Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma

In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account.
Silencing of galectin‐3 changes the gene expression and augments the sensitivity of gastric cancer cells to chemotherapeutic agents

Galectin‐3 is known to modulate cell proliferation and apoptosis and is highly expressed in human cancers, but its function in gastric cancer is still controversial. Here, we examined the role of galectin‐3 in gastric cancer cells by silencing it with synthetic double‐stranded siRNA. After silencing of galectin‐3, cell numbers decreased and cell shape changed. Galectin‐3 siRNA treatment also induced G1 arrest. DNA microarray analysis was used to assess changes in gene expression following galectin‐3 silencing. We found that silencing of galectin‐3 caused changes in gene expression. RT‐PCR and real‐time PCR were utilized for validation of the changes found in microarray studies. Western blot analysis confirmed changes in the expression of proteins of interest: cyclin D1, survivin, XIAP, XAF, PUMA, and GADD45α. Generally, it tended to increase the expression of several pro‐apoptotic genes, and to decrease the expression of cell cycle progressive genes. We also confirmed that changes in the expression of these genes were caused by galectin‐3 overexpression. Finally, we demonstrated that silencing of galectin‐3 enhanced apoptosis induction with chemotherapeutic agents by further reducing the expression of anti‐apoptotic and/or cell survival molecules such as survivin, cyclin D1, and XIAP, and increasing the expression of pro‐apoptotic XAF‐1. We conclude that galectin‐3 is involved in cancer progression and malignancy by modulating the expression of several relevant genes, and inhibition of galectin‐3 may be an approach to improve chemotherapy of gastric cancers. (Cancer Sci 2009)
Developmentally regulated masking of an intracellular epitope of the 180 kDa isoform of the neural cell adhesion molecule NCAM

The neural cell adhesion molecule NCAM is a cell surface glycoprotein that occurs in several isoforms. It was previously shown that the largest 180‐kDa isoform of NCAM (NCAM 180) accumulates at sites of cell contact and in postsynaptic densities and may be responsible for the stabilization of cell contacts by its interaction with the membrane‐cytoskeleton linker protein brain spectrin. In immunohistochemical studies on the expression of the NCAM 180, we noticed that two NCAM 180 specific monoclonal antibodies, termed 481 and D3, showed different patterns of immunoreactivity in sections of fresh‐frozen adult mouse brain. Here we show that the D3‐specific, but not the 481‐specific epitope becomes inaccessible to the antibody during development of the hippocampal formation, coincident with the establishment of stable cell‐cell contacts. In contrast, in the olfactory bulb with its continually regenerating olfactory nerve fibers, both NCAM 180 antibodies remain fully immunoreactive throughout development and adulthood. We also show that the D3‐specific epitope becomes inaccessible in primary cerebellar neuron cultures with time in culture. Electrophoretic separation of hippocampal membrane proteins under nondenaturating conditions showed NCAM to be present in protein complexes of different molecular weights at different developmental stages. We propose that NCAM is involved in the formation of developmentally regulated, noncovalent complexes with as yet unknown partner molecules that could be responsible for the masking of the D3‐specific epitope. J. Neurosci. Res. 49:161–175, 1997. © 1997 Wiley‐Liss, Inc.
Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans

The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 micrograms/ml in mice, rats, dogs, and humans, respectively. The volumes of distribution ranged between 1.1 liter/kg in mice and 0.7 liter/kg in humans, which are approximate to the values for total body water. Whole body autoradiography studies in mice following intravenous administration of [14C]UK-49,858 demonstrated that the drug was evenly distributed throughout the tissues, including the central nervous system and the gastrointestinal tract. Plasma protein binding was low (11 to 12%) in all species. Marked species differences were observed in elimination half-lives, with mean values of 4.8, 4.0, 14, and 22 h in mice, rats, dogs, and humans, respectively. The major route of elimination of the drug was renal clearance, with about 70% of the dose being excreted unchanged in the urine in each species. Studies with [14C]UK-49,858 on metabolism and excretion (intravenous and oral) in mice and dogs showed that about 90% of the dose was recovered as unchanged drug in urine and feces, confirming the metabolic stability of the drug. This pharmacokinetic profile is markedly different from that of imidazole antifungal drugs and undoubtedly contributes to the excellent efficacy of UK-49,858 in vivo.
Individualized guidelines for the management of aggression in dementia – Part 1: key concepts

ABSTRACT Background: Clinical guidelines have the potential to assist in the management of aggression in dementia. This study aims to develop a conceptual framework for the construction of individualized guidelines for this group. Methods: A concept map of the topic “How to manage aggression in dementia” was developed by reviewing research papers, clinical guidelines, and gray literature. Titles and abstracts of papers that met search criteria were manually scanned in an iterative process for the extraction of key ideas and terminology commonly used to describe the field. Essential ideas and concepts were recorded on a concept map and hierarchically arranged. The concept map was converted into an interactive PDF document for easy distribution and sharing. Results: Ten key concepts were found to be important when managing aggression in dementia clustered along three major dimensions: Patient, Disorder and Treatment. The dimension Patient was defined by the “Patient's individual characteristics,” the “Personal life story,” and the “Patient's environment. ” Disorder was defined by the “Presentation of symptoms” and “Theory of causation. ” Treatment was defined by “Goals and expectations,” “Non-pharmacological interventions,” “Pharmacological interventions,” “Ethics and Restraint Use,” and “Emergency treatment. ” Concepts relating to clinical guidelines themselves were also included in the interactive map, including “Support from evidence-based medicine,” “Regular updates,” “Disclosures,” and “Usability. ” Conclusion: Managing aggression in dementia requires consideration of a wide range of factors relating to the patient, the dementia and behavioral disturbance, and possible treatment options. An interactive and hierarchical concept map provides a framework to develop individualized clinical guidelines.
Lung ultrasound: routine practice for the next generation of internists.

BACKGROUND The lung is at the crossroads of ventilation and circulation and can provide a wealth of diagnostic information. In the past, lung ultrasound (LUS) was considered impossible. However, the interplay between air, fluid and pleurae creates distinctive artefacts. Combinations of these artefacts can help differentiate between various pathological processes, including pulmonary oedema, pneumonia, pulmonary embolism, obstructive airway disease and pneumothorax. LUS, when used by experienced physicians, is superior to chest X-ray and comparable to computed tomography for establishing a diagnosis in acutely dyspnoeic patients. LUS allows for rapid, non-invasive and bedside patient assessment. It is therefore unfortunate that unlike many other medical specialists in the Netherlands, internists have not yet incorporated LUS into their daily practice. OBJECTIVES This review aims to be the starting point for internists wanting to acquire competence in LUS. REVIEW CONTENT: This narrative review describes the principles of ultrasound equipment, LUS artefacts, gives practical guidance to perform LUS and provides a road map towards LUS competence. Furthermore, it presents a decision tree to differentiate between causes of acute dyspnoea. AUTHORS CONCLUSIONS LUS is a promising diagnostic technique that can be of great help for the internist. It can be applied directly at the bedside and can also be used to follow up on disease progression and therapy. It is our belief that it will replace the stethoscope and that it will be the most used imaging technique in the near future, especially in dyspnoeic patients.
Randomized controlled study of in‐hospital exercise training programs in children with cystic fibrosis

The aim of this study was to compare aerobic and resistance training in children with cystic fibrosis (CF) admitted to hospital with an intercurrent pulmonary infection with a control group. The subjects were randomized into three groups on the first day of admission. The fat‐free mass (FFM) was calculated, using the skin fold thickness from four sites (biceps, triceps, subscapular, and iliac crest). Pulmonary function tests were performed within 36 hr of admission and repeated on discharge from the hospital, and again at 1 month after discharge. All subjects performed an incremental treadmill exercise test, using a modified Bruce protocol. Lower limb strength was measured using a Cybex dynamometer. An assessment of quality of life was made using the Quality of Well Being Scale, as previously reported. Activity levels were measured using a 7‐day activity diary, and subjects also wore an accelerometer on their hips. There were no significant differences between the three groups in terms of disease severity, and length of stay in hospital. Subjects in all three groups received intravenous antibiotics and nutritional supplementation as determined by the physician. Children randomized to the aerobic training group participated in aerobic activities for five sessions, each of 30‐min duration, a week. The children randomized to the resistance training group exercised both upper and lower limbs against a graded resistance machine. Subjects in the control group received standard chest physiotherapy.
Optimized Allocation of Testing Budget for Missile Defense Vehicle

ARES Corporation was asked to help analyze the reliability of a subsystem composed only of demand type components ("one-shot" pyrotechnic devices) for a missile defense vehicle. The subsystem was composed of twenty component types and some seventy component instances arranged in various series parallel blocks. Each component was considered to be only as reliable as indicated by a relatively small set of tests in a relevant environment. ARES formulated a conjugate-pair Bayesian analysis approach, in which each component was associated with a uniform prior distribution on (0,1) - representing no information about reliability-combined with a binomial likelihood function on n tests and f failures. The result is a Beta posterior distribution on component reliability, which can be calculated easily in a spreadsheet. A Monte Carlo analysis on the system logic then derives the probability distribution at the system level. The client required that the testing budget be allocated to maximize the payoff in expected system reliability. The solution was an optimization algorithm which identifies, after each additional test has been added, that component which will yield the largest reliability gain per dollar at the system level given a single additional successful test. The model thus considers both the component reliability and the cost of an additional test on that component when designing a test plan. The current model evaluates the optimum allocation of tests among the various components to prove that the system has a specified reliability at a given confidence level, assuming that no failures occur in the additional tests. This methodology can be extended to account for a non-zero number of failures in additional tests, though at considerable expense in computation time
Characterization of Sm‐like proteins in yeast and their association with U6 snRNA

Seven Sm proteins associate with U1, U2, U4 and U5 spliceosomal snRNAs and influence snRNP biogenesis. Here we describe a novel set of Sm‐like (Lsm) proteins in Saccharomyces cerevisiae that interact with each other and with U6 snRNA. Seven Lsm proteins co‐immunoprecipitate with the previously characterized Lsm4p (Uss1p) and interact with each other in two‐hybrid analyses. Free U6 and U4/U6 duplexed RNAs co‐immunoprecipitate with seven of the Lsm proteins that are essential for the stable accumulation of U6 snRNA. Analyses of U4/U6 di‐snRNPs and U4/U6·U5 tri‐snRNPs in Lsm‐depleted strains suggest that Lsm proteins may play a role in facilitating conformational rearrangements of the U6 snRNP in the association–dissociation cycle of spliceosome complexes. Thus, Lsm proteins form a complex that differs from the canonical Sm complex in its RNA association(s) and function. We discuss the possible existence and functions of alternative Lsm complexes, including the likelihood that they are involved in processes other than pre‐mRNA splicing.
Insertion of the Membrane-proximal Region of the Neuronal SNARE Coiled Coil into the Membrane*

In the neuron, solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins assemble into an α-helical coiled coil that bridges the synaptic vesicle to the plasma membrane and drives membrane fusion, a required process for neurotransmitter release at the nerve terminal. How does coiled coil formation drive membrane fusion? To investigate the structural and energetic coupling between the coiled coil and membrane, the recombinant SNARE complex in the phospholipid bilayer was studied using fluorescence quenching and site-directed spin labeling EPR. Fluorescence analysis revealed that two native Trp residues at the membrane-proximal region of the coiled coil are inserted into the membrane, tightly coupling the coiled coil to the membrane. The EPR results indicate that the coiled coil penetrates into the membrane with an oblique angle, providing a favorable geometry for the basic residues to interact with negatively charged lipids. The result supports the proposition that core complex formation directly leads to the apposition of two membranes, which could facilitate lipid mixing. Trp residues and basic residues are abundant at the membrane-proximal region of transmembrane SNARE proteins, suggesting the generality of the proposed mechanism for the SNARE complex-membrane coupling.
High Prevalence of the I278T Mutation of the Human Cystathionine β-Synthase Detected by a Novel Screening Application

Summary Classical homocystinuria due to cystathionine beta-synthase deficiency is one of the disorders revealing a high risk of thromboembolic events and vascular disease. This autosomal-recessively inherited metabolic disorder is considered to be rare with an estimated prevalence of 1:130,000 in the German population. In this study, we developed a novel multiplex PCR generating allele specific fragment lengths to analyse individual genotypes of the two most frequent cystathionine beta-synthase alterations, the I278T mutation, which is worldwide found on up to the half of homocystinuric alleles, and the adjacent polymorphism 844ins68. Screening of 200 unrelated German control subjects revealed a frequency of heterozygosity of 1.5% for I278T corresponding to a calculated frequency of homozygosity of 1:17.800. Our data indicate that homocystinuria due to cystathionine β-synthase deficiency is a frequently unrecognized disorder resulting in a high risk of thromboembolic events.
O‐GlcNAcomics—Revealing roles of O‐GlcNAcylation in disease mechanisms and development of potential diagnostics

O‐linked‐β‐N‐acetylglucosamine (O‐GlcNAc) is a dynamic PTM of the 3′‐hydroxyl groups of serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. The cycling of this modification is regulated in response to nutrients, stress, and other extracellular stimuli by the catalytic activities of O‐GlcNAc transferase and O‐GlcNAcase. O‐GlcNAc is functionally similar to phosphorylation and has been demonstrated to play critical roles in numerous biological processes, including cell signaling, transcription, and disease etiology. Since its discovery nearly 30 years ago, studies have demonstrated that the O‐GlcNAc is highly abundant and widespread, like phosphorylation however, the development of methodologies to study O‐GlcNAc at the site level has been challenging. Recently, a number of studies have overcome these challenges and describe new tagging, enrichment, and mass spectrometric‐based approaches to study O‐GlcNAc in terms of its site identification, stoichiometry, and dynamics on proteins. The development of these methods are key for elucidation of O‐GlcNAc's functional crosstalk with phosphorylation and other PTMs, and will serve to provide the necessary information for the development of site‐specific antibodies, which will aid in the determination of a particular protein's site‐specific function. In this review, we describe these methods and summarize results obtained from them demonstrating the roles of O‐GlcNAc in diabetes, cancer, Alzheimer's, and in learning and memory, while also describing how these new strategies have implicated O‐GlcNAc as a potential diagnostic for the screening of patients for prediabetes.
Temperature and humidity monitoring system for storage rooms of industries

In today's world, Internet of Things (IoT) is a different development. With the help of IoT, all the physical objects can connect to the internet. And with this we can consider the two layers of the system viz: the sensor device which gathers data and links to cloud and next is the cloud service which hosts the information from th e en vironmen t. In th e storage rooms of industries we need a good environment for the products to be healthy for use. Here we develop a monitoring system with the help of IoT. The Internet of Things entrance is used as a part of this system. In this strategy we use several access methods such as Wi­Fi, GPRS, Ethernet etc. and also the data collected can be stored. In this IOT gateway we use ATmega 328 as the Microcontroller unit and pC/OS-III as the implanted OS. The application authenticates that the entrance is reliable. In this paper we try to develop an arrangement encompassing Arduino wireless sensor networks and cloud and then extend our work to develop a method for the transmission of data between them which can be of great use in monitoring the temperature and humidity. With the help of this monitoring system, the real time detection of the temperature and humidity of the storage rooms can be improved and the longevity of the products can be ensured.
Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis

Article abstract—MS is an immunologically mediated disease, as determined by observation of the response to immunotherapy and the existence of an animal model, experimental autoimmune encephalitis. Interferon (IFN) &bgr;-1b, IFN &bgr;-1a, and glatiramer acetate, the therapies used for relapsing or remitting MS, have mechanisms of action that address the immunologic pathophysiology of MS. The IFNs bind to cell surface-specific receptors, initiating a cascade of signaling pathways that end with the secretion of antiviral, antiproliferative, and immunomodulatory gene products. Glatiramer acetate, a synthetic molecule, inhibits the activation of myelin basic protein-reactive T cells and induces a T-cell repertoire characterized by anti-inflammatory effects. Although the two classes of drugs have some overlapping mechanisms of action, the IFNs rapidly block blood–brain barrier leakage and gadolinium (Gd) enhancement within 2 weeks, whereas glatiramer acetate produces less rapid resolution of Gd-enhanced MRI activity. IFN &bgr; has no direct effects in the CNS, but glatiramer acetate-specific T cells are believed to have access to the CNS, where they can exert anti-inflammatory and possibly neuroprotective effects.
Nuclear receptors in the cross-talk of drug metabolism and inflammation

Inflammation and infection have long been known to affect the activity and expression of enzymes involved in hepatic and extrahepatic drug clearance. Significant advances have been made to elucidate the molecular mechanisms underlying the complex cross-talk between inflammation and drug-metabolism alterations. The emergent role of ligand-activated transcriptional regulators, belonging to the nuclear receptor (NR) superfamily, is now well established. The NRs, pregnane X receptor, constitutive androstane receptor, retinoic X receptor, glucocorticoid receptor, and hepatocyte nuclear factor 4, and the basic helix-loop-helix/Per-ARNT-Sim family member, aryl hydrocarbon receptor, are the main regulators of the detoxification function. According to the panel of mediators secreted during inflammation, a cascade of numerous signaling pathways is activated, including nuclear factor kappa B, mitogen-activated protein kinase, and the Janus kinase/signal transducer and activator of transcription pathways. Complex cross-talk is established between these signaling pathways regulating either constitutive or induced gene expression. In most cases, a mutual antagonism between xenosensor and inflammation signaling occurs. This review focuses on the molecular and cellular mechanisms implicated in this cross-talk.