Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional importance of a conserved sequence motif in FhaC, a prototypic member of the TpsB/Omp85 superfamily

In Gram‐negative bacteria, the two‐partner secretion pathway mediates the secretion of TpsA proteins with various functions. TpsB transporters specifically recognize their TpsA partners in the periplasm and mediate their transport through a hydrophilic channel. The filamentous haemagglutinin adhesin (FHA)/FhaC pair represents a model two‐partner secretion system, with the structure of the TpsB transporter FhaC providing the bases to decipher the mechanism of action of these proteins. FhaC is composed of a β‐barrel preceded by two periplasmic polypeptide‐transport‐associated (POTRA) domains in tandem. The barrel is occluded by an N‐terminal helix and an extracellular loop, L6, folded back into the FhaC channel. In this article, we describe a functionally important motif of FhaC. The VRGY tetrad is highly conserved in the TpsB family and, in FhaC, it is located at the tip of L6 reaching the periplasm. Replacement by Ala of the invariant Arg dramatically affects the secretion efficiency, although the structure of FhaC and its channel properties remain unaffected. This substitution affects the secretion mechanism at a step beyond the initial TpsA–TpsB interaction. Replacement of the conserved Tyr affects the channel properties, but not the secretion activity, suggesting that this residue stabilizes the loop in the resting conformation of FhaC. Thus, the conserved motif at the tip of L6 represents an important piece of two‐partner secretion machinery. This motif is conserved in a predicted loop between two β‐barrel strands in more distant relatives of FhaC involved in protein transport across or assembly into the outer membranes of bacteria and organelles, suggesting a conserved function in the molecular mechanism of transport.
Autofluorescence characteristics of normal foveas and reconstruction of foveal autofluorescence from limited data subsets.

PURPOSE To develop mathematical and geometric models of the nonuniform autofluorescence (AF) patterns of foveas of normal subjects and to reconstruct these models from limited subsets of data. METHODS Confocal scanning laser ophthalmoscope (cSLO) AF fundus images of normal maculae were obtained from both eyes of 10 middle-aged subjects. They were filtered and contrast enhanced, to obtain elliptical isobars of equal gray levels (GLs) and determine the isobars' resolutions, eccentricities, and angles of orientation. The original image data were fit with a mathematical model of elliptic quadratic polynomials in two equal zones: the center and the remaining annulus. RESULTS The AF images segmented into nested concentric GL isobars with GLs that increased radially from the least-fluorescent center. The mean isobar resolution was 31 +/- 7 mum. The geometric eccentricity of the ellipses increased from 0.42 +/- 0.12 centrally to 0.52 +/- 0.14 peripherally (P = 0.0005), with mean axes of orientation peripherally 97.12 +/- 15.46 degrees . The model fits to the complete image data had mean absolute normalized errors ranging from 3.6% +/- 3.7% to 7.3% +/- 7.1%. The model fits to small subsets (1% to 2% of total image data) had mean absolute errors ranging from 3.7% +/- 3.8% to 7.3% +/- 7.2%. CONCLUSIONS Normal AF fundus images show finely resolved, concentric, elliptical foveal patterns consistent with the anatomic distribution of fluorescent lipofuscin, light-attenuating macular pigment (MP), cone photopigment, and retinal pigment epithelial (RPE) pigment in the fovea. A two-zone, elliptic, quadratic polynomial model can accurately model foveal data. This model may be useful for image analysis and for automated segmentation of pathology.
Remote ischaemic pre-conditioning in cardiac surgery: benefit or not?

This editorial refers to ‘Does remote ischaemic pre-conditioning with post-conditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote Ischaemic Preconditioning with Postconditioning Outcome Trial’†, by D.M. Hong et al. , doi:10.1093/eurheartj/eht346. Hong et al. 1 report the results of a randomized controlled trial in which 1280 patients who underwent elective cardiac surgery were randomized into a group who received remote ischaemic pre-conditioning (RIPC) combined with remote ischaemic post-conditioning (RIPostC) or a control group. In the group who received remote pre-conditioning, four cycles of 5 min of ischaemia and 5 min of reperfusion were administered twice to the upper limb, before cardiopulmonary bypass or coronary anastomoses in patients who had beating heart surgery, and after cardiopulmonary bypass or coronary anastomoses. As compared with the control group, RIPC with RIPostC did not reduce the primary endpoint, a composite of major adverse outcomes, including death, myocardial infarction, arrhythmia, stroke, coma, renal damage, respiratory failure, gastrointestinal complications, and multiorgan failure. There was no difference in each major adverse outcome. Lengths of intensive care unit and hospital stays were similar in the two groups. Furthermore, in the off-pump subgroup, RIPC with RIPostC was associated with a significantly increased composite endpoint. These results are of importance in the debate regarding the potential interest in RIPC in cardiac surgery. This clinical study has several strengths, including the randomization of a rather large population over a relatively short period of time and the inclusion of patients undergoing different cardiac surgical procedures, encompassing coronary artery bypass grafting, cardiac valve surgery, combined coronary and valvular procedures, ascending or transverse aortic surgery, and congenital heart defect repair, making it, to some extent, an ‘all-comer’ study. However, this heterogeneity probably introduced bias, as the authors correctly pointed out. Also, exclusion criteria were numerous; in particular, patients with poor left ventricular function who …
Segmentation of Chinese Tourists by Seasonal and Trend Patterns: The Case of Macao

ABSTRACT This study proposes a novel data-driven technique utilizing feature-based time series clustering to segment the huge Chinese market based on two distinct tourism phenomena, seasonality and growth trend. The study first extracted the temporal and spatial features from secondary time-series data of Macao tourist arrivals from 23 provinces/municipalities in mainland China and clustered, based on the extracted features, the tourists, thus splitting regions into five segments with distinct seasonal and growth patterns. The segments suggested there is an association between the tourism demand dynamic and the regions’ geographical and socio-economic characteristics. This exploratory study provides practical insights that could enable destination planners to target markets with high growth potential and to manage seasonal variation in tourism demand through formulating policies catering to different market segments.
Microsatellite analyses of recurrence or second primary tumor in head and neck cancer.

BACKGROUND In head and neck squamous cell carcinoma, distinguishing second primary tumours and recurrences may help to orient clinical decisions concerning therapy. PATIENTS AND METHODS A panel of eight microsatellite markers was used to analyse the loss of heterozygosity and genomic instability in a selected group of 32 patients experiencing a recurrence after having undergone surgery for oral or oropharyngeal carcinoma, in order to establish the clonality and origin of the recurrence. RESULTS Twenty-three patients showed genetic changes in primary and/or relapsing tumour DNA: clonally-related patterns were detected in six cases, whereas the different patterns between paired tumours indicated the presence of a second primary tumour in 17 cases. None of the markers was informative in nine cases. CONCLUSION Our observations suggest that only a small proportion of patients have primary and secondary tumours developing from a single contiguous altered field (thus indicating a common clonal origin), whereas the metachronous tumour arises in unrelated fields in the majority of cases.
Development of industrially feasible concentrated 30% and 40% nanoemulsions for intravenous drug delivery

Emulsions for parenteral nutrition loaded with drugs are used for optimized drug delivery, but in case of poorly oil soluble drugs, the injection volume can be too large when using commercial 10–20% oil emulsions. To reduce the injection volume, the feasibility of producing injectable, physically stable concentrated emulsions up to 40% oil content was investigated. Emulsions were made from fish oil, stabilized with egg lecithin, using high-pressure homogenization. Emulsions with oil contents of 10%–40% were investigated to assess basic correlations between increasing oil content, applied production pressures, homogenization cycles and resulting bulk droplet size, content of larger particles, zeta potential, viscosity and short-term stability. The observed correlations showed that in high-pressure homogenization, the contribution of the dispersive effect dominated the coalescence effect at low and Optimum production conditions for 30% and 40% nanoemulsions, i.e. 800 bar and 2 -3 homogenization cycles, were established on lab scale. These production conditions are industrially feasible. The obtained droplet sizes (about 200 nm) and the content of larger droplets were comparable to 10% commercial emulsions of parenteral nutrition, being important for in vivo tolerability and organ distribution. Despite the high oil concentration, the viscosity of the nanoemulsions was sufficiently low for injection. The short-term storage study showed physical stability for 1 month. A concentrated nanoemulsion base formulation from regulatory accepted excipients is now available, ready for loading with drugs.
Effects of Bromocriptine on Responses to Stress in Spontaneously Hypertensive Rats

SUMMARY Treatment of 2-montb-old spontaneously hypertensive rats (SHR) and age-matched Wlstar- Kyoto (WKY) normotensive controls with the dopamine agonist, bromocriptine, for 7 days significantly affected hormonal responses to immobilization stress in both groups. However, basal blood pressures and pressor responses to immobilization stress were significantly reduced only in SHR. Basal levels of catecholamines were similar in the two groups of rats, but catecbolamlne responses to immobilization stress following saline (vehicle) treatment were markedly greater in SHR; following bromocriptine treatment for 7 days, catecholamine responses were similar in the two groups. Basal serum prolactin levels and prolactin responses to immobilization were greater in SHR after saline treatment; after bromocriptine, they were similar in the two groups. Basal plasma renin activity (PRA) and PRA responses to immobilization were significantly less in SHR following saline treatment; after bromocriptine treatment, these responses were paradoxically greater in SHR without being significantly changed in WKY. Basal levels of plasma aldosterone and corticosterone following saline were significantly greater, but responses to immobilization less, in SHR. Bromocriptine treatment decreased aldosterone and corticosterone responses to stress in WKY but paradoxically increased these responses in SHR. These results suggest that increased pressor responses to stress are dependent on heightened sympathetic nerve activity, perhaps secondary to decreased central dopaminergic activity. Increased basal prolactin levels and stress-mediated prolactin responses may be related to decreased central dopaminergic activity. Paradoxical PRA, plasma aldosterone, and corticosterone responses to stress following bromocriptine suggest altered dopaminergic modulation of these hormones in the SHR.
Vaccinia Virus B18R Gene Encodes a Type I Interferon-binding Protein That Blocks Interferon α Transmembrane Signaling (*)

Poxviruses encode a large number of proteins that attenuate the inflammatory and immune responses to infection. In this report we demonstrate that a number of orthopoxviruses express a type I interferon (IFN)-binding protein, which is encoded by the B18R open reading frame in the WR strain of vaccinia virus. The B18R protein has significant regions of homology with the α subunits of the mouse, human, and bovine type I IFN receptors, bound human IFNα2 with high affinity, and inhibited transmembrane signaling as demonstrated by inhibition of Fc receptor factor γ1/γ2 and interferon-stimulated gene factor-3 formation as well as inhibition of the IFNα antiviral response. Among viral host response modifiers, the B18R protein is unique inasmuch as it exists as a soluble extracellular as well as a cell surface protein and thus should effectively block both autocrine and paracrine functions of IFN.
PSPC1, NONO, and SFPQ Are Expressed in Mouse Sertoli Cells and May Function as Coregulators of Androgen Receptor-Mediated Transcription1

Abstract In Sertoli cells of testis, androgen receptor-regulated gene transcription plays an indispensable role in maintaining spermatogenesis. Androgen receptor activity is modulated by a number of coregulators which are associated with the androgen receptor. Non-POU-domain-containing, octamer binding protein (NONO), a member of the DBHS-containing proteins, complexes with androgen receptor and functions as a coactivator for the receptor. Paraspeckle protein 1 alpha isoform (PSPC1, previously known as PSP1) and Splicing factor, proline- and glutamine-rich (SFPQ, previously known as PSF), other members of the DBHS-containing proteins, are also found in androgen receptor complexes, suggesting that these DBHS-containing proteins may cooperatively regulate androgen receptor-mediated gene transcription. We demonstrated that PSPC1, NONO, and SFPQ are coexpressed in Sertoli cell line TTE3 and interact reciprocally. The effect of the DBHS-containing proteins on the transcriptional activity was assessed using the construct containing androgen-responsive elements followed by a luciferase gene. The results showed that all the DBHS-containing proteins activate androgen receptor-mediated transcription, and PSPC1 is the most effective coactivator among them. Furthermore, we confirmed the presence of PSPC1, NONO, and SFPQ proteins in Sertoli cells of adult mouse testis sections. These observations suggest that PSPC1, NONO, and SFPQ form complexes with each other in Sertoli cells and may regulate androgen receptor-mediated transcriptional activity.
Use of Hyaluronidase in the Treatment of Granulomatous Hyaluronic Acid Reactions or Unwanted Hyaluronic Acid Misplacement

Background In the past, reactions or misplacement of soft tissue fillers has been fraught with anxiety because time has been the main thrust for improvement in spite of ancillary treatments. Hyaluronidase is an enzyme that dissolves hyaluronic acid in the skin and also assists in the management of granulomatous foreign-body reactions to hyaluronic acid. These reactions may be caused by allergy to the material or immunologic response to the protein contaminants in the hyaluronic acid preparations. Dissolution of material in erroneous placement of material and in allergic reactions can be a time saver and a deterrent to patient dissatisfaction. Objective To evaluate the use of hyaluronidase in the treatment of both allergic reactions and the erroneous misplacement of hyaluronic acid in the skin. Methods A case of persistent granulomatous reaction to injectable hyaluronic acid and a case of hyaluronic acid erroneous misplacement with their successful subsequent treatments using intracutaneous hyaluronidase are reported, along with illustrative examples of hyaluronidase use. Results The use of hyaluronidase reduced the patient discomfort within 24 to 48 hours, deterring any patient anxiety or patient dissatisfaction. Conclusions Hyaluronidase has a place in the treatment of allergic reactions to hyaluronidase and in the erroneous misplacement of the material.
Molecular switches under TGFβ signalling during progression from cardiac hypertrophy to heart failure

Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.
Toll‐like receptors 2 and 4 exert opposite effects on the contractile response induced by serotonin in mouse colon: role of serotonin receptors

What is the central question of this study? The action of Toll‐like receptors (TLRs) 2 and 4 on the motor response to serotonin in mouse colon has not previously been reported. What is the main finding and its importance? Toll‐like receptors 2 and 4 modulate the serotonin‐induced contractile response in mouse colon by modifying the expression of serotonin (5‐HT) receptors. Alterations in 5‐HT2A and 5‐HT2C receptors explain the increase of the response to serotonin in TLR2−/− mice. Alterations in 5‐HT2C and 5‐HT4 receptors explain the suppression of the response to serotonin in TLR4−/− mice.
Reexamining Syphilis: An Update on Epidemiology, Clinical Manifestations, and Management

Objective: To review the epidemiology, clinical features, diagnosis, and treatment of syphilis. Data Sources: Studies and reviews were abstracted from MEDLINE (1950–April 2007) using the search term syphilis. AN papers were cross-referenced to identify additional studies and reviews for inclusion. Study Selection and Data Extraction: Pertinent original research articles, review articles, and book chapters were evaluated. Data Synthesis: Syphilis is a spirochetal disease that has plagued mankind for centuries. Following a low incidence of syphilis in the US for the last 2 decades, rates are now increasing both in the US and other parts of (he world. Once acquired, syphilis can pass through 4 distinct stages of disease: primary syphilis. secondary syphilis, latent syphilis, and tertiary syphilis, with each stage being characterized by different symptoms and levels of infectivity. Diagnosis is made primarily by serologic assays with nontreponemal tests such as the Venereal Disease Research Laboratory and the Rapid Plasma Reagin assay used for screening. Treponemal tests including the Treponema pallidum particle agglutination and the fluorescent treponemal antibody absorption test are then used for confirmation. Recommended treatment regimens are based largely on uncontrolled trials and clinical experience. Penicillin is the treatment of choice, with the preparation and treatment duration varying for different stages. Benzathine penicillin is the treatment of choice lor all stages of syphilis except neurosyphilis, for which aqueous crystalline penicillin or procaine penicillin is used due to the central nervous system penetration of these formulations. Coinfection with both syphilis and HIV occurs frequently due to common risk factors. These 2 diseases interact with each other, making both diagnosis and treatment more complicated. Conclusions: Clinicians should be aware of the signs and symptoms of syphitis as well as current guidelines for the management and treatment of this disease.
Urothelial Cancer Stem Cells

There is mounting evidence supporting the idea that tumors, similar to normal adult tissues, arise from a specific stem-like cell population, the cancer stem cells (CSCs), which are considered as the real driving force behind tumor growth, the ability to metastasize, as well as resistance to conventional antitumor therapy. The concept that cancer growth recapitulates normal proliferative and/or regenerative processes, even though in very dysfunctional ways, has tremendous implications for cancer therapy. The rapid development of the CSC field, shoulder to shoulder with powerful genome-wide screening techniques, has provided cause for optimism for the development of more reliable therapies in the future. However, several important issues still lie ahead. Recent identification of a highly tumorigenic stem-like compartment and existence of urothelial differentiation programs in urothelial cell carcinomas (UCCs) raised important questions about UCC initiation and development. This review examines the present knowledge on CSCs in UCCs regarding the similarities between CSCs and the adult urothelial stem cells, potential origin of urothelial CSCs, main regulatory pathways, surface markers expression, and the current state of CSC-targeting therapeutic strategies.
Effects of Substrate and Oxygen Loading Rates on Gas‐Phase Toluene Removal in a Three‐Phase Biofilm Reactor

A three‐phase, circulating‐bed biofilm reactor using macroporous carriers removed toluene from a gas stream continuously for more than six months. Three steady states were established with toluene loading rates varying from 0.030 to 0.059 mol/m2▪d. For each steady state, short‐term experiments evaluated the effects of toluene and oxygen loading rates. At least 99% of the biomass in the system was accumulated inside the carrier macropores, and the total biomass was proportional to the toluene loading rate. Toluene removal ranged from approximately 100 to 55%. The lower toluene removals were associated with oxygen limitation, which also resulted in the accumulation of an intermediate (3‐methylcatechol) and nontoluene chemical oxygen demand. The results suggest that excessive biomass accumulation hurt process performance by depleting oxygen within the biofilm because increased endogenous respiration consumed more oxygen, while increased biomass density may have slowed oxygen diffusion.
Toxic species in amyloid disorders: Oligomers or mature fibrils

Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization) disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov) and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer′s Disease, Parkinson′s Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer′s Disease and Parkinson′s Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils) in amyloid cascade are also described.