Miracle-dz/UniFAR-FTUs huggingface dataset:
DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

ABSTRACT UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCFβ-TrCP E3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with β-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108UHRF1) within the DSG degron. Furthermore, we demonstrate that S108UHRF1 phosphorylation is catalyzed by casein kinase 1 delta (CK1δ) and is important for the recognition of UHRF1 by SCFβ-TrCP. Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108UHRF1 phosphorylation. Taken together, our data identify SCFβ-TrCP as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.
A factor from Trypanosoma cruzi induces repetitive cytosolic free Ca2+ transients in isolated primary canine cardiac myocytes

An unusual 120-kDa alkaline peptidase contained in a trypomastigote soluble fraction (TSF) of Trypanosoma cruzi is associated with the induction of repetitive Ca2+ transients and subsequent invasion by the parasite of a number of mammalian cell lines, including tissue culture L6E2 myoblasts (B. A. Burleigh and N. W. Andrews, J. Biol. Chem. 270:5172-5180, 1995; S. N. J. Moreno, J. Silva, A. E. Vercesi, and R. Docampo, J. Exp. Med. 180:1535-1540, 1994; A. Rodríguez, M. G. Rioult, A. Ora, and N. W. Andrews, J. Cell Biol. 129:1263-1273, 1995; I. Tardieux, M. H. Nathanson, and N. W. Andrews, J. Exp. Med. 179:1017-1022, 1994). Using single cell spectrofluorometry and whole-cell patch clamping, we show that TSF produces rapid repetitive cytosolic Ca2+ transients (each associated with cell contraction) in primary cardiac myocytes isolated from dogs. The response of myocytes to TSF was dose dependent in that increasing numbers of cells responded to increasing concentrations of TSF. The TSF-induced Ca2+ transients could be obliterated when TSF was heated or treated with trypsin or the protease inhibitor leupeptin. Aprotinin, pepstatin A, and E-64 did not affect TSF activity. The TSF-induced Ca2+ transients and trypomastigote cell invasion could not be inhibited by alpha (prazosin)- or beta (propanolol)-adrenergic blockers or L-type Ca2+ channel blockers (verapamil, nisoldipine, or cadmium) or by removal of extracellular Ca2+. However, inhibition of pertussis toxin-sensitive G proteins and Ca2+ release from the sarcoplasmic reticulum (with thapsigargin or ryanodine) prevented the TSF-induced Ca2+ transients and cell invasion by trypomastigotes. These data suggested that cardiac myocyte pertussis toxin-sensitive G proteins are associated with the regulation of TSF-induced Ca2+ transients and myocyte invasion by trypomastigotes but are independent of Ca2+ entry into the cytosol via L-type Ca2+ channels. The Ca2+ transients are dependent on release of Ca2+ from sarcoplasmic reticulum Ca2+ stores, but this release is not dependent on extracellular Ca2+ or on the classic model of Ca2+ -induced Ca2+ release in cardiac myocytes. Further, subthreshold depolarizations, together with cell contraction as demonstrated by whole-cell patch clamping, occurred with each Ca2+ transient. However, the depolarizations were of magnitude insufficient to generate an action potential, providing further evidence for a lack of dependence on L-type Ca2+ channels and other voltage-dependent channels (Na+ and K+ channels) in the generation of TSF-induced Ca2+ transients. Our findings suggest that primary canine cardiac myocytes respond to TSF and parasite invasion in ways similar to those of the in vitro cell lines studied to date. Since cardiac myocytes are primary targets for T. cruzi in the vertebrate host, our study indicates that TSF may play a role in the pathogenesis of Chagas' disease in humans.
Placoderm fishes, pharyngeal denticles, and the vertebrate dentition

The correlation of the origin of teeth with jaws in vertebrate history has recently been challenged with an alternative to the canonical view of teeth deriving from separate skin denticles. This alternative proposes that organized denticle whorls on the pharyngeal (gill) arches in the fossil jawless fish Loganellia are precursors to tooth families developing from a dental lamina along the jaw, such as those occurring in sharks, acanthodians, and bony fishes. This not only indicates that homologs of tooth families were present, but also illustrates that they possessed the relevant developmental controls, prior to the evolution of jaws. However, in the Placodermi, a phylogenetically basal group of jawed fishes, the state of pharyngeal denticles is poorly known, tooth whorls are absent, and the presence of teeth homologous to those in extant jawed fishes (Chondrichthyes + Osteichthyes) is controversial. Thus, placoderms would seem to provide little evidence for the early evolution of dentitions, or of denticle whorls, or tooth families, at the base of the clade of jawed fishes. However, organized denticles do occur at the rear of the placoderm gill chamber, but are associated with the postbranchial lamina of the anterior trunkshield, assumed to be part of the dermal cover. Significantly, these denticles have a different organization and morphology relative to the external dermal trunkshield tubercles. We propose that they represent a denticulate part of the visceral skeleton, under the influence of pharyngeal patterning controls comparable to those for pharyngeal denticles in other jawed vertebrates and Loganellia. J. Morphol. 257:289–307, 2003. © 2003 Wiley‐Liss, Inc.
Air pollution and lung cancer mortality in the vicinity of a nonferrous metal smelter in Sweden

To evaluate the importance of exposure to ambient air pollution for lung cancer risk, we conducted a case‐control study in the vicinity of a nonferrous metal smelter. The smelter started operations in 1930 and had very high emissions during the early decades, particularly of arsenic and SO2. Among subjects deceased 1961–1990 in the municipality where the smelter is located and who had not worked at the smelter, 209 male and 107 female lung cancer cases were identified and matched by sex and year of birth to 518 and 209 controls, respectively. Information on smoking habits, occupations and residences was collected by questionnaire to next‐of‐kin and from registry data. Living close to the smelter was associated with a relative risk (RR) for lung cancer of 1.38 [95% confidence interval (CI) 0.89–2.14] among men, adjusted for smoking and occupational exposures. No clear difference in risk was detected for men deceased 1961–1979 compared to men deceased 1980–1990 (RR point estimates 1.42 and 1.29, respectively). There appeared to be an increased risk especially for men exposed in the beginning of the operations (RR = 1.51, 95% CI 0.90–2.54), in particular combined with exposure duration shorter than 20 years (RR = 2.52, 95% CI 0.89–7.11). For women, however, no overall increased risk for lung cancer was observed. Although not significant, our findings thus indicated an increased risk of lung cancer among men living close to the nonferrous smelter. This increase appeared to concern primarily men exposed during the early years of operations, when emissions were very high. © 2003 Wiley‐Liss, Inc.
Factors Causing Loss of Normal Doppler Waveform of the Left Internal Jugular Vein: Evaluation on Chest Computed Tomography

Purpose To evaluate the presence and causes of left brachiocephalic vein (LBCV) steno-occlusive lesions in patients with loss of normal waveform in Doppler ultrasound of the left internal jugular vein (LIJV). Materials and Methods We performed Doppler ultrasound of both internal jugular veins in 1912 patients who received an implantable venous access port from August 2013 to January 2016. Among them, 106 patients showed loss of normal Doppler waveforms of the LIJV (56 men and 50 women; mean age, 61.4 ± 11.6 years). We retrospectively analyzed the presence and causes of the LBCV steno-occlusive lesions on contrast-enhanced chest computed tomography (CT) images. Results LBCV steno-occlusive lesions were present in 82 patients (77.4%). The causes of these lesions were anatomic structures (n = 70, 85.4%), tumorous lesions (n = 11, 13.4%), and thrombus (n = 1, 1.2%). The anterior anatomic structures to the LBCV causing stenosis were bony structures (n = 50), right upper lobe (n = 11), and mediastinal fat (n = 9). The posterior anatomic structures to the LBCV resulting in stenosis were right brachiocephalic artery (n = 58), left common carotid artery (n = 7), and aortic arch (n = 5). The tumorous lesions resulting in stenosis were mediastinal lymph node (n = 5), thymic lesions (n = 3), lymphoma (n = 1), lung cancer (n = 1), and bone tumor (n = 1). Conclusions It is necessary to suspect steno-occlusive lesion of the LBCV from various causes and to use caution when performing central venous catheterization in cases with loss of a normal Doppler waveform.
Microaerophilic degradation of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX) by three Rhodococcus strains

Aim: The goal of this study was to compare the degradation of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX) by three Rhodococcus strains under anaerobic, microaerophilic (<0·04 mg l−1 dissolved oxygen) and aerobic (dissolved oxygen (DO) maintained at 8 mg l−1) conditions.
Splittings and automorphisms of relatively hyperbolic groups

We study automorphisms of a relatively hyperbolic group G. When G is one-ended, we describe Out(G) using a preferred JSJ tree over subgroups that are virtually cyclic or parabolic. In particular, when G is toral relatively hyperbolic, Out(G) is virtually built out of mapping class groups and subgroups of GL_n(Z) fixing certain basis elements. When more general parabolic groups are allowed, these subgroups of GL_n(Z) have to be replaced by McCool groups: automorphisms of parabolic groups acting trivially (i.e. by conjugation) on certain subgroups. Given a malnormal quasiconvex subgroup P of a hyperbolic group G, we view G as hyperbolic relative to P and we apply the previous analysis to describe the group Out(P to G) of automorphisms of P that extend to G: it is virtually a McCool group. If Out(P to G) is infinite, then P is a vertex group in a splitting of G. If P is torsion-free, then Out(P to G) is of type VF, in particular finitely presented. We also determine when Out(G) is infinite, for G relatively hyperbolic. The interesting case is when G is infinitely-ended and has torsion. When G is hyperbolic, we show that Out(G) is infinite if and only if G splits over a maximal virtually cyclic subgroup with infinite center. In general we show that infiniteness of Out(G) comes from the existence of a splitting with infinitely many twists, or having a vertex group that is maximal parabolic with infinitely many automorphisms acting trivially on incident edge groups.
Low Dose Iron Treatments Induce a DNA Damage Response in Human Endothelial Cells within Minutes

Background Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron. Methodology Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types. Principal Findings Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization. Significance These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium, and induce a DNA damage response.
Procalcitonin increase after endotoxin injection in normal subjects.

As procalcitonin concentrations have been shown to be elevated in patients with septicemia and gram-negative infections in particular, we proceeded to investigate the effect of endotoxin, a product of gram-negative bacteria, on procalcitonin concentrations in normal human volunteers. Endotoxin from Escherichia coli 0113:H10:k, was injected i.v. at a dose of 4 mg/kg BW into these healthy volunteers. Blood samples were obtained before and 1, 2, 4, 6, 8, and 24 h after injection of the endotoxin. Each patient's cardiovascular and overall clinical status was monitored over this period. The patients developed chills and rigors, myalgia, and fever between 1-3 h. Tumor necrosis factor-alpha levels increased sharply at 1 h and peaked at 90 min, reaching the baseline concentration thereafter by 6 h. Interleukin-6 levels increased more gradually, peaking at 3 h and reaching the baseline concentration at 8 h. The procalcitonin concentration, which was undetectable (< 10 pg/mL) at 0, 1, and 2 h, was detectable at 4 h and peaked at 6 h, maintaining a plateau through 8 and 24 h (4 ng/mL). There was no elevation of calcitonin concentrations, which remained below 10 pg/mL, the lowest sensitivity of the assay. Procalcitonin was measured by a two-antibody immunoradiometric assay specific for this peptide, with no cross-reactivity with calcitonin, katacalcin, or calcitonin gene-related peptide. We conclude that endotoxin induces the release of procalcitonin systemically, that this increase is not associated with an increase in calcitonin, and that the increase in procalcitonin associated with septicemia in patients may be mediated through the effect of endotoxin described here. Whether procalcitonin participates in the mechanisms underlying inflammation remains to be investigated.
Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity

Abstract— The aim of the present study has been to confirm the existence of a transport pathway for a drug (cephalexin) to the cerebrospinal fluid (CSF) directly from the nasal cavity, by comparing the drug's concentrations in CSF after intranasal (i.n.), intravenous (i.v.) and intraduodenal (i.d.) administration. Higher levels of the drug were found in CSF following i.n. administration compared with the i.v. and i.d. routes, even though its plasma concentrations were similar. These findings suggest the existence of a direct transport pathway for cephalexin from the nasal cavity to the CSF. The concentration of drug in CSF at 15 min after i.n. administration was higher than that at 30 min. In contrast, its concentrations in CSF at 15 min after i.v. and i.d. administration were not significantly different from those at 30 min. The results confirm the presence of a direct transport pathway to CSF from the nasal cavity. This pathway may represent a new delivery route to CSF and possibly to brain parenchyma.
Differential expression of oxygen‐regulated genes in bovine blastocysts

Low oxygen conditions (2%) during post‐compaction culture of bovine blastocysts improve embryo quality, which is associated with a small yet significant increase in the expression of glucose transporter 1 (GLUT‐1), suggesting a role of oxygen in embryo development mediated through oxygen‐sensitive gene expression. However, bovine embryos to at least the blastocyst stage lack a key regulator of oxygen‐sensitive gene expression, hypoxia‐inducible factor 1α (HIF1α). A second, less well‐characterized protein (HIF2α) is, however, detectable from the 8‐cell stage of development. Here we use differential display to determine additional gene targets in bovine embryos in response to low oxygen conditions. While development to the blastocyst stage was unaffected by the oxygen concentration used during post‐compaction culture, differential display identified oxygen‐regulation of myotrophin and anaphase promoting complex 1 expression, with significantly lower levels observed following culture under 20% oxygen than 2% oxygen. These results further support the hypothesis that the level of gene expression of specific transcripts by bovine embryos alters in response to changes in the oxygen environment post‐compaction. Specifically, we have identified two oxygen‐sensitive genes that are potentially regulated by HIF2 in the bovine blastocyst. Mol. Reprod. Dev. © 2006 Wiley‐Liss, Inc.
Postcard intervention for repeat self-harm: randomised controlled trial

Background Self-harm and suicidal behaviour are common reasons for emergency department presentation. Those who present with self-harm have an elevated risk of further suicidal behaviour and death. Aims To examine whether a postcard intervention reduces self-harm re-presentations in individuals presenting to the emergency department. Method Randomised controlled trial conducted in Christchurch, New Zealand. The intervention consisted of six postcards mailed during the 12 months following an index emergency department attendance for self-harm. Outcome measures were the proportion of participants re-presenting with self-harm and the number of re-presentations for self-harm in the 12 months following the initial presentation. Results After adjustment for prior self-harm, there were no significant differences between the control and intervention groups in the proportion of participants re-presenting with self-harm or in the total number of re-presentations for self-harm. Conclusions The postcard intervention did not reduce further self-harm. Together with previous results this finding suggests that the postcard intervention may be effective only for selected subgroups.
Slow and Superluminal Light Pulses Via EIT in a 20-m Acetylene-Filled Photonic Microcell

We have developed an all-fiber system where we generate electromagnetically induced transparencies in a 20-m acetylene-filled photonic microcell. Using this system, pulses of probe light were delayed and advanced by up to 5 and 1 ns, respectively. The delay/advance is tunable through the probe detuning and the coupling Rabi frequency. Through optimization of experimental parameters such as acetylene pressure, coupling laser power and decoherence rates it is shown that a pulse delay of 7 ns/m is possible. Limitations imposed on the fiber length by resonance group velocity dispersion and spectral reshaping are also discussed. In addition to optical buffering, we suggest a slow-light-based fiber optical gyroscope with an enhanced SNR of ~92.
Predictive features in mild senile dementia of the Alzheimer type

Forty-three subjects with mild senile dementia of the Alzheimer type, diagnosed and staged by clinical research criteria, were studied with clinical, psychometric, EEG, visual evoked potential, and CT measures. During the 12 months following entry into the study, 21 subjects progressed to moderate or severe dementia, 21 remained mild, and one was lost to follow-up. Many of the clinical and psychometric measures of impairment were predictive of the progression to moderate or severe dementia. Electrophysiologic and CT measures were not. In a discriminant function analysis, the scores on two measures (the digit symbol subtest of the Wechsler Adult Intelligence Scale and an Aphasia Battery) correctly predicted the stage of dementia 1 year later in 95% of the subjects.
Differential diagnosis of benign and malign pancreatic masses with 18F-fluordeoxyglucose-positron emission tomography recorded with a dual-head coincidence gamma camera

Introduction Metabolic imaging using 18F-fluordeoxyglucose and a ring-positron emission tomography camera is an established method in the differential diagnosis of pancreatic masses. Ring-positron emission tomography cameras, however, are expensive and available in only few specialized centres. The aim of this study was to investigate how far 18F-fluordeoxyglucose scan with a conventional dual-head gamma-camera could differentiate between benign and malign pancreatic masses. Material and methods Forty-one patients (male/female: 25/16; mean age: 64.0 years; range: 41–86 years) with a pancreatic mass detected by ultrasound, computed tomography or MRI were included. In all patients 18F-fluordeoxyglucose scan was performed after overnight fasting and injection of 4 mCi 18F-fluordeoxyglucose using an ADAC Vertex MCD dual head gamma-camera (ADAC; Milpitas, California, USA), equipped with a 5/8-inch NaI-crystal. Images were acquired through a 180° grade rotation in the three dimensional mode. The chosen matrix was 128×128×16, a Butterworthfilter (ADAC) was used and data were transferred into visible sinograms via Fourier-Rebinning. Coronar, sagittal and transversal slices of 3.9 mm thickness each were acquired. Focal tracer enhancement was suspicious for a malignoma and therefore regarded as positive, diffuse or no tracer uptake was suspicious for a benign process and was regarded as negative for cancer. Definition of gold standards A diagnosis of cancer had to be confirmed histologically by specimens obtained by 18G-needle biopsy, surgical resection or at autopsy. A diagnosis of an inflammatory mass was considered proven, if no carcinoma could be found histologically in the surgically resected mass or at autopsy, or if there was no progression of the disease during a follow-up of at least 12 months. Results In 22 patients carcinoma was diagnosed (pancreatic cancer: n=17; endocrine tumour: n=3; carcinoma of the common bile duct: n=2). 18F-fluordeoxyglucose scan showed a focal tracer enhancement in 19 of these 22 patients (sensitivity: 86.4%). False negative results were acquired in two patients with cancer of the common bile duct and in one patient with poorly controlled insulin-dependent diabetes mellitus. In 19 patients the final diagnosis was an inflammatory pancreatic mass. 18F-fluordeoxyglucose scan showed a diffuse tracer enhancement in 15 of these 19 patients (specificity: 78.9%). False positive results were acquired in three patients whose blood tests showed signs of an acute episode of chronic pancreatitis. Positive and negative predictive values of 18F-fluordeoxyglucose scan were 82.6% and 83.3%, respectively. Conclusion 18F-fluordeoxyglucose scan with a conventional dual-head gamma-camera is a highly sensitive and specific method in the differential diagnosis of benign and malign pancreatic masses.