Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Efflux Pumps and Topoisomerase Mutations in Fluoroquinolone Resistance in Campylobacter jejuni and Campylobacter coli

ABSTRACT Point mutations in the topoisomerase (DNA gyrase A) gene are known to be associated with fluoroquinolone resistance in Campylobacter. Recent studies have shown that an efflux pump encoded by cmeABC is also involved in decreased susceptibilities to fluoroquinolones, as well as other antimicrobials. Genome analysis suggests that Campylobacter jejuni contains at least nine other putative efflux pumps. Using insertional inactivation and site-directed mutagenesis, we investigated the potential contributions of these pumps to susceptibilities to chloramphenicol, ciprofloxacin, erythromycin, and tetracycline in C. jejuni and Campylobacter coli. Insertional inactivation of cmeB resulted in 4- to 256-fold decreases in the MICs of chloramphenicol, ciprofloxacin, erythromycin, and tetracycline, with erythromycin being the most significantly affected. In contrast, inactivation of all other putative efflux pumps had no effect on susceptibility to any of the four antimicrobials tested. Mutation of gyrA at codon 86 (Thr-Ile) caused 128- and 64-fold increases in the MICs of ciprofloxacin and nalidixic acid, respectively. The replacement of the mutated gyrA with a wild-type gyrA allele resulted in a 32-fold decrease in the ciprofloxacin MIC and no change in the nalidixic acid MIC. Our findings indicate that CmeABC is the only efflux pump among those tested that influences antimicrobial resistance in Campylobacter and that a point mutation (Thr-86-Ile) in gyrA directly causes fluoroquinolone resistance in Campylobacter. These two mechanisms work synergistically in acquiring and maintaining fluoroquinolone resistance in Campylobacter species.
Prodomain Processing of Asp1 (BACE2) Is Autocatalytic*

Generation of the amyloid peptide through proteolytic processing of the amyloid precursor protein by β- and γ-secretases is central to the etiology of Alzheimer's disease. The highly elusive β-secretase was recently identified as a transmembrane aspartic proteinase, Asp2 (BACE). The Asp2 homolog Asp1 (BACE2/DRAP) has also been reported to exhibit β-secretase cleavage of amyloid precursor protein. Most aspartic proteinases are generated as inactive proenzymes, requiring removal of the prodomain to generate active proteinase. Here we show that prodomain processing of Asp1 occurs between Leu62 and Ala63 and is autocatalytic. Asp1 cleaved a maltose-binding protein-Asp1 prodomain fusion protein and a synthetic peptide at this site. Mutation of one of the conserved catalytic aspartic acid residues in the active site of Asp1 to asparagine (D110N) abolished this cleavage. Mutation of P1′ and P2′ residues in the substrate to phenylalanine reduced cleavage at this site. Asp1 expressed in cells was the mature form, and prodomain processing occurred intramolecularly within the endoplasmic reticulum/early Golgi. Interestingly, a proportion of mature Asp1 was expressed on the cell surface. When full-length Asp1(D110N) was expressed in COS-7 cells, it was not processed, suggesting that no other proteinase can activate Asp1 in these cells.
ACE genotype and the muscle hypertrophic and strength responses to strength training.

PURPOSE Previous studies have linked an insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene with variability in muscle strength responses to strength training (ST), though conclusions have been inconsistent across investigations. Moreover, most previous studies have not investigated the influence of sex on the association of ACE I/D genotype with muscle phenotypes. The purpose of this study was to investigate the association of ACE genotype with muscle phenotypes before and after ST in older men and women. METHODS Eighty-six inactive men and 139 inactive women, ages 50-85 yr (mean: 62 yr), were studied before and after 10 wk of unilateral knee extensor ST. The one-repetition maximum (1RM) test was used to assess knee extensor muscle strength, and computed tomography was used to measure quadriceps muscle volume (MV). Differences were compared among ACE genotype groups (II vs ID vs DD). RESULTS Across the entire cohort at baseline, ACE genotype was significantly associated with total lean mass and body weight, with higher values in DD genotype carriers (both P < 0.05). At baseline, DD genotype carriers exhibited significantly greater MV compared with II genotype carriers for both the trained leg (men: 1828 +/- 44 vs 1629 +/- 70; women: 1299 +/- 34 vs 1233 +/- 49; P = 0.02) and untrained leg (men: 1801 +/- 46 vs 1559 +/- 72; women: 1268 +/- 36 vs 1189 +/- 51; P = 0.01), with no significant genotype x sex interaction. No ACE genotype associations were observed for the 1RM or MV adaptations to ST in either men or women. CONCLUSIONS In the present study, ACE genotype was associated with baseline differences in muscle volume, but it was not associated with the muscle hypertrophic response to ST.
Blockade of Myocardial ATP‐sensitive Potassium Channels by Ketamine

Background: The adenosine triphosphate (ATP)‐sensitive potassium (K sub ATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Methods: Inside‐out and cell‐attached configurations of patch‐clamp techniques and 3 M potassium chloride‐filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Results: Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration‐dependent manner. In the inside‐out patches, the concentration of ketamine for half‐maximal inhibition and the Hill coefficient were 62.9 micro Meter and 0.54, respectively. In a concentration‐dependent manner, ketamine inhibited pinacidil‐ and 2,4‐dinitrophenol‐activated KATP channels in cell‐attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single‐channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration‐dependent manner. Conclusions: Ketamine inhibited KATP channel activity in a concentration‐dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.
Response to Dr. Castell

TO THE EDITOR: I am not sure how Dr. Castell got the impression that our paper represents "yet one more negative observation regarding the possible effect of acid control on this disease" (1). Quite the opposite, in Figure 1, we clearly show essentially lack of progression in patients with p53-negative initial biopsies treated with proton pump inhibitors, which are the majority of the patients. Patients who progressed had p53-positive initial biopsies, before proton pump inhibitor treatment was initiated, which means that they already had genetic instability in their Barrett's mucosa. We argued that in the subset of patients with p53-positive initial biopsies, acid suppression may not alter malignant progression, and the reason for this hypothesis is discussed in detail in the paper. The development of adenocarcinoma in Barrett's esophagus after total gastrectomy (references 12–14 in our paper) clearly indicates that such progression can occur even in the complete absence of acid; therefore, Dr. Castell's belief that such progression should not occur if acid control is adequate is not justified. None of the papers cited in Dr. Castell's letter (1) proves, even remotely, that adequate acid suppression prevents malignant progression in Barrett's. The experiments on cultured cells only show that acid can stimulate epithelial cell proliferation. However, proliferative activity does not equate malignancy or malignant transformation or progression, and is not considered a marker of malignant potential. The papers by Srinivasan et al. and by Peters et al., which he cites in support of his belief (1), do not deal with malignant progression in Barrett's, only the "endoscopic appearance" of the disease, and do not use biopsies or histological examination. Even the Clarke et al. abstract cited by Dr. Castell (1) does not support his statement. As apparent from the title of the abstract, proton pump inhibitor treatment "delays," and not prevents, the development of dysplasia.
Cul8/Rtt101 Forms a Variety of Protein Complexes That Regulate DNA Damage Response and Transcriptional Silencing*

The budding yeast, Saccharomyces cerevisiae, has three cullin proteins, which act as platforms for Cullin-based E3 ubiquitin ligases. Genetic evidence indicates that Cul8, together with Mms1, Mms22, and Esc4, is involved in the repair of DNA damage that can occur during DNA replication. Cul8 is thought to form a complex with these proteins, but the composition and the function of Cul8-based E3 ubiquitin ligases remain largely uncharacterized. Herein, we report a comprehensive biochemical analysis of Cul8 complexes. Cul8 was found to form a Cul8-Mms1-Mms22-Esc4 complex under physiological conditions, with Mms1 bridging Cul8 and Mms22 and Mms22 bridging Mms1 and Esc4. Domain analysis demonstrated that the N-terminal region of Mms1 and the C-terminal region of Mms22 are required for the Mms1-Mms22 interaction, whereas the N-terminal region of Mms22 is required for the Mms22-Esc4 interaction. We also found other Cul8-Mms1-binding proteins Ctf4, Esc2, and Orc5 using yeast two-hybrid screening. Esc4 and Ctf4 bound to Mms22 directly and bound to Cul8-Mms1 in the presence of Mms22, whereas Esc2 and Orc5 interacted with both Cul8 and Mms1, independently. We found that Cul8, Mms1, and Mms22 participated in the regulation of transcriptional silencing of yeast telomeres. These results suggest that Cul8-Mms1, as part of various protein complexes, is involved in the regulation of chromatin metabolism.
Linear time-varying filter with variable bandwidth

A linear time-varying filter with the characteristic of variable bandwidth is proposed for noise reduction of signals with time-varying bandwidth and decomposition of multicomponent signals into components. The proposed filters are composed of constant coefficients and differential operators with a time-varying coefficient. Frequency analysis of the proposed filter is given. Also, the compensation of time-varying delay due to linear phase is discussed
Phenotypic switching of variable surface lipoproteins in Mycoplasma bovis involves high-frequency chromosomal rearrangements

Mycoplasma bovis, an important pathogen of cattle, was recently shown to possess a family of phase- and size-variable membrane surface lipoprotein antigens (Vsps). These proteins spontaneously undergo noncoordinate phase variation between ON and OFF expression states, generating surface antigenic variation. In the present study, we show that the spontaneously high rate of Vsp phenotypic switching involves DNA rearrangements that occur at high frequency in the M. bovis chromosome. A 1.5-kb HindIII genomic fragment carrying the vspA gene from M. bovis PG45 was cloned and sequenced. The deduced VspA amino acid sequence revealed that 80% of the VspA molecule is composed of reiterated intragenic coding sequences, creating a periodic polypeptide structure. Four distinct internal regions of repetitive sequences in the form of in-tandem blocks extending from the N-terminal to the C-terminal portion of the Vsp product were identified. Southern blot analysis of phenotypically switched isogenic lineages representing ON or OFF phase states of Vsp products suggested that changes in the Vsp expression profile were associated with detectable changes at the DNA level. By using a synthetic oligonucleotide representing a sequence complementary to the repetitive vspA gene region as a probe, we could identify the vspA-bearing restriction fragment undergoing high-frequency reversible rearrangements during oscillating phase transition of vspA. The 1.5-kb HindIII fragment carrying the vspA gene (on state) rearranged and produced a 2.3-kb HindIII fragment (OFF state) and vice versa. Two newly discovered vsp genes (vspE and vspF) were localized on two HindIII fragments flanking the vsp gene upstream and downstream. Southern blot hybridization with vspE- and vspF-specific oligonucleotides as probes against genomic DNA of VspA phase variants showed that the organization and size of the fragments adjacent to the vspA gene remained unchanged during VspA ON-OFF switching. The mechanisms regulating the vsp genes are yet unknown; our findings suggest that a recombinative mechanism possibly involving DNA inversions, DNA insertion, or mobile genetic elements may play a role in generating the observed high-frequency DNA rearrangements.
Exercise Monitoring On Consumer Smart Phones Using Ultrasonic Sensing

Quantified self has been a trend over the last several years. An increasing number of people use devices, such as smartwatches or smartphones to log activities of daily life, including step count or vital information. However, most of these devices have to be worn by the user during the activities, as they rely on integrated motion sensors. Our goal is to create a technology that enables similar precision with remote sensing, based on common sensors installed in every smartphone, in order to enable ubiquitous application. We have created a system that uses the Doppler effect in ultrasound frequencies to detect motion around the smartphone. We propose a novel use case to track exercises, based on several feature extraction methods and machine learning classification. We conducted a study with 14 users, achieving an accuracy between 73 % and 92% for the different exercises.
The road less travelled: Australian women's experiences with vulval cancer

Despite advances in surgical treatments and the availability of more conservative treatment options, women treated for vulval cancer still experience significant complications such as urinary incontinence, lymphoedema, pruritus, sexual and intimacy issues. These issues can profoundly impact a woman's quality of life. The subjective experience of women diagnosed and treated for vulval cancer in the literature is limited, possibly due to its comparable rarity to other gynaecological and female cancers and because it was traditionally seen mainly in the elderly female population. Nonetheless, younger women are also being diagnosed with vulval cancer. This paper reports the findings from a qualitative study about twelve women's experiences with vulval cancer from diagnosis, through treatment and recovery. Women's feelings of isolation, their unmet information and support needs, physical concerns arising from vulval cancer, particularly after surgery, and the consequences for their body image and intimate relationships with partners, were highlighted within the data. The central findings from this study emphasise the need for further research to develop appropriate interventions for women with vulval cancer. It also highlights opportunities to improve clinical practice into the supportive care of women with this isolating disease.
Locomotion and nightwaking.

OBJECTIVE In this study we addressed the association between two major achievements of infancy: independent locomotion and 'sleeping through the night'. METHODS Mothers of 107 healthy infants aged between five and eight months completed a sleep questionnaire and a motor checklist. RESULTS AND CONCLUSIONS Infants who were already crawling had more bedtime difficulties and nightwaking than did pre-crawlers. Among 7- and 8-month-old infants, locomotion predicted 17% of nightwaking variance, after controlling for age and gender. In discussing the developmental implications of locomotion we suggest that crawling may not only 'broaden the mind' but also 'cost' sleep. More studies, across time, on how motor development and sleep-wake regulation interrelate are recommended.
Renal clearance of eighteen individual amino acids in human subjects.

Studies of renal clearance of individual amino acids have been comparatively few in number. With the exception of those of Sheffner, Kirsner, and Palmer (1) such investigations have been performed solely on experimental animals and in certain respects the results which they have yielded have been conflicting. In part, the conflict has arisen because of the limited specificity of the analytical methods which the earlier investigators were forced to employ (2-7). Beyer and his associates (8-12), and Kamin and Handler (13), using the more specific methods of microbiological assay, were able to define these areas of conflict as well as to confirm and extend certain of the earlier findings. The most important findings of these previous investigations and the present state
Comparison of effects of eye movements and stimulus movements on striate cortex neurons of the monkey.

AN IMAGE MOVES with respect to the retina both when our eves move a nd when the object moves, but in one case we perceive a stationary object, in the other case a moving object. How can we tell the difference? One approach to this question was proposed by Helmholtz (10) over a century ago. He suggested that when efferent impulses go to the eye muscles, other impulses go simultaneously to areas within the brain. The impulses to the brain would indicate that an eye movement is occurring and that movement of the image with respect to the retina is due to movement of the eye and not to movement of the object. W. James (12) vigorously disputed this hypothesis, but similar hypotheses have been suggested to explain how an insect differentiates between its own movement and movement generated by external forces (1 1), why salamanders make continuous circling movements after eye rotation (Is), and how stability of perceived space is maintained in man (19). The impulses from a motor area to a sensory system have been referred to as a “corollary discharge” (18, 19). If such a corollary discharge exists, one would expect to see a difference at some point in the visual system in the neural response depending on whether the retina moves past a stationary image or whether the image moves across a stationary retina. The purpose of the present experiments was to see whether in striate cortex neurons there is any difference between the response to rapid eye movements across a stationary stimulus and the response to rapid stimulus movements across a stationary eye. A brief report of these experiments has been published previously (22).
Developments in Ocular Genetics: 2013 Annual Review

PurposeTo highlight major advancements in ocular genetics from the year 2013. DesignLiterature review. MethodsA literature search was conducted on PubMed to identify articles pertaining to genetic influences on human eye diseases. This review focuses on articles published in print or online in the English language between January 1, 2013, and December 31, 2013. A total of 120 articles from 2013 were included in this review. ResultsSignificant progress has been made in our understanding of the genetic basis of a broad group of ocular disorders, including glaucoma, age-related macular degeneration, cataract, diabetic retinopathy, keratoconus, Fuchs endothelial dystrophy, and refractive error. ConclusionsThe latest next-generation sequencing technologies have become extremely effective tools for identifying gene mutations associated with ocular disease. These technological advancements have also paved the way for utilization of genetic information in clinical practice, including disease diagnosis, prediction of treatment response, and molecular interventions guided by gene-based knowledge.
The Effects of Talking on the Blood Pressure of Hypertensive and Normotensive Individuals

&NA; The use of a recently developed noninvasive automated blood‐pressure device has revealed a striking relationship between human communication and elevations in blood pressure in both normotensive and hypertensive individuals. Individuals with higher resting baseline pressures tended to show greater increases during talking than did those with lower pressures. In some hypertensive individuals increases blood pressure greater than 25‐40% occurred within 30 sec after the initiation of human speech. Links between difficulties surrounding human communication and elevations in blood pressure are discussed.
A single-switch high gain quadratic boost converter based on voltage-lift-technique

In this paper, based on the traditional voltage-lift-technique, a modified voltage-lift cell is proposed. A single-switch high gain quadratic boost converter is obtained by applying the modified voltage-lift cell to quadratic boost converter, the voltage gain of the converter is improved and the switch voltage stress of the converter is also reduced. The operation principle of the quadratic boost converter with modified voltage-lift cell is analyzed. Compared with quadratic boost converter and the other single-switch high gain boost converter, the voltage gain of quadratic boost converter with modified voltage-lift cell is highest, and the switch voltage stress of quadratic boost converter with modified voltage-lift cell is lowest. Experimental results are presented to verify the theoretical analysis results.
Pleiotropic functions of plasminogen activator inhibitor‐1

Summary. Plasminogen activator inhibitor‐1 (PAI‐1), a 45‐kDa serine proteinase inhibitor with reactive site peptide bond Arg345‐Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL−1. Besides the active inhibitory form of PAI‐1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1‐P1′ site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI‐1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI‐1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI‐1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
Graded cutaneous electrical vs thermal stimulation in humans shows different insular and cingulate cortex activation

Pain can result from various sensory input modalities. To elucidate the differences of cortical responses to graded electrical and thermal stimulation, functional magnetic resonance imaging (fMRI) results of two studies using the same stimulation paradigms but different modalities with 15 healthy subjects each are compared. During painful electrical stimulation contralateral dorsal posterior insula and ventral posterior anterior cingulate cortex (ACC) activated more. During thermal stimulation, there was more activation in ipsilateral primary motor area (MI)/primary sensory area (SI) complex and premotor areas as well as dorsal posterior ACC. Thus electrostimulation preferably activates structures of the lateral pain projection system resulting in contralateral dorsal posterior insula and ventral posterior ACC activation. During thermal stimulation, more dorsal areas of the posterior ACC activated. The activation of ipsilateral MI/SI complex and premotor areas may be attributed to the slower perception of thermal stimuli and resulting re-evaluation. This has to be taken into account in the interpretation of other cross-modality studies as well.