How to withhold or replace a prepotent response : an analysis of the underlying control processes and their temporal dynamics

http://ift.tt/2oSyxpc

Public Scholarship and the Evidence Movement: Understanding and Learning from Belgian Drug Policy Development

http://ift.tt/2p3xdft

In-vitro and in-vivo efficacy of LpxC inhibitor, CHIR-090, alone or combined with colistin against Pseudomonas aeruginosa biofilm. [PublishAheadOfPrint]

With the rapid spread of antimicrobial resistance in Gram-negative pathogens, biofilms-associated infections are increasingly harder to treat and combination therapy with colistin has become one of the most efficient therapeutic strategies. Our study aimed to evaluate the potential for synergy of colistin combined with CHIR-090, a potent LpxC inhibitor, against in-vitro and in-vivo Pseudomonas aeruginosa biofilms. Four P. aeruginosa isolates with varying colistin susceptibility were chosen for evaluation. Tested isolates of P. aeruginosa exhibited MIC values ranging from 1 to 64 and 0.0625 to 0.5 μg/ml for colistin and CHIR-090, respectively. Against 24h static biofilms, MBEC values ranged from 256 to 512 and 8 to >128 μg/ml for colistin and CHIR-090, respectively. Interestingly, sub-inhibitory concentrations of CHIR-090 contributed to eradicate subpopulations of P. aeruginosa with highest colistin MIC values. Combination of colistin and CHIR-090 at sub-inhibitory concentrations demonstrated synergistic activity, both in-vivo and in-vitro, and prevented the formation of colistin tolerant sub-populations in in-vitro biofilms. In summary, our study highlights the in-vivo and in-vitro synergistic activity of colistin and CHIR-090 combination against both colistin-susceptible and non-susceptible P. aeruginosa biofilms. Further studies are warranted to investigate the clinical relevance of the combination of these two antimicrobials and outline the underlying mechanism for their synergistic action.

http://ift.tt/2pReMOU

Population Pharmacokinetic Modeling as a Tool to Characterize the Decrease in Ciprofloxacin free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats [PublishAheadOfPrint]

Biofilm formation plays an important role in the persistence of pulmonary infections, for example in cystic fibrosis patients. So far, little is known about antimicrobials lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm infected rats and to develop a comprehensive model to describe the CIP disposition in both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg). Plasma and microdialysate were sampled in different animal groups and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model, that successfully described all data, consisted of an arterial and a venous central compartment, two peripheral distribution compartments and lung disposition was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals leading to a significant higher plasma CIP exposure (AUC_0- 27.3 ± 12.1 μg⋅h/mL and 13.3 ± 3.5 μg⋅h/mL, infected and healthy, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue/plasma ratio (fT = 0.44 and fT = 1.69, infected and healthy, respectively), a lung clearance was added to the model for these animals (CL_lung = 0.643 L h^-1 kg^-1) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

http://ift.tt/2qy2NSR

Competitive fitness of fluconazole-resistant, clinical Candida albicans strains [PublishAheadOfPrint]

The pathogenic yeast Candida albicans can develop resistance to the widely used antifungal agent fluconazole, which inhibits ergosterol biosynthesis. Resistance is often caused by gain-of-function mutations in the transcription factors Mrr1, Tac1, and Upc2, which result in constitutive overexpression of multidrug efflux pumps and ergosterol biosynthesis genes, respectively. However, the deregulated gene expression that is caused by hyperactive forms of these transcription factors also reduces the fitness of the cells in the absence of the drug. To investigate whether fluconazole-resistant, clinical C. albicans have overcome the fitness costs of drug resistance, we assessed the relative fitness of C. albicans isolates containing resistance mutations in these transcription factors in competition with matched drug-susceptible isolates from the same patients. Most of the fluconazole-resistant isolates were outcompeted by the corresponding drug-susceptible isolates when grown in rich medium without fluconazole. On the other hand, some resistant isolates with gain-of-function mutations in MRR1 did not exhibit reduced fitness under these conditions. In a mouse model of disseminated candidiasis, three out of four tested fluconazole-resistant clinical isolates did not exhibit a significant fitness defect. However, all four fluconazole-resistant isolates were outcompeted by the matched susceptible isolates in a mouse model of gastrointestinal colonization, demonstrating that the effects of drug resistance on in vivo fitness depend on the host niche. Collectively, our results indicate that the fitness costs of drug resistance in C. albicans are not easily remediated, especially when proper control of gene expression is required for a successful adaptation to life within a mammalian host.

http://ift.tt/2pRbZFv

In vitro evaluation of antileishmanial activity of computationally screened compounds against Ascorbate Peroxidase: Combating Amphotericin B drug resistance [PublishAheadOfPrint]

In Visceral Leishmaniasis (VL), the host macrophages generate oxidative stress to destroy the pathogen, while Leishmania combat the harmful effect of radicals by redox homeostasis through its unique trypanothione cascade. L. donovani Ascorbate Peroxidase (LdAPx) is a redox enzyme that regulates trypanothione cascade and detoxify the effect of H₂O₂. Absence of LdAPx homologue in human makes it an excellent drug target. In this study, the homology model of LdAPx was built including heme and diverse compounds were prefiltered (PAINS, ADMET and Lipinski's 5) thereafter screened against the LdAPx model. Compounds having good affinity in terms of Glide XP score were clustered to select diverse compounds for experimental validation. A total of 26 cluster representatives were procured and tested on promastigotes culture yielding 12 compounds with good antileishmanial activity. Out of them six compounds were safer on the BALB/c peritoneal macrophages and were also effective on disease causing intracellular amastigotes. Three out of six compounds inhibited recombinant LdAPx in non-competitive manner and also demonstrated partial reversion of resistant property in AmB resistant strain that may be due to increased level of ROS and decrease of GSH content. However, inhibition of LdAPx in resistant parasite enhanced annexin V staining, activation of metacaspase-like proteases activity which may help in DNA fragmentation and apoptotic like cell death.

Thus, the present study will help in search for specific hits and templates of potential therapeutic interest and therefore may facilitate the development of new drugs for combination therapy against VL.

http://ift.tt/2qyiVUk

KNOCKDOWN OF HOST ANTIOXIDANT DEFENSE GENES ENHANCES THE EFFECT OF GLUCANTIME ON INTRACELLULAR Leishmania braziliensis IN HUMAN MACROPHAGES [PublishAheadOfPrint]

Leishmaniasis is a neglected tropical disease affecting millions of people worldwide and represents a major public health problem. Information on protein expression patterns and functional roles within the context of Leishmania-infected human monocyte-derived macrophages (MDMs) under drug treatment conditions are essential to understand the role of these cells in leishmaniasis treatment. We analyzed functional changes in expression of human MDM genes and proteins during in vitro infection by Leishmania braziliensis and treatment with Glucantime (Sb^V) using quantitative polymerase chain reaction (qPCR) arrays, western blotting, confocal microscopy and short-interfering RNA (siRNA) human gene-inhibition assays. Comparison of the results from gene transcription and protein expression analyses revealed that GSTP1, GCLM, GSR, GSS, TXN, and ABCB5 were strongly upregulated at both mRNA and protein levels in human MDMs infected and treated compared to the control group. Subcellular localization studies showed a primarily phagolysosomal location for the ABCB5 transporter, indicating that this protein may be involved in the transport of Sb^V. By inducing a decrease in L. braziliensis intracellular survival in THP-1 macrophages, siRNA silencing of GSTP1, GSS and ABCB5 resulted in an increased leishmanicidal effect of Sb^V exposure in vitro. Our results suggest that human MDMs infected with L. braziliensis and treated with Sb^V express increased levels of genes participating in antioxidant defense, whereas our functional analyses provide evidence for the involvement of human MDMs in drug detoxification. Therefore, we conclude that proteins GSS, GSTP1 and ABCB5 represent potential targets for enhancing the leishmanicidal activity of Glucantime.

http://ift.tt/2pRddk9

Crystal structure of the new investigational drug candidate VT-1598 in complex with Aspergillus fumigatus sterol 14{alpha}-demethylase provides insights into its broad-spectrum antifungal activity. [PublishAheadOfPrint]

Within the past decades, the incidence and complexity of human fungal infections have increased, and therefore the need for safer and more efficient, broad-spectrum antifungal agents is high. Herein, we characterize the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungi Aspergillus fumigatus. VT-1598 displayed a high binding affinity to the enzyme in solution (with the K_d of 13±1 nM) and in the reconstituted enzymatic reaction revealed the inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex has been determined depicting the distinctive binding mode of the inhibitor in the enzyme active site and suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His-374, the CYP51 residue that is highly conserved across fungal pathogens and fungi-specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and C. albicans CYP51/VT-1161 complexes supports the role of H-bonding in fungal CYP51-inhibitor complexes, and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (32820 and 1022) displayed direct correlation between the effects of the drugs on the CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.

http://ift.tt/2qxW0sr

Impaired inhibition by avibactam and resistance to the ceftazidime-avibactam combination due to the D179Y substitution in the {beta}-lactamase KPC-2 [PublishAheadOfPrint]

The ceftazidime-avibactam combination was recently shown to be at risk of emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a KPC-2 β-lactamase harboring the D¹⁷⁹Y substitution. We show that impaired inhibition by avibactam combined with significant residual activity for ceftazidime hydrolysis accounts for resistance. In contrast, the D¹⁷⁹Y substitution abolished hydrolysis of aztreonam and imipenem indicating these drugs might provide therapeutic alternatives.

http://ift.tt/2pRg1Oc

NDM-5 and OXA-181 beta-lactamases: a significant threat continues to spread in the Americas [PublishAheadOfPrint]

Among Gram-negative bacteria, carbapenem resistant (CR) infections pose a serious and life threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a CR Klebsiella pneumoniae ST147 isolate harboring bla_NDM-5 and bla_OXA-181, from a young man who underwent abdominal surgery in India. bla_NDM-5 was located on an IncFII plasmid of 90Kb, while bla_OXA-181 was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS26 and a "hotspot region" in the IncFII plasmid.

http://ift.tt/2qy8GPU

Structure of EV71 3Cpro in complex with NK-1.8k: Indications for the development of anti-enterovirus protease inhibitor [PublishAheadOfPrint]

Hand-foot-and-mouth disease (HFMD) caused by enterovirus is a threat to public health in worldwide. Up-to-date, enterovirus 71 (EV71) becomes one of the major causative agents of HFMD in Pacific-Asia region and causes millions of infections from its outbreak. However, no drug is currently available for clinical therapeutics. In our previous works, we developed a set of protease inhibitors (PIs) targeting EV71 3C^pro, among which NK-1.8k and NK-1.9k with various active group have high potency and selectivity. Here we determine the structures of PI NK-1.8k in complex with wild-type (WT) and drug-resistant EV71 3C^pro. Comparison with unliganded EV71 3C^pro and its complex with AG7088, these structures indicated the mutation of N69 to a serine residue destabilized S2 pocket. Thus the mutation influenced the cleavage activity of EV71 3C^pro and the inhibitory activity of NK-1.8k in vitro protease assay and highlighted Site-69 as an additional key site for PI design. More information for the optimization of P1' -P4 groups of PI are also obtained from these structures. Together with our previous works, these results in-depth elucidate inhibitory mechanism of PIs and shed the light to develop clinically-used PIs to treat the infections of EV71 and other enteroviruses.

http://ift.tt/2pReEPq

Genetic determinants of the pharmacokinetic variability of rifampicin in Malawian adults with pulmonary tuberculosis [PublishAheadOfPrint]

Variable exposure to anti-tuberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampicin. We evaluated the contribution of Single Nucleotide Polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC, CES-1) to inter-individual pharmacokinetic variability in Malawi. 174 adults with pulmonary TB underwent sampling of plasma rifampicin concentrations at 2- and 6-hours post-dose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2^©, using a two-stage strategy to improve information during the absorption phase. Contrary to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC_0- of rifampicin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampicin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as non-genetic sources of inter-individual variability, should be further explored in geographically diverse, adequately powered cohorts.

http://ift.tt/2qy2hnI

Phenotypic and molecular evaluation of echinocandin susceptibility of Candida glabrata, Candida bracarensis and Candida nivariensis strains isolated during 30 years in Argentina. [PublishAheadOfPrint]

The echinocandin susceptibility of 122 C. glabrata complex strains (including 5 C. nivariensis and 3 C. bracarensis) were evaluated by microdilution and compared with a molecular tool able to detect FKS mutations. No echinocandin resistance was detected. PCR results coincide with MIC data in 99.25% of the cases (1 C. glabrata was misidentified as resistant) but were 20 hours faster. C. nivariensis FKSs were sequenced showing differences with C. glabrata FKSs.

http://ift.tt/2pReIib

Bacteriophage Lysin CF-301: a Potent Anti-Staphylococcal Biofilm Agent [PublishAheadOfPrint]

Biofilms pose a unique therapeutic challenge because of the antibiotic tolerance of constituent bacteria. Treatments for biofilm-based infections represent a major unmet medical need, requiring novel agents to eradicate mature biofilms. Our objective was to evaluate bacteriophage lysin CF-301 as a new agent to target Staphylococcus aureus biofilms. We used minimum biofilm eradicating concentration (MBEC) assays on ninety-five S. aureus strains to obtain a MBEC₉₀ value of ≤0.25 μg/ml for CF-301. Mature biofilms of coagulase-negative staphylococci, Streptococcus pyogenes, and Streptococcus agalactiae were also sensitive to disruption, with MBEC₉₀ values ranging from 0.25-8 μg/ml. The potency of CF-301 was demonstrated against S. aureus biofilms formed on polystyrene, glass, surgical mesh, and catheters. In catheters, CF-301 removed all biofilm within 1 hour and killed all released bacteria by 6 hours. Mixed-species biofilms, formed by S. aureus and S. epidermidis on several surfaces, were removed by CF-301, as were S. aureus biofilms either enriched for small colony variants (SCVs) or grown in human synovial fluid. The antibacterial activity of CF-301 was further demonstrated against S. aureus persister cells in exponential and stationary phase populations. Finally, the anti-biofilm activity of CF-301 was greatly improved in combinations with the cell wall hydrolase lysostaphin when tested against a range of S. aureus strains. In all, the data shows CF-301 is highly effective at disrupting biofilms and killing biofilm bacteria, and, as such, may be an efficient new agent for treating staphylococcal infections with a biofilm component.

http://ift.tt/2qy2GXw

Comprehensive analysis of parotid mass: A retrospective study of 369 cases

Publication date: Available online 1 May 2017
Source:Auris Nasus Larynx
Author(s): Senol Comoglu, Erkan Ozturk, Mehmet Celik, Hakan Avci, Said Sonmez, Bora Basaran, Erkan Kiyak
ObjectiveTo present the results of patients who underwent superficial or total parotidectomy because of parotid gland tumors in our tertiary care clinic.MethodsThe data of 362 patients who underwent parotid surgery from January 2008 to November 2015 were collected and analyzed in demographic, histopathological features, and complications.ResultsThree hundred sixty-nine cases (performed in 359 patients) were analyzed and we assessed complications of parotid surgery such as transient or permanent facial paralysis and Frey's syndrome. Pleomorphic adenomas and Warthin's tumors consisted 74% of all parotid gland tumors. These tumors were generally located in the superficial lobe and tail of the parotid gland (81%). Also, tumor size in the positive surgical margin group was larger than in the negative surgical margin group (p=0.012).ConclusionsMost of parotid gland tumors are benign. However, the frequency of malignancy increases in deep lobe of parotid gland. High grade malignant tumors have more tendency to have positive surgical margin during surgery, and facial paresis preoperatively.



http://ift.tt/2p2vruR

Clinical practice guidelines for the diagnosis and management of otitis media with effusion (OME) in children in Japan, 2015

Publication date: Available online 1 May 2017
Source:Auris Nasus Larynx
Author(s): Makoto Ito, Haruo Takahashi, Yukiko Iino, Hiromi Kojima, Sho Hashimoto, Yosuke Kamide, Fumiyo Kudo, Hitome Kobayashi, Haruo Kuroki, Atsuko Nakano, Hiroshi Hidaka, Goro Takahashi, Haruo Yoshida, Takeo Nakayama
ObjectiveTo (1) indicate the definition, the disease state, methods of diagnosis, and testing for otitis media with effusion (OME) in childhood (<12 years); and (2) recommend methods of treatment in accordance with the evidence-based consensus reached by the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of OME in Children.MethodsWe produced Clinical Questions (CQs) concerning the treatment of OME and searched the literature published until April 2014 according to each theme including CQ, the definition, the disease state, the method of diagnosis, and examination. The recommendations are based on the results of the literature review and the expert opinion of the Subcommittee.ResultsBecause children with Down's syndrome and cleft palate are susceptible to OME, we categorized OME into low-risk and high-risk groups (e.g., Down's syndrome and cleft palate), and recommended the appropriate treatment for each group.ConclusionIn the clinical management of OME in children, Japanese Clinical Practice Guidelines recommend management not only of OME itself, such as effusion in the middle ear and pathological changes in the tympanic membrane, but also pathological abnormality in surrounding organs, such as infectious or inflammatory diseases.



http://ift.tt/2oRGmeO

Is corticosteroid a treatment choice for the management of peritonsillar abscess?

Publication date: Available online 1 May 2017
Source:Auris Nasus Larynx
Author(s): Hasan Emre Koçak, Harun Acıpayam, Mustafa Suphi Elbistanlı, Ayşe Pelin Yiğider, Wesam M.E. Alakhras, Mehmet Nurettin Kıral, Fatma Tülin Kayhan
ObjectiveTo investigate the effect of the single systemic use of corticosteroid following drainage procedure in patients with peritonsillar abscess (PTA).MethodsThis retrospective case-control trial included 32 patients with the diagnosis of PTA between December 2013 and January 2016 in our clinic. Patients were divided into two groups based on the approaches of two authors for the treatment after PTA drainage. The study group included the patients treated with single dose systemic corticosteroid after PTA drainage. Other patients who had no corticosteroid treatment were in the control group. Two groups were compared based on time to oral intake, grade of trismus, pain severity and duration of hospitalization.ResultsStatistically significant differences between two groups were observed in terms of time to oral intake, grade of trismus, pain severity and length of hospitalization. The degree of trismus and pain severity significantly decreased in study group comparing to control group at the end of the first day. This difference disappeared at Day 7. Time to oral intake and the duration of hospitalization were shorter in the study group than in control group.ConclusionCorticosteroid treatment following drainage procedure in patients with peritonsillar abscess improves pain severity and trismus thus it decreases time to oral intake and duration of hospitalization.



http://ift.tt/2p2A3Bd

Comprehensive analysis of parotid mass: A retrospective study of 369 cases

To present the results of patients who underwent superficial or total parotidectomy because of parotid gland tumors in our tertiary care clinic.

http://ift.tt/2qrik7s

Novel application of a rigid curved larygno-pharyngoscope for examination and treatment of hypopharyngeal lesions

In endoscopic laryngo-pharyngeal surgery (ELPS), a rigid curved laryngo-pharyngoscope, which was invented by Dr. Sato et al., is necessary to obtain excellent surgical view of both hypopharynx and even the entrance of the esophagus. We have used this instrument for the examination and treatment of several diseases other than cancer located in the hypopharynx, such as difficult-to-find buried fish bones, retropharyngeal abscess, and congenital pyriform sinus fistula. In the result, we could acquire better view of hypopharynx and completed the intended procedure safely, especially for uncovering difficult-to-find fish bone buried in the mucosa.

http://ift.tt/2ppBT1u

Clinical practice guidelines for the diagnosis and management of otitis media with effusion (OME) in children in Japan, 2015

To (1) indicate the definition, the disease state, methods of diagnosis, and testing for otitis media with effusion (OME) in childhood (<12 years); and (2) recommend methods of treatment in accordance with the evidence-based consensus reached by the Subcommittee of Clinical Practice Guideline for Diagnosis and Management of OME in Children.

http://ift.tt/2qrhIyZ

Is corticosteroid a treatment choice for the management of peritonsillar abscess?

To investigate the effect of the single systemic use of corticosteroid following drainage procedure in patients with peritonsillar abscess (PTA).

http://ift.tt/2ppDFQk

ACOX2 deficiency in primary malignant cardiac tumors [Biological Sciences]

ACOX2 (acyl-CoA oxidase 2) is a peroxisomal enzyme that plays a key role in the metabolism of bile acid intermediates and the oxidation of branched-chain fatty acids. A recent PNAS paper by Vilarinho et al. (1) on ACOX2 deficiency in an 8-y-old male with elevated transaminase levels identifies a homozygous...

http://ift.tt/2p1JNM8

Variable mortality during the 1918 influenza pandemic in Chicago [Biological Sciences]

In their study of influenza mortality in Chicago in 1918, Grantz et al. (1) conclude that pandemic-related mortality was related to "neighborhood level social factors" (e.g., illiteracy, homeownership, unemployment). Because "social factors" do not directly cause influenza illness or mortality, they must be surrogates for other factors. Other studies of...

http://ift.tt/2p1uGCw

Reply to Shanks and Brundage: Many plausible mechanisms of pandemic mortality disparities [Biological Sciences]

In our recently published paper (1), we find evidence that several metrics of socioeconomic status were associated with influenza and pneumonia mortality during the 1918 pandemic. We agree with Shanks and Brundage (2) that there are many possible causal mechanisms behind this association and appreciate the hypotheses that they add...

http://ift.tt/2oQEG5j

Correction for Naviaux et al., Metabolic features of chronic fatigue syndrome [Correction]

MEDICAL SCIENCES Correction for "Metabolic features of chronic fatigue syndrome," by Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon, which appeared in issue 37, September 13, 2016, of Proc Natl Acad Sci USA...

http://ift.tt/2oQL38T

Correction for Mann, Core Concept: Unraveling the enigma of fast radio bursts [Correction]

CORE CONCEPTS Correction for "Core Concept: Unraveling the enigma of fast radio bursts," by Adam Mann, which appeared in issue 13, March 28, 2017, of Proc Natl Acad Sci USA (114:3269–3271; 10.1073/pnas.1703512114). Victoria Kaspi was incorrectly identified as the principal investigator of the Canadian Hydrogen Intensity Mapping Experiment. Kaspi should...

http://ift.tt/2p260cZ

Ctf4-related protein recruits LHP1-PRC2 to maintain H3K27me3 levels in dividing cells in Arabidopsis thaliana [Plant Biology]

Polycomb Repressive Complex (PRC) 2 catalyzes the H3K27me3 modification that warrants inheritance of a repressive chromatin structure during cell division, thereby assuring stable target gene repression in differentiated cells. It is still under investigation how H3K27me3 is passed on from maternal to filial strands during DNA replication; however, cell division...

http://ift.tt/2oQHn70

Zeaxanthin-dependent nonphotochemical quenching does not occur in photosystem I in the higher plant Arabidopsis thaliana [Plant Biology]

Nonphotochemical quenching (NPQ) is the process that protects the photosynthetic apparatus of plants and algae from photodamage by dissipating as heat the energy absorbed in excess. Studies on NPQ have almost exclusively focused on photosystem II (PSII), as it was believed that NPQ does not occur in photosystem I (PSI)....

http://ift.tt/2p1RzFI

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina [Neuroscience]

Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration—i.e., selective cell-loss paradigms akin to degenerative disease—are...

http://ift.tt/2p229N0

Defective synaptic connectivity and axonal neuropathology in a human iPSC-based model of familial Parkinson’s disease [Neuroscience]

α-Synuclein (αSyn) is the major gene linked to sporadic Parkinson's disease (PD), whereas the G209A (p.A53T) αSyn mutation causes a familial form of PD characterized by early onset and a generally severe phenotype, including nonmotor manifestations. Here we generated de novo induced pluripotent stem cells (iPSCs) from patients harboring the...

http://ift.tt/2p22z6b

Effect of cholesterol on the molecular structure and transitions in a clinical-grade lung surfactant extract [Chemistry]

The lipid–protein film covering the interface of the lung alveolar in mammals is vital for proper lung function and its deficiency is related to a range of diseases. Here we present a molecular-level characterization of a clinical-grade porcine lung surfactant extract using a multitechnique approach consisting of H1–C13 solid-state nuclear...

http://ift.tt/2oQAVNn

Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART [Microbiology]

Little is known about the fraction of human immunodeficiency virus type 1 (HIV-1) proviruses that express unspliced viral RNA in vivo or about the levels of HIV RNA expression within single infected cells. We developed a sensitive cell-associated HIV RNA and DNA single-genome sequencing (CARD-SGS) method to investigate fractional proviral...

http://ift.tt/2p1WIgR

SNAT7 is the primary lysosomal glutamine exporter required for extracellular protein-dependent growth of cancer cells [Biochemistry]

Lysosomes degrade cellular components sequestered by autophagy or extracellular material internalized by endocytosis and phagocytosis. The macromolecule building blocks released by lysosomal hydrolysis are then exported to the cytosol by lysosomal transporters, which remain undercharacterized. In this study, we designed an in situ assay of lysosomal amino acid export based...

http://ift.tt/2p23EKY

Dissociation of Per1 and Bmal1 circadian rhythms in the suprachiasmatic nucleus in parallel with behavioral outputs [Neuroscience]

The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and...

http://ift.tt/2p28xnk

Using microsecond single-molecule FRET to determine the assembly pathways of T4 ssDNA binding protein onto model DNA replication forks [Biophysics and Computational Biology]

DNA replication is a core biological process that occurs in prokaryotic cells at high speeds (∼1 nucleotide residue added per millisecond) and with high fidelity (fewer than one misincorporation event per 107 nucleotide additions). The ssDNA binding protein [gene product 32 (gp32)] of the T4 bacteriophage is a central integrating...

http://ift.tt/2oQEFON

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells [Physiology]

Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca2+- and voltage-dependent BK-type K+ channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca2+, suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26...

http://ift.tt/2p1WOW3

Structural features and lipid binding domain of tubulin on biomimetic mitochondrial membranes [Biophysics and Computational Biology]

Dimeric tubulin, an abundant water-soluble cytosolic protein known primarily for its role in the cytoskeleton, is routinely found to be associated with mitochondrial outer membranes, although the structure and physiological role of mitochondria-bound tubulin are still unknown. There is also no consensus on whether tubulin is a peripheral membrane protein...

http://ift.tt/2p1ONAh

Neurophysiological dynamics of phrase-structure building during sentence processing [Neuroscience]

Although sentences unfold sequentially, one word at a time, most linguistic theories propose that their underlying syntactic structure involves a tree of nested phrases rather than a linear sequence of words. Whether and how the brain builds such structures, however, remains largely unknown. Here, we used human intracranial recordings and...

http://ift.tt/2oQEUcw

NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice [Medical Sciences]

Sensory nerves emanating from the dorsal root extensively innervate the surfaces of mammalian bone, a privileged location for the regulation of biomechanical signaling. Here, we show that NGF-TrkA signaling in skeletal sensory nerves is an early response to mechanical loading of bone and is required to achieve maximal load-induced bone...

http://ift.tt/2oQAti4

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy [Neuroscience]

Anti-MAG (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. Because the pathogenicity and demyelinating properties of anti-MAG autoantibodies are...

http://ift.tt/2oQPdxt

Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis [Microbiology]

Despite the wide administration of several effective vaccines, rotavirus (RV) remains the single most important etiological agent of severe diarrhea in infants and young children worldwide, with an annual mortality of over 200,000 people. RV attachment and internalization into target cells is mediated by its outer capsid protein VP4. To...

http://ift.tt/2p1JLnu

Skin Lightening Under Fire as Indians Seek Whiter Shade of Pale

Mirror, mirror on the wall - who is the fairest of them all? The one with the palest skin, of course.
Reuters Health Information

http://ift.tt/2qf4s2X

Bacterial microbiome of the nose of healthy dogs and dogs with nasal disease

by Barbara Tress, Elisabeth S. Dorn, Jan S. Suchodolski, Tariq Nisar, Prajesh Ravindran, Karin Weber, Katrin Hartmann, Bianka S. Schulz

The role of bacterial communities in canine nasal disease has not been studied so far using next generation sequencing methods. Sequencing of bacterial 16S rRNA genes has revealed that the canine upper respiratory tract harbors a diverse microbial community; however, changes in the composition of nasal bacterial communities in dogs with nasal disease have not been described so far. Aim of the study was to characterize the nasal microbiome of healthy dogs and compare it to that of dogs with histologically confirmed nasal neoplasia and chronic rhinitis. Nasal swabs were collected from healthy dogs (n = 23), dogs with malignant nasal neoplasia (n = 16), and dogs with chronic rhinitis (n = 8). Bacterial DNA was extracted and sequencing of the bacterial 16S rRNA gene was performed. Data were analyzed using Quantitative Insights Into Microbial Ecology (QIIME). A total of 376 Operational Taxonomic Units out of 26 bacterial phyla were detected. In healthy dogs, Moraxella spp. was the most common species, followed by Phyllobacterium spp., Cardiobacteriaceae, and Staphylococcus spp. While Moraxella spp. were significantly decreased in diseased compared to healthy dogs (p = 0.005), Pasteurellaceae were significantly increased (p = 0.001). Analysis of similarities used on the unweighted UniFrac distance metric (p = 0.027) was significantly different when nasal microbial communities of healthy dogs were compared to those of dogs with nasal disease. The study showed that the canine nasal cavity is inhabited by a highly species-rich bacterial community, and suggests significant differences between the nasal microbiome of healthy dogs and dogs with nasal disease.

http://ift.tt/2oQ4jDw

Latex Allergy: Can We Keep Clinicians and Patients Safer?

Latex allergies provoke a variety of reactions, from the annoying to the deadly. Contact prevention is challenging, and clinicians are among the most widely affected. What can we do?
Medscape Allergy & Immunology

http://ift.tt/2owBECZ

Bacterial microbiome of the nose of healthy dogs and dogs with nasal disease

by Barbara Tress, Elisabeth S. Dorn, Jan S. Suchodolski, Tariq Nisar, Prajesh Ravindran, Karin Weber, Katrin Hartmann, Bianka S. Schulz

The role of bacterial communities in canine nasal disease has not been studied so far using next generation sequencing methods. Sequencing of bacterial 16S rRNA genes has revealed that the canine upper respiratory tract harbors a diverse microbial community; however, changes in the composition of nasal bacterial communities in dogs with nasal disease have not been described so far. Aim of the study was to characterize the nasal microbiome of healthy dogs and compare it to that of dogs with histologically confirmed nasal neoplasia and chronic rhinitis. Nasal swabs were collected from healthy dogs (n = 23), dogs with malignant nasal neoplasia (n = 16), and dogs with chronic rhinitis (n = 8). Bacterial DNA was extracted and sequencing of the bacterial 16S rRNA gene was performed. Data were analyzed using Quantitative Insights Into Microbial Ecology (QIIME). A total of 376 Operational Taxonomic Units out of 26 bacterial phyla were detected. In healthy dogs, Moraxella spp. was the most common species, followed by Phyllobacterium spp., Cardiobacteriaceae, and Staphylococcus spp. While Moraxella spp. were significantly decreased in diseased compared to healthy dogs (p = 0.005), Pasteurellaceae were significantly increased (p = 0.001). Analysis of similarities used on the unweighted UniFrac distance metric (p = 0.027) was significantly different when nasal microbial communities of healthy dogs were compared to those of dogs with nasal disease. The study showed that the canine nasal cavity is inhabited by a highly species-rich bacterial community, and suggests significant differences between the nasal microbiome of healthy dogs and dogs with nasal disease.

http://ift.tt/2oQ4jDw

Change Trumps Tradition: The Atlantis project of Léon Krier, 1986 - 1992

http://ift.tt/2p1nJkR

Developing a Birth Plan

 

Epidural or no epidural? Who will cut the cord — and when? Dr. Camaryn Chrisman Robbins is back this week with Abby on Belly to Baby to talk about what should — and shouldn't — be included in your birth plan.

The post Developing a Birth Plan appeared first on ChildrensMD.

http://ift.tt/2qpQTLy

Hands-on Workshop: The Born Digital Record of the Writing Process. Discussing Concepts of Representation for the DSE

http://ift.tt/2oYkY2G

Diepe hersenstimulatie bij een patiënt met een juveniele vorm van de ziekte van Parkinson

The medical history of a 23-year-old patient who underwent deep brain stimulation as a therapy for young onset Parkinson's disease, is reported. Deep brain stimulation is a generally accepted treatment for patients with advanced Parkinson's disease. In most patients, a clear improvement in motoric symptoms and an increase in quality of life are observed. However, there are also indications that deep brain stimulation has a major impact on affection, cognition, behavior, identity, personality and self-perception. Little is known about these psychosocial effects and their repercussions on the individual patient, this is consequently accompanied by ethical ramifications. As the therapy is relatively recent, the long-term effects of deep brain stimulation are still largely unknown, which means caution should be exercised in a younger population. It is important to acknowledge all aspects of the patient's life and to avoid only focusing on the improvement of the clinical motoric symptoms.

http://ift.tt/2pAIruS

Provider Training in Increasing Patient Tobacco Cessation Counseling and Referrals for Patients With Cancer Undergoing Radiation Therapy

Conditions:   Breast Carcinoma;   Caregiver;   Head and Neck Carcinoma;   Lung Carcinoma;   Prostate Carcinoma;   Tobacco Use
Interventions:   Other: Communication Skills Training;   Other: Medical Chart Review;   Other: Questionnaire Administration;   Other: Tobacco Cessation Counseling
Sponsors:   OHSU Knight Cancer Institute;   National Cancer Institute (NCI)
Not yet recruiting - verified April 2017

http://ift.tt/2qvBfNY

Image Guided Surgery for Margin Assessment of Head and Neck Cancer Using Cetuximab-IRDye800CW cONjugate

Conditions:   Head and Neck Squamous Cell Carcinoma;   Margin Assessment
Intervention:   Drug: Cetuximab-IRDye800CW
Sponsors:   University Medical Center Groningen;   UMC Utrecht;   Erasmus Medical Center, Rotterdam
Not yet recruiting - verified April 2017

http://ift.tt/2pOLCQI

Wound Complications in Head and Neck Surgery

Conditions:   Hypothyroidism; Surgery;   Head and Neck Cancer;   Wound Heal;   Laryngeal Cancer;   Laryngeal Fistula
Intervention:   Drug: Levothyroxine
Sponsor:   University of Michigan
Not yet recruiting - verified April 2017

http://ift.tt/2qvDkcG

The masquerading presentation of a systemic anaplastic large cell lymphoma, ALK positive: a case report and review of the literature.

http://ift.tt/2pzWZuK