine and albumin to creatinine ratio, while significant and indirect correlation with EGFR. As regards IL6, there were statistically significant and direct correlations between IL6 and TNF, serum BUN, serum creatinine and albumin to creatinine ratio, while significant and indirect correlation with BMI and EGFR. As regards TNF, there were statistically significant and direct correlations between TNF and serum BUN and albumin to creatinine ratio. There is no statistical difference between the studied groups as regard sex, age, BMI, SBP, DBP. Conclusion The current study could find that NLR, IL-6 and TNF-α were significantly associated with albuminuria in Type 2 Diabetic patients with DN and that they can be used as evident biomarkers in assessing the progression of deteriorating renal function and different stages of renal disease in patients with DN.

Morphological structure of enamel caries in the dynamic process of demineralization and remineralization

According to modern ideas, the carious process at the white spot stage is reversible, so all the attention of scientists is directed to the development of means to restore the crystal lattice of tooth enamel. The purpose of the study is to evaluate morphological changes in caries at the white spot stage and the process of structural remineralization of the carious lesion area. Clinically active initial lesions were detected visually, using optical magnification and positive staining. Structural changes in enamel were studied by scanning electron microscopy of surface impressions obtained from the surface of demineralized enamel. Remineralizing therapy was carried out by applying ApaCare restorative gel (Germany) with nanodispersed highly active hydroxyapatite. Determination of the intensity of dental caries by the DMFT and dmft index showed 9.04 ± 0.40 points on average in the group of subjects, children with code 1 according to the ICDAS index made up 50.8%. Colour reactions showed 7.80 ± 0.21 points on average in the group. SEM visualized characteristic structural changes in the area of the carious spot – an increase in the porosity of the enamel surface with exposure of the fine crystalline structure and destruction of interprismatic fibrillar structures. When using a remineralizing agent, a roller-like deposition of an amorphous remineralizing substance is characteristic, and at the final stage, a smooth enamel surface with a fine crystal lattice is restored. The restoration of the prismatic structure of the enamel occurs due to the mineralization of the preserved fibrillar walls in the interprismatic space. Clinically, at this stage, the enamel visually restores its original shine, smoothness, and colour. In 81.8% of cases, the dye did not penetrate the previously demineralized enamel. The high level of non-cavitated active caries lesions can be largely controlled by the use of remineralizing agents. Further research involves studying the quantitative characteristics of the processes of de- and remineralization of tooth enamel.

Extraction and modification of protein from sesame oil cake by the application of emerging technologies

Present work evaluated the extraction yield and quality of protein from defatted sesame meal (DSM) using ultrasound-assisted extraction (UAE), low-temperature microwave-assisted extraction (MAE), and moderate electric field-assisted extraction (MEFAE). It was observed that the application of emerging technologies as pre-treatments significantly increased protein yield from 26.4% (without pre-treatments) to 38.9% (with UAE 450 W–20 min), 36.05% for MAE (with 500 W–20 min) and 32.75% for MEFAE (with 100 V–30 min) and improved the functional properties of Sesame protein isolate (SPI). FTIR revealed Amide I to III bands in SPI, with characteristic changes in protein secondary structure. The treated sample showed higher thermal stability evident from the denaturation temperature increase from 203.41 to 221.40 °C. The protein's microstructure in this study was transformed using various extraction techniques into a compact structure with a wrinkled surface. MAE-SPI showed maximum Invitro protein digestibility as 94.44%. The molecular weight profile revealed that the SPI samples' protein bands had molecular weights between 6.5 and 200 kDa. SDS-PAGE results revealed a change in the intensity of protein bands, and all of the main allergen protein bands were degraded.

Effect of fermented heat-treated rice bran on performance and possible role of intestinal microbiota in laying hens.

Rice bran is a high-quality and renewable livestock feed material rich in nutrients and bioactive substances. To investigate the effects of dietary supplementation with fermented heat-treated rice bran on the performance, apparent digestibility of nutrients, cecal microbiota and metabolites in laying hens, a total of 128 18-week-old Hy-Line brown layers were randomly assigned to four treatment groups: 2.5% HRB (basal diet contained 2.5% heat-treated rice bran), 5.0% HRB (5.0% heat-treated rice bran), 2.5% FHRB (2.5% fermented heat-treated rice bran), 5.0% FHRB (5.0% fermented heat-treated rice bran). Results showed that FHRB supplementation significantly increased the average daily feed intake (ADFI) during 25-28 weeks, and improved apparent digestibility of dry matter (DM), crude protein (CP), ether extract (EE) and crude fiber (CF) in laying hens. Moreover, feeding 5.0% of HRB and FHRB resulted higher egg production (EP) and average egg weight (AEW) during the feeding period, and decreased the feed conversion ratio (FCR) during 21 to 28 weeks. The alpha and beta diversity indices indicated that FHRB altered the cecal microbiota. In particular, dietary supplementation with FHRB significantly increased the relative abundances of Lachnospira and Clostridium. Compared with the 2.5% level of supplementation, supplementing 5.0% HRB and 5.0% FHRB increased the relative abundances of Firmicutes, Ruminococcus and Peptococcus, and lowered the relative abundance of Actinobacteria. Furthermore, dietary FHRB supplementation significantly increased the concentration of short-chain fatty acids in cecum and changed the overall metabolome. The results of correlation analysis showed a close interaction between cecal microbiota, metabolites and apparent digestibility of nutrients. Taken together, we revealed that FHRB supplementation can induce characteristic structural and metabolic changes in the cecal microbiome, which could potentially promote nutrient digestion and absorption, and improve the production performance of laying hens.

Modulation of Bleomycin-induced Oxidative Stress and Pulmonary Fibrosis by Ginkgetin in Mice via AMPK.

Ginkgetin, a flavonoid extracted from Ginkgo biloba, has been shown to exhibit broad anti-inflammatory, anticancer, and antioxidative bioactivity. Moreover, the extract of Ginkgo folium has been reported on attenuating bleomycin-induced pulmonary fibrosis, but the anti-fibrotic effects of ginkgetin are still unclear. This study was intended to investigate the protective effects of ginkgetin against experimental pulmonary fibrosis and its underlying mechanism. In vivo, bleomycin (5 mg/kg) in 50 μL saline was administrated intratracheally in mice. One week after bleomycin administration, ginkgetin (25 or 50 mg/kg) or nintedanib (40 mg/kg) was administrated intragastrically daily for 14 consecutive days. In vitro, the AMPK-siRNA transfection in primary lung fibroblasts further verified the regulatory effect of ginkgetin on AMPK. Administration of bleomycin caused characteristic histopathology structural changes with elevated lipid peroxidation, pulmonary fibrosis indexes, and inflammatory mediators. The bleomycin- induced alteration was normalized by ginkgetin intervention. Moreover, this protective effect of ginkgetin (20 mg/kg) was equivalent to that of nintedanib (40 mg/kg). AMPK-siRNA transfection in primary lung fibroblasts markedly blocked TGF-β1-induced myofibroblasts transdifferentiation and abolished oxidative stress. All these results suggested that ginkgetin exerted ameliorative effects on bleomycininduced oxidative stress and lung fibrosis mainly through an AMPK-dependent manner.

Structural brain changes in patients with post-COVID fatigue: a prospective observational study

Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity. We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18-69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5-9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue. Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness. Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications. Deutsche Forschungsgemeinschaft (DFG) and German Ministry of Education and Research (BMBF).

Minimum Ganglion Cell Layer Thickness is the Best Structural Predictor of Visual Function in Leber Hereditary Optic Neuropathy

Background: Patients with Leber hereditary optic neuropathy, a genetic cause of severe optic atrophy and blindness, demonstrate characteristic structural changes measurable through optical coherence tomography, including initial swelling of the retinal nerve fiber layer and progressive thinning of the ganglion cell layer. After symptomatic conversion, patients experience progressive vision loss, often with dense central scotomas. Aims: This study aims to explore the predictive potential of ocular structural measurements to visual function in patients with Leber hereditary optic neuropathy. Methods: Medical records were reviewed retrospectively for patients with Leber hereditary optic neuropathy clinical testing. Structural measurements, including the average thickness of the ganglion cell layer, the retinal nerve fiber layer, and minimum thickness of the ganglion cell layer, measured through optical coherence tomography were obtained along with measures of visual function such as visual acuity and mean deviation of visual field testing. Simple and multivariable linear regressions were performed to determine correlations between structural measurements and visual functions. Analyses were conducted for all patients, and subgroup of symptomatic patients. Results: Overall, 92 eyes were included with 78 symptomatic eyes. Across all patients, the minimum ganglion cell layer thickness had the highest correlation coefficient with visual acuity (Beta -0.632, adjusted R2 0.396) and with visual field function (Beta 0.572, adj. R2 0.320) compared to the average thickness of the ganglion cell layer (Beta 0.474, adj. R2 0.216) and retinal nerve fiber layer (Beta 0.481, adj. R2 0.223). In multivariate analysis, the minimum ganglion cell layer thickness was the only significant measurement that correlated with visual acuity across all eyes (Beta -0.527, P&lt;0.001) and symptomatic eyes (Beta -0.479, P&lt;0.001). The minimum ganglion cell layer thickness (Beta 0.440, P&lt;0.001) and retinal nerve fiber layer average thickness (0.258, P=0.023) were significant structural measurements correlating to visual field function. Conclusion: The minimum ganglion cell layer thickness is the best structural measure predictor for visual field and visual acuity compared to other common structural measurements in patients with Leber hereditary optic neuropathy. It is a good predictor even when evaluating only symptomatic eyes. Additional attention toward the minimum ganglion cell layer thickness may offer further insight into a patient’s visual potential and the natural history of this disease.

Mechanistic Impact of Different Ligand Scaffolds on FXR Modulation Suggests Avenues to Selective Modulators.

The bile-acid sensing nuclear farnesoid X receptor (FXR) is an attractive target for the treatment of hepatic and metabolic diseases, but application of this chemotherapeutic concept remains limited due to adverse effects of FXR activation observed in clinical trials. To elucidate the mechanistic basis of FXR activation at the molecular level, we have systematically studied FXR co-regulator interactions and dimerization in response to seven chemically diverse FXR ligands. Different molecular effects on FXR activation mediated by different scaffolds were evident and aligned with characteristic structural changes within the ligand binding domain of FXR. A partial FXR agonist acted mainly through co-repressor displacement from FXR and caused an FXR-regulated gene expression pattern markedly differing from FXR agonist effects. These results suggest selective modulation of FXR dimerization and co-regulator interactions for different ligands, offering a potential avenue for the design of gene- or tissue-selective FXR modulators.

Long-term chemically protected sodium butyrate supplementation in broilers as an antibiotic alternative to dynamically modulate gut microbiota

Chemically protected sodium butyrate (CSB) is a new kind of sodium butyrate. Our previous study found that 1,000 mg/kg of CSB had the potential capacity of improving growth performance and promoting early development of small intestine in broilers. This study aimed to investigate the effect of long-term antibiotics or CSB supplementation for intestinal microflora dynamical regulation in broilers. One hundred ninety-two 1-day-old Arbor Acres male broilers were randomly allocated into 3 dietary treatment (8 replicates per treatment) and fed with a basal diet (CON), a diet supplemented with the antibiotics (enramycin, 8 mg/kg and aureomycin, 100 mg/kg) (ANT), or a diet supplemented with 1,000 mg/kg of CSB, respectively. Results showed that dietary supplementation of CSB or ANT treatment elevated the weight gain and feed conversion ratio (FCR; P < 0.05), as compared with control (CON) group. Additionally, CON, CSB, or ANT administration dynamically altered the gut microbiota composition as time goes on. The increased presence of potential pathogens, such as Romboutsia and Shuttleworthia, and decreased beneficial bacteria such as Alistipes, Akkermansia, and Bacteroides were verified in new gut homeostasis reshaped by long-term antibiotics treatment, which has adverse effects on intestinal development and health of broilers. Conversely, CSB supplementation could dynamically enhance the relative abundance of Bacteroides, and decrease Romboutsia and Shuttleworthia in new microflora, which has positive effects on intestinal bacteria of broilers compared with CON group. Meanwhile, CSB supplementation was significantly increased the concentration of propionic acid and total short chain fatty acids (total SCFA; P < 0.05) in comparison with CON and ANT groups. Moreover, CSB treatment significantly increased anti-inflammatory and antioxidative capacities (P < 0.05) of broilers compared with ANT group. Taken together, we revealed characteristic structural changes of gut microbiota throughout long-term CSB or ANT supplementation in broilers, which provided a basic data for evaluating the mechanism of action affecting intestinal health by CSB or ANT administration and CSB as an alternative to antibiotics in the broilers industry.

Proteomic analysis of exercise-induced hypertrophy reveals sex-related mitochondrial differences mediated by AMPK

Abstract Background Regular physical activity results in characteristic structural and functional changes in the heart, which are collectively referred to as the athlete's heart. However, the extent of exercise-induced left ventricular (LV) hypertrophy and functional changes show significant differences between men and women, the molecular background of which is not fully elucidated. Objective The aim of this study was to provide a proteomic characterization of long-term, intense exercise-induced LV myocardial hypertrophy in a rat model, with a focus on sex-related differences. Methods Our rats were divided into trained (FEx) and control female (FCo) as well as trained (MEx) and control male (MCo) groups. In the trained groups, athlete's heart was induced by a 12-week swimming protocol. Myocardial hypertrophy was confirmed by echocardiography and functional adaptation by pressure-volume analysis. Proteomic measurements based on liquid chromatograph-coupled mass spectrometry were performed on proteins isolated from our LV myocardial samples. Results Echocardiography and post-mortem myocardial mass showed significant LV hypertrophy in both sexes, which was more pronounced in female animals (tibial length normalized LV muscle mass: + 17.4% MEx vs. MCo, + 31.0% FEx vs. FCo). LV contractility increased to the same extent in both sexes. Relative expression of 3074 proteins were determined by proteomics. There was a significant change in expression of 229 proteins in males and 599 in females compared to the level of same-sex controls. Based on our gene ontological analysis, physiological LV remodeling in females is characterized by increased expression of proteins in mitochondrial function (cellular respiration and fatty acid oxidation) and biogenesis, whereas in males, proteins that bind to the actin cytoskeleton is primarily increased. Further investigation revealed that the quantity of AMP-activated protein kinase (AMPK) and sirtuin 3 (SIRT3) was increased only in female animals. Conclusions Our data suggests that physiological LV hypertrophy resulting from regular, balanced exercise is associated with sex-specific changes in the myocardial proteome. The main differences might be associated with different regulation of mitochondrial function and biogenesis, related to AMPK pathway. Our results contribute to the understanding of the development of physiological myocardial hypertrophy. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bolyai János Research Scholarship (BO/00837/21) to OANational Research, Development and Innovation Office (NKFIH) K135076 to B.M.