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https://www.readbyqxmd.com/read/28646115/genome-analysis-of-endomicrobium-proavitum-suggests-loss-and-gain-of-relevant-functions-during-the-evolution-of-intracellular-symbionts
#1
Hao Zheng, Carsten Dietrich, Andreas Brune
Bacterial endosymbionts of eukaryotes show progressive genome erosion, but detailed investigations of the evolutionary processes involved in the transition to an intracellular lifestyle are generally hampered by the lack of extant free-living lineages. Here, we characterize the genome of the recently isolated, free-living Endomicrobium proavitum, the second member of the Elusimicrobia phylum brought into pure culture, and compare it to the closely related "Candidatus Endomicrobium trichonymphae" strain Rs-D17, a previously described but uncultured endosymbiont of termite gut flagellates...
June 23, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28645941/a-first-time-in-human-study-of-gsk2636771-a-phosphoinositide-3-kinase-beta-selective-inhibitor-in-patients-with-advanced-solid-tumors
#2
Joaquin Mateo, Gopinath Ganji, Charlotte Lemech, Howard A Burris, Sae-Won Han, Karen E Swales, Shaun Decordova, Maurice P DeYoung, Deborah A Smith, Shanker Kalyana-Sundaram, Jiuhua Wu, Monica Motwani, Rakesh Kumar, Jerry M Tolson, Sun Young Rha, Hyun Cheol Chung, Joseph Paul Eder, Sunil Sharma, Yung-Jue Bang, Jeffrey R Infante, Li Yan, Johann S de Bono, Hendrik-Tobias Arkenau
The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on and off target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.<br /><br />Experimental Design: <p>We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended Phase II dose (RP2D)...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28645833/binding-kinetics-and-pathways-of-ligands-to-gpcrs
#3
REVIEW
Andrea Strasser, Hans-Joachim Wittmann, Roland Seifert
Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug-target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD)...
June 20, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28644970/overexpression-of-populus%C3%A3-canescens-isoprene-synthase-gene-in-camelina-sativa-leads-to-alterations-in-its-growth-and-metabolism
#4
Lorenzo Rossi, Monica Borghi, Jinfen Yang, De-Yu Xie
Isoprene (2-methyl-1,3-butadiene) is a hemiterpene molecule. It has been estimated that the plant kingdom emits 500-750 million tons of isoprene in the environment, half of which results from tropical broadleaf trees and the remainder from shrubs. Camelina (Camelina sativa (L.) Crantz) is an emerging bioenergy plant for biodiesel. In this study, we characterized isoprene formation following a diurnal/nocturnal cycle in wild-type Camelina plants. To understand the potential effects of isoprene emission on this herbaceous plant, a gray poplar Populus×canescens isoprene synthase gene (PcISPS) was overexpressed in Camelina...
June 13, 2017: Journal of Plant Physiology
https://www.readbyqxmd.com/read/28640392/calcineurin-inhibitors-exacerbate-coronary-arteritis-via-the-myd88-signaling-pathway-in-a-murine-model-of-kawasaki-disease
#5
Kenji Murata, Yoshitomo Motomura, Tamami Tanaka, Shunsuke Kanno, Takahisa Yano, Mitsuho Onimaru, Atsushi Shimoyama, Hisanori Nishio, Yasunari Sakai, Masatsugu Oh-Hora, Hiromitsu Hara, Koichi Fukase, Hidetoshi Takada, Satohiro Masuda, Shouichi Ohga, Sho Yamasaki, Toshiro Hara
Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (Nod1) in wild-type, SCID, CARD9(-/-) , and MyD88(-/-) mice...
June 22, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28637006/the-effect-of-ca125-on-metastasis-of-ovarian-cancer-old-marker-new-function
#6
Qin Yuan, Jiayin Song, Weiwei Yang, Hongyan Wang, Qianyu Huo, Jie Yang, Xiaoxu Yu, Yunde Liu, Chen Xu, Huijing Bao
CA125 has been used extensively to screen for neoplasms, especially in ovarian cancer. The serum CA125 level can be used as a better prognosis evaluation and it may dynamic monitoring the disease progression. We explored the effect of CA125 on ovarian cancer cell migration and its underlying mechanism. Transwell assays showed that exposure to 0.2 μg/ml or 0.4 μg/ml CA125 for 48 h increased migration of A2780 and OVCAR-3 ovarian cancer cells. This effect of CA125 was blocked addition of 200 ng/ml DKK-1, a Wnt pathway inhibitor...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28631415/highlights-from-the-9th-cachexia-conference
#7
Nicole Ebner, Stephan von Haehling
This article highlights updates of pathways as well as pre-clinical and clinical studies into the field of wasting disorders that were presented at the 9th Cachexia Conference held in Berlin, Germany, December 2016. This year, some interesting results from clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new diagnostic tools and cut-offs of detecting skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival...
June 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/28630151/assembly-mechanism-of-the-%C3%AE-pore-forming-toxin-cytolysin-a-from-escherichia-coli
#8
REVIEW
Daniel Roderer, Rudi Glockshuber
The cytolytic toxin cytolysin A (ClyA) from Escherichia coli is probably one of the best-characterized examples of bacterial, α-pore-forming toxins (α-PFTs). Like other PFTs, ClyA exists in a soluble, monomeric form that assembles to an annular, homo-oligomeric pore complex upon contact with detergent or target membranes. Comparison of the three-dimensional structures of the 34 kDa monomer and the protomer in the context of the dodecameric pore complex revealed that ClyA undergoes one of the largest conformational transitions described for proteins so far, in which 55% of the residues change their position and 16% of the residues adopt a different secondary structure in the protomer...
August 5, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28625564/crispr-system-in-filamentous-fungi-current-achievements-and-future-directions
#9
REVIEW
Huaxiang Deng, Ruijie Gao, Xiangru Liao, Yujie Cai
As eukaryotes, filamentous fungi share many features with humans, and they produce numerous active metabolites, some of which are toxic. Traditional genetic approaches are generally inefficient, but the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system that has been widely used for basic research on bacteria, mammals and plants offers a simple, fast, versatile technology for systemic research on filamentous fungi. In this review, we summarized the current knowledge on Cas9 and its variants, different ways used to detect off-target, and different approaches used to express and transform the CRISPR complex...
June 15, 2017: Gene
https://www.readbyqxmd.com/read/28623188/gli1-induced-deubiquitinase-usp48-aids-glioblastoma-tumorigenesis-by-stabilizing-gli1
#10
Aidong Zhou, Kangyu Lin, Sicong Zhang, Li Ma, Jianfei Xue, Saint-Aaron Morris, Kenneth D Aldape, Suyun Huang
Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP48 activates Gli-dependent transcription by stabilizing Gli1 protein. Mechanistically, USP48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis...
June 16, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28620897/enhanced-recovery-pathway-in-elderly-patients-undergoing-colorectal-surgery-is-there-an-effect-of-increasing-ages-results-from-the-perioperative-italian-society-registry
#11
Marco Braga, Luigi Beretta, Nicolò Pecorelli, Marianna Maspero, Umberto Casiraghi, Felice Borghi, Luca Pellegrino, Stefano Bona, Roberta Monzani, Gianluigi Ferrari, Danilo Radrizzani, Riccardo Iuliani, Carlo Bima, Marco Scatizzi, Giancarlo Missana, Marco Azzola Guicciardi, Andrea Muratore, Michele Crespi, Hedayat Bouzari, Andrea Pisani Ceretti, Ferdinando Ficari
Previous studies reported that enhanced recovery pathway (ERP) is safe in elderly who did not require a specifically tailored protocol. In previous studies, elderly have been considered as a homogeneous cohort and the cut-off value to identify them was different. The aim of the present study is to assess the compliance to ERP and its impact on postoperative outcome in three subgroups of elderly patients with increasing ages. Prospectively collected data entered in an electronic Italian registry specifically designed for ERP were reviewed...
June 15, 2017: Updates in Surgery
https://www.readbyqxmd.com/read/28620044/let-there-be-light-how-to-use-photoswitchable-cross-linker-to-reprogram-proteins
#12
REVIEW
Daniel Hoersch
Azobenzene is a photo-isomerizing molecule whose end-to-end distance changes upon external illumination. When combined with site-specific reactive groups, it can be used as molecular tweezers to remote-control the structure and function of protein targets. The present study gives a brief overview over the rational design strategies that use an azobenzene-based photoswitchable cross-linker to engineer ON/OFF switches into functional proteins or to reprogram proteins for novel functions. The re-engineered proteins may be used as remote controls for cellular pathways, as light-gated drug delivery platforms or as light-powered machinery of synthetic cells and micro-scaled factories...
June 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28617863/the-use-of-metabolic-profiling-to-identify-insulin-resistance-in-veal-calves
#13
Andre J Pantophlet, Han Roelofsen, Marcel P de Vries, Walter J J Gerrits, Joost J G C van den Borne, Roel J Vonk
Heavy veal calves (4-6 months old) are at risk of developing insulin resistance and disturbed glucose homeostasis. Prolonged insulin resistance could lead to metabolic disorders and impaired growth performance. Recently, we discovered that heavy Holstein-Friesian calves raised on a high-lactose or high-fat diet did not differ in insulin sensitivity, that insulin sensitivity was low and 50% of the calves could be considered insulin resistant. Understanding the patho-physiological mechanisms underlying insulin resistance and discovering biomarkers for early diagnosis would be useful for developing prevention strategies...
2017: PloS One
https://www.readbyqxmd.com/read/28616764/abrupt-salinity-stress-induces-oxidative-stress-via-the-nrf2-keap1-signaling-pathway-in-large-yellow-croaker-pseudosciaena-crocea
#14
Lin Zeng, Chun-Xiang Ai, Yong-Hong Wang, Jian-She Zhang, Chang-Wen Wu
The aim of the present study was to evaluate the effects of abrupt salinity stress (12, 26 (control), and 40) on lipid peroxidation, activities and mRNA levels of antioxidant enzymes (Cu/Zn-SOD, CAT, GPx, and GR), and gene expression of the Nrf2-Keap1 signaling molecules at different times (6, 12, 24, and 48 h) in the liver of large yellow croaker Pseudosciaena crocea. The results showed that lipid peroxidation was sharply reduced at 6 h and increased at 12 h before returning to control levels in the hypo-salinity group...
June 14, 2017: Fish Physiology and Biochemistry
https://www.readbyqxmd.com/read/28611595/mtorc1-is-a-local-postsynaptic-voltage-sensor-regulated-by-positive-and-negative-feedback-pathways
#15
Farr Niere, Kimberly F Raab-Graham
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pathways, in a branch-specific manner, to maintain neuronal excitability within an optimal range...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28611180/papers-of-note-in-nature546-7657
#16
Annalisa M VanHook
This week's articles highlight an unusual mechanism for switching off GPCR signaling; the structural basis of activation of the GLP-1 receptor; a critical role for the B cell receptor in some lymphoma cells; and how cancer cells exploit nutrient sensing and acquisition pathways.
June 13, 2017: Science Signaling
https://www.readbyqxmd.com/read/28605593/simultaneous-drug-targeting-of-the-promoter-myc-g-quadruplex-and-bcl2-i-motif-in-diffuse-large-b-cell-lymphoma-delays-tumor-growth
#17
Samantha Kendrick, Andrea Muranyi, Vijay Gokhale, Laurence H Hurley, Lisa M Rimsza
Secondary DNA structures are uniquely poised as therapeutic targets due to their molecular switch function in turning gene expression on or off and scaffold-like properties for protein and small molecule interaction. Strategies to alter gene transcription through these structures thus far involve targeting single DNA conformations. Here we investigate the feasibility of simultaneously targeting different secondary DNA structures to modulate two key oncogenes, cellular-myelocytomatosis (MYC) and B-cell lymphoma gene-2 (BCL2), in diffuse large B-cell lymphoma (DLBCL)...
June 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28605052/effects-of-pedunculopontine-nucleus-stimulation-on-human-bladder-function
#18
Holly A Roy, Debbie Pond, Christopher Roy, Beth Forrow, Thomas Foltynie, Ludvic Zrinzo, Harith Akram, Tipu Z Aziz, James J FitzGerald, Alexander L Green
AIMS: The pedunculopontine nucleus (PPN) is a deep brain stimulation target for Parkinson's disease (PD). Unilateral PPN stimulation has been described in a previous case report to provoke urinary frequency, urgency and detrusor overactivity, due to probable activation of the pontine micturition center. Our aim was to evaluate the effect of bilateral PPN DBS on urodynamic parameters and to investigate the likely mechanisms using probabilistic tractography. METHODS: Six male PD subjects with bilateral PPN deep brain stimulators were recruited...
June 12, 2017: Neurourology and Urodynamics
https://www.readbyqxmd.com/read/28603537/flowering-locus-c-flc-is-a-potential-major-regulator-of-glucosinolate-content-across-developmental-stages-of-aethionema-arabicum-brassicaceae
#19
Setareh Mohammadin, Thu-Phuong Nguyen, Marco S van Weij, Michael Reichelt, Michael E Schranz
The biochemical defense of plants can change during their life-cycle and impact herbivore feeding and plant fitness. The annual species Aethionema arabicum is part of the sister clade to all other Brassicaceae. Hence, it holds a phylogenetically important position for studying crucifer trait evolution. Glucosinolates (GS) are essentially Brassicales-specific metabolites involved in plant defense. Using two Ae. arabicum accessions (TUR and CYP) we identify substantial differences in glucosinolate profiles and quantities between lines, tissues and developmental stages...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28603140/mining-the-genome-for-therapeutic-targets
#20
Jose C Florez
Current pharmacological options for type 2 diabetes do not cure the disease. Despite the availability of multiple drug classes that modulate glycemia effectively and minimize long-term complications, these agents do not reverse pathogenesis, and in practice they are not selected to correct the molecular profile specific to the patient. Pharmaceutical companies find drug development programs increasingly costly and burdensome, and many promising compounds fail before launch to market. Human genetics can help advance the therapeutic enterprise...
June 11, 2017: Diabetes
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