Miracle-dz/UniFAR-FTUs huggingface dataset:
A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda

Porphyria cutanea tarda (PCT), the most common form of porphyria in humans, is due to reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Previous studies have demonstrated that protein levels of URO-D do not change when catalytic activity is reduced, suggesting that an inhibitor of URO-D is generated in hepatocytes. Here, we describe the identification and characterization of an inhibitor of URO-D in liver cytosolic extracts from two murine models of PCT: wild-type mice treated with iron, δ-aminolevulinic acid, and polychlorinated biphenyls; and mice with one null allele of Uro-d and two null alleles of the hemochromatosis gene (Uro-d+/−, Hfe−/−) that develop PCT with no treatments. In both models, we identified an inhibitor of recombinant human URO-D (rhURO-D). The inhibitor was characterized by solid-phase extraction, chromatography, UV-visible spectroscopy, and mass spectroscopy and proved to be uroporphomethene, a compound in which one bridge carbon in the uroporphyrinogen macrocycle is oxidized. We synthesized uroporphomethene by photooxidation of enzymatically generated uroporphyrinogen I or III. Both uroporphomethenes inhibited rhURO-D, but the III isomer porphomethene was a more potent inhibitor. Finally, we detected an inhibitor of rhURO-D in cytosolic extracts of liver biopsy samples of patients with PCT. These studies define the mechanism underlying clinical expression of the PCT phenotype, namely oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of URO-D. The oxidation reaction is iron-dependent.
Rift Valley Fever Virus Lacking the NSs and NSm Genes Is Highly Attenuated, Confers Protective Immunity from Virulent Virus Challenge, and Allows for Differential Identification of Infected and Vaccinated Animals

ABSTRACT Rift Valley fever (RVF) virus is a mosquito-borne human and veterinary pathogen associated with large outbreaks of severe disease throughout Africa and more recently the Arabian peninsula. Infection of livestock can result in sweeping “abortion storms” and high mortality among young animals. Human infection results in self-limiting febrile disease that in ∼1 to 2% of patients progresses to more serious complications including hepatitis, encephalitis, and retinitis or a hemorrhagic syndrome with high fatality. The virus S segment-encoded NSs and the M segment-encoded NSm proteins are important virulence factors. The development of safe, effective vaccines and tools to screen and evaluate antiviral compounds is critical for future control strategies. Here, we report the successful reverse genetics generation of multiple recombinant enhanced green fluorescent protein-tagged RVF viruses containing either the full-length, complete virus genome or precise deletions of the NSs gene alone or the NSs/NSm genes in combination, thus creating attenuating deletions on multiple virus genome segments. These viruses were highly attenuated, with no detectable viremia or clinical illness observed with high challenge dosages (1.0 × 104 PFU) in the rat lethal disease model. A single-dose immunization regimen induced robust anti-RVF virus immunoglobulin G antibodies (titer, ∼1:6,400) by day 26 postvaccination. All vaccinated animals that were subsequently challenged with a high dose of virulent RVF virus survived infection and could be serologically differentiated from naïve, experimentally infected animals by the lack of NSs antibodies. These rationally designed marker RVF vaccine viruses will be useful tools for in vitro screening of therapeutic compounds and will provide a basis for further development of RVF virus marker vaccines for use in endemic regions or following the natural or intentional introduction of the virus into previously unaffected areas.
Machine Learning and Molecular Dynamics Based Insights into Mode of Actions of Insulin Degrading Enzyme Modulators.

BACKGROUND Alzheimer's disease (AD) is one of the most common lethal neurodegenerative disorders having impact on the lives of millions of people worldwide. The disease lacks effective treatment options and the unavailability of the drugs to cure the disease necessitates the development of effectual anti-Alzheimer drugs. Several mechanisms have been reported underlying the association of the two disorders, diabetes and dementia, one among which is the insulin-degrading enzyme (IDE) which is known to degrade insulin as well beta-amyloid peptides. METHODS The present study is aimed to generate accurate classification models using machine learning techniques, which could identify IDE modulators from a bioassay dataset consisting of IDE inhibitors as well as non-inhibitors. The identified compounds were subjected to docking and Molecular dynamics (MD) studies for an in-depth analysis of the binding modes along with the complex stability. This study proposes that the identified potential active compounds, STK026154 (PubChem ID: CID2927418) with Glide score of -7.70 kcal/mol and BAS05901102 (PubChem ID: CID3152845) with Glide score of -7.06 kcal/mol, could serve as promising leads for the development of novel drugs against AD. CONCLUSION The present study shows that such in silico approaches can be effectively used to discover and select active compounds from unseen data for accelerated drug development process. The machine learning models generated in the present study were used to screen Traditional Chinese Medicine (TCM) database to identify the phytocompounds already been reported to have therapeutic effects against AD.
The Effect of Dexamethasone on Symptoms of Posttraumatic Stress Disorder and Depression After Cardiac Surgery and Intensive Care Admission: Longitudinal Follow-Up of a Randomized Controlled Trial

Objective:Cardiac surgery and postoperative admission to the ICU may lead to posttraumatic stress disorder and depression. Perioperatively administered corticosteroids potentially alter the risk of development of these psychiatric conditions, by affecting the hypothalamic-pituitary-adrenal axis. However, findings of previous studies are inconsistent. We aimed to assess the effect of a single dose of dexamethasone compared with placebo on symptoms of posttraumatic stress disorder and depression and health-related quality of life after cardiac surgery and ICU admission. Design:Follow-up study of a randomized clinical trial. Setting:Five Dutch heart centers. Patients:Cardiac surgery patients (n = 1,244) who participated in the Dexamethasone for Cardiac Surgery trial. Interventions:A single intraoperative IV dose of dexamethasone or placebo was administered in a randomized, double-blind way. Measurements and Main Results:Symptoms of posttraumatic stress disorder, depression, and health-related quality of life were assessed with validated questionnaires 1.5 years after randomization. Data were available for 1,125 patients (90.4%); of which 561 patients received dexamethasone and 564 patients received placebo. Overall, the prevalence of psychopathology was not influenced by dexamethasone. Posttraumatic stress disorder and depression were present in, respectively, 52 patients (9.3%) and 69 patients (12.3%) who received dexamethasone and in 66 patients (11.7%) and 78 patients (13.8%) who received placebo (posttraumatic stress disorder: odds ratio, 0.82; 95% CI, 0.55–1.20; p = 0.30; depression: odds ratio, 0.92; 95% CI, 0.64–1.31; p = 0.63). Subgroup analysis revealed a lower prevalence of posttraumatic stress disorder (odds ratio, 0.23; 95% CI, 0.07–0.72; p < 0.01) and depression (odds ratio, 0.29; 95% CI, 0.11–0.77; p < 0.01) in female patients after dexamethasone administration. Health-related quality of life did not differ between groups and was not associated with psychopathology. Conclusions:Overall, our findings suggest that exogenous administration of the glucocorticoid receptor agonist dexamethasone—compared with placebo—during cardiac surgery does not positively or negatively affect the prevalence of posttraumatic stress disorder and depression. However, in female patients, beneficial effects on the occurrence of posttraumatic stress disorder and depression may be present.
Erythroblast cell lines transformed by a temperature‐sensitive mutant of avian erythroblastosis virus: A model system to study erythroid differentiation in vitro

A continuous chicken erythroblast cell line transformed by the temperature‐sensitive mutant ts34 of avian erythroblastosis virus was developed. This cell line, designated HD3, could be induced to terminally differentiate by shift to the nonpermissive temperature. The differentiated cells resembled erythrocytes as judged by morphology, expression of hemoglobin as determined by benzidine staining and radioimmunoassay, and by the expression of differentiation‐specific cell surface antigens. Terminal differentiation was dependent on an erythropoietin‐like activity present in anemic chicken serum. In contrast, induction of differentiation in the same cells by butyric acid was erythropoietin independent and did not lead to the formation of erythrocytes. In addition, we found that the responsiveness to temperature inducibility and to butyric acid could be dissociated in variant sublines of HD3 and that both types of differentiation inducers appear to act via different pathways.
Planar Endfire Circularly Polarized Antenna Using Combined Magnetic Dipoles

A novel planar circularly polarized antenna with endfire radiation beam in parallel with the antenna substrate's plane is proposed. The operation principle of the antenna is analyzed and design guidelines are laid down. Then, an optimized loop-aperture combined antenna is designed and demonstrated to exhibit an endfire beam in parallel with its plane within 5.74-5.88 GHz for |S11| lower than -10 dB and axial ratio smaller than 3 dB. The proposed antenna can be used as a low-profile, cost-effective, hand-held reader antenna for radio frequency identification systems .
Short dental implants as compared to maxillary sinus augmentation procedure for the rehabilitation of edentulous posterior maxilla: Three‐year results of a randomized clinical study

BACKGROUND Several treatment options exist for the implant-supported rehabilitation of edentulous posterior maxilla. PURPOSE To compare maxillary sinus floor augmentation associated to standard length implants, with direct placement of implants of reduced length in the available residual bone. MATERIALS AND METHODS Patients with edentulous posterior maxilla and a residual height of 4-7 mm were randomly allocated to the test (short implants [SIs], 6.5 to 8.5mm long) or the control (sinus augmentation [SA] and implants ≥10mm long) group. Anorganic bovine bone was the grafting material for the control group. In both groups pure platelet-rich plasma was used to bioactivate implant surface prior to insertion. Implant and prosthesis survival, clinical variables, radiographic bone level change, quality of life, and patient satisfaction were assessed. RESULTS Twenty-five patients were treated in the control group (58 standard length implants) and 27 in the test group (42 SIs). After 3 years of follow-up no implant failure and biological or mechanical complications were recorded. Marginal bone loss, soft tissue, and oral hygiene parameters were similar in the 2 groups at both 1 and 3 years' follow-up. Postoperative pain, swelling and other symptoms and daily activities were better in the SIs group than in the SA group, while patients' satisfaction after 1 year was similar. CONCLUSIONS In spite of comparable medium-term clinical and radiographic outcomes, when the residual ridge height is sufficient for a safe placement, SIs may be preferred due to simplified protocol, less invasiveness, shorter treatment time, and reduced postoperative discomfort as compared to SA.
Enhanced efficiency of swine wastewater treatment by the composite of modified zeolite and a bioflocculant enriched from biological sludge

ABSTRACT A high-ammonia-resistant strain was firstly isolated from activated sludge and applied to harvest a bioflocculant from a swine wastewater. Enhancement of swine wastewater treatment was investigated by a composite of the harvested bioflocculant and a zeolite modified by integrating calcinations with MgO at 400°C. Results have demonstrated that 71.8% of Chemical Oxygen Demand (COD), 54.5% of ammonia, and 81.2% of turbidity can be removed from the swine wastewater by the bioflocculant alone. Results have also demonstrated that 73.4% of ammonia could be removed from the swine wastewater by the modified zeolite alone, while almost no COD was removed. Thus, the bioflocculant and modified zeolite were used simultaneously to enhance swine wastewater treatment, and response surface methodology (RSM) was employed to optimize the treatment process. Under the optimal treatment conditions of bioflocculant of 12 mg/L, modified zeolite of 8 g/L, pH of 7.5, and agitation speed of 200 r/min, obtained by the RSM, 88.6% of COD, 85.8% of ammonia, and 95.5% of turbidity could be removed from swine wastewater, which were significantly improved compared with that by the bioflocculant or modified zeolite alone. The use of the composite exerted advantages of the bioflocculant and modified zeolite, and provided a feasible way to improve pollutants’ removal from wastewaters.
Expression of CYP2W1 in colon tumors: regulation by gene methylation.

INTRODUCTION CYP2W1 is a novel enzyme shown to be selectively expressed in rat fetal colon and in human colon cancer and has previously been suggested as a potential drug target for cancer therapy. Here, the expression and gene methylation of CYP2W1 were analyzed in human colon carcinoma cell lines, colon tumors and in corresponding normal colon tissue. METHODS CYP2W1 mRNA and protein expression in HepG2 and Caco-2TC7 cells and normal colon and colon tumor tissue samples were analyzed using real-time PCR and Western blotting. CYP2W1 gene methylation status in the same samples was analyzed using the sodium bisulfite sequencing method. RESULTS & DISCUSSION CYP2W1 mRNA was detected in all (n = 39) tumor samples analyzed. Moreover, in 60% (12/20) of the colon tumors, CYP2W1 mRNA levels were substantially higher than in corresponding normal tissues. CYP2W1 protein was detected in most of the colon tumor samples analyzed (n = 16), which appeared to be of two apparent phenotypes: those with five- to ten-fold induced CYP2W1 (approximately 50% of the tumors), and those with low expression, harboring similar or only slightly higher amounts of CYP2W1 as compared with surrounding control tissue. Methylation analysis of the CpG island in the exon 1-intron 1 junction of the CYP2W1 gene from both cell lines, tumors and normal tissues revealed that demethylated CpG dinucleotides appeared as a requirement for high CYP2W1 gene expression. CONCLUSION The expression of CYP2W1 is colon tumor-specific and is associated with methylation status of the CYP2W1 gene, suggesting a potential causal link between the gene hypomethylation and its enhanced expression.
Intermediate conformational states of apocytochrome c.

Horse apocytochrome c has been assumed to be a typical unfolded protein. At low ionic strength, the far- and near-UV circular dichroism spectra are typical of an unfolded protein at all pH values between 2 and 9. On the other hand, in the presence of high concentrations of salt, substantial secondary structure is present at both neutral and acidic pH. At low pH, perchlorate anion, either from salt or from acid, stabilizes an intermediate state (the A state) with secondary structure similar to that previously observed in the molten globule state of holocytochrome c. To further characterize the conformational states of apocytochrome c as a function of pH and salt, a fluorescence-labeled derivative was prepared, in which the two cysteine residues were labeled with N-(iodoacetyl)-N'-(5-sulfo-1- naphthyl)ethylenediamine(IAEDANS). The conformational transitions of the fluorescence-labeled apocytochrome c measured by circular dichroism were similar to those of unmodified apocytochrome c, indicating that the effects of the modification on the conformation and stability are small. Fluorescence energy transfer from tryptophan to the fluorescence label revealed several salt- and pH-dependent transitions. At very low ionic strength, apocytochrome c became compact as the pH was increased with a transition midpoint at pH 4.5. At acidic pH, increasing concentration of perchlorate induced a more compact state with a transition midpoint similar to that observed by circular dichroism. In contrast, at neutral pH, increasing perchlorate concentration had little effect on the compactness, as determined by a lack of change in the energy-transfer efficiency (but did increase the amount of secondary structure). (ABSTRACT TRUNCATED AT 250 WORDS)
Maintaining Low Ca2+ Level in the Endoplasmic Reticulum Restores Abnormal Endogenous F508del‐CFTR Trafficking in Airway Epithelial Cells

The most common mutation in cystic fibrosis, F508del, results in cystic fibrosis transmembrane conductance regulator protein (CFTR) that is retained in the endoplasmic reticulum (ER). Retention is dependent on chaperone proteins, many of which, like calnexin, require calcium for optimal activity. Here, we show that a limited and a maintained ER calcium level is sufficient to inhibit the F508del–CFTR/calnexin interaction and to restore the cAMP‐dependent CFTR chloride transport, thus showing the correction of abnormal trafficking. We used Western blot analysis, iodide efflux and calcium measurement techniques applied to the human airway epithelial cystic fibrosis cell line CF15 (F508del/F508del). The inhibition of ER calcium pump, with thapsigargin, curcumin, 2,5‐di(t‐butyl)hydroquinone or cyclopiazonic acid, maintains a threshold levels of calcium that is correlated to the recovery of endogenous F508del‐CFTR transport activity. In particular, cyclopiazonic acid restores a 2‐aminoethyoxydiphenyl borate‐sensitive F508del‐CFTR trafficking with an EC50 of 915 nm. By contrast, the 1,4,5‐trisphosphate or IP3 receptor activators, i.e., ATP and histamine, while transiently emptying the ER intracellular calcium store, did not affect the trafficking of F508del‐CFTR. Our data suggest that decreasing the ER calcium level is not sufficient to restore the defective trafficking of F508del‐CFTR, whereas decreasing and also maintaining low ER calcium level allow correction of defective biosynthetic pathway of endogenous F508del‐CFTR in human airway epithelial cells.
Nephroureterostomy-drained percutaneous nephrolithotomy: modification combining safety with decreased morbidity.

BACKGROUND AND PURPOSE Percutaneous nephrolithotomy (PCNL) has become well established as the standard procedure for the management of certain renal calculi. To minimize patient discomfort and reduce the hospital stay, a novel modification of our previous technique was evaluated. A smaller internal/external nephroureterostomy catheter (NUC) placed at the completion of the procedure was compared with the larger Malecot nephrostomy tube. PATIENTS AND METHODS We conducted a 2:1 matched cohort study with historical controls. In 2002, a consecutive series of 30 PCNL procedures at a single teaching hospital were carried out in the conventional fashion. At the end of the procedure, an 8.5F/6.0F internal/external NUC was placed in the percutaneous tract instead of the traditional 24F Malecot tube. These patients were compared with a cohort of matched cases (60) performed between 1992 and 1997 on the basis of age, sex, and site of access (supracostal or infracostal). The endpoints were patient discomfort (morphine equivalents used), safety (postoperative hemoglobin drop), and length of hospital stay. RESULTS The mean morphine equivalents used in the first 24 postoperative hours were significantly different in the two groups (study 16.5 mg and controls 47.8 mg; P<0.001). The percentage difference between the preoperative and postoperative hemoglobin values was comparable in the two groups (mean study 12.8% and mean controls 13.4%; P=0.80). The median length of hospital stay was significantly shorter in the study group than in the control group, 1 v 4 days, respectively (P<0.001). CONCLUSION Our data suggest that the NUC diminishes postoperative pain while maintaining ureteral patency and nephrostomy access and decreases hospital stay.
Transcription factor CAAT/enhancer‐binding protein is involved in regulation of expression of sterol carrier protein x in Spodoptera litura

The Spodoptera litura sterol carrier protein x (SlSCPx) gene is expressed in various tissues throughout the life cycle and plays important role in sterol absorption and transport. In this study, the effects of insect hormones (20‐hydroexcdysone and juvenile hormone) and lipids (arachidonic acid, cholesterol) on the expression of SlSCPx was analysed by reverse‐transcriptase PCR. The results showed that none of these substances significantly induced the expression of SlSCPx in Spodoptera litura‐221 (Spli‐221) cells. To identify the transcription factors responsible for regulation of SlSCPx expression, a 3311‐bp promoter sequence of the gene was cloned. Transcriptional activity of the promoter was studied using an in vivo promoter/reporter system and a 29‐bp sequence between −1000 and −1029 nucleotides (nt) upstream of this gene was found to be responsible for the up‐regulation of the gene. Over‐expression of CAAT/enhancer‐binding protein (C/EBP) in Spli‐221 cells increased the promoter activity 5.57‐fold. An electrophoretic mobility shift assay showed that two nuclear proteins bound to this sequence. Recombinant C/EBP specifically bound with a putative cis‐regulatory element (CRE). Mutation of the C/EBP CRE abolished the binding of the C/EBP with the CRE. These results suggest that the transcription factor C/EBP may regulate the expression of SlSCPx by binding to the CRE in the promoter of this gene.
A Test Phantom for Estimating Changes in the Effective Frequency of an Ultrasonic Scanner

Objective. Ultrasonic frequency is an important performance feature of B‐mode scanners. It is particularly relevant when comparing instruments from different manufacturers and reporting clinical results. We investigated a test phantom to independently measure an effective imaging frequency, including effects of depth‐dependent attenuation and frequency filtering during echo reception. Methods. The approach capitalizes on variations of the frequency dependence of backscatter with scatterer size. A tissue‐mimicking phantom containing 48‐μm‐diameter scatterers was constructed. Embedded at depths of 1, 3, 7, and 9 cm were sets of cylindrical inclusions, each containing tissue‐mimicking material with a different scatterer size and number density. Computer simulations helped establish scatterer parameters for the cylinder bodies that resulted in image contrast versus the background that varied with frequency, with each cylinder transitioning from negative to positive contrast at a different frequency. Acoustic properties of the phantom were verified by a laboratory apparatus. Initial tests of the effectiveness of the phantom were done by imaging with several scanners using various frequency and imaging settings on transducers. Results. Images were obtained with 2 clinical scanners in which modest changes in the image acquisition parameters were adjusted. Image contrast between test cylinders and background corresponded to operating frequency with a multihertz transducer. Changes in observable contrast consistent with a shift in operating frequency were not always accompanied by visual indicators that such changes in the scanning protocol had occurred. Conclusions. The test phantom performs as predicted by computer simulations and theoretical calculations of backscatter versus frequency. Contrast on images of the test phantom produced by clinical systems correlates with scanner frequency settings, showing feasibility. Relative shifts in effective frequency and operating bandwidth can be assessed from these contrast differences between settings with this test phantom.