Network Models of BACE-1 Inhibitors: Exploring Structural and Biochemical Relationships.

This study investigates the clustering patterns of human ß-secretase 1 (BACE-1) inhibitors using complex network methodologies based on various distance functions, including Euclidean, Tanimoto, Hamming, and Levenshtein distances. Molecular descriptor vectors such as molecular mass, Merck Molecular Force Field (MMFF) energy, Crippen partition coefficient (ClogP), Crippen molar refractivity (MR), eccentricity, Kappa indices, Synthetic Accessibility Score, Topological Polar Surface Area (TPSA), and 2D/3D autocorrelation entropies are employed to capture the diverse properties of these inhibitors. The Euclidean distance network demonstrates the most reliable clustering results, with strong agreement metrics and minimal information loss, indicating its robustness in capturing essential structural and physicochemical properties. Tanimoto and Hamming distance networks yield valuable clustering outcomes, albeit with moderate performance, while the Levenshtein distance network shows significant discrepancies. The analysis of eigenvector centrality across different networks identifies key inhibitors acting as hubs, which are likely critical in biochemical pathways. Community detection results highlight distinct clustering patterns, with well-defined communities providing insights into the functional and structural groupings of BACE-1 inhibitors. The study also conducts non-parametric tests, revealing significant differences in molecular descriptors, validating the clustering methodology. Despite its limitations, including reliance on specific descriptors and computational complexity, this study offers a comprehensive framework for understanding molecular interactions and guiding therapeutic interventions. Future research could integrate additional descriptors, advanced machine learning techniques, and dynamic network analysis to enhance clustering accuracy and applicability.

Transcriptome-wide analysis uncovers regulatory elements of the antennal transcriptome repertoire of bumblebee at different life stages.

Bumblebees are crucial pollinators, providing essential ecosystem services and global food production. The success of pollination services relies on the interaction between sensory organs and the environment. The antenna functions as a versatile multi-sensory organ, pivotal in mediating chemosensory/olfactory information, and governs adaptive responses to environmental changes. Despite an increasing number of RNA-sequencing studies on insect antenna, comprehensive antennal transcriptome studies at the different life stages were not elucidated systematically. Here, we quantified the expression profile and dynamics of coding/microRNA genes of larval head and antennal tissues from early- and late-stage pupa to the adult of Bombus terrestris as suitable model organism among pollinators. We further performed Pearson correlation analyses on the gene expression profiles of the antennal transcriptome from larval head tissue to adult stages, exploring both positive and negative expression trends. The positively correlated coding genes were primarily enriched in sensory perception of chemical stimuli, ion transport, transmembrane transport processes and olfactory receptor activity. Negatively correlated genes were mainly enriched in organic substance biosynthesis and regulatory mechanisms underlying larval body patterning and the formation of juvenile antennal structures. As post-transcriptional regulators, miR-1000-5p, miR-13b-3p, miR-263-5p and miR-252-5p showed positive correlations, whereas miR-315-5p, miR-92b-3p, miR-137-3p, miR-11-3p and miR-10-3p exhibited negative correlations in antennal tissue. Notably, based on the inverse expression relationship, positively and negatively correlated microRNA (miRNA)-mRNA target pairs revealed that differentially expressed miRNAs predictively targeted genes involved in antennal development, shaping antennal structures and regulating antenna-specific functions. Our data serve as a foundation for understanding stage-specific antennal transcriptomes and large-scale comparative analysis of transcriptomes in different insects.

Low relapse rate in patients with giant cell arteritis in a multi-centre retrospective Turkish Registry.

OBJECTIVES: Glucocorticoids (GC) are widely accepted as the standard first-line treatment for giant cell arteritis (GCA). However, relapse rates are reported up to 80% on GC-only protocol arms in controlled trials of tocilizumab and abatacept in 12-24 months. Herein, we aimed to assess the real-life relapse rates retrospectively in patients with GCA from Turkey. METHODS: We assembled a retrospective cohort of patients with GCA diagnosed according to ACR 1990 criteria from tertiary rheumatology centres in Turkey. All clinical data were abstracted from medical records. Relapse was defined as any new manifestation or increased acutephase response leading to the change of the GC dose or use of a new therapeutic agent by the treating physician. RESULTS: The study included 330 (F/M: 196/134) patients with GCA. The mean age at disease onset was 68.9±9 years. The most frequent symptom was headache. Polymyalgia rheumatica was also present in 81 (24.5%) patients. Elevation of acute phase reactants (ESR>50 mm/h or CRP>5 mg/l) was absent in 25 (7.6%) patients at diagnosis. Temporal artery biopsy was available in 241 (73%) patients, and 180 of them had positive histopathological findings for GCA. For remission induction, GC pulses (250-1000 methylprednisolone mg/3-7 days) were given to 69 (20.9%) patients, with further 0.5-1 mg/kg/day prednisolone continued in the whole group. Immunosuppressives as GC-sparing agents were used in 252 (76.4%) patients. During a follow-up of a median 26.5 (6-190) months, relapses occurred in 49 (18.8%) patients. No confounding factor was observed in relapse rates. GC treatment could be stopped in only 62 (23.8%) patients. Additionally, GC-related side effects developed in 64 (24.6%) patients, and 141 (66.2%) had at least one Vasculitis Damage Index (VDI) damage item present during follow-up. CONCLUSIONS: In this first multi-centre series of GCA from Turkey, we observed that only one-fifth of patients had relapses during a mean follow-up of 26 months, with 76.4% given a GC-sparing IS agent at diagnosis. At the end of follow-up, GC-related side effects developed in one-fourth of patients. Our results suggest that patients with GCA had a low relapse rate in real-life experience of a multi-centre retrospective Turkish registry, however with a significant presence of GC-associated side effects during follow-up.

Paraneoplastic arthritis: a series of 92 cases.

OBJECTIVES: Paraneoplastic arthritis (PA) is one of the paraneoplastic syndromes. Both laboratory and clinical findings similar to rheumatological diseases can be seen. In this study, we aimed to present the clinical and laboratory findings, malignancy type, and pathological diagnoses of patients with paraneoplastic arthritis. METHODS: In a multicentre retrospective study, 92 patients with PA from the last 10 years were included in the study. RESULTS: Patients with PA and hematological malignancies detected the highest ratio of lymphomas (25,6%). The most common cancer detected in patients with solid malignancy and PA was lung cancer (41.5%). All malignant patients with PA had significant Anti-CCP positivity compared with the healthy control group (P= 0.014). CONCLUSION: As a result, although PA is a rare condition, it can be confused with many rheumatological diseases. The most commonly involved joint is the knee joint, followed by the ankle and hand-wrist. Autoantibody negativity, high LDH level, and arthritis unresponsive to treatment constitute important clues for diagnosis.

Empirical investigation on how wellbeing-related infrastructure shapes economic growth: Evidence from the European Union regions.

One of the most important policies of the European Union is regional development, which comprises measures of enhancing economic growth and citizens' living standards via strategic investment. Considering that economic growth and wellbeing are intertwined from the perspective of EU policies, this study examines the relationship between wellbeing-related infrastructure and economic growth in 212 NUTS 2 regional subdivisions across the members of Eu-28 during the period 2001-2020. We therefore analyzed data from 151 Western Europe regions and 61 Central and Eastern Europe regions by means of a panel data analysis with the first-difference generalized method of moments estimator. Our main interest was to determine the degree to which Western Europe regions responded to predictors as compared to Central and Eastern Europe regions. According to the empirical results, the predictors with the strongest influence for Western Europe regions were disposable household income, inter-regional mobility, housing indicator, labor force and participation. For Central and Eastern Europe regions, the largest impact was triggered by the housing indicator, internet broadband access and air pollution. In addition, we determined a relational weighted multiplex between all variables of interest by using dynamic time warping and we introduced topological measures in a multilayer multiplex model for both regional subsamples.

Discrete Geodesic Distribution-Based Graph Kernel for 3D Point Clouds.

In the structural analysis of discrete geometric data, graph kernels have a great track record of performance. Using graph kernel functions provides two significant advantages. First, a graph kernel is capable of preserving the graph's topological structures by describing graph properties in a high-dimensional space. Second, graph kernels allow the application of machine learning methods to vector data that are rapidly evolving into graphs. In this paper, the unique kernel function for similarity determination procedures of point cloud data structures, which are crucial for several applications, is formulated. This function is determined by the proximity of the geodesic route distributions in graphs reflecting the discrete geometry underlying the point cloud. This research demonstrates the efficiency of this unique kernel for similarity measures and the categorization of point clouds.

A Series-Based Deep Learning Approach to Lung Nodule Image Classification.

Although many studies have shown that deep learning approaches yield better results than traditional methods based on manual features, CADs methods still have several limitations. These are due to the diversity in imaging modalities and clinical pathologies. This diversity creates difficulties because of variation and similarities between classes. In this context, the new approach from our study is a hybrid method that performs classifications using both medical image analysis and radial scanning series features. Hence, the areas of interest obtained from images are subjected to a radial scan, with their centers as poles, in order to obtain series. A U-shape convolutional neural network model is then used for the 4D data classification problem. We therefore present a novel approach to the classification of 4D data obtained from lung nodule images. With radial scanning, the eigenvalue of nodule images is captured, and a powerful classification is performed. According to our results, an accuracy of 92.84% was obtained and much more efficient classification scores resulted as compared to recent classifiers.

Influence of anti-TNF-α treatment on liver and kidney functions in patients with ankylosing spondylitis: A retrospective longitudinal study.

OBJECTIVE: To retrospectively evaluate the effect of anti-tumor necrosis factor-alpha (TNF-α) drugs on hepatic and renal functions in patients with ankylosing spondylitis (AS). METHODS: A total of 148 patients (89 male, 59 female) who were followed up for a minimum duration of 1 year on newly started anti TNF-α therapy were included. Patients were divided into 5 groups based on the TNF-α treatment received. Initially, pre-treatment BASDAI (Bath Ankylosing Spondylitis Disease Activity) scores and laboratory results were compared between the groups before the treatment. Also, ESR (erythrocyte sedimentation rate), C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine values were compared before treatment and at 3, 6, and 12 months after treatment. Also presence of hematuria and proteinuria was examined. RESULTS: Of the overall group, 68 (45%), 33 (22%), 23 (15%), 18 (12%), and 6 (4%) received golimumab, certolizumab, etanercept, adalimumab, and infliximab. Baseline demographic characteristics, disease activity scores, and laboratory parameters were comparable between the groups (P > .05). There was a significant decline in BASDAI scores from baseline at 12 months (pre-treatment 5.24 ± 0.5, 3.01 ± 0.48 post-treatment at 12 months, P < .001). Although there was an increase in AST and ALT from baseline to 3, 6, and 12 months of treatment, the values remained within normal range (P > .05). Also, there were no significant changes in mean creatinine levels (P > .05). There were no correlations between disease activity parameters (ESR, CRP, and BASDAI) and hepatic and renal functions (P > .05). CONCLUSION: No hepatotoxicity or nephrotoxicity were found in association with the use of anti-TNF-α agents over a 1 year period. However, hepatotoxicity and nephrotoxicity are among known adverse effects of these agents. Based on the existing literature data, routine monitoring of patients in terms of potential hepatic and renal toxicity before and after treatment remains a valid recommendation in clinical practice.

Budd-Chiari syndrome in Behçet's disease: a retrospective multicenter study.

OBJECTIVE: To compare the clinical features, laboratory findings, and prognosis of Behçet's disease (BD) patients with and without Budd-Chiari syndrome (BCS). METHODS: This multicenter retrospective study investigated 61 (M/F: 41/20) patients with BD, having coexistent BCS, and 169 (M/F:100/69) BD patients as the control group without BCS from 22 different centers of Turkey diagnosed between 1990 and 2017. RESULTS: Of the total 61 BD patients with BCS, the onset of the first symptom and the median age of diagnosis were earlier in contrast to BD patients without BCS (p = 0.005 and p = 0.007). Lower extremity deep vein and inferior vena cava (IVC) thrombosis were more common in patients with BCS (all; p < 0.01) compared to the control group. Mortality was significantly higher in BD-BCS patients with IVC thrombosis than in the controls (p = 0.004). Since most of the cases in our cohort had chronic and silent form of BCS, mortality rate was 14.8%, which was on the lower range of mortality rate reported in literature (14-47%). While all BD-BCS patients received immunosuppressive (IS) agents, only half of them received additional anticoagulant treatments. Among IS agents, interferon treatment was more frequently used in this cohort (19%), compared to other series reported in literature (2.3%). CONCLUSION: To our knowledge, this is the largest series of BD patients with BCS. Our patients had earlier disease onset and diagnosis, higher frequency of IVC thrombosis, and higher mortality rate, compared to BD patients without BCS. Mortality was significantly higher in BD-BCS patients with IVC thrombosis compared to controls. Key Points • Mortality rate is higher in BD-associated BCS patients with IVC involvement. • Chronic and silent form of BD-associated BCS has a better prognosis. • The main treatment options are corticosteroids and immunosuppressive agents, whereas anticoagulant treatment remains controversial.

Investigation of Genes Associated With Atherosclerosis in Patients With Systemic Lupus Erythematosus.

OBJECTIVES: In this study, we aimed to identify patients with systemic lupus erythematosus (SLE) who are genetically at risk for developing atherosclerosis. PATIENTS AND METHODS: Between November 2014 and May 2016, a total of 38 patients with SLE (36 females, 2 males; mean age: 37.6 years; range, 18 to 71 years) and 32 healthy females (mean age: 31.5 years; range, 19 to 54 years) were included in the study. Carotid intima-media thickness (CIMT) was measured using high-resolution B-mode ultrasonography. SurePrint G3 Human Gene Expression 8x60K Microarray kit was used in our study. Genes showing differences in expression between the groups were identified by using GeneSpring GX 10.0 program. Pathway analyses of gene expressions were performed using Ingenuity Pathways Analysis (IPA). Gene ontology analyses were performed using the Protein Analysis Through Evolutionary Relationships (PANTHER). RESULTS: Clinical findings of SLE patients were mainly photosensitivity (71.1%), arthritis (63.2%), lupus nephritis (55.3%), thrombocytopenia (26.3%), and autoimmune hemolytic anemia (21.1%). A total of 155 genes showing expression level difference were detected between SLE patients and healthy controls. In molecular network analysis, 28.2% of all genes were found to be directly or indirectly associated with atherosclerosis and cardiovascular disease. CONCLUSION: In SLE patients, many genes are expressed differently from healthy individuals. Expression of these genes is important in the pathogenesis of SLE. Genes identified differently in gene expression analysis can help us to identify SLE patients at risk for atherosclerosis in the Turkish population.

Evaluation of corneal safety in systemic lupus erythematosus patients undergoing long-term hydroxychloroquine treatment.

PURPOSE: The aim of this study was to examine the effects of long-term use of hydroxychloroquine (HQ) on the pachymetric, aberrometric, and densitometric values of the cornea and corneal endothelium in lupus patients. METHOD: Twenty-two eyes (study group) of 22 patients using HQ for treatment of lupus and 25 eyes (control group) of 25 healthy individuals were included in this prospective study. A specular microscopy was used to measure corneal endothelial cell density (ECD), percentage of hexagonal cells (HEX%), coefficient of variation of the cell size (CV). Then, a Pentacam® HR corneal tomography system was used to measure central corneal thickness (CCT), corneal aberrometry values in 6-mm pupil diameters and corneal densitometry values in 6-mm corneal zones (0-2 mm and 2-6 mm). RESULTS: While ECD was significantly lower in the study group than in the control group (p = 0.034), CCT was significantly higher in the study group (p = 0.032). The higher-order aberrations values and the anterior corneal densitometry values in the 0-2 mm and 2-6 mm corneal zones in the study group were found to be significantly higher than the control group (p = 0.021, p = 0.007 and p = 0.013). CONCLUSION: Prolonged use of HQ may cause some changes in the cornea. In the follow-up of these cases, detailed examination of the cornea as well as the macula may be important for the protection of corneal health.

Hierarchies in communities of UK stock market from the perspective of Brexit.

Nowadays, increase of analyzing stock markets as complex systems lead graph theory to play a key role. For instance, detecting graph communities is an important task in the analysis of stocks, and as planar maximally filtered graphs let us to get important information for the topology of the market. In this study, we first obtain correlation network representation of UK's leading stock market network by using a novel threshold method. Then, we determine vertex clusters by using modularity and analyze clusters in planar maximally filtered graph substructures. Our analyze include a new measure called weighted Gini index for measuring the sparsity. The main goal of this paper is to study the hierarchical evolution of the market communities throughout the Brexit referendum, which is known as the stress period for the stock market. Hence, the overall sample is divided into two sub-periods of pre-referendum, and post-referendum to obtain communities and hierarchical structures. Our results indicate that financial companies are leading elements of the clusters. Moreover, the significant changes within the network topologies are observed for insurance, consumer goods, consumer services, mining, and technology sectors whereas oil and gas and health care sectors have not been affected by Brexit stress.

Nationwide Experience With Off-Label Use of Interleukin-1 Targeting Treatment in Familial Mediterranean Fever Patients.

OBJECTIVE: Approximately 30-45% of patients with familial Mediterranean fever (FMF) have been reported to have attacks despite colchicine treatment. Currently, data on the treatment of colchicine-unresponsive or colchicine-intolerant FMF patients are limited; the most promising alternatives seem to be anti-interleukin-1 (anti-IL-1) agents. Here we report our experience with the off-label use of anti-IL-1 agents in a large group of FMF patients. METHODS: In all, 21 centers from different geographical regions of Turkey were included in the current study. The medical records of all FMF patients who had used anti-IL-1 treatment for at least 6 months were reviewed. RESULTS: In total, 172 FMF patients (83 [48%] female, mean age 36.2 years [range 18-68]) were included in the analysis; mean age at symptom onset was 12.6 years (range 1-48), and the mean colchicine dose was 1.7 mg/day (range 0.5-4.0). Of these patients, 151 were treated with anakinra and 21 with canakinumab. Anti-IL-1 treatment was used because of colchicine-resistant disease in 84% and amyloidosis in 12% of subjects. During the mean 19.6 months of treatment (range 6-98), the yearly attack frequency was significantly reduced (from 16.8 to 2.4; P < 0.001), and 42.1% of colchicine-resistant FMF patients were attack free. Serum levels of C-reactive protein, erythrocyte sedimentation rate, and 24-hour urinary protein excretion (5,458.7 mg/24 hours before and 3,557.3 mg/24 hours after) were significantly reduced. CONCLUSION: Anti-IL-1 treatment is an effective alternative for controlling attacks and decreasing proteinuria in colchicine-resistant FMF patients.

The epidemiology of dermatomyositis in northwestern Thrace region in Turkey: epidemiology of dermatomyositis in Turkey.

Dermatomyositis (DM) is a rare disease that may affect the skeletal muscles and the skin. Literature data on its incidence and prevalence are limited. There are no data on its incidence or prevalence in Turkey. Patients diagnosed with DM at the Trakya University Medical Faculty, Department of Rheumatology from November 2004 to November 2014 were reviewed retrospectively. Patients' clinical and demographic features, laboratory data, treatment modalities, follow-up durations, disease courses, outcomes, and complications were evaluated. Our study included 23 patients with DM; 14 were females and 9 were males (female/male: 1.55). Over the course of the study, the annual incidence of DM was 3.7 per million (95% CI 0-18.8) person years, and the overall prevalence was 32.2 per million (95% CI 18.1-46.3). Incidence in women was higher (4.6/1,000,000 person years) compared to men (2.9/1,000,000 person years). The frequencies of most common findings were as follows: heliotrope rash (82.6%), Gottron papules (87%), proximal myopathy (78.3%), and facial erythema (60.9%). In our hospital-based study, the frequency of DM was lower than those reported in North America; however, they were similar to European countries.

The management of gout in different clinical specialties in Turkey: a patient-based survey.

Although gout is potentially curable, the management of this disease is often suboptimal. In this study, we investigated the treatment of gout in Turkey and also compared the management approaches to gout in different clinical specialties. Three hundred and nineteen consecutive patients (mean age 58.60 ± 12.8 years; 44 females, 275 males) were included in this multicenter study. A standardized form was generated to collect data about the patient's first admission to health care, the specialty of the doctor first diagnosed the gout, the treatment options for gout including attack management, patient referral, chronic treatment including medical treatment, and life style modifications. Forty patients were referred to another center without any treatment (12.8 %), and referral rate is most common among the primary care physicians (28.8 %). Colchicine was more commonly used for attack prophylaxis than allopurinol. Ninety-two patients had never been treated with allopurinol (28.8 %). Allopurinol prescription was less common among the primary care physicians and orthopedists, and highest among the rheumatologists. Recommendation of diet and life style modifications was less common among the primary care physicians and orthopedists, and highest among the rheumatologists. The rates of life style modification recommendation and long-term allopurinol prescription were 83.7 and 77.6 %, respectively, among the rheumatologists. Both acute and chronic management of gout is suboptimal in Turkey especially among the primary care physicians and orthopedists. Moreover, chronic treatment is even suboptimal among rheumatologists.

Performance of the new American College of Rheumatology classification criteria in Turkish systemic sclerosis patients: a multicenter study.

In our study, we compared the sensitivity and specificity of the new ACR/EULAR 2013 criteria to the ACR 1980 criteria in our systemic sclerosis (SSc) population. Three rheumatology centers from Turkey participated into this study. The medical records of SSc patients diagnosed between 2008 and 2014 were retrospectively reviewed, and their features at disease onset were recorded. Patients admitted to each center within the same time period for conditions other than SSc, in whom ANA was positive and was deemed necessary within the diagnostic workup, were included as controls. One hundred and ninety-seven SSc patients (174 females, 23 males) and 103 controls (96 females, 7 males) were included. Limited cutaneous SSc was present in 68 % of patients, and 30.5 % had diffuse SSc. The sensitivity of ACR/EULAR 2013 and ACR 1980 criteria were, respectively, 94.4 and 85.3 % (p = 0.003). The specificity of ACR/EULAR 2013 and ACR 1980 criteria were, respectively, 98.1 and 100 %. According to the new criteria, 13 patients were misclassified; however, according to the ACR 1980 criteria, 29 patients were misclassified (p = 0.005). The sensitivity of ACR/EULAR 2013 criteria was significantly better than that of the ACR 1980 criteria in limited cutaneous SSc group (94.8 vs. 82.8 %). In patients whose disease duration was <3 years, the new criteria had better sensitivity than the previous criteria (92.7 vs. 78.1 %, p = 0.006). The new ACR/EULAR 2013 criteria for SSc had better sensitivity in Turkish SSc patients, and less patients were misclassified.