Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel ATP-Binding Cassette Transporter Involved in Multidrug Resistance in the Phytopathogenic FungusPenicillium digitatum

ABSTRACT Demethylation inhibitor (DMI)-resistant strains of the plant pathogenic fungus Penicillium digitatum were shown to be simultaneously resistant to cycloheximide, 4-nitroquinoline-N-oxide (4NQO), and acriflavine. APMR1 (Penicillium multidrug resistance) gene encoding an ATP-binding cassette (ABC) transporter (P-glycoprotein) was cloned from a genomic DNA library of a DMI-resistant strain (LC2) ofPenicillium digitatum by heterologous hybridization with a DNA fragment containing an ABC-encoding region from Botrytis cinerea. Sequence analysis revealed significant amino acid homology to the primary structures of PMR1 (protein encoded by thePMR1 gene) and ABC transporters of Saccharomyces cerevisiae (PDR5 and SNQ2), Schizosaccharomyces pombe(HBA2), Candida albicans (CDR1), and Aspergillus nidulans (AtrA and AtrB). Disruption of the PMR1 gene of P. digitatum DMI-resistant strain LC2 demonstrated that PMR1 was an important determinant of resistance to DMIs. The effective concentrations inhibiting radial growth by 50% (EC50s) and the MICs of fenarimol and bitertanol for the PMR1disruptants (Δpmr1 mutants) were equivalent to those for DMI-sensitive strains. Northern blot analysis indicated that severalfold more PMR1 transcript accumulated in the DMI-resistant strains compared with those in DMI-sensitive strains in the absence of fungicide. In both DMI-resistant and -sensitive strains, transcription of PMR1 was strongly enhanced within 10 min after treatment with the DMI fungicide triflumizole. These results suggested that the toxicant efflux system comprised of PMR1 participates directly in the DMI resistance of the fungus.
Optical microscopy of antibody‐dependent phagocytosis and lysis of erythrocytes by living normal and chronic granulomatous disease neutrophils: A role of superoxide anions in extra‐ and intra‐cellular lysis

Novel optical microscopic techniques have been developed to observe neutrophil‐mediated effector functions at the level of individual cells. Conventional absorption spectrophotometry has shown that exposure of hemoglobin to superoxide anions decreases the intensity of the Soret band and shifts it to lower wavelengths. This oxidative event can be visualized within intact erythrocytes using bright‐field microscopy in conjunction with violet illumination at 430 nm. The sequential oxidation of lgG‐opsonized sheep erythrocytes bound to normal human neutrophils can be observed. Chronic granulomatous disease (CGD) neutrophils which do not generate superoxide anions were not capable of influencing target absorption at 430 nm. Cytolytic events were visualized by fluorescence microscopy. Cytosolic or membrane compartments of sheep erythrocytes were labeled with eosin Y or fluorescein isothiocyanate, respectively. Time‐dependent studies of erythrolysis show that targets are lysed extra‐ and intra‐cellularly. The fluorescent diffusion gradient generated at the site of membrane rupture suggests that a pore of approximately 30 nm in diameter is formed in the target membrane. The site of pore formation is not found at the target‐effector cell interface. CGD neutrophils did not display these cytolytic phenomena. Furthermore, the cytosolic label eosin Y could be followed into an associated granule compartment; we suggest that the phenomenon of piranhalysis may participate in antibody‐dependent effector mechanisms. Phagocytosis can also be observed using fluorescently‐labeled erythrocytes. Determinations of phagocytic index are more reliable with this approach. These microscopical methods are both simple and efficient. To our knowledge, these are the first direct microscopic studies of effector cell‐mediated target cell oxidation and cytolysis. These experiments provide a fresh approach to the study of phagocyte effector functions at the cellular level and illuminate the importance of superoxide anions in antibody‐dependent erythrolysis.
Blood pressure effects of long‐term stimulant use in disorders of hypersomnolence

Untoward cardiovascular effects have been implicated as a deterrent to long‐term central nervous system (CNS) stimulant use in disorders of hypersomnolence. In this study, we reviewed the relationship between blood pressure and long‐term stimulant use. Medical records of 54 patients with narcolepsy and idiopathic CNS hyper‐ somnolence (ICH) were reviewed. The overall mean number of months of follow‐up for the entire group was 45.6 (95% CI: 42–49). Both simple linear regression and multiple regression utilizing generalized estimating equations were used to show relationships between blood pressure (BP), time and other covariates. In the simple linear regression model, the average slope of the line of systolic BP (SBP) on time for the entire group was 0.06 (95% CI: ‐0.09, 0.13) and the line of diastolic BP (DBP) on time was 0.01 (95% CI: ‐0.05, 0.07). Two multiple regression equations were fitted for the continuous response variables SBP and DBP. Covariates in the model included: time, hypertension, weight at baseline, weight, SBP baseline (SBPBL), DBP baseline (DBPBL), high vs. low dose stimulant therapy and age at starting treatment. For SBP, the covariates weight at baseline, weight and SBPBL were significant (P< 0.05) predictors. For DBP, covariates reaching statistical significance (P< 0.05) included weight and DBPBL. There was no significant change in SBP or DBP over time in either model. Two different statistical models support the conclusion that there was no significant change in SBP or DBP over time in this population.
p-capped GaN-AlGaN-GaN high-electron mobility transistors (HEMTs)

A novel p-capped GaN-AlGaN-GaN high-electron mobility transistor has been developed to minimize radio-frequency-to-dc (RF-DC) dispersion before passivation. The novel device uses a p-GaN cap layer to screen the channel from surface potential fluctuations. A low-power reactive ion etching gate recess combined with angle evaporation of the gate metal has been used to prevent gate extension and maintain breakdown voltage. Devices with gate lengths of 0.7 /spl mu/m have been produced on sapphire. Current-gain cutoff frequencies (f/sub /spl tau//) of 20 GHz and maximum frequencies of oscillation (f/sub max/) of 38 GHz have been achieved. Unpassivated devices demonstrated a saturated output power of 3.0 W/mm and peak power-added efficiency of 40% at 4.2 GHz (V/sub DS/ = +20 V).
Evaluation of distance and near stereoacuity and fusional vergence in intermittent exotropia

Aim: To evaluate the role of distance and near stereoacuity and fusional vergence in patients with intermittent exotropia [X(T)] and their change after surgery. Materials and Methods: This prospective interventional institution-based clinical study included 31 cases of X(T) requiring surgery and 33 age, sex-matched controls. All subjects underwent complete orthoptic assessment including near stereopsis (Randot stereogram) and distance stereopsis by polaroid stereo- projector apparatus using special paired slides and fusional vergence assessment at distance and near prism bar at baseline and one week, one month, three months and six months after surgery in X(T). Results: The successful surgical alignment rate was 74.2%. Preoperatively, cases demonstrated significantly poor distance and near stereoacuity, compared to controls (P < 0.001). Mean distance stereoacuity (sec of arc) in normals, (X)T preoperatively and postoperatively was 344.8 ± 139.5, 1149.2 ± 789.4 and 450.1 ± 259 while mean near stereoacuity was 34.7 ± 9.5, 68.7 ± 31.1 and 47.4 ± 22.6 respectively. Postoperatively at six months, significant improvement in stereoacuity was observed both at near and distance (P < 0.05). Mean distance fusional convergence (in prism diopter) in normals, X(T) preoperatively and postoperatively was 20.7 ± 4.7, 18.0 ± 3.3 and 21.4 ± 3.6 respectively, mean near fusional convergence was 27.8 ± 6.3, 24.1 ± 5.5 and 29.1 ± 5.5 respectively. There was good correlation between fusional vergence amplitudes for distance and near indicating any one would suffice. Conclusion: Early detection of abnormal stereoacuity (near and if possible distance) and near fusional vergence amplitudes may help to decide proper timing of surgery in X(T).
Integrated charger with wireless charging and boost functions for PHEV and EV applications

Integrated charger topologies that have been researched so far with dc-dc converters and the charging functionality have no isolation in the system. Isolation is an important feature that is required for user interface systems that have grid connections and therefore is a major limitation that needs to be addressed along with the integrated functionality. The topology proposed in this paper is a unique and a first of its kind topology that integrates a wireless charging system and the boost converter for the traction drive system. The new topology is also compared with an on-board charger system from a commercial electric vehicle (EV). The ac-dc efficiency of the proposed system is 85.1% and the specific power and power density of the onboard components is ~455 W/kg and ~320 W/l.
Serotonin Infusions Inhibit Sensory Input From the Dural Vasculature

Intravenous infusions of serotonin (5-hydroxtryptamine creatinine sulphate, 5HT, 50-300 μg/kg/min) in cats reversibly inhibited the responses of cervical spinal cord neurons to electrical stimulation of the superior sagittal sinus. Inhibition developed over 20-30 min and resolved over the same time course, suggesting a dependence on accumulation of 5HT in the central nervous system. Inhibition was suppressed by prior intravenous injection of the 5HT antagonists methysergide (1 mg/kg) and methiothepin (1 mg/ kg). Infusions of 5HT (50 μg/kg/min) caused a rise in whole blood levels of 5HT by a factor of 1.5 of control values. 5HT levels in platelet-free plasma rose by a factor of 50. Levels of 5HT and 5 hydroxyindole acetic acid released into the cerebrospinal fluid rose significantly. The results suggest that earlier clinical observations that 5HT infusions can ameliorate the pain of migraine may not have been due to cranial vasoconstriction alone, but could have involved a central action of 5HT.
Constant Current Drive for Resistive Sensors Based on Generalized Impedance Converter

A generalized impedance converter (GIC) is presented in this paper as a programmable current source. A study of its properties and limitations is shown. Its current efficiency is compared with that of Howland topologies, and it is improved in this paper. The contribution of the operational amplifier static offsets to the current source is obtained by presenting typical values of these parameters, and an equivalent circuit with its differential and common modes is presented. The calculated and experimental GIC input impedances are obtained, showing its bandwidth limitation and proposing the possibility of extending the input impedance frequency response without varying its low-frequency value. In this paper, the GIC is used to provide constant current to a series sensor loop and a magnetoresistive current sensor (Wheatstone bridge), which are located within the GIC itself. In both cases, the GIC works under the DC regime, unlike usual AC use.
Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

Atopic dermatitis, a chronic inflammatory skin disease with increasing prevalence, is closely associated with skin barrier defects. A cytokine related to disease severity and inhibition of keratinocyte differentiation is IL-31. To identify its molecular targets, IL-31–dependent gene expression was determined in three-dimensional organotypic skin models. IL-31–regulated genes are involved in the formation of an intact physical skin barrier. Many of these genes were poorly induced during differentiation as a consequence of IL-31 treatment, resulting in increased penetrability to allergens and irritants. Furthermore, studies employing cell-sorted skin equivalents in SCID/NOD mice demonstrated enhanced transepidermal water loss following s.c. administration of IL-31. We identified the IL-1 cytokine network as a downstream effector of IL-31 signaling. Anakinra, an IL-1R antagonist, blocked the IL-31 effects on skin differentiation. In addition to the effects on the physical barrier, IL-31 stimulated the expression of antimicrobial peptides, thereby inhibiting bacterial growth on the three-dimensional organotypic skin models. This was evident already at low doses of IL-31, insufficient to interfere with the physical barrier. Together, these findings demonstrate that IL-31 affects keratinocyte differentiation in multiple ways and that the IL-1 cytokine network is a major downstream effector of IL-31 signaling in deregulating the physical skin barrier. Moreover, by interfering with IL-31, a currently evaluated drug target, we will have to consider that low doses of IL-31 promote the antimicrobial barrier, and thus a complete inhibition of IL-31 signaling may be undesirable.
[Boost effect of recombinant IL-4 on protection of Schistosoma japonicum cathepsin B DNA vaccine in mice against the parasite].

OBJECTIVE To investigate the enhancement effect of IL-4 expression plasmid on cathepsin B DNA vaccine of Schistosoma japonicum (Sj) in mice. METHODS The recombinant IL-4 plasmid constructed by cloning PCR amplified product of murine IL-4 gene into eukaryotic expression vector pcDNA3.1 was co-injected intramuscularly with Sj cathepsin B expression plasmid DNA to mice as the test group. The other three groups of mice were set up as control including IL-4 expression plasmid, Sj cathepsin B expression plasmid and two vacant vector plasmids. The expression of IL-4 and cathepsin B was visualized by immunohistochemistry. Challenge infection in mice was carried out 3 weeks after the last vaccination and immune protection was assessed by worm and egg reduction rates. RESULTS The recombinant mIL-4 plasmid and cathepsin B DNA vaccine were expressed in muscular cells of the vaccinated mice. Immunization with cathepsin B DNA plus recombinant mIL-4 plasmid yielded a 43.2 % of worm reduction rate and a 76.6% of egg reduction rate, showing a significant difference (P<0.01, P<0.05) compared with that of cathepsin B DNA vaccine alone. CONCLUSION As an adjuvant, IL-4 DNA can improve the protective effect of cathepsin B DNA vaccine in mice against S. japonicum infection.
On the inherent precision of mcDESPOT

A statistical analysis of the mcDESPOT protocol for characterizing two exchanging water proton pools—a seven‐dimensional problem that fits to multiple flip angle measurements of both spoiled and refocused gradient echoes—is presented. Theoretical calculations of the Cramér‐Rao lower bounds of the variance of fitted model parameters were made using a variety of model system parameters, meant to mimic those expected in human white matter. The results, validated by Monte Carlo simulations, indicated that mcDESPOT signals acquired at feasibly attainable signal‐to‐noise ratios cannot provide parameter estimates with useful levels of precision. Precision can be greatly improved by constraining solutions with a priori model information, although this will generally lead to biased parameter estimates with less specificity. These results indicate that previous, apparently successful applications of mcDESPOT to human white matter may have used data fitting methods that implicitly constrained parameter solutions, or that the two‐pool model of white matter may not be sufficient to describe the observed water proton signal in mcDESPOT acquisitions. In either case, mcDESPOT‐derived estimates of two‐pool model parameters cannot yet be unambiguously related to specific tissue characteristics. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.
Association of Binge Eating Behavior with Total and Abdominal Adipose Tissue in a Large Sample of Participants Starting a Weight Loss or Maintenance Program

ABSTRACT Objective: It is not clear whether binge eating (BE) behavior is associated with body composition independently of body mass index (BMI). Our aim has been to evaluate the BMI-independent contribution of BE severity and BE status on the total amount of fat mass and abdominal fat distribution in a large sample of participants. Method: We performed a cross-sectional study among 8524 participants followed at a nutritional center. BMI and waist circumference (WC) were measured, body fat (BF) was estimated by skinfold measurement, and abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues were measured by ultrasonography. BE was assessed using the Binge Eating Scale (BES). The association between the continuous BES score (BE severity) and adiposity was assessed in the whole sample after adjustment for BMI and other confounders. The effect of BE status on adiposity was also assessed by matching binge eaters (BES ≥ 18), for sex, age, and BMI, with non-binge eaters (BES < 18). Results: We found that 17.7% of the participants were binge eaters. Continuous BES score was associated with increasing WC (0.03 cm, 95% confidence interval [CI], 0.02 to 0.05 every 1 BES unit, p < 0.001) and decreasing BF (0.01%, 95% CI, −0.02 to −0.00 every 1 BES unit, p = 0.003). No association was found between BE severity and VAT and SAT. After matching, the BF of binge eaters was 0.29% (95% CI, −0.50 to −0.07, p = 0.01) lower than that of non-binge eaters. Conclusions: Given the very small effect size, BE severity and status are not associated in a biologically meaningful manner with BF content and distribution.
A Flexible Estimating Equations Approach for Mapping Function-Valued Traits

In genetic studies, many interesting traits, including growth curves and skeletal shape, have temporal or spatial structure. They are better treated as curves or function-valued traits. Identification of genetic loci contributing to such traits is facilitated by specialized methods that explicitly address the function-valued nature of the data. Current methods for mapping function-valued traits are mostly likelihood-based, requiring specification of the distribution and error structure. However, such specification is difficult or impractical in many scenarios. We propose a general functional regression approach based on estimating equations that is robust to misspecification of the covariance structure. Estimation is based on a two-step least-squares algorithm, which is fast and applicable even when the number of time points exceeds the number of samples. It is also flexible due to a general linear functional model; changing the number of covariates does not necessitate a new set of formulas and programs. In addition, many meaningful extensions are straightforward. For example, we can accommodate incomplete genotype data, and the algorithm can be trivially parallelized. The framework is an attractive alternative to likelihood-based methods when the covariance structure of the data is not known. It provides a good compromise between model simplicity, statistical efficiency, and computational speed. We illustrate our method and its advantages using circadian mouse behavioral data.
Recent advances in automated protein design and its future challenges

ABSTRACT Introduction: Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered: The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.
Global burden of gastric cancer attributable to Helicobacter pylori

We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti‐H. pylori antibodies than ELISA, the detection method used in our previous analysis. The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori after briefly reviewing new evidence, and to reassess the global burden of cancer attributable to H. pylori. We therefore reviewed the literature for studies comparing the risk of developing non‐cardia gastric cancer (NCGC) in cases and controls, using both ELISA and multiple antigen immunoblot for detection of H. pylori. The results from prospective studies were combined, and the new pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection‐related cancers worldwide. Using the immunoblot‐based data, the worldwide AF for H. pylori in NCGC increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers). These updated estimates reinforce the role of H. pylori as a major cause of cancer.
VH3-21 Gene Usage in Chronic Lymphocytic Leukemia – Characterization of a New Subgroup with Distinct Molecular Features and Poor Survival

During recent years it has become evident that lymphoproliferative diseases of B-cell origin display preferential immunoglobulin (Ig) variable heavy chain (VH) gene usage. For instance, the VH1-69 and VH4-34 genes were early found to be overexpressed in B-cell chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. The implications of biased VH gene usage have been speculated to be a result of stimulation of unknown antigens, which gives increased proliferation of B-cells with certain VH gene configuration and consequently higher probability to undergo transformation. Thus, VH gene usage may play a role in development of leukemias and lymphomas. Recently, we could confirm the over usage of the VH1-69 and VH4-34 genes in CLL, but a novel finding was that the VH3-21 gene was preferentially utilized in CLL patients with mutated VH genes. These VH3-21+ Ig rearrangements showed molecular peculiarities such as shorter lengths of the third complementarity determining region (CDR) and had similar amino acid composition of their CDR3s, implicating recognition of the same antigen in individual tumors. Most of the VH3-21+ patients also showed a predominance of λ chain expression and biased usage of 1 specific Vλ gene, V2-14. Furthermore, overall survival appeared to correlate with VH3-21 usage and, regardless of VH gene mutation status, VH3-21+ patients had a poor outcome. All in all, it appears that VH3-21 gene usage define a new entity of CLL. The remaining question now to be clarified is if antigen(s) actually are involved in the pathogenesis of VH3-21+ CLL.