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Objectives Several metabolic disturbances are seen in acromegaly however, data regarding the contribution of irisin to these disturbances is currently insufficient. In a cohort of patients with acromegaly, we measured serum irisin levels in active and controlled cases and determined independent factors that effect serum irisin including fibronectin type III domain-containing protein 5 (FNDC5) genotyping. Methods A cross-sectional case-control study including 46 patients with acromegaly (28 F/18 M, age: 50.3 ± 12.1 year, BMI: 30.7 ± 5.1 kg/m2) and 81 age-, gender-, body mass index- and body composition-matched healthy controls was conducted. 15 acromegalic patients (33%) had active disease. Irisin levels were measured by enzyme-linked immunosorbent assay. Three different regions (rs3480, rs1746661, and rs16835198) of FNDC5 were subjected to polymorphism analyses. Results Both groups were overweight and had similar body composition. Irisin levels were lower in patients with acromegaly than controls (median [IQR]: 44.8 [41.7–46.7] ng/mL vs. 51.7 [45.5–60.1] ng/mL, p≤0.001, respectively). Active and controlled patients had similar irisin levels. Irisin was not correlated with growth hormone (GH), insulin-like growth factor 1 (IGF-1), and IGF-1 index. In multiple linear regression model, somatostatin receptor ligand use (β=−20.30, 95% CI [−34]–[−6], p=0.006) was determined as the only independent factor that affect serum irisin. Conclusions Serum irisin levels are low in patients with acromegaly who are on somatostatin receptor ligand therapy. Single nucleotide polymorphisms (SNPs) of FNDC5 have no independent effects on circulating irisin levels under somatostatin ligand action. Endocrine muscle functions also seem to be regulated by somatostatin action, which requires further studies.

Innovation roadmaps are important, because they encourage the actors in an innovation ecosystem to creatively imagine multiple possible science future(s), while anticipating the prospects and challenges on the innovation trajectory. In this overarching context, this expert review highlights the present unmet need for therapeutic innovations for pituitary neuroendocrine tumors (PitNETs), also known as pituitary adenomas. Although there are many drugs used in practice to treat PitNETs, many of these drugs can have negative side effects and show highly variable outcomes in terms of overall recovery. Building innovation roadmaps for PitNETs' treatments can allow incorporation of systems biology approaches to bring about insights at multiple levels of cell biology, from genes to proteins to metabolites. Using the systems biology techniques, it will then be possible to offer potential therapeutic strategies for the convergence of preventive approaches and patient-centered disease treatment. Here, we first provide a comprehensive overview of the molecular subtypes of PitNETs and therapeutics for these tumors from the past to the present. We then discuss examples of clinical trials and drug repositioning studies and how multi-omics studies can help in discovery and rational development of new therapeutics for PitNETs. Finally, this expert review offers new public health and personalized medicine approaches on cases that are refractory to conventional treatment or recur despite currently used surgical and/or drug therapy.

New graph invariants, named exponential Zagreb indices, are introduced for more than one type of Zagreb index. After that, in terms of exponential Zagreb indices, lists on equality results over special graphs are presented as well as some new bounds on unicyclic, acyclic, and general graphs are obtained. Moreover, these new graph invariants are determined for some graph operations.

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to UBE3B gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the UBE3B gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.

Algebraic study of graphs is a relatively recent subject which arose in two main streams: One is named as the spectral graph theory and the second one deals with graphs over several algebraic structures. Topological graph indices are widely-used tools in especially molecular graph theory and mathematical chemistry due to their time and money saving applications. The Wiener index is one of these indices which is equal to the sum of distances between all pairs of vertices in a connected graph. The graph over the nite dot product of monogenic semigroups has recently been dened and in this paper, some results on the Wiener index of the dot product graph over monogenic semigroups are given.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neurons that mainly affects the motor cortex, brainstem, and spinal cord. Under disease conditions, microglia could possess two distinct profiles, M1 (toxic) and M2 (protective), with the M2 profile observed at disease onset. SOD1 (superoxide dismutase 1) gene mutations account for up to 20% of familial ALS cases. Comparative gene expression differences in M2-protective (early) stage SOD1

Background A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. Objective The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. Methods Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. Results DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. Conclusion Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

In contrast to the mouse, functional assets of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in the human spleen remain to be better elucidated. Here, we report that the spleen in gastric and pancreatic cancer adopts an immune regulatory character, harbors excessive amount of PMN-MDSC, and anatomically enables their interaction with T cells. Compared to the peripheral blood, the spleen from cancer patients contained significantly higher levels of low-density PMN-MDSC, but not early-stage MDSC (e-MDSC) and monocytic-MDSC (M-MDSC). Low-density fraction of polymorphonuclear (PMN) cells was enriched in immature myeloid cells and displayed higher levels of CD10, CD16, and ROS than their blood-derived counterparts. They were also positive for PD-L1, LOX-1, and pSTAT3. The white pulp and periarteriolar lymphoid sheath (PALS) were strategically surrounded by PMN cells that were in contact with T cells. Unlike those from the blood, both low-density and normal-density PMN cells from the human spleen suppressed T cell proliferation and IFN-γ production. Independent of clinical grade, high PMN-MDSC percentages were associated with decreased survival in gastric cancer. In summary, our results outline the immune regulatory role of the spleen in cancer where neutrophils acquire MDSC functions and feasibly interact with T cells.

Advances in omics technologies have made it possible to unravel biomarkers from different biological levels. Intensive studies have been carried out to uncover the dysregulations in psoriasis and to identify molecular signatures associated with the pathogenesis of psoriasis. In this review, we presented an overview of the current status of the omics-driven biomarker research and emphasized the transcriptomic, epigenomic, proteomic, metabolomic, and glycomic signatures proposed as psoriasis biomarkers. Furthermore, insights on the limitations and future directions of the current biomarker discovery strategies were discussed, which will continue to comprehend broader visions of psoriasis research, diagnosis, and therapy especially in the context of personalized medicine.

Background We have investigated the role of a cardiomyokine, follistatin-like 1 (FSTL1), and its single nucleotide polymorphism on acromegalic cardiomyopathy. Methods The study was performed as a cross-sectional case research in a Tertiary Referral Centre. Forty-six patients with acromegaly (29 F-17 M, mean age: 50.3 ± 12.1 years) were included. FSTL1 levels were measured and the rs1259293 region of the FSTL1 gene was subjected to polymorphism analysis. 1.5 Tesla MRI was used to obtain cardiac images. Results There were 15 active (6 F-9M) and 31 (22 F-9M) controlled patients. Active patients had a higher left ventricular mass (LVM) and left ventricular mass index (LVMi). GH levels were positively correlated with left ventricular end-diastolic volume index (LVEDVi), stroke volume index (SVi), cardiac index (Ci), LVM and LVMi; r = 0.35, 0.38, 0.34, 0.39 and 0.39, respectively. IGF-1 index was positively correlated with LVEDVi, left ventricular end-systolic volume index (LVESVi), SVi, Ci, LVM and LVMi; r = 0.36, 0.34, 0.32, 0.31, 0.42 and 0.42, respectively. Twenty out of 46 patients with acromegaly (43.5%) had myocardial fibrosis. FSTL1 levels were neither correlated with disease activity nor with any functional and structural cardiac parameter. Multivariate linear regression analysis revealed no association between FSTL1 and any study parameters. The rs1259293 variant genotype CC was significantly associated with low left ventricular mass. Conclusions Serum FSTL1 levels are not associated with functional and structural measures of myocardium in patients with acromegaly. However, the risk of left ventricular hypertrophy is reduced in CC genotyped individuals of FSTL1.

Introduction: BRAF(V600E) activating mutation is the most frequent genetic abnormality in the pathogenesis of papillary thyroid carcinoma. We aimed to evaluate the association between BRAF(V600E )mutation and well-established prognostic clinicopathological characteristics as well as iodine exposure. Material and methods: From 2000 to 2012, the data of PTC patients admitted to Dr. Lutfi Kirdar Kartal Education and Research Hospital in Turkey were reviewed retrospectively. Clinicopathological parameters were collected. BRAF(V600E) mutation was analysed by DNA sequencing method in tumour specimens. We hypothesised that BRAF(V600E) mutation prevalence is positively correlated with prolonged iodine exposure and expected to be higher in the second half of the recruitment period due to the increment in time spent from the iodisation process of the table salt in our country. Thus, iodine exposure was categorised as short-term (2000-2006) and long-term (2006-2012). Results: A total of 197 patients were accrued. The study population predominantly consisted of conventional variant. A statistically significant relationship was observed between BRAF(V600E) mutation presence and age (p = 0.03), conventional variant PTC (p = 0.00002), T4 stage (p= 0.002), vascular invasion (p= 0.036), thyroid capsule invasion (p < 0.00001), extrathyroidal tissue invasion (p < 0.00001), and lymph node metastasis (p < 0.00001). When categorised as long-term and short-term, iodine exposure was not statistically significantly related with BRAF(V600E) mutation; however, there were far more PTC cases in the long-term group (86.3% vs. 13.7%). Conclusion: We revealed that BRAF(V600E) mutation is associated with adverse clinicopathological parameters. There appeared to be no relation between long-term iodine exposure and BRAF(V600E). Research Fund of the Tekirdag Namik Kemal University [NKUBAP.01, YL.16.021] This work was supported by a grant of the Research Fund of the Tekirdag Namik Kemal University (Project number: NKUBAP.01.YL.16.021).

Background: Despite prolonged survival, the mortality rate of acromegalic patients is still higher. Cardiovascular disorders continue to be the most common cause of death. The exact pathophysiologic mechanisms of acromegalic cardiomyopathy (AC) remain to be established. In this study, we investigated the role of FSTL1 levels and FSTL1 gene polymorphisms on AC and assessed the functional and structural properties of cardiac muscle by cardiac MRI. Finally, we examined the relationship between FSTL1 levels, FSTL1 gene polymorphism and cardiac MRI findings. Materials and Methods: Forty-six acromegalic patients (28F/18M, age: 50.3±12.1 yrs) with a median disease duration of eight years and 81 age-sex matched healthy controls (48F/33M, age: 48.4±7.2 yrs) were included in the study. The rs1259293 region of the FSTL1 gene was subjected to polymorphism analysis. SNPs were identified (TT, TC and CC). A 1.5 Tesla scanner was used to obtain cardiac images. Results: The median serum IGF- 1 level and IGF-1 index were 232.5 ng/mL (50-1278) and 0.69 (0.17-3.1), respectively. Acromegalic patients had significantly lower levels of FSTL1 (median, IQR; A: 0.88, 0.44-2.13 ng/mL, C: 1.54, 0.85-3.16 ng/mL, p=0.04). FSTL1 levels were not different among polymorphism groups (TT, TC and CC). Left ventricular (LV) mass was increased in 18 patients (41%). In 20 acromegalic patients (45.4%), regional late gadolinium enhancement (LGE) was determined. Serum IGF-1 index was positively correlated with LV end-diastolic volume index, end-systolic volume index, stroke volume index, cardiac index and cardiac mass index; r: 0.36, 0.34, 0.32, 0.31 and 0.42, p: 0.02, 0.03, 0.03, 0.04 and 0.004 respectively. The IGF-1 index was defined as an independent risk factor for LV hypertrophy (95 % CI OR: 0.89-18.84); on the other hand, the CC polymorphism was shown to be an independent protective factor (95 % CI OR: 0.06-0.87). Discussion: Our study is the first study that assesses the role of serum FSTL1 levels and FSTL1 polymorphisms in AC. We found low FSTL1 levels in patients with acromegaly. FSTL-1 prevents hypertrophy in cardiomyocytes. In a previous report, homozygous deletion of FSTL1 in mice was shown to result in enlargement of heart. The relatively low abundance of FSTL1 in acromegalic patients could be an underlying mechanism for AC. Almost half of the acromegalic patients had increased LV mass and LGE. Contrary to the previous report, we show that LV hypertrophy and regional fibrosis are common findings in acromegaly. The IGF-1 index was found to be associated with hyperdynamic cardiac functions. Furthermore, we demonstrate that high IGF-1 index is an independent risk factor for increased LV mass. Finally, we revealed that the CC polymorphism is a protective factor against the LV mass increase. Conclusions: FSTL1 can have roles in the pathogenesis of AC. Specific polymorphism at the FSTL1 gene may prevent the growth of the LV.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR, Highlights • Molecular transcriptomes alterations of the lung epithelial cells in response to SARS-CoV-2 were detected. • Significant molecular pathways altered in COVID-19 revealed. • Hub proteins were detected as novel drug targets for COVID-19. • Molecular regulatory signatures were identified. • Repurposable drugs were identified for COVID-19.

Metabolic systems engineering is being used to redirect microbial metabolism for the overproduction of chemicals of interest with the aim of transforming microbial hosts into cellular factories. In this study, a genome-based metabolic systems engineering approach was designed and performed to improve biopolymer biosynthesis capability of a moderately halophilic bacterium Halomonas smyrnensis AAD6T producing levan, which is a fructose homopolymer with many potential uses in various industries and medicine. For this purpose, the genome-scale metabolic model for AAD6T was used to characterize the metabolic resource allocation, specifically to design metabolic engineering strategies for engineered bacteria with enhanced levan production capability. Simulations were performed in silico to determine optimal gene knockout strategies to develop new strains with enhanced levan production capability. The majority of the gene knockout strategies emphasized the vital role of the fructose uptake mechanism, and pointed out the fructose-specific phosphotransferase system (PTSfru) as the most promising target for further metabolic engineering studies. Therefore, the PTSfru of AAD6T was restructured with insertional mutagenesis and triparental mating techniques to construct a novel, engineered H. smyrnensis strain, BMA14. Fermentation experiments were carried out to demonstrate the high efficiency of the mutant strain BMA14 in terms of final levan concentration, sucrose consumption rate, and sucrose conversion efficiency, when compared to the AAD6T. The genome-based metabolic systems engineering approach presented in this study might be considered an efficient framework to redirect microbial metabolism for the overproduction of chemicals of interest, and the novel strain BMA14 might be considered a potential microbial cell factory for further studies aimed to design levan production processes with lower production costs.

Ecballium elaterium, common name squirting cucumber juice is used for the symptomatic treatment of rhinosinusitis in folk medicine. There are reports of allergic reactions of this plant in the literature. It has strong anti-inflammatory effect and people in the eastern Mediterranean region widely use this fruit juice for rhinitis and sinusitis. We presented a case of uvular edema caused by this plant.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) lack robust diagnostics and prognostic biomarkers. Metabolomics is a postgenomics field that offers fresh insights for biomarkers of common complex as well as rare diseases. Using data on metabolite-disease associations published in the previous decade (2006-2016) in PubMed, ScienceDirect, Scopus, and Web of Science, we identified 101 metabolites as putative biomarkers for these three neurodegenerative diseases. Notably, uric acid, choline, creatine, L-glutamine, alanine, creatinine, and N-acetyl-L-aspartate were the shared metabolite signatures among the three diseases. The disease-metabolite-pathway associations pointed out the importance of membrane transport (through ATP binding cassette transporters), particularly of arginine and proline amino acids in all three neurodegenerative diseases. When disease-specific and common metabolic pathways were queried by using the pathway enrichment analyses, we found that alanine, aspartate, glutamate, and purine metabolism might act as alternative pathways to overcome inadequate glucose supply and energy crisis in neurodegeneration. These observations underscore the importance of metabolite-based biomarker research in deciphering the elusive pathophysiology of neurodegenerative diseases. Future research investments in metabolomics of complex diseases might provide new insights on AD, PD, and ALS that continue to place a significant burden on global health.