Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging.

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.

Protocol registration issues of systematic review and meta-analysis studies: a survey of global researchers.

BACKGROUND: Although protocol registration of systematic reviews/meta-analysis (SR/MA) is still not mandatory, it is highly recommended that authors publish their SR/MA protocols prior to submitting their manuscripts for publication as recommended by the Cochrane guidelines for conducting SR/MAs. our aim was to assess the awareness, obstacles, and opinions of SR/MA authors about the protocol registration process. METHODS: A cross-sectional survey study included the authors who published SR/MAs during the period from 2010 to 2016, and they were contacted for participation in our survey study. They were identified through the literature search of SR/MAs in Scopus database. An online questionnaire was sent to each participant via e-mail after receiving their approval to join the study. We have sent 6650 emails and received 275 responses. RESULTS: A total of 270 authors responses were complete and included in the final analysis. Our results has shown that PROSPERO was the most common database used for protocol registration (71.3%). The registration-to-acceptance time interval in PROSPERO was less than 1 month (99.1%). Almost half of the authors (44.2%) did not register their protocols prior to publishing their SR/MAs and according to their opinion that the other authors lack knowledge of protocol importance and mandance to be registered, was the most commonly reported reason (44.9%). A significant percenatge of respondents (37.4%) believed that people would steal their ideas from protocol databases, while only 5.3% reported that their SR/MA had been stolen. However, the majority (72.9%) of participants have agreed that protocol registries play a role in preventing unnecessary duplication of reviews. Finally, 37.4% of participants agree that SR/MA protocol registration should be mandatory. CONCLUSION: About half of the participants believes that the main reason for not registering protocols, is that the other authors lack knowledge concerning obligation and importance to register the SR/MA protocols in advance. Therefore, tools should be available to mandate protocol registration of any SRs beforehand and increasing awareness about the benefits of protocol registration among researchers.

Expression of CXCR7 in colorectal adenoma and adenocarcinoma: Correlation with clinicopathological parameters.

Colorectal carcinoma (CRC) is one of the most lethal malignancies, it ranks third in cancer-related morbidity and mortality. Although great progress has been made in early diagnosis and combined treatment of CRC, the prognosis of patients remains poor owing to the high rate of recurrence and distant metastasis. CXCR7 belongs to chemokine receptor family and has been identified as a novel receptor for CXCL12. It plays an important role in development and in progression of cancer to metastatic stage. THE AIM OF STUDY: To evaluate the immunohistochemical expression of CXCR7 in colorectal adenoma and carcinoma and to analyze its correlation with clinicopathological factors. This is retrospective study including 58 colonic adenocarcinoma specimens and 18 cases of colonic adenoma. RESULTS: CXCR7 showed positive cytoplasmic expression in two out 18 cases of colorectal adenoma (11%) and 42 out of 58 cases of CRC (72.4%) with a significant difference between both (p < 0.001). We found a significant correlation between upregulation of CXCR7 and presence of lymphovascular tumor emboli, presence of lymph node metastasis and advanced TNM stage of the CRC. The association of the CXCR7 with patient age, sex, tumor size, depth of invasion and tumor cell differentiation was found to be non-significant. Regarding colonic adenoma, we found no significant association between CXCR7 expression on one hand and patient age, sex, tumor size, histologic type and degree of dysplasia on the other hand. CONCLUSION: CXCR7 in CRC may act as a novel predictive indicator for prognosis and even be a potential molecular target for anticancer therapies.

Cytotoxicity of propolis nanopreparations in cancer cell monolayers: multimode of action including apoptotsis and nitric oxide production.

Natural products are invaluable resource of anticancer drug discovery. They generally viewed as safe but weak, within the framework of nanotechnology, they can serve as template for potent anticancer drugs. We first evaluated the cytotoxic activity of different propolis extracts (water, 70% ethanol, absolute ethanol and hexane) in many cancer cell lines, then the solid nanoparticles from the organic solvent extracts were prepared and their cytotoxicity was evaluated as well. Finally, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes were prepared from the most cytotoxic organic solvent extract and their cytotoxicity was also evaluated. All results collectively showed that hexane extract and its solid nanoparticles as well as its liposomal form exhibited high cytotoxic activity. DPPC/DOPC-hexane extract cytotoxicity selectively depends on the cell line and DOPC liposomal form was characterized by reduced IC50 compared with the other preparations/extracts, the average IC50 value is 165.8 ± 3 µg/ml. The antiproliferative activity of propolis was associated to multiple modes of actions including apoptosis and nitric oxide production and as indicated by the HPLC and FTIR results, it is functioning in many propolis ingredients rather than a single component and influenced by the presence of more lipophilic components within the extract and not by the extract mass yield. These results may have an impact on the multidrug resistivity issue.

Expression of galectin-1 and galectin-3 in renal cell carcinoma; immunohistochemical study.

BACKGROUND AND AIMS: Galectins comprise a large family of calcium independent lectins. Galectin-1 and galectin-3 contribute to neoplastic transformation, angiogenesis, and tumor metastasis in some cancers. This study aimed at studying the immunohistochemical expression of both galectin-1 and galectin-3 in renal cell carcinoma (RCC) variants and detecting the possible association of galectins with various clinicopathological parameters. MATERIALS AND METHODS: Sections from 67 formalin-fixed paraffin-embedded tissue blocks of RCC variants were stained with galectin-1 and galectin-3. Expression was assessed in tumor tissue and adjacent renal parenchyma and was correlated with clinicopathological criteria. RESULTS: In apparently normal renal parenchyma adjacent to tumor tissue, galectin-1 was expressed in 27 (40.2%) of specimens in renal tubules and glomeruli, while 34 (50.7%) of specimens showed galectin-3 expression in renal tubules sparing glomeruli. In tumor tissue, galectin-1 showed high expression in 47 (70.1%) and low expression in 20 (29.9%) of specimens. Galectin-3 had high expression in 15 (22.4%) and low expression in 52 (77.6%) of specimens. Significant association was detected between expression of galectin-1 and galectin-3 and the type of RCC (P = 0.032) and (P = 0.006), respectively. Significant inverse association was detected between the expression of galectin-3 and the presence of tumor haemorrhage and necrosis (P = 0.014) and (P = 0.039), respectively. CONCLUSION: Galectin-1 and galectin-3 are overexpressed in RCC with different percentage in different subtypes. Galactin-1expression is more in tumor tissue than surrounding renal parenchyma suggesting that it has a carcinogenic role. Galectin-1 and galectin-3 overexpression in chromophobe RCC suggests that they may have diagnostic role.

Infrared spectroscopic investigation of erythrocyte membrane-smoke interactions due to chronic cigarette smoking.

Cigarette smoking is a serious health problem throughout the world, with a complicated and not totally clear bio-effect. In this study, erythrocytes were obtained from healthy male volunteers aged 22 ± 2 years and, the possible effects of three cigarette smoking rates namely 10, 15 and 20 cigarette/day on erythrocytes membrane characteristics were examined by Fourier transform infrared spectroscopy (FTIR). The results of this study indicate many smoking-dependent variations on erythrocytes membrane without an obvious dose-response relationship. There was disruption in the acyl chain packing; changes in membrane order and phases as well as membrane proteins becoming more folded. These physico-chemical changes should have an impact on the function of erythrocytes and may explain the complex interaction of cigarette smoke mainstream with erythrocyte membrane and to some extent clarify the pathological processes associated with cigarette smoking.

Novel method for determination of anthracene by coupling dispersive liquid-liquid extraction to first-derivative synchronous spectrofluorimetry.

A novel method could be adopted successfully for determination of anthracene in environmental samples, utilizing dispersive liquid-liquid extraction followed by first-derivative synchronous fluorimetry at a constant wavelength difference Δλ = 165 nm, where a linear calibration curve was obtained in a concentration range of 0.5-100 ng mL(-1) at 244 nm. The detection limit was 0.1 ng mL(-1). The method can be easily adopted for determination of anthracene in aqueous media including tap water and river water. The recoveries obtained were 85.40-108.02%. The proposed method was validated according to International Conference of Harmonization (ICH) guide lines and successfully applied to determine anthracene in pure form and in water samples including real life water samples from different sources. All the results obtained were compared with those of published method, where no a significant difference was observed.

A Subcutaneous Alar Base (SCAB) flap to restore symmetry of the ala in primary cleft-lip nose repair.

Primary surgical correction of cleft-lip nose deformity is now well accepted. Despite various surgical techniques proposed, perfect nasal symmetry has not been persistently attained. The main reason is that the maxillary deficiency is frequently overlooked.This paper presents 62 cases of unilateral cleft lip repaired over the last 20 years by using the author's modification of the Millard primary lip nose repair. Each of these patients had a minimum follow-up of 1 year (range 1-12 years).The technique consists of raising a small subcutaneous alar base flap (SCAB) from the nasolabial region. The flap is turned over like a book page to add bulk to the deficient maxilla and to elevate the depressed ala. It also controls alar rotation and permits its permanent fixation to the anterior nasal spine.The results show that this modification has improved the alar contour and symmetry in patients undergoing primary cleft-lip nasal repair. There was minimal increase in the operating time and the final scar is similar to the original Millard technique.

Synchronous spectrofluorimetric determination of naphthalene in water samples using mixed micellar medium.

A mixed micellar medium of sodium dodecyl sulfate and Pluronic F-127 was used to enhance the fluorescence of naphthalene and to obtain lower LODs. The method was based upon measuring the first-derivative synchronous fluorescence spectrum of naphthalene by using a mixed micellar medium at a constant wavelength difference delta lambda = 60 nm, where a greater fluorescence enhancement was observed if compared to using a single surfactant separately. A linear fluorimetric calibration curve was obtained for naphthalene in a concentration range of 10-200 ng/mL. The LOD was 7.13 ng/mL, which is well below the health advisory limit for naphthalene in drinking water as suggested by the U.S. Environmental Protection Agency. The method can be easily adopted for determination of naphthalene in aqueous media including tap water and river water. The recoveries obtained were 95.979-115.645%. The proposed method was validated according to International Conference on Harmonization guidelines and successfully applied to determine naphthalene in real life water samples from different sources.

Hydrochemical and geological controls on dissolved radium and radon in northwestern Algeria hydrothermal groundwaters.

This study presents the results of the first investigation on natural occurrence of radium and radon in Algerian thermal water systems. Activity concentrations of Rn and Ra isotopes were measured in sixteen hydrothermal springs of northwestern Algeria. Samples displayed high activities, especially for 222Rn, 224Ra and 226Ra (up to 377 × 103 Bq/m3, 730 Bq/m3 and 4470 Bq/m3, respectively). Approximately, 50% of the investigated springs displayed activities of combined long-lived Ra (226Ra + 228Ra) in excess of the maximum contaminant level (MCL) of the WHO and EPA for drinking water. Factors controlling the distribution of radionuclides in the aquifer system are investigated. The observed correlation between Ra isotope and TDS suggests that adsorption/desorption is not the dominant process controlling the distribution of Ra in waters. Our results indicate that the excess SO42- limits the concentration of dissolved Ba2+ and thereby, the elevated Ra activities in these hydrothermal systems are not simply limited by co-precipitation with BaSO4 (barite). The data shows that Ra activities are likely dominated by the recoil process of parent isotopes in the aquifer solids. The minimal abundance of clay minerals and oxides in the aquifer, in addition to thermal activities in northwestern Algeria, significantly enhances the mobilization of Ra into waters.

Influence of Microstructure and Alloy Composition on the Machinability of α/ß Titanium Alloys.

A comparative study was conducted for the machining of two α/ß titanium alloys, namely Ti-6Al-4V (Ti64) and Ti-6Al-7Nb (Ti67), using wire electric discharge machining (WEDM). The influence of cutting speed and cutting mode on the machined surfaces in terms of surface roughness (Ra), recast layer (RL), and micro-hardness have been evaluated. Rough cut (RC) mode at a cutting speed of 50 µm/s resulted in thermal damage; Ra was equal to 5.68 ± 0.44 and 4.52 ± 0.35 µm for Ti64 and Ti67, respectively. Trim-cut mode using seven cuts (TRC-VII) at the same speed decreased the Ra to 1.02 ± 0.20 µm for Ti64 and 0.92 ± 0.10 µm for Ti67. At 100 µm/s, Ra reduced from 2.34 ± 0.28 µm to 0.88 ± 0.12 µm (Ti64), and from 1.42 ± 0.15 µm to 0.90 ± 0.08µm (Ti67) upon changing from TRC-III to TRC-VII. Furthermore, a thick recast layer of 30 ± 0.93 µm for Ti64 and 14 ± 0.68 µm for Ti67 was produced using the rough mode, while TRC-III and TRC-VII modes produced layers of 12 ± 1.31 µm and 5 ± 0.72 µm for Ti64 and Ti67, respectively. Moreover, rough cut and trim cut modes of WEDM played a significant role in promoting the surface hardness of Ti64 and Ti67. By employing the Response Surface Methodology, it was found that the machining mode followed by cutting speed and the interaction between them are the most influential parameters on surface roughness. Finally, mathematical models correlating machining parameters to surface roughness were successfully developed. The results strongly promote the trim-cut mode of WEDM as a promising machining route for two-phase titanium alloys.

Multimodality Imaging in Aortic Stenosis.

Aortic stenosis (AS) is the most common cardiac valve lesion in the adult population, with an incidence increasing as the population ages. Accurate assessment of AS severity is necessary for clinical decision-making. Echocardiography is currently the diagnostic method of choice for assessing and managing AS. Transthoracic echocardiography is usually sufficient in most situations. Transesophageal echocardiography and stress echocardiography may also be utilized when there is inadequate image quality and/or discordance in the results and the clinical presentation. There is a role for other imaging modalities such as cardiac computed tomography, magnetic resonance imaging, and catheterization in selected cases. The following describes in some detail the role of these modalities in the diagnosis and assessment of AS.

In Silico Docking, Resistance Modulation and Biofilm Gene Expression in Multidrug-Resistant Acinetobacter baumannii via Cinnamic and Gallic Acids.

Despite the mounting global burden of antimicrobial resistance (AMR), the generation of new classes of effective antimicrobials still lags far behind. The interplay between multidrug resistance and biofilm formation in Acinetobacter baumannii has drastically narrowed the available therapeutic choices. The use of natural compounds holds promise as an alternate option for restoring the activity of existing antibiotics and attenuating virulence traits through reduced biofilm formation. This study aimed to evaluate the modulatory effect of combining cinnamic and gallic acids at ½MIC with various antibiotics against multidrug-resistant (MDR) A. baumannii clinical isolates as well as study the effect on the expression of the biofilm-associated genes (bap, csuE, ompA) via quantitative, real-time PCR. Combining cinnamic or gallic acid with imipenem, amikacin or doxycycline resulted in significant reduction of resistance (p < 0.05). On the contrary, no effect was recorded when both acids were combined with levofloxacin, and only cinnamic acid had a synergistic effect with colistin. The transcriptomic changes of biofilm-related genes in the presence of gallic acid at ½MIC were compared with untreated control samples. The fold expression values proved that gallic acid substantially down-regulated the respective genes in all five strong biofilm formers. Molecular docking studies of gallic and cinnamic acids on target genes revealed good binding affinities and verified the proposed mechanism of action. To the best of our knowledge, this is the first report on the effect of gallic acid on the expression of bap, csuE and ompA genes in A. baumannii, which may permit its use as an adjunct anti-virulence therapeutic strategy.

The role of serum gastric peptide ghrelin hormone level in irritable bowel syndrome at Zagazig University Hospitals.

Generalized dysmotility of the gastrointestinal tract develops in individuals with irritable bowel syndrome (IBS). The ghrelin hormone appears to be critical in controlling gastrointestinal motility. We aimed to evaluate serum ghrelin levels in people with IBS and to demonstrate its role in IBS pathophysiology. This study included 32 individuals with IBS (16 with constipation and 16 with diarrhea) and 16 healthy individuals as controls. Blood specimens were collected from patients and controls following an overnight fast. Total ghrelin level was detected in plasma by commercially available ELISA Kit. There were significant differences in the serum levels of ghrelin between the control group and both types of IBS. The mean±SD of ghrelin level in the control group was 2.608±0.714 pg/ml, and that of both types of IBS was 5.782±2.450 pg/ml (P-value<0.001). There was a significant variation between the control and IBS-D groups (mean±SD: 7.838±1.687 pg/ml, p-value<0.001). Also, we indicated a considerable difference between the control and IBS-C groups (mean±SD: 3.726±0.740 pg/ml, P-value<0.001). In comparing the IBS-D group and IBS-C group, we found a highly considerable variation between the two groups (p-value<0.001). This means that serum ghrelin levels were significantly greater in IBS-D than in IBS-C and the control group. Our findings concluded that serum ghrelin level was higher among the IBS-D group than in the IBS-C and control groups. The ghrelin hormone may play a vital role in IBS pathophysiology.

Elevated radium levels in Nubian Aquifer groundwater of Northeastern Africa.

The Nubian Sandstone Aquifer System in Northeast Africa and the Middle East is a huge water resource of inestimable value to the population. However, natural radioactivity impairs groundwater quality throughout the aquifer posing a radiological health risk to millions of people. Here we present measurements of radium isotopes in Nubian Aquifer groundwater from population centers in the Western Desert of Egypt. Groundwater has 226Ra and 228Ra activities ranging from 0.01 to 2.11 and 0.03 to 2.31 Bq/L, respectively. Most activities (combined 226Ra + 228Ra) exceed U.S. EPA drinking water standards. The estimated annual radiation doses associated with ingestion of water having the highest measured Ra activities are up to 138 and 14 times the WHO-recommended maxima for infants and adults, respectively. Dissolved Ra activities are positively correlated with barium and negatively correlated with sulfate, while barite is approximately saturated. In contrast, Ra is uncorrelated with salinity. These observations indicate the dominant geochemical mechanisms controlling dissolved Ra activity may be barite precipitation and sulfate reduction, along with input from alpha-recoil and dissolution of aquifer minerals and loss by radioactive decay. Radium mitigation measures should be adopted for water quality management where Nubian Aquifer groundwater is produced for agricultural and domestic consumption.

Multidrug Resistant Acinetobacter baumannii Biofilms: Evaluation of Phenotypic-Genotypic Association and Susceptibility to Cinnamic and Gallic Acids.

Acinetobacter baumannii armed with multidrug resistance (MDR) and biofilm-forming ability is increasingly recognized as an alarming pathogen. A deeper comprehension of the correlation between these two armories is required in circumventing its infections. This study examined the biofilm-forming ability of the isolates by crystal violet staining and the antibiotic susceptibility by broth microdilution method. The genetic basis of the MDR and biofilm-forming phenotypes was screened by polymerase chain reaction. The antimicrobial activities of cinnamic and gallic acids against planktonic cells and biofilms of A. baumannii were investigated, and the findings were confirmed with scanning electron microscopy (SEM). Among 90 A. baumannii isolates, 69 (76.6%) were MDR, and all were biofilm formers; they were classified into weak (12.2%), moderate (53.3%), and strong (34.5%) biofilm formers. Our results underlined a significant association between MDR and enhanced biofilm formation. Genotypically, the presence of bla VIM and bla OXA-23 genes along with biofilm-related genes (ompA, bap, and csuE) was statistically associated with the biofilm-forming abilities. Impressively, both gallic and cinnamic acids could significantly reduce the MDR A. baumannii biofilms with variable degrees dependent on the phenotype-genotype characteristics of the tested isolates. The current findings may possess future therapeutic impact through augmenting antimicrobial arsenal against life-threatening infections with MDR A. baumannii biofilms.

Efficacy of adipose-derived stromal vascular fraction cells in the management of chronic ulcers: a randomized clinical trial.

Background: Cell therapy is a promising method for improving healing in chronic ulcers through delivery of isolated adipose-derived stromal vascular fraction. Objectives: This study investigates the autologous stem cell yield of adipose tissue and its efficacy in chronic ulcers compared with conventional methods. Methods: This study was a randomized controlled trial. After the study design and protocol were established and ethical committee approval was obtained, we enrolled 100 patients divided into study and control groups. In the study group, we performed debridement and autologous stem cell injection every 3 weeks. The control group was treated with debridement and conventional dressing. Assessments included clinical and histological parameters. Results: The study group showed improved healing. Conclusion: Using autologous adipose-derived stromal vascular fraction cells is an effective treatment method for chronic ulcers. This study was registered on the Pan-African Clinical Trial Registry and the number of the registry was PACTR201709002519185.

Genetic diversity, LC-ESI-MS chemical profile and in vivo antitumor activity of three Egyptian soybean cultivars.

Soybean (Glycine max L.) is one of the most important and widely consumed food plants worldwide. The objective of this study was to investigate the metabolite profiling of three Egyptian soybean cultivars (Giza 22, Giza 35 and Giza 111) and their in vivo antitumor effect. Random amplified polymorphic DNA (RAPD) analysis developed polymorphism level of 75% in 72 distinct markers. Applying LC-ESI-MS analysis, twenty-nine metabolites were recognized from the 80% methanol extract of all cultivars. In vivo antitumor activity of the 80% methanolic extract against solid Ehrlich ascites carcinoma (EAC) inoculated in mice model, showed a significant diminishing in tumor volume and reduced Glutathione (rGSH) and a significant increase in malondialdehyde (MDA) which was supported by histopathological examination. Among the studied cultivars, Giza 22 cultivar contained the highest total phenolic content (TPC) that may contribute to its impressive antioxidant capacity and antitumor activity.

Right Atrial Pseudoaneurysm Complicating Epithelioid Hemangioendothelioma.

Cardiac pseudoaneurysm is uncommon among young adults with trauma. Infection, prior cardiac procedure, or cardiac operations are the most common reported causes. Right atrial pseudoaneurysm (RAPA) is extremely rare. Although often challenging to diagnose, advances in noninvasive imaging have improved the ability to diagnose cardiac pseudoaneurysms. We present a case of RAPA, highlighting the diagnostic accuracy of echocardiography in this rare entity.

Safe Echocardiographic Practice in Hamad Medical Corporation during the Coronavirus Disease 2019 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has strained our healthcare system. Certain changes in practice were mandatory to protect our sonographers who carry a very high risk of being infected, and the patients whom we serve. This article aims to share this experience with you.