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In this paper the conditions and the findings of a simulation study is presented for assessing the effect size of users’ consciousness to the computer network vulnerability in risky cyber attack situations at a certain business. First a simple model is set up to classify the groups of users according to their skills and awareness then probabilities are assigned to each class describing the likelihood of committing dangerous reactions in case of a cyber attack. To quantify the level of network vulnerability a metric developed in a former work is used. This metric shows the approximate probability of an infection at a given business with well specified parameters according to its location, the type of the attack, the protections used at the business etc. The findings mirror back the expected tendencies namely if the number of conscious user is on the

Hadarics et. al. gave a Mathematical Model for Distributed Vulnerability Assessment. In this model the extent of vulnerability of a specific company IT infrastructure is measured by the probability of at least one successful malware attack when the users behaviour is also incorporated into the model. The different attacks are taken as independent random experiments and the probability is calculated accordingly. The model uses some input probabilities related to the characteristics of the different threats, protections and user behaviours which are estimated by the corresponding relative frequencies. In this paper this model is further detailed, improved and a numerical example is also presented.

We sought to develop a whole-cell biosensor for the detection of arsenic in drinking water, a major problem in Bangladesh and West Bengal. In contrast to previously described systems, our biosensor would give a pH change as output, allowing simple detection with a pH electrode or pH indicator solution. We designed and modelled a system based on the arsenate-responsive promoter of the Escherichia coli arsenic detoxification system, using urease to increase pH in the absence of arsenate, and β-galactosidase (LacZ) to decrease pH in the presence of arsenate. The pH-reducing β-galactosidase part of the system was constructed and tested, and was found to give a clear response to arsenate concentrations as low as 5 ppb arsenic, well below the World Health Organisation (WHO) recommended limit of 10 ppb. [ABSTRACT FROM AUTHOR]

András Vereczkei, Laura Bognár, András Papp, Örs Péter Horváth Department of Surgery, University of Pécs, Pécs, Hungary Abstract: Achalasia is a motility disorder of the esophagus characterized by the defective peristaltic activity of the esophageal body and impaired relaxation of the lower esophageal sphincter due to the degeneration of the inhibitory neurons in the myenteric plexus of the esophageal wall. The histopathological and pathophysiological changes in achalasia have been well described. However, the exact etiological factors leading to the disease still remain unclear. Currently, achalasia is believed to be a multifactorial disease, involving both extrinsic and intrinsic factors. Based on our experience and the review of literature, we believe that gastroesophageal reflux disease (GERD) might be one of the triggering factors leading to the development of achalasia. However, it is also stated that the two diseases can simultaneously appear independently from each other. Considering the large number and routine treatment of patients with GERD and achalasia, the rare combination of the two may even remain unnoticed; thus, the analysis of larger patient groups with this entity is not feasible. In this context, we report four cases where long-standing reflux symptoms preceded the development of achalasia. A literature review of the available data is also given. We hypothesize that achalasia following the chronic acid exposure of the esophagus is not accidental but either a consequence of a chronic inflammation or a protective reaction of the organism in order to prevent aspiration and lessen reflux-related symptoms. This hypothesis awaits further clinical confirmation. Keywords: achalasia, gastroesophageal reflux disease, Barrett’s esophagus, Nissen fundoplication

Meningioma is among the most frequent brain tumours predominantly affecting elderly women. Epidemiological studies have shown that at the age of fertility the incidence is relatively low. The biological behaviour of meningioma in pregnancy is different from other meningiomas. The possible explanation is rooted in the complex physiological changes and hormonal differences during pregnancy. The increased meningioma growth observed in pregnancy is presumably the result of endocrine mechanisms. These include increase in progesterone, human placental lactogen (hPL) and prolactin (PRL) serum levels. In contrast, levels of pituitary hormones such as follicle stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) produced by the placenta are decreasing in the mother prior to childbirth. Besides, vascular factors also play a crucial role. Peritumoral brain edema (PTBE), with well-known causative association with vascular endothelial growth factor (VEGF), can often be seen both with imaging and in the surgical specimens. Our aim is to assess published research on this topic including diagnostic and therapeutic guidelines, and to provide a clinically useful overview on the pathophysiology and biological behaviour of this rare complication of pregnancy.

The correct wiring of neuronal circuits is one of the most complex processes in development, since axons form highly specific connections out of a vast number of possibilities. Circuit structure is genetically determined in vertebrates and invertebrates, but the mechanisms guiding each axon to precisely innervate a unique pre-specified target cell are poorly understood. We investigated Drosophila embryonic motoneurons using single-cell genomics, imaging, and genetics. We show that a cell-specific combination of homeodomain transcription factors and downstream immunoglobulin domain proteins is expressed in individual cells and plays an important role in determining cell-specific connections between differentiated motoneurons and target muscles. We provide genetic evidence for a functional role of five homeodomain transcription factors and four immunoglobulins in the neuromuscular wiring. Knockdown and ectopic expression of these homeodomain transcription factors induces cell-specific synaptic wiring defects that are partly phenocopied by genetic modulations of their immunoglobulin targets. Taken together, our data suggest that homeodomain transcription factor and immunoglobulin molecule expression could be directly linked and function as a crucial determinant of neuronal circuit structure., (©2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling., Competing Interests: Declaration of Interests P.B. and R.B. receive grant funding from the Novartis Institute of Biomedical Research for an unrelated project. J.R.H. has received compensation for consultation from Bayer for unrelated work., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this work was to explore two novel operation modalities of the rotating gamma systems (RGS) that could expand its clinical application to lesions in close proximity to critical organs at risk (OAR)., Methods: The approach taken in this study consists of two components. First, a Geant4-based Monte Carlo (MC) simulation toolkit is used to model the dosimetric properties of the RGS Vertex 360™ for the normal, intensity modulated radiosurgery (IMRS), and speed modulated radiosurgery (SMRS) operation modalities. Second, the RGS Vertex 360™ at the Rotating Gamma Institute in Debrecen, Hungary is used to collect experimental data for the normal and IMRS operation modes. An ion chamber is used to record measurements of the absolute dose. The dose profiles are measured using Gafchromic EBT3 films positioned within a spherical water equivalent phantom., Results: A strong dosimetric agreement between the measured and simulated dose profiles and penumbra was found for both the normal and IMRS operation modes for all collimator sizes (4, 8, 14, and 18 mm diameter). The simulated falloff and maximum dose regions agree better with the experimental results for the 4 and 8 mm diameter collimators. Although the falloff regions align well in the 14 and 18 mm collimators, the maximum dose regions have a larger difference. For the IMRS operation mode, the simulated and experimental dose distributions are ellipsoidal, where the short axis aligns with the blocked angles. Similarly, the simulated dose distributions for the SMRS operation mode also adopt an ellipsoidal shape, where the short axis aligns with the angles where the orbital speed is highest. For both modalities, the dose distribution is highly constrained with a sharper penumbra along the short axes., Conclusions: Dose modulation of the RGS can be achieved with the IMRS and SMRS modes. By providing a highly constrained dose distribution with a sharp penumbra, both modes could be clinically applicable for the treatment of lesions in close proximity to critical OARs., (© 2018 American Association of Physicists in Medicine.)

The Arabidopsis circadian clock orchestrates gene regulation across the day/night cycle. Although a multiple feedback loop circuit has been shown to generate the 24-hr rhythm, it remains unclear how robust the clock is in individual cells, or how clock timing is coordinated across the plant. Here we examine clock activity at the single cell level across Arabidopsis seedlings over several days under constant environmental conditions. Our data reveal robust single cell oscillations, albeit desynchronised. In particular, we observe two waves of clock activity; one going down, and one up the root. We also find evidence of cell-to-cell coupling of the clock, especially in the root tip. A simple model shows that cell-to-cell coupling and our measured period differences between cells can generate the observed waves. Our results reveal the spatial structure of the plant clock and suggest that unlike the centralised mammalian clock, the Arabidopsis clock has multiple coordination points., Competing Interests: PG, MD, MG, IT, HR, LK, AH, JL No competing interests declared, (© 2018, Gould et al.)

Background: Ischemia-reperfusion injury may lead to insufficient microcirculation and results in partial flap loss during the free flap surgeries., Objective: This study aimed to investigate the effect of trimetazidine (TMZ) on oxidative stress, inflammation and histopathological changes, using the epigastric skin flap model in rats., Methods: 40 male Wistar rats were used, that were divided into four groups. Control group, non-treated ischemic (I/R)-group and two trimetazidine treated groups (preischemically, postischemically) were established. To create ischemia in the skin flap, the superficial epigastric vessels were clamped for six hours, followed by twenty-four hours of reperfusion. Blood samples and biopsies from skin flaps were collected at the end of the reperfusion period. The inflammatory response, the degree of oxidative stress (by measuring the plasma level of malondialdehyde (MDA), reduced glutathione (GSH); sulfhydryl (-SH) groups) and histopathological changes were evaluated., Results: Inflammatory response, and oxidative stress were significantly attenuated in the trimetazidine treated groups, compared to the non-treated ischemic group. Histopathological findings were also correlated with the biochemical results., Conclusion: In our study trimetazidine could reduce the ischaemia-reperfusion injury, even after an unexpected ischemic period, so it is a promising drug during free tissue transfer, replantation or during revascularization procedures in the future.

Competent nurse managers of outpatient hemodialysis (HD) units are invaluable in enhancing patient safety, creating a culture of safety, and preventing adverse events. Yet little is known regarding the characteristics of a professional work environment that supports their important managerial role. The purpose of this qualitative study was to identify those organizational characteristics that outpatient HD unit nurse managers describe as important to a supportive managerial work environment. A total of six major themes with descriptive categories and exemplars emerged from the analysis. Findings from this study can inform HD administrators in their efforts to create and sustain work environments that support the professional practice of outpatient HD unit nurse managers. Notably, findings can also provide guidelines for nurse managers considering employment opportunities in that they can be used to assess and compare the work environments of outpatient HD facilities and organizations., Competing Interests: The author reported no actual or potential conflict of interest in relation to this continuing nursing education activity., (Copyright© by the American Nephrology Nurses Association.)

A multi-site descriptive retrospective study of physiologic, demographic, and psychosocial factors associated with 30-day readmissions for heart failure was conducted in six Magnet-designated hospitals. Results can be used to plan effective nursing interventions to target readmitted patients.

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

Brassinosteroid (BR)-regulated growth and development in Arabidopsis depends on BRASSINOSTEROID INSENSITIVE 1 (BRI1), the BR receptor that is responsible for initiating the events of BR signalling. We analysed the temporal and spatial regulation of BRI1 expression using stable transgenic lines that carried BRI1 promoter:reporter fusions. In both seedlings and mature plants the tissues undergoing elongation or differentiation showed elevated BRI1 gene activity, and it could be demonstrated that in the hypocotyl this was accompanied by accumulation of the BRI1 transcript and its receptor protein product. In seedlings the BRI1 promoter was also found to be under diurnal regulation, determined primarily by light repression and a superimposed circadian control. To determine the functional importance of transcriptional regulation we complemented the severely BR insensitive bri1-101 mutant with a BRI1-luciferase fusion construct that was driven by promoters with contrasting specificities. Whereas the BRI1 promoter-driven transgene fully restored the wild phenotype, expression from the photosynthesis-associated CAB3 and the vasculature-specific SUC2 and ATHB8 promoters resulted in plants with varying morphogenic defects. Our results reveal complex differential regulation of BRI1 expression, and suggest that by influencing the distribution and abundance of the receptor this regulation can enhance or attenuate BR signalling.

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.

Purpose: Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles., Patients and Methods: We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas., Results: TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors., Conclusion: Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.

The authors report a rare case of the peripheral obstruction of a ventriculoperitoneal shunt. Premature baby was operated on hydrocephalus due to germinal matrix bleeding. After two months of implantation of venticuloperitoneal shunt peripheral insufficiency of the system was emerged. During the shunt revision extensive knot formation became visible. We simply cut the catheter above the knot and the working shunt was replaced into the abdominal cavity. The postoperative course was uneventful and the baby was free of complaints for more than one year. The pathomechanism of knot formation is not clear thus the discovery of the problem during the operation is an unexpected event. In our opinion tight knot cannot be spontaneously formed intraabdominally. Loose knots can be developed and can reduce the capacity of liquor flow. We think that the knot tightens during pulling out. Longer peritoneal catheters can precipitate multiple looping and/or axial torquations and increase the peripheral resistance of the shunt. In such cases when the pulling out is challenged conversion to laparotomy is suggested.

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30% of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15% of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15% of pediatric HGGs (11/73) and 8% of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.