The Role of microRNAs in Development of Colitis-Associated Colorectal Cancer

Colorectal cancer (CRC) is the third most deadly cancer worldwide, and inflammatory bowel disease (IBD) is one of the critical factors in CRC carcinogenesis. IBD is responsible for an unphysiological and sustained chronic inflammation environment favoring the transformation. MicroRNAs (miRNAs) belong to a class of highly conserved short single-stranded segments (18–25 nucleotides) non-coding RNA and have been extensively discussed in both CRC and IBD. However, the role of miRNAs in the development of colitis-associated CRC (CAC) is less clear. The aim of this review is to summarize the major upregulated (miR-18a, miR-19a, miR-21, miR-31, miR-155 and miR-214) and downregulated (miR-124, miR-193a-3p and miR-139-5p) miRNAs in CAC, and their roles in genes’ expression modulation in chronic colonic-inflammation-induced carcinogenesis, including programmed cell-death pathways. These miRNAs dysregulation could be applied for early CAC diagnosis, to predict therapy efficacy and for precision treatment.     

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas

The recorded number of patients with central hyperthyroidism due to TSH-secreting pituitary adenoma doubled in the last few years after the introduction of ultrasensitive TSH assays in the assessment of thyroid function; however, information about the results and the criteria for cure after pituitary surgery is scanty. Seventeen patients with a TSH-secreting adenoma, diagnosed on the basis of detectable TSH levels in the face of high free thyroid hormone concentrations and pituitary lesion at neuroimaging, underwent pituitary surgery. Hypersecretion of other pituitary hormones was diagnosed in 5 of 17 patients. Four patients were initially misdiagnosed and treated with thyroid surgery or radioiodine therapy. The majority (86%) of hyperthyroid patients normalized thyroid hormone concentrations and regained euthyroidism, although pituitary imaging, alpha-subunit, and alpha-subunit/TSH molar ratio normalized in only 47%, 54%, and 58% of patients, respectively. Moreover, TSH secretion was normally suppressed by T3 in 40% of the patients. Interestingly, the finding of undetectable TSH levels 7 days after surgery was highly predictive of successful outcome. During long term follow-up, there was one relapse of hyperthyroidism. Early diagnosis of TSH-secreting adenomas permits a high rate of remission of hyperthyroidism after surgery. However, normalization of thyroid function alone does not necessarily reflect complete removal of the tumor, and more comprehensive criteria of cure based on pituitary imaging, hormone measurement, and suppression of TSH during T3 administration should be used. Lastly, all patients need an accurate long term follow-up to monitor the possible recurrence of the adenoma.     

The Strategic Control of Multiple Routes in Imitation of Actions.

The aim of this study was to bring to the surface the strategic use of imitative processes in the context of a 2-route model: (a) direct imitation, used in reproducing new, meaningless actions, and (b) imitation based on stored semantic knowledge of familiar meaningful actions. Three experiments were carried out with healthy participants who reproduced meaningful and meaningless actions within an established time limit. The study investigated 3 factors that could potentially affect the selection of processes used for imitation: (a) the composition of the experimental list (blocked or mixed presentation), (b) the presence-absence of instructions (Experiments 1 and 2), and (c) the relative proportions of the stimuli (Experiment 3). Overall, the results suggest that each of these factors influences the selection of imitative strategies in healthy individuals with temporarily reduced capacities, as happens in the case of brain-damaged patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synthesis and Evaluation of Voltage-Gated Sodium Channel Blocking Pyrroline Derivatives Endowed with Both Antiarrhythmic and Antioxidant Activities

Under the hypothesis that cardioprotective agents might benefit from synergism between antiarrhythmic activity and antioxidant properties, a small series of mexiletine analogues were coupled with the 2,2,5,5-tetramethylpyrroline moiety, known for its antioxidant effect, in order to obtain dual-acting drugs potentially useful in the protection of the heart against post-ischemic reperfusion injury. The pyrroline derivatives reported herein were found to be more potent as antiarrhythmic agents than mexiletine and displayed antioxidant activity. The most interesting tetramethylpyrroline congener, a tert-butyl-substituted analogue, was at least 100 times more active as an antiarrhythmic than mexiletine.     

Intelligent planning and the design of a new risk-based,intelligent flight plan

A safe flight starts with effective performance of the pre-flight flight planning and briefing task. However, several problems related to the execution of this task can be identified. Potentially, the introduction of an improved flight plan provides an opportunity to improve the quality and availability of information provided to Flight Crew, thereby enhancing the quality of crew briefings. The proposed risk-based, intelligent flight plan is designed from the perspective of the current operational concept (e.g. fixed routes and ATC managerial role for separation), and associated airline Flight Planning and Dispatch functions. In this case, the focus is sharing information across specific airline stakeholders (e.g. Flight Operations Management and Safety functions) and Maintenance, to support a safe and efficient flight operation. Overall, the introduction of this new flight plan will result in the definition of new operational and organisational processes, along with a new way of performing the pre-flight, planning and briefing task. It is anticipated that this will impact positively on the operational and safety outcome of the flight.     

Universal constructions that ensure disjoint-access parallelism and wait-freedom

A universal construction is a general mechanism for obtaining a concurrent implementation of an object from its sequential code. We show that there is no universal construction that is both disjoint-access parallel (guaranteeing the processes operating on different parts of an implemented object do not interfere with one another) and wait-free (guaranteeing progress for each nonfaulty process when accessing an object). In contrast, we present a universal construction which results in disjoint-access parallel, wait-free implementations of any object provided there is a bound on the number of data items accessed by each operation supported by the object.     

Microglia and Alzheimer’s Disease

There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) and neuroinflammation seems to be one of the most fascinating solutions. The primary cell type that performs immunosurveillance and helps clear out unwanted chemicals from the brain is the microglia. Microglia work to reestablish efficiency and stop further degeneration in the early stages of AD but mainly fail in the illness’s later phases. This may be caused by a number of reasons, e.g., a protracted exposure to cytokines that induce inflammation and an inappropriate accumulation of amyloid beta (Aβ) peptide. Extracellular amyloid and/or intraneuronal phosphorylated tau in AD can both activate microglia. The activation of TLRs and scavenger receptors, inducing the activation of numerous inflammatory pathways, including the NF-kB, JAK-STAT, and NLRP3 inflammasome, facilitates microglial phagocytosis and activation in response to these mediators. Aβ/tau are taken up by microglia, and their removal from the extracellular space can also have protective effects, but if the illness worsens, an environment that is constantly inflamed and overexposed to an oxidative environment might encourage continuous microglial activation, which can lead to neuroinflammation, oxidative stress, iron overload, and neurotoxicity. The complexity and diversity of the roles that microglia play in health and disease necessitate the urgent development of new biomarkers that identify the activity of different microglia. It is imperative to comprehend the intricate mechanisms that result in microglial impairment to develop new immunomodulating therapies that primarily attempt to recover the physiological role of microglia, allowing them to carry out their core function of brain protection.     

Molecular Genetics of GLUT1DS Italian Pediatric Cohort: 10 Novel Disease-Related Variants and Structural Analysis

GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients, clinically suspect of GLUT1DS from both sporadic and familial cases, have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift, and splice site variants. Their structural mapping on the X-ray structure of GLUT1 strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters.     

Quantitative Analysis of Plant Cytosolic Calcium Signals in Response to Water Activated by Low-Power Non-Thermal Plasma

Non-thermal plasma technology is increasingly being applied in the plant biology field. Despite the variety of beneficial effects of plasma-activated water (PAW) on plants, information about the mechanisms of PAW sensing by plants is still limited. In this study, in order to link PAW perception to the positive downstream responses of plants, transgenic Arabidopsis thaliana seedlings expressing the Ca²⁺-sensitive photoprotein aequorin in the cytosol were challenged with water activated by low-power non-thermal plasma generated by a dielectric barrier discharge (DBD) source. PAW sensing by plants resulted in the occurrence of cytosolic Ca²⁺ signals, whose kinetic parameters were found to strictly depend on the operational conditions of the plasma device and thus on the corresponding mixture of chemical species contained in the PAW. In particular, we highlighted the effect on the intracellular Ca²⁺ signals of low doses of DBD-PAW chemicals and also presented the effects of consecutive plant treatments. The results were discussed in terms of the possibility of using PAW-triggered Ca²⁺ signatures as benchmarks to accurately modulate the chemical composition of PAW in order to induce environmental stress resilience in plants, thus paving the way for further applications in agriculture.