Miracle-dz/UniFAR-FTUs huggingface dataset:
Two distinct mutations in gyrA lead to ciprofloxacin and nalidixic acid resistance in Campylobacter coli and Campylobacter jejuni isolated from chickens and beef cattle *

Aims: The aim of this study was to identify point mutations in the gyrA quinolone resistance determining region (QRDR) of Campylobacter coli (n = 27) and Campylobacter jejuni (n = 26) that confer nalidixic acid (NAL) resistance without conferring resistance to ciprofloxacin (CIP).
Systematic review and meta-analysis of the interaction between Plasmodium falciparum and Plasmodium vivax in humans.

OBJECTIVES This study aimed to quantify the interaction between Plasmodium falciparum and R vivax and the sources of heterogeneity between studies. METHODS We systematically reviewed three databases: Medline (1966-2001), Embase (1980-2001) and CAB-health (1976-2001). Random effects meta-analysis was applied to the data of 62 selected populations. Meta-regression was used to assess the following potential sources of heterogeneity: age-group, presence of fever, continent, temporal and spatial span of studies, and endemicity level. RESULTS The summary odds ratio (OR) between P. falciparum and P. vivax was 0.6 (95% CI: 0.49-0.79). The minimum and maximum observed ORs were 0.01 and 10.9, respectively, and the heterogeneity test was highly significant (tau2 = 0.92, p < 0.0001)--the ORs varied over a very wide range. The ORs in longer studies and in those from areas with higher prevalence yielded smaller, more strongly negative association. This is consistent with the idea that any difference in the species' temporal patterns should decrease the OR, and more so over longer periods of time. INTERPRETATION & CONCLUSION Although such odds ratios between Plasmodium species may be partly due to missed mixed infections when reading blood slides, the negative association between the OR and prevalence supports the existence of biological interactions such as suppression or cross-immunity between species.
Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: A case of Erlotinib

EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine-imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate-determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors.
Prognostic relevance of TTF-1 expression in stage I adenocarcinoma

Tyroid transcription factor-1 (TTF-1) motivates the differentiation and development of bronchioloalveolar cells. The association of TTF-1 expression with prognosis in stage I adenocarcinoma is unclear. This study enrolled patients with resected stage I pulmonary adenocarcinoma who had TTF-1 immunostaining. All the corresponding clinicopathologic data including sex, age, smoking history, pathologic T stage, pathologic disease stage, surgical procedure, subtypes, follow-up records and adjuvant chemotherapy were investigated. Totally, 126 adenocarcinomas with TTF-1− and 2687 adenocarcinomas with TTF-1+ were subjected to the study. Among adenocarcinomas with TTF-1−, the major subtype was acinar-predominant adenocarcinomas, followed by invasive mucinous and papillary subtypes while acinar, papillary and minimally invasive adenocarcinoma were in the majority among adenocarcinomas with TTF-1+. The status of TTF-1 expression was not a significant factor for relapse-free survival (RFS) and overall survival (OS). Furthermore, there was no survival difference between the two groups (RFS: p = 0.2474; OS: p = 0.1480). When confined to stage IB adenocarcinomas with TTF-1−, whether received adjuvant chemotherapy made no difference to RFS and OS (RFS: p = 0.2707; OS: p = 1.000), as was the case in stage IB adenocarcinomas with TTF-1+ (RFS: p = 0.9161; OS: p = 0.1100). Within follow-up period, there was significant difference in post-recurrence survival (PRS) for TTF-1− patients compared with those TTF-1+ patients (Log-rank p = 0.0113). However, regarding to the recurrence site, there was no difference between TTF-1− patients and TTF-1+ patients in patients with stage I adenocarcinoma (p = 0.771) In conclusion, there is no significant difference in RFS and OS between TTF-1− group and TTF-1+ group, but TTF-1 negative adenocarcinoma has significantly worse PFS in patients with stage I adenocarcinoma. Moreover, chemotherapeutic efficacy between TTF-1+ and TTF-1− stage IB adenocarcinomas did not differ.
Inward rectifier potassium (Kir2.1) channels as end‐stage boosters of endothelium‐dependent vasodilators

Increase in endothelial cell (EC) calcium activates calcium‐sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium‐dependent vasodilatation. Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium‐dependent vasodilatation is not clear. In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform. Endothelium‐dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown. These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders.
Continuous nicotine administration produces selective, age‐dependent structural alteration of pyramidal neurons from prelimbic cortex

Emerging evidence indicates that adolescence represents a developmental window of enhanced nicotine‐induced neuroplasticity in rat forebrain. However, whether nicotine produces age‐dependent structural alteration of neurons from medial prefrontal cortex remains to be determined. We characterized the dendritic morphology of layer V pyramidal neurons from prelimbic cortex following adolescent (P29‐43) or adult (P80‐94) nicotine pretreatment. Nicotine administration was via osmotic pump [initial dose 2.0 mg/(kg day), free base]. Five weeks after drug administration concluded, brains were processed for Golgi‐Cox staining and pyramidal neurons digitally reconstructed for morphometric analysis. Overall, nicotine pretreatment produced increased basilar, but not apical, dendritic length of pyramidal cells, a finding consistent with previous work using adult animals. Given the compelling evidence for morphologically distinct functional subtypes of cortical pyramidal neurons, we endeavored to determine whether nicotine‐induced dendritic alteration was specific to putative structural subtypes. Neurons were segregated into two groups based on the extent of dendritic arbor at the distal portion of the apical tree (i.e., the apical tuft). The size of the apical tuft was quantitatively determined using principal component analysis. Cells with small and elaborate apical tufts were classified as simple and complex, respectively. We found that adult nicotine pretreatment produced increased basilar dendritic length and branch number in simple but not complex pyramidal cells. In contrast, adolescent nicotine pretreatment produced a modest but significant increase in basilar dendritic length in complex but not simple cells. These data suggest that nicotine alters dendritic morphology of specific subpopulations of pyramidal neurons and that the subpopulation affected is dependent on the age of drug exposure. Synapse 62:31–39, 2008. © 2007 Wiley‐Liss, Inc.
Evaluation of Opsonophagocytic Dysfunctions in Severely Burned Patients by Luminol‐Dependent Chemiluminescence

We compared the luminol‐dependent chemiluminescence (CL) response of peripheral blood from severely burned patients with that from normal controls to evaluate the primary defense level against bacterial infection in the patients. The CL was measured upon addition to diluted whole blood of a soluble stimulus, phorbol myristate acetate (PMA) or particulate stimuli such as bacteria or zymosan without special opsonization. In the early post‐burn days, the initial rate of whole blood CL induced with the particulate stimulus was much lower than that in the normal controls, whereas the rate was higher when PMA was used as a stimulus. The number of granulocytes in the patients' blood had increased and isolated polymorphonuclear leukocytes (PMNs) from the patients exhibited higher CL responses to the particulate or soluble stimulus as compared with those of normal controls. The results suggest that the PMNs in burn patients were activated and normally mobilized in the early post‐burn period but the opsonizing capacity in the blood decreased. In fact, the serum levels of complement, immunoglobulins and fibronectin were found to be lower in the blood from the patients than those from normal controls and a supplement of freshly frozen plasma of human immunoglobulin preparations restored the initial rate of the whole blood CL upon phagocytosis. The prognosis is still poor when severe infection occurs in the patients with decreased CL response of whole blood. Recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) enhanced the CL response of PMNs from burn patients. The administration of rhG‐CSF may be useful for decreasing the morbidity of severe infection following burn injury in the near future.
Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome

Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10–20%, however, have progressive disease. It is currently not possible to predict long‐term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome.
Performance analysis of conventional STATCOMs and STATCOMs with energy storage in electric arc furnace applications

This paper analyzes the performance and power losses of 2.1 MVA conventional STATCOMs and STATCOMs with energy storage (ESTATCOM), in electric arc furnace applications. The research was conducted by computer simulations with Matlab Simulink software. According to the simulation results load compensation reduces the required current rating of the supply grid transformer and cables by approximately 30 %, and the maximum drop of the reference point (RP) voltage to 2 % compared to 15 % caused by the non-compensated case. The conventional STATCOM attenuates the RP voltage flicker by a factor of 5.9 and the ESTATCOM by a factor of 11.7. The voltage source converters (VSC) of both compensators could be designed for the same rated current, despite the active power compensation capabilities of the ESTATCOM. The system losses are minimized when a 3-level VSC is used instead of a 2-level VSC, and the compensating device is connected to the lowest studied network voltage of 690 V. The energy storage system losses are minimized when the energy storage is connected to the dc link using two separate DC/DC converters instead of a large single converter. This occurs because the system converters can be implemented with IGBTs of lowest rated voltage.
ATF6 as a Transcription Activator of the Endoplasmic Reticulum Stress Element: Thapsigargin Stress-Induced Changes and Synergistic Interactions with NF-Y and YY1

ABSTRACT ATF6, a member of the leucine zipper protein family, can constitutively induce the promoter of glucose-regulated protein (grp) genes through activation of the endoplasmic reticulum (ER) stress element (ERSE). To understand the mechanism ofgrp78 induction by ATF6 in cells subjected to ER calcium depletion stress mediated by thapsigargin (Tg) treatment, we discovered that ATF6 itself undergoes Tg stress-induced changes. In nonstressed cells, ATF6, which contains a putative short transmembrane domain, is primarily associated with the perinuclear region. Upon Tg stress, the ATF6 protein level dropped initially but quickly recovered with the additional appearance of a faster-migrating form. This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence. Optimal ATF6 stimulation requires at least two copies of the ERSE and the integrity of the tripartite structure of the ERSE. Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility. In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity. The ERSE stimulatory activity of ATF6 exhibits properties distinct from those of human Ire1p, an upstream regulator of the mammalian unfolded protein response. The requirement for a high-affinity NF-Y site for ATF6 but not human Ire1p activity suggests that they stimulate the ERSE through diverse pathways.
Histological correlates of optical coherence tomography in non‐melanoma skin cancer

Non‐melanoma skin cancer (NMSC) is rarely fatal but is now the most common malignancy occurring in white populations, accounting for 70% of the cost of managing skin cancer. Optical coherence tomography (OCT) has the potential to improve diagnostic accuracy and help delineate pre‐surgical margins in NMSC. Its widespread clinical acceptance awaits the accumulation of evidence from studies of direct histological comparisons.
Cross‐species comparison of mammalian saliva using an LC–MALDI based proteomic approach

Despite the importance of saliva in the regulation of oral cavity homeostasis, few studies have been conducted to quantitatively compare the saliva of different mammal species. Aiming to define a proteome signature of mammals’ saliva, an in‐depth SDS‐PAGE–LC coupled to MS/MS (GeLC–MS/MS) approach was used to characterize the saliva from primates (human), carnivores (dog), glires (rat and rabbit), and ungulates (sheep, cattle, horse). Despite the high variability in the number of distinct proteins identified per species, most protein families were shared by the mammals studied with the exception of cattle and horse. Alpha‐amylase is an example that seems to reflect the natural selection related to digestion efficacy and food recognition. Casein protein family was identified in all species but human, suggesting an alternative to statherin in the protection of hard tissues. Overall, data suggest that different proteins might assure a similar role in the regulation of oral cavity homeostasis, potentially explaining the specific mammals’ salivary proteome signature. Moreover, some protein families were identified for the first time in the saliva of some species, the presence of proline‐rich proteins in rabbit's saliva being a good example.
A recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumor is caused by a mutation in FIBP gene

Clinical classification of overgrowth syndromes represents a challenge since a wide spectrum of disorders result in marked overgrowth. Therefore, there is a continuous effort to identify the genetic basis of these disorders that will eventually facilitate their molecular classification. Here, we have identified the genetic etiology and the pathogenetic mechanism underlying a rare autosomal recessive overgrowth syndrome in three affected siblings. The overgrowth phenotype in the patients was accompanied by developmental delay, learning disabilities, and variable congenital abnormalities. To elucidate the genetic etiology of the disorder, whole‐genome genotyping and whole‐exome sequencing were used. The disease was mapped to 3p21.1‐p14.2 and 11q13.1‐q13.4, where an in‐frame insertion (c.175_176insTAA) in FIBP gene was revealed. The resulting indel (p.H59LN) was predicted to change the protein conformation with likely deleterious effect on its function as one of the fibroblast growth factor signaling mediators. In vitro cellular proliferation assay and in situ hypridization in vivo were then performed to understand the pathophysiology of the disease. The patients’ skin fibroblasts showed an increased proliferation capacity compared to the controls’ explaining the observed overgrowth phenotype. In addition, we detected Fibp expression most notably in the brains of mice embryos suggesting a possible effect on cognitive functions early in development. To date, only one patient has been reported with a homozygous nonsense mutation in FIBP exhibiting an overgrowth syndrome with multiple congenital abnormalities. Taken all together, these findings provide convincing evidence implicating FIBP aberrations in the newly recognized overgrowth syndrome and expand the associated phenotypes to include possible Wilms tumor predisposition. © 2016 Wiley Periodicals, Inc.
Differential responses of global airway, terminal airway, and tissue impedances to histamine.

The forced oscillation and alveolar capsule techniques were applied to determine the input impedance of the lungs and the airway transfer impedances between 0.2 and 20 Hz in six open-chest dogs in the control state, during intravenous infusion of histamine at seven rates between 0.25 and 16 micrograms.kg-1.min-1, and after the infusion. In each condition, the input impedances seen from the alveolar capsules, i.e., terminal airway impedance (Zaw,ter), were measured by imposing 2- to 200-Hz oscillations from the capsules (B. L. K. Davey and J. H. T. Bates. Respir. Physiol. 91:165-182, 1993). Airway resistance (Raw) and inertance and tissue damping and elastance were derived from the lung impedance data. For all dogs, histamine progressively increased Raw and the real part of airway transfer impedance (airway transfer resistance), reaching, at 16 micrograms.kg-1.min-1, 241 +/- 109 (SD) and 370 +/- 186%, respectively, of the control value but caused greater, although locally highly variable, increases (769 +/- 716% of the control value) in the real part of Zaw,ter extrapolated to zero frequency (R0). With increasing doses of histamine, the changes in R0 always preceded those in Raw and airway transfer resistance implying that bronchoconstriction developed first in the lung periphery. It is therefore concluded that the measurement of Zaw,ter offers a sensitive method for the detection of early nonuniform responses to bronchoconstrictor stimuli that are not yet reflected by the values of the overall Raw. In one-half of the cases, significant increases in tissue damping and elastance occurred before any change in R0; this suggests that the mechanisms of airway and parenchymal constrictions may be unrelated.
[Regulatory role of hypoxia inducible factor-1 alpha in the changes of contraction of vascular smooth muscle cell induced by hypoxia].

OBJECTIVE To observe the regulatory role and mechanism of hypoxia inducible factor-1 alpha (HIF-1 alpha) in the contractile changes of vascular smooth muscle cell (VSMC) induced by hypoxia. METHODS Cells were divided into three groups: normal, hypoxia and oligomycin treated groups. VSMC and vascular endothelial cell (VEC) were co-cultured in Transwell models with the hypoxic time of 0, 0.5, 1, 2, 3, 4 and 6 hours respectively. The contractile response of VSMC to norepinephrine were determined by measuring the fluorescent infiltration rate in the lower chamber. The mRNA expression of HIF-1 alpha, endothelial-nitric oxide synthase (eNOS), inducible-nitric oxide synthase(iNOS), heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS VSMC contraction was increased at the early stage of hypoxia with the 1.53-fold increase at 0.5 hour as compared to the normal group (P<0 .01), and decreased gradually at the prolonged period of hypoxia with the drop of 30% at 6 hours as compared to the normal group (P<0.05). Oligomycin treatment significantly inhibited the increase of VSMC contraction at early stage, while improved it at late hypoxic period with the 6 hours increase of 12.8% (P<0.05). HIF-1 alpha, iNOS, COX-2 and HO-1 mRNA exhibited a time-dependent increase following hypoxia, and peaked at 6, 2, 3 and 4 hours respectively, they were increased 1.62, 3.23, 2.26 and 2.86-folds as compared with normal group (all P<0.01). iNOS, COX-2 and HO-1 mRNA expression were fluctuated in the normal range following oligomycin administration (all P>0.05). CONCLUSION Hypoxia can elicit a biphasic changes of VSMC contraction, and HIF-1 alpha seems to play an important role in the regulation of VSMC contraction induced by hypoxia by regulating eNOS, iNOS, COX-2 and HO-1 expression.
Binding sites for cholesterol on Ca(2+)-ATPase studied by using a cholesterol-containing phospholipid.

Phosphatidylcholines have been synthesized containing a cholesterol moiety at the 2-position of the glycerol backbone. Fluorescence quenching studies show that cholesterol-containing phosphatidylcholines can bind at the lipid-protein interface of the Ca(2+)-ATPase from skeletal muscle sarcoplasmic reticulum, with an affinity half that of dioleoylphosphatidylcholine. The ATPase activity measured for the ATPase reconstituted with the cholesterol-containing phosphatidylcholine containing an oleoyl fatty acyl chain, (C18:1, CHS)PC, is less than that measured for the ATPase reconstituted with dioleoylphosphatidylcholine. The activity measured for the ATPase reconstituted with the cholesterol-containing phosphatidylcholine containing a myristoleoyl fatty acyl chain, (C14:1, CHS)PC, is less than that measured in (C18:1,CHS)PC and is comparable to that measured in dimyristoleoylphosphatidylcholine (di(C14: 1)PC. The stoichiometry of Ca2+ binding to the ATPase is two Ca2+ ions bound per ATPase molecule in the native membrane or in (C18:1,CHS)PC, but one bound per ATPase molecule in di(C14:1)PC or (C14: 1,CHS)PC. Addition of cholesterol to the ATPase in di(C14:1)PC or (C14:1,CHS)PC increases the Ca2+ binding stoichiometry to the usual 2:1, but the binding stoichiometry remains 1:1 in mixtures of di(C14: 1)PC and (C14:1,CHS)PC. Removal of Ca2+ from the Ca(2+)-bound ATPase results in a decrease in tryptophan fluorescence intensity for the ATPase in the native membrane, but an increase in fluorescence intensity for the ATPase in di(C14:1)PC or (C14:1,CHS)PC. Addition of cholesterol to the ATPase in di(C14:1)PC or (C14:1,CHS)PC reverses this change. It is concluded that cholesterol linked to a phospholipid molecule can interact with the ATPase only at the lipid-protein interface. (ABSTRACT TRUNCATED AT 250 WORDS)