Miracle-dz/UniFAR-FTUs huggingface dataset:
Confocal laser endomicroscopy and ultrasound endoscopy during the same endoscopic session for diagnosis and staging of gastric neoplastic lesions.

INTRODUCTION Confocal LASER endomicroscopy (CLE) is a newly developed endoscopic technique which allows subsurface in vivo histological assessment during ongoing endoscopy and targeted biopsies. Ultrasound endoscopy (EUS) is a useful tool in staging upper GI malignant lesions. We describe for the first time the use of both techniques during the same endoscopic session, in a pilot study, in order to increase the diagnostic yield of histological assessment and provide the staging of the gastric neoplastic lesions thus decreasing the time to therapeutic decision. AIMS & METHODS CLE has been performed with the Pentax EG-3870CIK confocal endomicroscope after a 5 ml intravenous 10% fluorescein injection; EUS has been performed subsequently, during the same endoscopic Propofol sedation session, using a standard radial EUS-scope. RESULTS Eleven patients have been investigated, 4 females, 7 males, mean age 59.7 +/- 12.3 years. The indication of CLE/EUS exploration was the presence of a gastric polypoid lesion in 37% of cases, atypical gastric ulcer in 27% of patients, gastric lymphoma 18%, suspicion of gastric cancer recurrence after resection 9% and infiltrating type gastric cancer 9%. Histological assessment after targeted biopsy has established the diagnosis of gastric adenocarcinoma in 55% of cases, gastric lymphoma in 18% of cases, gastric adenoma, gastric GIST and gastric foveolar hyperplasia in 9% of cases respectively. CLE has allowed targeted biopsies in 81.8% of cases. In 2 patients - one case with suspected recurrent gastric cancer after surgery and one case of gastric lymphoma, CLE has indicated normal gastric mucosa. The EUS evaluation has shown TO lesion in two cases, T1 in 3 cases, T2 in 3 cases, T3 in one case. The EUS evaluation showed in one gastric lymphoma patient a lesion interesting the mucosa and submucosa with regional adenopathy and a submucosal lesion with regional adenopathy in the other gastric lymphoma case. The therapeutic decision was surgery in 73% of cases, chemotherapy and follow-up in 18% of cases and follow-up in 9% of cases. No complications were registered during the CLE/EUS explorations. CONCLUSION CLE and EUS can be successfully associated during the same endoscopic session, for upper GI neoplastic lesions allowing targeted biopsies for histological assessment and disease staging for optimal therapeutic decision.
Structural variability of C3larvin toxin. Intrinsic dynamics of the α/β fold of the C3-like group of mono-ADP-ribosyltransferase toxins

C3larvin toxin is a new member of the C3 class of the mono-ADP-ribosyltransferase toxin family. The C3 toxins are known to covalently modify small G-proteins, e.g. RhoA, impairing their function, and serving as virulence factors for an offending pathogen. A full-length X-ray structure of C3larvin (2.3 Å) revealed that the characteristic mixed α/β fold consists of a central β-core flanked by two helical regions. Topologically, the protein can be separated into N and C lobes, each formed by a β-sheet and an α-motif, and connected by exposed loops involved in the recognition, binding, and catalysis of the toxin/enzyme, i.e. the ADP-ribosylation turn–turn and phosphate–nicotinamide PN loops. Herein, we provide two new C3larvin X-ray structures and present a systematic study of the toxin dynamics by first analyzing the experimental variability of the X-ray data-set followed by contrasting those results with theoretical predictions based on Elastic Network Models (GNM and ANM). We identify residues that participate in the stability of the N-lobe, putative hinges at loop residues, and energy-favored deformation vectors compatible with conformational changes of the key loops and 3D-subdomains (N/C-lobes), among the X-ray structures. We analyze a larger ensemble of known C3bot1 conformations and conclude that the characteristic ‘crab-claw’ movement may be driven by the main intrinsic modes of motion. Finally, via computational simulations, we identify harmonic and anharmonic fluctuations that might define the C3larvin ‘native state. ’ Implications for docking protocols are derived.
Loss of functional NADPH oxidase 2 protects against alcohol-induced bone resorption in female p47phox-/- mice.

BACKGROUND In bone, NADPH oxidase (NOX)-derived reactive oxygen species (ROS) superoxide and/or hydrogen peroxide are an important stimulus for osteoclast differentiation and activity. Previously, we have demonstrated that chronic ethanol (EtOH) consumption generates excess NOX-dependent ROS in osteoblasts, which functions to stimulate nuclear factor kappa-β receptor ligand (RANKL)-RANK signaling, thus increasing osteoclastogenesis and activity. This activity can be blocked by co-administration of EtOH with the pan-NOX inhibitor diphenylene idonium (DPI). METHODS To test whether EtOH-induced bone loss is dependent on a functional NOX2 enzyme, 6-week-old female C57BL/6J-Ncf1/p47phox(-/-) (p47phox KO) and wild-type (WT) mice were pair-fed EtOH diets for 40 days. Bone loss was assessed by 3-point bending, micro-computed tomography and static histomorphometric analysis. Additionally, ST2 cultured cells were co-treated with EtOH and NOX inhibitors, DPI, gliotoxin, and plumbagin, after which changes in ROS production, and in RANKL and NOX mRNA expression were analyzed. RESULTS In WT mice, EtOH treatment significantly reduced bone density and mechanical strength, and increased total osteoclast number and activity. In EtOH-treated p47phox KO mice, bone density and mechanical strength were completely preserved. EtOH p47phox KO mice had no changes in osteoclast numbers or activity, and no elevations in serum CTX or RANKL gene expression (p < 0.05). In both WT and p47phox KO mice, EtOH feeding reduced biochemical markers of bone formation (p < 0.05). In vitro EtOH exposure of ST2 cells increased ROS, which was blocked by pretreating with DPI or the NOX2 inhibitor gliotoxin. EtOH-induced RANKL and NOX2 gene expression were inhibited by the NOX4-specific inhibitor plumbagin. CONCLUSIONS These data suggest that NOX2-derived ROS is necessary for EtOH-induced bone resorption. In osteoblasts, NOX2 and NOX4 appear to work in tandem to increase RANKL expression, whereas EtOH-mediated inhibition of bone formation occurs via a NOX2-independent mechanism.
Control of intracellular chloride concentration and GABA response polarity in rat retinal ON bipolar cells

GABAergic modulation of retinal bipolar cells plays a crucial role in early visual processing. It helps to form centre‐surround receptive fields which filter the visual signal spatially at the bipolar cell dendrites in the outer retina, and it produces temporal filtering at the bipolar cell synaptic terminals in the inner retina. The observed chloride transporter distribution in ON bipolar cells has been predicted to produce an intracellular chloride concentration, [Cl−]i, that is significantly higher in the dendrites than in the synaptic terminals. This would allow dendritic GABA‐gated Cl− channels to generate the depolarization needed for forming the lateral inhibitory surround of the cell's receptive field, while synaptic terminal GABA‐gated Cl− channels generate the hyperpolarization needed for temporal shaping of the light response. In contrast to this idea, we show here that in ON bipolar cells [Cl−]i is only slightly higher in the dendrites than in the synaptic terminals, and that GABA‐gated channels in the dendrites may generate a hyperpolarization rather than a depolarization. We also show that [Cl−]i is controlled by movement of Cl− through ion channels in addition to transporters, that changes of [K+]o alter [Cl−]i and that voltage‐dependent equilibration of [Cl−]i in bipolar cells will produce a time‐dependent adaptation of GABAergic modulation with a time constant of 8 s after illumination‐evoked changes of membrane potential. Time‐dependent adaptation of [Cl−]i to voltage changes in retinal bipolar cells may add a previously unsuspected layer of temporal processing to signals as they pass through the retina.
Non‐repetitive AT‐rich sequences are found in intergenic regions of Methanococcus voltae DNA.

AT‐rich DNA, which constitutes a distinct fraction of the cellular DNA of the archaebacterium Methanococcus voltae, was shown to consist of non‐repetitive sequences dispersed on the chromosome and to lack continuous open reading frames in five out of six randomly analyzed cases. Upon subsequent analysis of intergenic regions, AT‐rich sequences were again detected. Transcription start points were mapped in front of three open reading frames. The 5′ ends of the transcripts were found in variable positions relative to the AT‐rich sequences in the different cases. Shine‐Dalgarno type sequences complementary to the 3′ end of 16S rRNA were discovered at suitable distances from the 5′ ends of the genes.
URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells*

URI (unconventional prefoldin RPB5 interactor protein) is an unconventional prefoldin, RNA polymerase II interactor that functions as a transcriptional repressor and is part of a larger nuclear protein complex. The components of this complex and the mechanism of transcriptional repression have not been characterized. Here we show that KAP1 (KRAB-associated protein 1) and the protein phosphatase PP2A interact with URI. Mechanistically, we show that KAP1 phosphorylation is decreased following recruitment of PP2A by URI. We functionally characterize the novel URI-KAP1-PP2A complex, demonstrating a role of URI in retrotransposon repression, a key function previously demonstrated for the KAP1-SETDB1 complex. Microarray analysis of annotated transposons revealed a selective increase in the transcription of LINE-1 and L1PA2 retroelements upon knockdown of URI. These data unveil a new nuclear function of URI and identify a novel post-transcriptional regulation of KAP1 protein that may have important implications in reactivation of transposable elements in prostate cancer cells.
Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson's disease

Fatigue has been shown to be a consistent and common problem in Parkinson's disease (PD) in multiple countries and cultures. It is one of the most disabling of all symptoms, including motor dysfunction, and appears early, often predating the onset of motor symptoms. Several studies of the epidemiology of fatigue have been published, often using different scales, but few on treatment. The Movement Disorder Society (MDS) commissioned a task force to assess available clinical rating scales, critique their psychometric properties, summarize their clinical properties, and evaluate the evidence in support of their use in clinical studies in PD. Six clinical researchers reviewed all studies published in peer reviewed journals of fatigue in PD, evaluated the scales' previous use, performance parameters, and quality of validation data, if available. Scales were rated according to criteria provided by the MDS. A scale was “recommended” if it has been used in clinical studies beyond the group that developed it, has been used in PD and psychometric studies have established that it is a valid, reliable and sensitive to change in people with PD. Requiring a scale to have demonstrated sensitivity to change in PD specifically rather than in other areas in order to attain a rating of “recommended” differs from the use of this term in previous MDS task force scale reviews. “Suggested” scales failed to meet all the criteria of a “recommended” scale, usually the criterion of sensitivity to change in a study of PD. Scales were “listed” if they had been used in PD studies but had little or no psychometric data to assess. Some scales could be used both to screen for fatigue as well as to assess fatigue severity, but some were only used to assess severity. The Fatigue Severity Scale was “recommended” for both screening and severity rating. The Fatigue Assessment Inventory, an expanded version of the Fatigue severity Scale, is “suggested” for both screening and severity. The Functional Assessment of Chronic Illness Therapy‐Fatigue was “recommended” for screening and “suggested” for severity. The Multidimensional Fatigue Inventory was “suggested” for screening and “recommended” for severity. The Parkinson Fatigue Scale was “recommended” for screening and “suggested” for severity rating. The Fatigue Severity Inventory was “listed” for both screening and severity. The Fatigue Impact Scale for Daily Use, an adaptation of the Fatigue Impact Scale was “listed” for screening and “suggested” for severity. Visual Analogue and Global Impression Scales are both “listed” for screening and severity. The committee concluded that current scales are adequate for fatigue studies in PD but that studies on sensitivity and specificity of the scales are still needed. © 2010 Movement Disorder Society
QRS-complex of ECG-based biometrics in a two-level classifier

This research is based on an ECG biometrics system which segments the QRS-complex, extracts the non-fiducial features and sends the data to a two-level classifier. For spectral analysis, the discrete Fourier transform (DFT), and discrete cosine transform (DCT) were used to transform the signal, before principal component analysis (PCA) is used to reduce the feature vectors. From here, statistical parameters were computed for the classifier, where the first level is denoted called feature matching (FM) and the second level is the Neural Networks algorithm (NN). The system is tested on two databases. Database I consists of 45 subjects with 10 recordings each (recorded on the same day) while Database II consists of 35 subjects with 20 recordings each (recorded on separate days). The accuracy measures were is 99.176% and 96.67% respectively.
Activation of E2F-mediated Transcription by Human T-cell Leukemia Virus Type I Tax Protein in a p16 INK4A -negative T-cell Line*

The human T-cell leukemia virus type I (HTLV-I) is a causative agent of adult T-cell leukemia. Although the exact mechanism by which HTLV-I contributes to leukemogenesis is still unclear, the Tax protein is thought to play a major role in this process. This 40-kDa polypeptide is able to interact with the tumor suppressor p16 INK4A . Consequently, Tax can activate the signaling pathway that lead to the release of E2F that in turn induces expression of factors required for cell cycle progression. In this paper, we demonstrate that Tax can also activate E2F-mediated transcription independently of p16 INK4A . Indeed, when Tax is coexpressed with the E2F-1 transcription factor in CEM T-cells, which lack expression of p16 INK4A , it strongly potentiates the E2F-dependent activation of a reporter construct driven by a promoter containing E2F binding sites. This stimulation is abrogated by mutations affecting the E2F-binding sites. In addition, Tax also stimulates the transcription of the E2F-1 gene itself. Using Tax mutants that fail to activate either ATF- or NF-κB-dependent promoters and different 5′ truncation mutants of the E2F-1 promoter, we show that the Tax-dependent transcriptional control of the E2F1 gene involves, at least in part, the ATF binding site located in the E2F-1 promoter.
Blood Pressure in Adulthood and Life Expectancy With Cardiovascular Disease in Men and Women: Life Course Analysis

Limited information exists about the consequences of hypertension during adulthood on residual life expectancy with cardiovascular disease. We aimed to analyze the life course of people with high blood pressure levels at age 50 in terms of total life expectancy and life expectancy with and without cardiovascular disease compared with normotensives. We constructed multistate life tables for cardiovascular disease, myocardial infarction, and stroke using data from 3128 participants of the Framingham Heart Study who had their 50th birthday while enrolled in the study. For the life table calculations, we used hazard ratios for 3 transitions (healthy to death, healthy to disease, and disease to death) by categories of blood pressure level and adjusted by age, sex, and confounders. Irrespective of sex, 50-year-old hypertensives compared with normotensives had a shorter life expectancy, a shorter life expectancy free of cardiovascular disease, myocardial infarction, and stroke, and a longer life expectancy lived with these diseases. Normotensive men (22% of men) survived 7.2 years (95% confidence interval, 5.6 to 9.0) longer without cardiovascular disease compared with hypertensives and spent 2.1 (0.9 to 3.4) fewer years of life with cardiovascular disease. Similar differences were observed in women. Compared with hypertensives, total life expectancy was 5.1 and 4.9 years longer for normotensive men and women, respectively. Increased blood pressure in adulthood is associated with large reductions in life expectancy and more years lived with cardiovascular disease. This effect is larger than estimated previously and affects both sexes similarly. Our findings underline the tremendous importance of preventing high blood pressure and its consequences in the population.
Pathophysiology of stress-induced visceral hypersensitivity

Visceral hypersensitivity is observed in the majority of patients with IBS and considered a pathophysiological mechanism. The aim of the work described in this thesis was to obtain a better understanding of the stress-related pathophysiology of visceral hypersensitivity. Investigations were carried out in the rat model of maternal separation. Because others already indicated that mast cells may be involved in post-stress visceral hypersensitivity, we first set out to confirm these observations in our animal model in chapter 2. Next we investigated the role of nerve growth factor (NGF) because, in addition to histamine, it is one of the mast cell mediators known to modulate transient receptor ion channel 1 (TRPVl). We used two different TRPVl antagonists to evaluate the functional role of TRPVl in post-stress visceral hypersensitivity. In chapter 3 we focused on the possible role of corticotrophin-releasing hormone (CRH). We evaluated whether there is such a thing as prolonged post-stress mast cell-dependent visceral hypersensitivity in maternally separated rats using the antagonist α-helical CRF (9-41). In chapter 4, we tested two peripherally restricted H1R antagonists for their capacity to reverse post-stress visceral hypersensitivity. IBS transfer across generations may largely depend on environmental factors. Therefore, in chapter 5, we used our animal model to investigate whether susceptibility to stress-induced visceral hypersensitivity in maternally separated Long Evans rats can be transferred across generations without further separation protocols and, if so, whether this depends on maternal care.
Collection of platelets and peripheral progenitor cells with the Fresenius AS.TEC 204 blood cell separator

The aim of the present study was to clinically evaluate the blood cell separator AS. TEC 204. One hundred fifteen platelet collections were carried out with the dual or single needle procedure. Platelet yield was 3.21 ± 0.80 × 1011 (mean ± standard deviation) and 59.1% of the collections showed platelet counts >3.0 × 1011. Leukocyte contamination was 1.77 ± 2.81 × 106 and 89.0% of the platelet concentrates had a white blood cell content <5 × 106. Using a dual needle technique with an alternating interface adjustment, all of the products were contaminated with less than 1 × 106 leukocytes.
Signal Integration at Elongation Factor 2 Kinase

Eukaryotic elongation factor 2 kinase (eEF-2K), the only calmodulin (CaM)-dependent member of the unique α-kinase family, impedes protein synthesis by phosphorylating eEF-2. We recently identified Thr-348 and Ser-500 as two key autophosphorylation sites within eEF-2K that regulate its activity. eEF-2K is regulated by Ca2+ ions and multiple upstream signaling pathways, but how it integrates these signals into a coherent output, i.e. phosphorylation of eEF-2, is unclear. This study focuses on understanding how the post-translational phosphorylation of Ser-500 integrates with Ca2+ and CaM to regulate eEF-2K. CaM is shown to be absolutely necessary for efficient activity of eEF-2K, and Ca2+ is shown to enhance the affinity of CaM toward eEF-2K. Ser-500 is found to undergo autophosphorylation in cells treated with ionomycin and is likely also targeted by PKA. In vitro, autophosphorylation of Ser-500 is found to require Ca2+ and CaM and is inhibited by mutations that compromise binding of phosphorylated Thr-348 to an allosteric binding pocket on the kinase domain. A phosphomimetic Ser-500 to aspartic acid mutation (eEF-2K S500D) enhances the rate of activation (Thr-348 autophosphorylation) by 6-fold and lowers the EC50 for Ca2+/CaM binding to activated eEF-2K (Thr-348 phosphorylated) by 20-fold. This is predicted to result in an elevation of the cellular fraction of active eEF-2K. In support of this mechanism, eEF-2K knock-out MCF10A cells reconstituted with eEF-2K S500D display relatively high levels of phospho-eEF-2 under basal conditions. This study reports how phosphorylation of a regulatory site (Ser-500) integrates with Ca2+ and CaM to influence eEF-2K activity.
Smart Energy-Efficient Clock Synthesizer for Duty-Cycled Sensor SoCs in 65 nm/28nm CMOS

Duty-cycled low-rate Internet-of-things (IoT) sensors are employed in diverse applications, requiring configurable and energy-efficient on-chip and on-demand clock synthesis. We present an all-digital frequency-locked loop (AD-FLL) capable of generating an accurate clock selectively in stand-alone operation or locked to a 32kHz reference. We report measurement results of two prototypes in 65nm and 28nm CMOS offering a configurable clock multiplication factor of up to 32 786, resulting in a wide tuning-range from a few MHz to 2.4GHz and 1.6GHz, respectively. The challenges of slow start-up and deterministic jitter are addressed by a fast hybrid-mode start-up procedure and by various jitter reduction modes. We also introduce the concept of Transient Clocking that leverages the capabilities of the proposed AD-FLL to make a system operational after cold-start or wake-up before the supply voltage has stabilized. We study two application examples that highlight the versatility of the concept in IoT applications and show its potential to amortize the time and energy cost of typical system start-up tasks, like state-restoration or wake-up event classification.
Polymerase chain reaction in the detection of Helicobacter pylori infection.

OBJECTIVE To determine the presence of Helicobacter pylori (H. pylori) infection, in patients suffering from gastritis and peptic ulcer disease by polymerase chain reaction (PCR) and correlate the results with the histological diagnosis. DESIGN Analytical, comparative study. PLACE AND DURATION OF STUDY Section of Gastroenterology, Department of Medicine and Pathology, Aga Khan University Hospital and School of Life Sciences and Chemical Technology, Ngee Ann Polytechnic, Singapore from November, 2001 to December, 2002. PATIENTS AND METHODS Gastric antral biopsies were obtained from 64 patients attending the Gastroenterology Section of Aga Khan University Hospital. Patients on nonsteroidal-anti-inflammatory drugs (NSAIDS) were excluded. Gastric biopsies were sent for histopathology and used for DNA extraction and PCR amplification of H. pylori 16S ribosomal RNA (rRNA) gene. Results were compared and statistically analyzed. RESULTS H. pylori were not visible by histology in 57.6 % (34/59) and could be seen in 42.4 % (25/59). PCR test was negative for H. pylori DNA in 44.1 % (26/59) and positive in 55.9 % (33/59) with p<0.001. CONCLUSION PCR H. pylori DNA is a sensitive method for the diagnosis of H. pylori infection and its use as a diagnostic tool along with histology increases the detection rate of H. pylori infection. Two different staining methods for the organism should be used to avoid missing diagnosis of H. pylori infection.