Galectin-9, a pro-survival factor inducing immunosuppression, leukemic cell transformation and expansion.

Leukemia is a malignancy of the bone marrow and blood originating from self-renewing cancerous immature blast cells or transformed leukocytes. Despite improvements in treatments, leukemia remains still a serious disease with poor prognosis because of disease heterogeneity, drug resistance and relapse. There is emerging evidence that differentially expression of co-signaling molecules play a critical role in tumor immune evasion. Galectin-9 (Gal-9) is one of the key proteins that leukemic cells express, secrete, and use to proliferate, self-renew, and survive. It also suppresses host immune responses controlled by T and NK cells, enabling leukemic cells to evade immune surveillance. The present review provides the molecular mechanisms of Gal-9-induced immune evasion in leukemia. Understanding the complex immune evasion machinery driven by Gal-9 expressing leukemic cells will enable the identification of novel therapeutic strategies for efficient immunotherapy in leukemic patients. Combined treatment approaches targeting T-cell immunoglobulin and mucin domain-3 (Tim-3)/Gal-9 and other immune checkpoint pathways can be considered, which may enhance the efficacy of host effector cells to attack leukemic cells.

A comparison of chlorhexidine and povidone-iodine solutions in neonatal intensive care units.

BACKGROUND: Povidone-iodine (10%; PI) and 2% chlorhexidine in 70% isopropyl alcohol (CHG-IA) solutions are among the most widely used disinfectants in the neonatal intensive care units. This study compares the use of these disinfectants and helps decide which is superior to the other for neonatal use. METHODS: All term and preterm infants born and hospitalized in Bursa Uludag University Hospital between July 2018-March 2020 were included. The infants were randomized into two disinfectant groups before birth. The application site was cleaned with the assigned disinfectant before intervention. The infants were screened for rates of neonatal sepsis, thyroid-stimulating hormone (TSH) levels, free thyroxine (fT4) levels, skin reactions to the assigned solution, and acute neurological side effects. RESULTS: We enrolled 208 term and preterm infants (PI:104 vs. CHG-IA: 104) in the study. The prematurity rates were identical (PI: 74.0%; CHG-IA: 72.1%; p = 0.755). Neonatal sepsis rates among these groups were not statistically different (PI: 8.7%; CHG-IA: 4.8%; p = 0.406). The median TSH value of the PI group was high (4.05 mIU/L) in comparison with that of the CHG-IA group (3.09 mIU/L; p = 0.016). No cutaneous or neurological side effects were recorded in patients treated with CHG-IA solution. CONCLUSIONS: Although these two solutions were equally protective against infections, the CHG-IA solution was a better alternative to PI for neonatal use. Considering that the PI solution may be responsible for impaired thyroid function, the CHG-IA solution is a good alternative because it provides sufficient protection with a safer adverse effect profile.

Psychometric Properties of the Turkish Version of the Activity Diversity Questionnaire for Older Adults.

INTRODUCTION: The Activity Diversity Questionnaire consists of 20 items that assess activity diversity using Shannon's entropy. Comparing the relationship between health outcomes and activity diversity is important for older adults. There is no scale in Turkish that can be used to evaluate the activity diversity. The aim of this study is to investigate the relevance of the Activity Diversity Questionnaire for Turkish older adults and the effectiveness of its clinical use. METHODS: 220 older adults were included in the study. In order to determine the reliability of the Activity Diversity Questionnaire, internal consistency and test-retest analyzes were applied. Similar scale validity and confirmatory factor analysis were used to determine its validity. RESULTS: The Turkish version of the Activity Diversity Questionnaire showed high levels of internal consistency and test-retest reliability (Cronbach α = 0.868, ICC = 0.93). Statistically positive, moderate (r = 0.47, p < .001) and strong (r = 0.71, p < .001) correlations were found between the Activity Diversity Questionnaire and the Barthel Activities of Daily Living Index and the Lawton Instrumental Activities of Daily Living Scale, respectively. As a result of Confirmatory Factor Analysis, it was found that the fit index values found acceptable fit compared to the reference values. CONCLUSIONS: The Turkish version of the Activity Diversity Questionnaire has appropriate psychometric properties, including validity and reliability.

Efficacy of malachite green mediated photodynamic therapy on treatment of Cutaneous Leishmaniasis: In vitro study.

BACKGROUND: Leishmaniasis is a common zoonotic disease that is transmitted by phlebotomus and causes several clinical conditions, from self healing lesion to deadly internal organ involvement. Photodynamic therapy (PDT) is a treatment method that leads to the generation of cytotoxic species and consequently to cell death and tissue destruction by visible light in the presence of a photosensitizer and oxygen. The aim of this study was to investigate effect of malachite green (MG)-mediated PDT in Leishmania tropica (L. tropica) promastigotes. MATERIAL AND METHODS: Parasites were incubated with 0.19, 0.39, 1.56, 3.25 and 6.25 µM of MG for one hour and subjected to 46.4 J/cm2 light irradiation. Trypan blue assay was used to evaluate the viability of the cells and mitochondirial activity alteration was determined by MTT. Morphological changes were analyzed by Giemsa staining and Scanning electron microscopy (SEM) analyses. Flow cytometry was used to quantify the fluorescence emitted by cell volume, JC-1, Cell Cycle and Annexin V/PI staining reagents. RESULTS: Malachite green mediated photodynamic therapy at 1.56 and 3.125 µM decreased the viability of the L. tropica promastigotes and induced changes in the mitochondrial membrane potential. L.tropica promastigotes was bloked in G0/G1 phase. The morphology of the parasite was affected at the 1.56 and 3.125 µM MG+PDT, resulting in rounded cells with loss of flagellum and irregular shape. CONCLUSIONS: This study demonstrated that antileishmanial effects through mitochondrial dysfunction, cell cycle arrest, and apoptosis-like cell death to parasites. This work showed PDT with MG effectedparasites. Therefore, MG-mediated PDT may provide a promising approach for L. tropica promastigotes.

'Stepchildren of the Ministry': an examination of the difficulties endured by family physicians in Istanbul during the course of the COVID-19 pandemic.

Introduction Efforts to contain the SARS-CoV-2 virus would fall short without strong primary health care. Aim In this study, we aimed to understand family physicians' experiences of coronavirus disease 2019 (COVID-19) in Istanbul, focusing on their coping strategies in order to draw lessons for the future management of pandemics. Methods Twelve community-based physicians working in Istanbul participated in semi-structured interviews between January and May 2021. Purposive sampling was used to ensure a range of physicians' characteristics. Individual interviews were conducted with each participant on an online platform. Participants were asked 26 open-ended questions. Phenomenological analysis was performed to describe experiences of physicians. Results The physical conditions of participants' health centres were insufficient to provide service safely during the COVID-19 pandemic. Most physicians were uncomfortable about the quality and quantity of personal protective equipment received from the Ministry of Health and took additional measures themselves. Vaccine supply was thought to be insufficient and there were problems with the associated software. Many family physicians highlighted the inadequate communication from the Ministry. Insufficient knowledge about the disease caused anxiety and fear for the physicians and hindered their performance at the beginning of the pandemic. Physicians who live with their families were more anxious than those who did not. Discussion Despite challenges, routine procedures have mostly been continued, but newly added responsibilities during the COVID-19 pandemic have had significant impact on physicians' lives.

Evaluation of arterial stiffness and central blood pressure by oscillometric method in normotensive offspring of hypertensive parents.

Children with a family history of hypertension have higher blood pressure and hypertensive pathophysiological changes begin before clinical findings. Here, the presence of arterial stiffness was investigated using central blood pressure measurement and pulse wave analysis in normotensive children with at least one parent with essential hypertension. Twenty-four-hour ambulatory pulse wave analysis monitoring was performed by oscillometric method in a study group of 112 normotensive children of hypertensive parents aged between 7 and 18 comparing with a control group of 101 age- and gender-matched normotensive children of normotensive parents. Pulse wave velocity, central systolic and diastolic blood pressure, systolic, diastolic and mean arterial blood pressure values were higher in the study group than the control group (p < 0.001, p = 0.002, p = 0.008, p = 0.001, p = 0.005, p = 0.001, p = 0.001, respectively). In all age groups (7-10, 11-14, and 15-18 years), pulse wave velocity was higher in the study group than the control group (p < 0.001). Pulse wave velocity was higher in children whose both parents are hypertensive compared to the children whose only mothers are hypertensive (p = 0.011). Pulse wave velocity values were positively correlated with age, weight, height, and body mass index (p < 0.05). Higher pulse wave velocity, central systolic and diastolic blood pressure values detected in the study group can be considered as early signs of hypertensive vascular changes. Pulse wave analysis can be a reliable, non-invasive, and reproducible method that can allow taking necessary precautions regarding lifestyle to prevent disease and target organ damage by detecting early hypertensive changes in genetically risky children.

MXene Materials for Designing Advanced Separation Membranes.

MXenes are emerging rapidly as a new family of multifunctional nanomaterials with prospective applications rivaling that of graphenes. Herein, a timely account of the design and performance evaluation of MXene-based membranes is provided. First, the preparation and physicochemical characteristics of MXenes are outlined, with a focus on exfoliation, dispersion stability, and processability, which are crucial factors for membrane fabrication. Then, different formats of MXene-based membranes in the literature are introduced, comprising pristine or intercalated nanolaminates and polymer-based nanocomposites. Next, the major membrane processes so far pursued by MXenes are evaluated, covering gas separation, wastewater treatment, desalination, and organic solvent purification. The potential utility of MXenes in phase inversion and interfacial polymerization, as well as layer-by-layer assembly for the preparation of nanocomposite membranes, is also critically discussed. Looking forward, exploiting the high electrical conductivity and catalytic activity of certain MXenes is put into perspective for niche applications that are not easily achievable by other nanomaterials. Furthermore, the benefits of simulation/modeling approaches for designing MXene-based membranes are exemplified. Overall, critical insights are provided for materials science and membrane communities to navigate better while exploring the potential of MXenes for developing advanced separation membranes.

"Smart poisoning" of Co/SiO2 catalysts by sulfidation for chirality-selective synthesis of (9,8) single-walled carbon nanotubes.

The chirality-selective synthesis of relatively large (diameter > 1 nm) single-walled carbon nanotubes (SWCNTs) is of great interest for a variety of practical applications, but only a few catalysts are available so far. Previous studies suggested that S (compounds) can enhance the chirality-selectivity of Co catalysts in SWCNT synthesis, however, the mechanism behind is not fully understood, and no tailorable methodology has yet been developed. Here, we demonstrate a facile approach to achieve the chirality-selective synthesis of SWCNTs by the sulfidation-based poisoning of silica-supported Co catalysts using a mixture of H2S and H2. The UV-vis-NIR, photoluminescence, and Raman spectroscopy results together show that the resulting SWCNTs have a narrow diameter distribution of around 1.2 nm, and (9,8) nanotubes have an abundance of ∼38% among the semiconducting species. More importantly, the carbon yield achieved by the sulfided catalyst (2.5 wt%) is similar to that of the nonsulfided one (2.7 wt%). The characterization of the catalysts by X-ray diffraction, X-ray photoelectron spectroscopy, X-ray fluorescence, and H2 temperature-programmed reduction shows that the sulfidation leads to the formation of Co9S8 nanoparticles. However, Co9S8 nanoparticles are reduced back to regenerate metallic Co nanoparticles during the synthesis of SWCNTs, which maintain a high carbon yield. In this process, Co9S8 nanoparticles seemingly intermediate the production of Co nanoparticles with narrow size distribution. Due to the fact that the poisoning step improves the quality of the end-product rather than hampering the growth process, we have coined the process developed as "smart poisoning". This study not only reveals the mechanism behind the beneficial role of S in the selective synthesis of relatively large SWCNTs but also presents a promising method to create chirality-selective catalysts with high activity for scalable synthesis.

Shadow-casted ultrathin surface coatings of titanium and titanium/silicon oxide sol particles via ultrasound-assisted deposition.

Ultrasound-assisted deposition (USAD) of sol nanoparticles enables the formation of uniform and inherently stable thin films. However, the technique still suffers in coating hard substrates and the use of fast-reacting sol-gel precursors still remains challenging. Here, we report on the deposition of ultrathin titanium and titanium/silicon hybrid oxide coatings using hydroxylated silicon wafers as a model hard substrate. We use acetic acid as the catalyst which also suppresses the reactivity of titanium tetraisopropoxide while increasing the reactivity of tetraethyl orthosilicate through chemical modifications. Taking the advantage of this peculiar behavior, we successfully prepared titanium and titanium/silicon hybrid oxide coatings by USAD. Varying the amount of acetic acid in the reaction media, we managed to modulate thickness and surface roughness of the coatings in nanoscale. Field-emission scanning electron microscopy and atomic force microscopy studies showed the formation of conformal coatings having nanoroughness. Quantitative chemical state maps obtained by x-ray photoelectron spectroscopy (XPS) suggested the formation of ultrathin (<10nm) coatings and thickness measurements by rotating analyzer ellipsometry supported this observation. For the first time, XPS chemical maps revealed the transport effect of ultrasonic waves since coatings were directly cast on rectangular substrates as circular shadows of the horn with clear thickness gradient from the center to the edges. In addition to the progress made in coating hard substrates, employing fast-reacting precursors and achieving hybrid coatings; this report provides the first visual evidence on previously suggested "acceleration and smashing" mechanism as the main driving force of USAD.

The emerging role of galectins in cardiovascular disease.

Galectins are an ancient family of ß-galactoside-specific lectins and consist of 15 different types, each with a specific function. They play a role in the immune system, inflammation, wound healing and carcinogenesis. In particular the role of galectin in cancer is widely studied. Lately, the role of galectins in the development of cardiovascular disease has gained attention. Worldwide cardiovascular disease is still the leading cause of death. In ischemic heart disease, atherosclerosis limits adequate blood flow. Angiogenesis and arteriogenesis are highly important mechanisms relieving ischemia by restoring perfusion to the post-stenotic myocardial area. Galectins act ambiguous, both relieving ischemia and accelerating atherosclerosis. Atherosclerosis can ultimately lead to myocardial infarction or ischemic stroke, which are both associated with galectins. There is also a role for galectins in the development of myocarditis by their influence on inflammatory processes. Moreover, galectin acts as a biomarker for the severity of myocardial ischemia and heart failure. This review summarizes the association between galectins and the development of multiple cardiovascular diseases such as myocarditis, ischemic stroke, myocardial infarction, heart failure and atrial fibrillation. Furthermore it focuses on the association between galectin and more general mechanisms such as angiogenesis, arteriogenesis and atherosclerosis.

IFN-ß affects the angiogenic potential of circulating angiogenic cells by activating calpain 1.

Circulating angiogenic cells (CACs) are monocyte-derived cells with endothelial characteristics, which contribute to both angiogenesis and arteriogenesis in a paracrine way. Interferon-ß (IFN-ß) is known to inhibit these divergent processes in animals and patients. We hypothesized that IFN-ß might act by affecting the differentiation and function of CACs. CACs were cultured from peripheral blood mononuclear cells and phenotypically characterized by surface expression of monocytic and endothelial markers. IFN-ß significantly reduced the number of CACs by 18-64%. Apoptosis was not induced by IFN-ß, neither in mononuclear cells during differentiation, nor after maturation to CACs. Rather, IFN-ß impaired adhesion to, and spreading on, fibronectin, which was dependent on α5ß1 (VLA-5)-integrin. IFN-ß affected the function of VLA-5 in mature CACs, leading to rounding and detachment of cells, by induction of calpain 1 activity. Cell rounding and detachment was completely reversed by inhibition of calpain 1 activity in mature CACs. During in vitro capillary formation, CAC addition and calpain 1 inhibition enhanced sprouting of endothelial cells to a comparable extent, but were not sufficient to rescue tube formation in the presence of IFN-ß. We show that the IFN-ß-induced reduction of the numbers of in vitro differentiated CACs is based on activation of calpain 1, resulting in an attenuated adhesion to extracellular matrix proteins via VLA-5. In vivo, this could lead to inhibition of vessel formation due to reduction of the locally recruited CAC numbers and their paracrine angiogenic factors.

Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol.

A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.

Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages.

Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR)-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1). In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1) and reduced numbers of CD206-positive (M2) macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular patients.

Interferon-Beta, a Decisive Factor in Angiogenesis and Arteriogenesis.

In this review we discuss the current literature on the effects of type I interferons (IFN) and their downstream effectors on vascular growth in experimental models in vitro and in vivo. In addition to its well-documented role in angiogenesis, that is, the growth of new capillaries from existing vessels, we will also describe emerging evidence and mechanisms by which type I IFN may inhibit arteriogenesis, that is, the expansive remodeling of existing collateral arteries. Crucial in both processes is the common role of circulating monocytes, which are known to act as pivotal cellular modulators in revascularization through secreted chemokines, proteases, and growth factors. These secreted molecules, which are all modulated by IFN signaling, act via degradation of the extracellular matrix and by stimulating the proliferation of vascular smooth muscle cells and endothelial cells. Thus, next to the antiviral and immunomodulatory activities of type I IFNs, a potent role of IFN-ß as modulator of revascularization is now emerging and may be considered a potential clinical target for the stimulation of angiogenesis and arteriogenesis in ill-perfused tissues.

Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction.

Acute myocardial infarction (AMI) is accompanied by increased expression of Toll like receptors (TLR)-2 and TLR4 on circulating monocytes. In animal models, blocking TLR2/4 signaling reduces inflammatory cell influx and infarct size. The clinical consequences of TLR activation during AMI in humans are unknown, including its role in long-term cardiac functional outcome Therefore, we analyzed gene expression in whole blood samples from 28 patients with an acute ST elevation myocardial infarction (STEMI), enrolled in the EXenatide trial for AMI patients (EXAMI), both at admission and after 4-month follow-up, by whole genome expression profiling and real-time PCR. Cardiac function was determined by cardiac magnetic resonance (CMR) imaging at baseline and after 4-month follow-up. TLR pathway activation was shown by increased expression of TLR4 and its downstream genes, including IL-18R1, IL-18R2, IL-8, MMP9, HIF1A, and NFKBIA. In contrast, expression of the classical TLR-induced genes, TNF, was reduced. Bioinformatics analysis and in vitro experiments explained this noncanonical TLR response by identification of a pivotal role for HIF-1α. The extent of TLR activation and IL-18R1/2 expression in circulating cells preceded massive troponin-T release and correlated with the CMR-measured ischemic area (R=0.48, p=0.01). In conclusion, we identified a novel HIF-1-dependent noncanonical TLR activation pathway in circulating leukocytes leading to enhanced IL-18R expression which correlated with the magnitude of the ischemic area. This knowledge may contribute to our mechanistic understanding of the involvement of the innate immune system during STEMI and may yield diagnostic and prognostic value for patients with myocardial infarction.

Alternative promoter usage and splicing of the human SCN5A gene contribute to transcript heterogeneity.

The sodium channel isoform Na(v)1.5 mediates sodium current, excitability, and electrical conduction in the human heart. Recent studies have indicated alternative splicing within the protein-coding portion of its gene, SCN5A, as a mechanism to generate diversity in Na(v)1.5 protein structure and function. In the present study we identified several novel SCN5A transcripts in human heart, displaying distinct 5'-untranslated regions but identical protein-coding sequences. These transcripts originated from the splicing of alternative exons 1 (designated 1A, 1B, 1C, and 1D) to the translational start codon-containing exon 2, and were preferentially expressed in the heart as compared to other tissues. Comparison of their expression level between adult and fetal heart demonstrated that exon 1C- and 1D-derived sequences were more prominent in adult than in fetal heart. Two new promoters (designated P2 and P3) for the SCN5A gene were identified and functionally characterized in myocardial- and nonmyocardial-derived cell lines. Translation of the transcript containing exon 1D-derived sequences proved to be significantly impaired in these cell lines, which could be restored by mutation of an upstream translational start codon. These results implicate the usage of alternative promoters and 5'-untranslated regions as new mechanisms in the regulation of human Na(v)1.5 expression.

In calcineurin-induced cardiac hypertrophy expression of Nav1.5, Cx40 and Cx43 is reduced by different mechanisms.

Alterations in expression levels of Na(v)1.5, Cx43 and Cx40 have been frequently reported in cardiac disease and are associated with the development of arrhythmias, but little is known about the underlying molecular mechanisms. In this study we investigated electrical conduction and expression of Na(v)1.5, Cx43 and Cx40 in hearts of transgenic mice overexpressing a constitutively active form of calcineurin (MHC-CnA). ECG recordings showed that atrial, atrioventricular and ventricular activation were significantly prolonged in MHC-CnA hearts as compared to wildtype (WT) littermates. Epicardial activation and arrhythmia susceptibility analysis revealed increased ventricular activation thresholds and arrhythmia vulnerability. Moreover, epicardial ventricular activation patterns in MHC-CnA mice were highly discontinuous with multiple areas of block. These impaired conduction properties were associated with severe reductions in Na(v)1.5, Cx43 and Cx40 protein expression in MHC-CnA hearts as visualized by immunohistochemistry and immunoblotting. Real-time RT-PCR demonstrated that the decreased protein levels for Na(v)1.5 and Cx40, but not for Cx43, were accompanied by corresponding reductions at the RNA level. Cx43 RNA isoform analysis indicated that the reduction in Cx43 protein expression is caused by a post-transcriptional mechanism rather than by RNA isoform switching. In contrast, RNA isoform analysis for Cx40 and Na(v)1.5 provided additional evidence that in calcineurin-induced hypertrophy the downregulation of these proteins originates at the transcriptional level. These results provide the molecular rationale for Na(v)1.5, Cx43 and Cx40 downregulation in this model of hypertrophy and failure and the development of the pro-arrhythmic substrate.