bluuebunny/crossref_metadata_2025 huggingface dataset:
A Method to Estimate the Microstructures of Low‐Alloy Cold‐Rolled TRIP Steels
Authors: Fu Bo , Sun Xiaoyang , Yang Wangyue , Li Longfei , Zhao Zhenye
Published: October 2017

A method is implemented in the present study to estimate the microstructures of low‐alloy cold‐rolled TRIP steels. This method includes simulations of intercritical annealing (IA) process and calculations of isothermal bainitic transformation (IBT) process. The evolutions of volume fractions and elements concentration profiles with temperatures and holding times for ferrite phase and austenite phase could be acquired assisted by Thermo‐Calc and DICTRA during IA process. Bainitic transformation from austenite, with chemical compositions determined at the end of IA, takes place during the subsequent IBT process. By taking into account the martensitic transformation during cooling from IA to IBT and/or from IBT to room temperature (RT) and avoiding the complex discussions of bainitic transformation kinetics, the volume fractions of bainite, martensite and retained austenite could be approximately determined after IBT and subsequent water quench. At the same time, the experimental validation of this method is conducted with well agreements. This implemented method is expected to relate chemical compositions and heat treatment parameters to the final microstructures of low‐alloy cold‐rolled TRIP steels and be beneficial for optimizing TRIP microstructures without amounts of experiments.
Interaction entropy for computational alanine scanning in protein–protein binding
Authors: Qiu Linqiong , Yan Yuna , Sun Zhaoxi , Song Jianing , Zhang John Z.H.
Published: October 2017

Protein–protein interactions (PPIs) are at the heart of signal transduction and are central to the function of protein machine in biology. The highly specific protein–protein binding is quantitatively characterized by the binding free energy whose accurate calculation from first principle is a grand challenge in computational biology. Accurate prediction of critical residues along with their specific and quantitative contributions to protein–protein binding free energy is extremely helpful to reveal binding mechanisms and identify drug‐like molecules that alter PPIs. In this overview, we describe an interaction entropy (IE) approach combined with the MM/GBSA method for solvation to compute residue‐specific protein–protein binding free energy. In this approach, the entropic contribution to binding free energy of individual residue is explicitly computed by using the IE method from a single MD trajectory. Studies for an extensive set of realistic protein–protein interaction systems demonstrated that by including the entropic contribution, the agreement between the computed residue‐specific binding free energies and the corresponding experimental data is systematically improved. We also show application of the current approach to the important major histocompatibility complex (MHC)‐antigen binding to provide important information on hot spots with potential application for use in cancer vaccine. WIREs Comput Mol Sci 2018, 8:e1342. doi: 10.1002/wcms.1342

This article is categorized under:

Structure and Mechanism > Computational Biochemistry and Biophysics

Molecular and Statistical Mechanics > Free Energy Methods

Software > Simulation Methods
Implantation of Right Kidneys: Is the Risk of Technical Graft Loss Real?
Authors: Khan Taqi T. , Ahmad Nadeem , Siddique Kashif , Fourtounas Konstantinos
Published: October 2017

Background

The left kidney (LK) is preferred by transplant surgeons, because its vein is always of good length and has a thick wall that enables safe suturing. On the other hand, the right renal vein is generally shorter and thinner walled, and well known for its technical difficulty during venous anastomosis, and can result in graft loss. We examined our living (LD) and deceased donor (DD) recipient data and compared the incidence of technical graft loss and early graft function in right and left kidneys.

Methods

A cohort of 58 adult and pediatric recipients received an LD or DD kidney between January 2015 and December 2016. The donor and recipient data were retrieved and retrospectively analyzed. Technical graft loss was defined as graft thrombosis within the 7 days after transplant.

Results

Right kidneys (RKs) were not a risk factor for technical graft loss, and no graft was lost for technical reasons in either LD or DD transplants. Early graft function in LK and RKs was also comparable in the LD cohort, and there were no LKs in the DD cohort.

Conclusion

Based on our data, the use of RKs was not a risk factor for technical graft loss and early graft function was comparable to LKs.
Women's Understanding and Attitudes towards Down Syndrome and Other Genetic Conditions in the Context of Prenatal Screening
Authors: Long Sarah , O'Leary Peter , Lobo Roanna , Dickinson Jan E.
Published: October 2017

In order to explore the impact of potential new technologies in the area of prenatal screening, we conducted a baseline study using qualitative interviews to explore women's attitudes and knowledge regarding current and future prenatal screening technology and methods. Three cohorts were interviewed, including healthy women without children, healthy women with healthy children, and healthy women with children who have de novo genetic disorders. This study aimed to assess the baseline understanding and attitudes of women in Western Australia. Women from each cohort demonstrated adequate knowledge of the differences between screening and diagnostic tests, but were mostly unaware of the conditions for which screening is currently available except Down syndrome. Women who had children with de novo genetic conditions were generally aware of more genetic conditions than women with or without healthy children. Most women recognised the genetic basis for the conditions mentioned. Two thirds of women understood that Down syndrome is a chromosomal condition; just one third recognised that the phenotype is variable. Most women expressed a positive attitude towards Down syndrome. Social acceptance of children with Down syndrome was commonly mentioned as a concern. While the majority of women with children supported screening for Down syndrome, they emphasised that it must be an autonomous choice. General knowledge of genetic conditions illustrated that women are exposed to diverse conditions from lived experience as well as the media.
Spatially Differentiated, Temporally Variegated: The Study of Life Cycles for a Better Understanding of Suburbia in German City Regions
Authors: Hesse Markus , Polívka Jan , Reicher Christa
Published: October 2017

This paper takes a spatially differentiated and temporally variegated perspective on suburban areas. It proposes a conceptual framework for studying the temporal variation and related trajectories of the subject matter, with suburban lifecycles being the key to our analysis. In empirical terms, the paper summarises the findings of research undertaken in 12 selected locales of four major metropolitan regions in Germany. Against the background of assessing the broader socioeconomic development of these regions, detailed local case studies have been conducted in order to reconstruct past and current development trajectories. Our analyses detected particular life cycles (and related segments) in the study areas, based on age and social composition, the physical conditions of the built environment and broader developments in the real-estate market. The different cycles include, in most cases, growth, maturity, transition and resilience, and they are also discussed in terms of their relevance for strategies responding to recent changes.
Prenatal Screening Strategies in Localities with Limited Resources
Authors: Cuckle Howard , Neiger Ran
Published: October 2017

Several important developments have been made in prenatal screening and diagnosis of serious fetal abnormalities, and prevention of common adverse pregnancy outcomes. However, full implementation is not cost-neutral and in localities with limited resources, compromises are needed. This review considers options for maternal plasma cell free DNA (cfDNA); prenatal microarray analysis; and multi-marker screening for preeclampsia (PE). Although not new, use of first trimester nuchal translucency and additional ultrasound markers is also considered as this is not routinely available in many limited resource localities. In order to benefit from recent advances in prenatal screening, even in adequately resourced localities, public health decision-makers have to make difficult choices. Options include: secondary and contingent cfDNA screening following a positive conventional test, microarray only when there are ultrasound indications, first trimester PE and screening using biochemistry alone, ideally with additional serum markers.
Transient Hypokalemic Quadriplegia After a Lumbar Transforaminal Epidural Dexamethasone Injection: A Case Report
Authors: Tahmasbi Sohi Maryam , Sullivan William J. , Anderson Dustin J.M.
Published: October 2017

A 30‐year‐old man with no significant medical history presented with hypokalemic quadriplegia 4 hours after he received a lumbar transforaminal epidural steroid injection (ESI) containing dexamethasone and lidocaine. A comprehensive workup ruled out acquired and hereditary causes of hypokalemic paralysis. Symptoms gradually resolved within hours after potassium restoration with no residual neurologic deficits. Paralysis after transforaminal ESI is uncommon but has been associated with particulate steroids that can coalesce into aggregates and occlude vessels. To our knowledge, there have been no case reports of paralysis after ESI with dexamethasone, a nonparticulate steroid. This transient paralysis is possibly caused by the effects of glucocorticoids on Na‐K channels and insulin resistance resulting in hyperglycemia and subsequent hypokalemia. We reviewed the differential diagnosis of transient paralysis after epidural steroid injection in this report.

Level of Evidence

IV
Regional population differences of the brown planthopper (Nilaparvata lugens Stål) in Cambodia using genotyping-by-sequencing
Authors: Matsukawa M. , Tasaki Mikako , Doi Kazuyuki , Ito Kasumi , Kawakita Kazuhito , Tanaka Toshiharu
Published: October 2017

The brown planthopper Nilaparvata lugens Stål (BPH) can be found year-round in tropical region and causes severe damage to rice. Although there has been documented BPH damage to rice crops in the past decade in Cambodia, the extent of this epidemic is poorly understood. Here, we examined the time variation of BPH population in the abundance of morphotypes in 13 main rice-producing provinces (86 sites) by aspirator method and in the Takeo Province (five sites) by yellow sticky trap method. At least three generations were observed during the 3-month collection period in the rainy growing season. Regarding the occurrence of BPH morphotypes, in July the macropterous adults were restricted to south Cambodia and in August all morphotypes, adults (macropterous and brachypterous) and nymphs, appeared in all sampling sites. To explain the difference of regional distribution, the genetic differentiation was analyzed in south and northwest Cambodia (three sites) by using single nucleotide polymorphisms (SNP) analysis via genotyping-by-sequencing (GBS) using next-generation sequencing. The 2455 SNPs obtained by GBS clarified the three sub-populations and they corresponded to the expected dissemination patterns. These results provide a clue to understand the differentiation and epidemic of BPH in Cambodia.
In vivo evaluation of the efficacy of Sophora moorcroftiana alkaloids in combination with Bacillus Calmette–Guérin (BCG) treatment for cystic echinococcosis in mice
Authors: Zhang G. , Wang J. , Luo Y. , Yuan M. , Gao Q. , Gao H. , Song X. , Shi Y. , Dong K. , Ma X.
Published: October 2017

Human cystic echinococcosis is a widespread, chronic, endemic, helminthic zoonosis caused by larval tapeworms of the species Echinococcus granulosus. At present, there is no rational and effective therapy for patients with echinococcosis. The present study evaluated whether the combination of alkaloids from Sophora moorcroftiana seeds (SMSa2) and Bacillus Calmette–Guérin (BCG) was effective in the treatment of experimental echinococcosis. After 20 weeks of secondary infection with protoscoleces, mice were randomly allocated to five groups and treated for 6 weeks by daily intragastric administration of albendazole (ABZ, 100 mg/kg), SMSa2 (100 mg/kg), BCG (abdominal subcutaneous injection at 5 × 106 CFU), SMSa2 + BCG (100 mg/kg SMSa2 and 5 × 106 CFU BCG) or normal saline (untreated group), respectively. The results indicated a significant reduction in the weight of hydatid cysts in the SMSa2 + BCG group compared with the untreated, SMSa2 and BCG groups. The rate of inhibition of hydatid cyst growth in the SMSa2 + BCG group (76.1%) was obviously increased compared with that in the SMSa2 (25.7%) and BCG (26.6%) groups, respectively. Compared with the untreated control, the SMSa2 + BCG group showed a non-significant increase in serum interleukin-4 (IL-4). Furthermore, the serum levels of interferon-γ (IFN-γ) between the untreated and SMSa2 + BCG groups were not statistically different. Therefore, the combination of alkaloids from S. moorcroftiana seeds and BCG can reduce cyst burden and is an effective therapeutic regimen against echinococcosis.
Darwin's aliens
Authors: Levin Samuel R. , Scott Thomas W. , Cooper Helen S. , West Stuart A.
Published: October 2017

Making predictions about aliens is not an easy task. Most previous work has focused on extrapolating from empirical observations and mechanistic understanding of physics, chemistry and biology. Another approach is to utilize theory to make predictions that are not tied to details of Earth. Here we show how evolutionary theory can be used to make predictions about aliens. We argue that aliens will undergo natural selection – something that should not be taken for granted but that rests on firm theoretical grounds. Given aliens undergo natural selection we can say something about their evolution. In particular, we can say something about how complexity will arise in space. Complexity has increased on the Earth as a result of a handful of events, known as the major transitions in individuality. Major transitions occur when groups of individuals come together to form a new higher level of the individual, such as when single-celled organisms evolved into multicellular organisms. Both theory and empirical data suggest that extreme conditions are required for major transitions to occur. We suggest that major transitions are likely to be the route to complexity on other planets, and that we should expect them to have been favoured by similarly restrictive conditions. Thus, we can make specific predictions about the biological makeup of complex aliens.
Church Receives 2017 G. K. Gilbert Award
Authors:   AGU
Published: October 2017

Michael Church will receive the 2017 G. K. Gilbert Award in Surface Processes at the 2017 American Geophysical Union Fall Meeting, to be held 11–15 December in New Orleans, La. The award recognizes a scientist who has made “a single significant advance or sustained significant contributions to the field of Earth and planetary surface processes” and “also promoted an environment of unselfish cooperation in research and the inclusion of young scientists into the field.”
Functional heterogeneity of gut‐resident regulatory T cells
Authors: Luu Maik , Steinhoff Ulrich , Visekruna Alexander
Published: October 2017

Regulatory T cells (Treg cells) have a central role in the maintenance of intestinal homeostasis by restraining inappropriate immune responses in the healthy gut. Although distinct intestinal immune cell populations have been described to exhibit regulatory activity, several genetic and functional studies provided a strong evidence for a pivotal role of forkhead box P3 (Foxp3)+CD4+ Treg cells in prevention of dysregulated mucosal immune reactions and development of chronic immunological disorders such as celiac disease, food allergies and inflammatory bowel disease. Treg cells provide an important layer of intestinal defense by suppressing immune responses against innocuous food and commensal‐derived antigens. Recent functional studies suggest that Treg cells are also involved in several other processes such as controlling microbial diversity in the gut, immunoglobulin A selection and supporting tissue repair in response to intestinal tissue damage. A better understanding of the functional heterogeneity as well as of the molecular signals, which regulate distinct intestinal Treg cell subsets, will encourage strategies aimed at transplanting the optimal Treg cell subset for cellular therapy in humans.
Optogenetically stimulating intact rat corticospinal tract post-stroke restores motor control through regionalized functional circuit formation
Authors: Wahl A. S. , Büchler U. , Brändli A. , Brattoli B. , Musall S. , Kasper H. , Ineichen B. V. , Helmchen F. , Ommer B. , Schwab M. E.
Published: October 2017

Current neuromodulatory strategies to enhance motor recovery after stroke often target large brain areas non-specifically and without sufficient understanding of their interaction with internal repair mechanisms. Here we developed a novel therapeutic approach by specifically activating corticospinal circuitry using optogenetics after large strokes in rats. Similar to a neuronal growth-promoting immunotherapy, optogenetic stimulation together with intense, scheduled rehabilitation leads to the restoration of lost movement patterns rather than induced compensatory actions, as revealed by a computer vision-based automatic behavior analysis. Optogenetically activated corticospinal neurons promote axonal sprouting from the intact to the denervated cervical hemi-cord. Conversely, optogenetically silencing subsets of corticospinal neurons in recovered animals, results in mistargeting of the restored grasping function, thus identifying the reestablishment of specific and anatomically localized cortical microcircuits. These results provide a conceptual framework to improve established clinical techniques such as transcranial magnetic or transcranial direct current stimulation in stroke patients.
Sortilin limits EGFR signaling by promoting its internalization in lung cancer
Authors: Al-Akhrass Hussein , Naves Thomas , Vincent François , Magnaudeix Amandine , Durand Karine , Bertin François , Melloni Boris , Jauberteau Marie-Odile , Lalloué Fabrice
Published: October 2017

Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signaling pathways. Internalization and degradation of EGFR after ligand binding limits the intensity of proliferative signaling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumor progression. Here we report that sortilin is a key regulator of EGFR internalization. Loss of sortilin in tumor cells promoted cell proliferation by sustaining EGFR signaling at the cell surface, ultimately accelerating tumor growth. In lung cancer patients, sortilin expression decreased with increased pathologic grade, and expression of sortilin was strongly correlated with survival, especially in patients with high EGFR expression. Sortilin is therefore a regulator of EGFR intracellular trafficking that promotes receptor internalization and limits signaling, which in turn impacts tumor growth.
Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX
Authors: Hoelper Dominik , Huang Hongda , Jain Aayushi Y. , Patel Dinshaw J. , Lewis Peter W.
Published: October 2017

The ATRX–DAXX histone chaperone complex incorporates the histone variant H3.3 at heterochromatic regions in a replication-independent manner. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We use single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and ATRX-independent functions of DAXX. We find that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: the ATRX–DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX–SETDB1–KAP1–HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We find that histone H3.3 stabilizes DAXX protein levels and can affect DAXX-regulated gene expression without incorporation into nucleosomes. Our study demonstrates a nucleosome-independent function for the H3.3 histone variant.
Structure-based insights into self-cleavage by a four-way junctional twister-sister ribozyme
Authors: Zheng Luqian , Mairhofer Elisabeth , Teplova Marianna , Zhang Ye , Ma Jinbiao , Patel Dinshaw J. , Micura Ronald , Ren Aiming
Published: October 2017

Here we report on the crystal structure and cleavage assays of a four-way junctional twister-sister self-cleaving ribozyme. Notably, 11 conserved spatially separated loop nucleotides are brought into close proximity at the ribozyme core through long-range interactions mediated by hydrated Mg2+ cations. The C62–A63 step at the cleavage site adopts a splayed-apart orientation, with flexible C62 directed outwards, whereas A63 is directed inwards and anchored by stacking and hydrogen-bonding interactions. Structure-guided studies of key base, sugar, and phosphate mutations in the twister-sister ribozyme, suggest contributions to the cleavage chemistry from interactions between a guanine at the active site and the non-bridging oxygen of the scissile phosphate, a feature found previously also for the related twister ribozyme. Our four-way junctional pre-catalytic structure differs significantly in the alignment at the cleavage step (splayed-apart vs. base-stacked) and surrounding residues and hydrated Mg2+ ions relative to a reported three-way junctional pre-catalytic structure of the twister-sister ribozyme.
Design rules for light-emitting electrochemical cells delivering bright luminance at 27.5 percent external quantum efficiency
Authors: Tang Shi , Sandström Andreas , Lundberg Petter , Lanz Thomas , Larsen Christian , van Reenen Stephan , Kemerink Martijn , Edman Ludvig
Published: October 2017

The light-emitting electrochemical cell promises cost-efficient, large-area emissive applications, as its characteristic in-situ doping enables use of air-stabile electrodes and a solution-processed single-layer active material. However, mutual exclusion of high efficiency and high brightness has proven a seemingly fundamental problem. Here we present a generic approach that overcomes this critical issue, and report on devices equipped with air-stabile electrodes and outcoupling structure that deliver a record-high efficiency of 99.2 cd A−1 at a bright luminance of 1910 cd m−2. This device significantly outperforms the corresponding optimized organic light-emitting diode despite the latter employing calcium as the cathode. The key to this achievement is the design of the host–guest active material, in which tailored traps suppress exciton diffusion and quenching in the central recombination zone, allowing efficient triplet emission. Simultaneously, the traps do not significantly hamper electron and hole transport, as essentially all traps in the transport regions are filled by doping.
Blood Pressure Management for Acute Intracerebral Hemorrhage: A Meta-Analysis
Authors: Shi Ligen , Xu Shenbin , Zheng Jingwei , Xu Jing , Zhang Jianmin
Published: October 2017

Inconsistent data from the randomized trials ignites controversy on intensive blood pressure (BP) reduction for acute intracerebral hemorrhage (ICH). This study aims to examine the association between BP lowering and clinical outcomes among patients with acute ICH. We conducted this meta-analysis based on the published randomized controlled trials (RCTs). Data were included from 6 RCTs involving 4412 patients. No significant improvements were observed in hematoma growth at 24 hours, neurologic improvement at 24 hours, hypotension at 72 hours, death or dependency at 90 days, mortality at 90 days, and serious adverse events at 90 days between intensive and conservative BP lowering groups. High heterogeneity was observed between estimates in hematoma growth (I2 = 49). Univariate meta-regression and subgroup analysis showed that intensive BP lowering showed a significant decrease in hematoma growth in age ≤62 years, time from symptoms onset to treatment ≤6 hours, baseline hematoma volume ≤15 mL, and combined intraventricular hemorrhage ≤25% subgroups. In conclusion, intensive BP management in patients with ICH is safe. Intensive BP lowering could reduce hematoma growth in those patients (≤62 years old) with ICH volume less than 15 mL receiving BP management within 6 hours after randomization.
Comparative metabolomics study on therapeutic mechanism of electro-acupuncture and moxibustion on rats with chronic atrophic gastritis (CAG)
Authors: Liu Cai-chun , Chen Jiao-long , Chang Xiao-rong , He Qi-da , Shen Jia-cheng , Lian Lin-yu , Wang Ya-dong , Zhang Yuan , Ma Fu-qiang , Huang Hui-ying , Yang Zong-bao
Published: October 2017

Some studies have proved that both acupuncture and moxibustion are very effective for the treatment of CAG. However, little is known about therapeutic mechanism of electro-acupuncture and moxibustion on CAG as well as the difference between them. On the other hand, metabolomics is a ‘top-down’ approach to understand metabolic changes of organisms caused by disease or interventions in holistic context, which consists with the holistic thinking of electro-acupuncture and moxibustion treatment. In this study, the difference of therapeutic mechanism between electro-acupuncture and moxibustion on CAG rats was investigated by a1H NMR-based metabolomics analysis of multiple biological samples (serum, stomach, cerebral cortex and medulla) coupled with pathological examination and molecular biological assay. For all sample types, both electro-acupuncture and moxibustion intervention showed beneficial effects by restoring many CAG-induced metabolic changes involved in membrane metabolism, energy metabolism and function of neurotransmitters. Notably, the moxibustion played an important role in CAG treatment mainly by regulating energy metabolism in serum, while main acting site of electro-acupuncture treatment was nervous system in stomach and brain. These findings are helpful to facilitate the therapeutic mechanism elucidating of electro-acupuncture and moxibustion on CAG rats. Metabolomics is promising in mechanisms study for traditional Chinese medicine (TCM).
Mir-21 Mediates the Inhibitory Effect of Ang (1–7) on AngII-induced NLRP3 Inflammasome Activation by Targeting Spry1 in lung fibroblasts
Authors: Sun Na-Na , Yu Chang-Hui , Pan Miao-Xia , Zhang Yue , Zheng Bo-Jun , Yang Qian-Jie , Zheng Ze-Mao , Meng Ying
Published: October 2017

MicroRNA-21 (mir-21) induced by angiotensin II (AngII) plays a vital role in the development of pulmonary fibrosis, and the NLRP3 inflammasome is known to be involved in fibrogenesis. However, whether there is a link between mir-21 and the NLRP3 inflammasome in pulmonary fibrosis is unknown. Angiotensin-converting enzyme 2/angiotensin(1–7) [ACE2/Ang(1–7)] has been shown to attenuate AngII-induced pulmonary fibrosis, but it is not clear whether ACE2/Ang(1–7) protects against pulmonary fibrosis by inhibiting AngII-induced mir-21 expression. This study’s aim was to investigate whether mir-21 activates the NLRP3 inflammasome and mediates the different effects of AngII and ACE2/Ang(1–7) on lung fibroblast apoptosis and collagen synthesis. In vivo, AngII exacerbated bleomycin (BLM)-induced lung fibrosis in rats, and elevated mir-21 and the NLRP3 inflammasome. In contrast, ACE2/Ang(1–7) attenuated BLM-induced lung fibrosis, and decreased mir-21 and the NLRP3 inflammasome. In vitro, AngII activated the NLRP3 inflammasome by up-regulating mir-21, and ACE2/Ang(1–7) inhibited NLRP3 inflammasome activation by down-regulating AngII-induced mir-21. Over-expression of mir-21 activated the NLRP3 inflammasome via the ERK/NF-κB pathway by targeting Spry1, resulting in apoptosis resistance and collagen synthesis in lung fibroblasts. These results indicate that mir-21 mediates the inhibitory effect of ACE2/Ang(1–7) on AngII-induced activation of the NLRP3 inflammasome by targeting Spry1 in lung fibroblasts.
IP-10 Kinetics in the First Week of Therapy are Strongly Associated with Bacteriological Confirmation of Tuberculosis Diagnosis in HIV-Infected Patients
Authors: García-Basteiro Alberto L. , Mambuque Edson , den Hertog Alice , Saavedra Belén , Cuamba Inocencia , Oliveras Laura , Blanco Silvia , Bulo Helder , Brew Joe , Cuevas Luis E. , Cobelens Frank , Nhabomba Augusto , Anthony Richard
Published: October 2017

Simple effective tools to monitor the long treatment of tuberculosis (TB) are lacking. Easily measured host derived biomarkers have been identified but need to be validated in larger studies and different population groups. Here we investigate the early response in IP-10 levels (between day 0 and day 7 of TB therapy) to identify bacteriological status at diagnosis among 127 HIV-infected patients starting TB treatment. All participants were then classified as responding or not responding to treatment blindly using a previously described IP-10 kinetic algorithm. There were 77 bacteriologically confirmed cases and 41 Xpert MTB/RIF® and culture negative cases. Most participants had a measurable decline in IP-10 during the first 7 days of therapy. Bacteriologically confirmed cases were more likely to have high IP-10 levels at D0 and had a steeper decline than clinically diagnosed cases (mean decline difference 2231 pg/dl, 95% CI: 897–3566, p = 0.0013). Bacteriologically confirmed cases were more likely to have a measurable decline in IP-10 at day 7 than clinically diagnosed cases (48/77 (62.3%) vs 13/41 (31.7%), p < 0.001). This study confirms the association between a decrease in IP-10 levels during the first week of treatment and a bacteriological confirmation at diagnosis in a large cohort of HIV positive patients.
In-silico gene essentiality analysis of polyamine biosynthesis reveals APRT as a potential target in cancer
Authors: Pey Jon , San José-Eneriz Edurne , Ochoa María Carmen , Apaolaza Iñigo , de Atauri Pedro , Rubio Angel , Cendoya Xabier , Miranda Estíbaliz , Garate Leire , Cascante Marta , Carracedo Arkaitz , Agirre Xabier , Prosper Felipe , Planes Francisco J.
Published: October 2017

Constraint-based modeling for genome-scale metabolic networks has emerged in the last years as a promising approach to elucidate drug targets in cancer. Beyond the canonical biosynthetic routes to produce biomass, it is of key importance to focus on metabolic routes that sustain the proliferative capacity through the regulation of other biological means in order to improve in-silico gene essentiality analyses. Polyamines are polycations with central roles in cancer cell proliferation, through the regulation of transcription and translation among other things, but are typically neglected in in silico cancer metabolic models. In this study, we analysed essential genes for the biosynthesis of polyamines. Our analysis corroborates the importance of previously known regulators of the pathway, such as Adenosylmethionine Decarboxylase 1 (AMD1) and uncovers novel enzymes predicted to be relevant for polyamine homeostasis. We focused on Adenine Phosphoribosyltransferase (APRT) and demonstrated the detrimental consequence of APRT gene silencing on different leukaemia cell lines. Our results highlight the importance of revisiting the metabolic models used for in-silico gene essentiality analyses in order to maximize the potential for drug target identification in cancer.
Exosomal microRNA signatures in multiple sclerosis reflect disease status
Authors: Ebrahimkhani Saeideh , Vafaee Fatemeh , Young Paul E. , Hur Suzy S. J. , Hawke Simon , Devenney Emma , Beadnall Heidi , Barnett Michael H. , Suter Catherine M. , Buckland Michael E.
Published: October 2017

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is currently no single definitive test for MS. Circulating exosomes represent promising candidate biomarkers for a host of human diseases. Exosomes contain RNA, DNA, and proteins, can cross the blood-brain barrier, and are secreted from almost all cell types including cells of the CNS. We hypothesized that serum exosomal miRNAs could present a useful blood-based assay for MS disease detection and monitoring. Exosome-associated microRNAs in serum samples from MS patients (n = 25) and matched healthy controls (n = 11) were profiled using small RNA next generation sequencing. We identified differentially expressed exosomal miRNAs in both relapsing-remitting MS (RRMS) (miR-15b-5p, miR-451a, miR-30b-5p, miR-342-3p) and progressive MS patient sera (miR-127-3p, miR-370-3p, miR-409-3p, miR-432-5p) in relation to controls. Critically, we identified a group of nine miRNAs (miR-15b-5p, miR-23a-3p, miR-223-3p, miR-374a-5p, miR-30b-5p, miR-433-3p, miR-485-3p, miR-342-3p, miR-432-5p) that distinguished relapsing-remitting from progressive disease. Eight out of nine miRNAs were validated in an independent group (n = 11) of progressive MS cases. This is the first demonstration that microRNAs associated with circulating exosomes are informative biomarkers not only for the diagnosis of MS, but in predicting disease subtype with a high degree of accuracy.
The Effects of Serum Proteins on Magnesium Alloy Degradation in Vitro
Authors: Johnson Ian , Jiang Wensen , Liu Huinan
Published: October 2017

Magnesium (Mg) alloys are promising materials for biodegradable implants, but their clinical translation requires improved control over their degradation rates. Proteins may be a major contributing factor to Mg alloy degradation, but are not yet fully understood. This article reports the effects of fetal bovine serum (FBS), a physiologically relevant mixture of proteins, on Mg and Mg alloy degradation. FBS had little impact on mass loss of pure Mg during immersion degradation, regardless of whether or not a native oxide layer was present on the sample surface. FBS reduced the mass loss of Mg-Yttrium (MgY) alloy with an oxidized surface during immersion degradation, but increased the mass loss for the same alloy with a metallic surface (surface oxides were removed). FBS also influenced the mode of degradation by limiting the depth of pit formation during degradation processes on commercially pure Mg with metallic or oxidized surfaces and on MgY alloy with oxidized surfaces. The results demonstrated that serum proteins had significant interactions with Mg-based biodegradable metals, and these interactions may be modified by alloy composition and processing. Therefore, proteins should be taken into account when designing experiments to assess degradation of Mg-based implants.
NADPH oxidase 4 modulates hepatic responses to lipopolysaccharide mediated by Toll-like receptor-4
Authors: Singh Anand , Koduru Bhargav , Carlisle Cameron , Akhter Hasina , Liu Rui-Ming , Schroder Katrin , Brandes Ralf P. , Ojcius David M.
Published: October 2017

Chronic inflammation plays a key role in development of many liver diseases. Stimulation of Toll-like receptor 4 (TLR4) by bacterial lipopolysaccharide (LPS) initiates inflammation and promotes development of hepatocellular carcinoma and other liver diseases. NADPH oxidases contribute to LPS-induced reactive oxygen species (ROS) production and modulate TLR responses, but whether these enzymes function in TLR4 responses of hepatocytes is unknown. In the present work, we examined the role of NADPH oxidase 4 (Nox4) in LPS-induced TLR4 responses in human hepatoma cells and wildtype and Nox4-deficient mice. We found that LPS increased expression of Nox4, TNF-α, and proliferating cell nuclear antigen (PCNA). Nox4 silencing suppressed LPS-induced TNF-α and PCNA increases in human cells. The LPS-induced TNF-α increases were MyD88-dependent, and were attenuated in primary hepatocytes isolated from Nox4-deficient mice. We found that Nox4 mediated LPS-TLR4 signaling in hepatocytes via NF-ĸB and AP-1 pathways. Moreover, the effect of Nox4 depletion was time-dependent; following six weeks of repeated LPS stimulationin vivo, hepatic TNF-α and PCNA responses subsided in Nox4-deficient mice compared with wildtype mice. Therefore, our data suggest that Nox4 mediates LPS-TLR4 signaling in human hepatoma cells and murine hepatocytes and may contribute to the ability of LPS to stimulate liver pathology.
Effects of gas sorption-induced swelling/shrinkage on the cleat compressibility of coal under different bedding directions
Authors: Peng Shoujian , Fang Zhiming , Shen Jian , Xu Jiang , Wang Geoff
Published: October 2017

The cleat compressibility of coal is a key parameter that is extensively used in modeling the coal reservoir permeability for Coal Bed Methane (CBM) recovery. Cleat compressibility is often determined from the permeability measurement made at different confining pressures but with a constant pore pressure. Hence, this parameter ignores the sorption strain effects on the cleat compressibility. By using the transient pulse decay (TPD) technique, this study presents the results from a laboratory characterization program using coal core drilled from different bedding directions to estimate gas permeability and coal cleat compressibility under different pore pressures while maintaining effective stress constant. Cleat compressibility was determined from permeability and sorption strain measurements that are made at different pore pressures under an effective stress constant. Results show that the cleat compressibility of coal increases slightly with the increase of pore pressure. Moreover, the cleat compressibility of Sample P (representing the face cleats in coal) is larger than that of Sample C (representing the butt cleats in coal). This result suggests that cleat compressibility should not be regarded as constant in the modeling of the CBM recovery. Furthermore, the compressibility of face cleats is considerably sensitive to the sorption-induced swelling/shrinkage and offers significant effects on the coal permeability.
Learning an unknown transformation via a genetic approach
Authors: Spagnolo Nicolò , Maiorino Enrico , Vitelli Chiara , Bentivegna Marco , Crespi Andrea , Ramponi Roberta , Mataloni Paolo , Osellame Roberto , Sciarrino Fabio
Published: October 2017

Recent developments in integrated photonics technology are opening the way to the fabrication of complex linear optical interferometers. The application of this platform is ubiquitous in quantum information science, from quantum simulation to quantum metrology, including the quest for quantum supremacy via the boson sampling problem. Within these contexts, the capability to learn efficiently the unitary operation of the implemented interferometers becomes a crucial requirement. In this letter we develop a reconstruction algorithm based on a genetic approach, which can be adopted as a tool to characterize an unknown linear optical network. We report an experimental test of the described method by performing the reconstruction of a 7-mode interferometer implemented via the femtosecond laser writing technique. Further applications of genetic approaches can be found in other contexts, such as quantum metrology or learning unknown general Hamiltonian evolutions.
Submaximal exercise training improves mitochondrial efficiency in the gluteus medius but not in the triceps brachii of young equine athletes
Authors: White Sarah. H. , Warren Lori K. , Li Chengcheng , Wohlgemuth Stephanie E.
Published: October 2017

We tested the hypothesis that, similar to humans and rodents, exercise training would enhance mitochondrial (Mt) biogenesis and function in skeletal muscle of young horses. Twenty-four Quarter Horse yearlings were randomly assigned to either submaximal exercise training or no forced exercise (untrained). Biopsies were collected from the gluteus medius and triceps brachii before and after 9 wk of treatment. Citrate synthase activity was lower (P < 0.0001) and cytochrome c oxidase activity per Mt unit was higher (P < 0.0001) in gluteus compared to triceps, but neither changed over the trial period. From wk 0 to 9, intrinsic Mt respiration (P
CI
, P
CI+II
; P = 0.008) and electron transport capacity (E
CI+II
; P = 0.01) increased, and LEAK-related flux control factor (FCFL; P = 0.02) decreased in both muscles. After 9 wk of training, gluteus muscle exhibited higher (P < 0.05) intrinsic P
CI
, P
CI+II
, E
CI+II
, and FCFCI and FCF
CI+II
, and lower FCFL (P = 0.0002). Mitochondrial content did not change from wk 0 to 9, and also not in response to submaximal exercise training. Improvements in Mt function were most directly related to ongoing growth of horses independent of muscle group, and training further enhanced Mt function in the gluteus medius.
The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes
Authors: Pereira Ana , Fernandes Rosa , Crisóstomo Joana , Seiça Raquel M. , Sena Cristina M.
Published: October 2017

In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.
Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients
Authors: Liu Jessica , Hu Hui-Han , Lee Mei-Hsuan , Korenaga Masaaki , Jen Chin-Lan , Batrla-Utermann Richard , Lu Sheng-Nan , Wang Li-Yu , Mizokami Masashi , Chen Chien-Jen , Yang Hwai-I
Published: October 2017

This study examines the role of M2BPGi, a novel seromarker for chronic hepatitis, in predicting hepatocellular carcinoma (HCC) among untreated chronic hepatitis B (CHB) patients. In this nested case-control study, 1070 samples were assayed for M2BPGi, including 357 samples from HCC cases, and 713 samples from non-HCC controls, collected at various times throughout follow-up. HCC case samples were stratified according to years prior to diagnosis. Associations between M2BPGi and HCC were examined with multivariate logistic regression. M2BPGi, α-fetoprotein (AFP), and hepatitis B surface antigen (HBsAg) levels were significant independent short-term predictors of HCC, while M2BPGi was insignificant in long-term analyses. Compared to M2BPGi levels <1.0 cut-off index (COI), those with levels ≥2.0 COI had multivariate odds ratios (95% CI) for HCC of 7.40 (2.40–22.78), 6.46 (2.58–16.18), and 2.24 (0.97–5.15), respectively, for prediction of HCC within 1-2, 2–5, and ≥5 years. Higher proportions of individuals had M2BPGi levels ≥2.0 COI in samples closer to HCC diagnosis. Areas under receiver operating characteristic curves for models with M2BPGi, AFP, and HBsAg levels predicting HCC within 1–2, 2–5, and >5 years were 0.84, 0.81, and 0.75. M2BPGi is a strong and independent short-term predictor of HCC in CHB patients.
Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity
Authors: Park Spencer , Shevlin Enda , Vedvyas Yogindra , Zaman Marjan , Park Susan , Hsu Yen-Michael S. , Min Irene M. , Jin Moonsoo M.
Published: October 2017

Adoptive transfer of high-affinity chimeric antigen receptor (CAR) T cells targeting hematological cancers has yielded impressive clinical results. However, safety concerns regarding target expression on healthy tissue and poor efficacy have hampered application to solid tumors. Here, a panel of affinity-variant CARs were constructed targeting overexpressed ICAM-1, a broad tumor biomarker, using its physiological ligand, LFA-1. Anti-tumor T cell potencyin vitrowas directly proportional to CAR affinity and ICAM-1 density. In a solid tumor mouse model allowing simultaneous monitoring of anti-tumor potency and systemic off-tumor toxicity, micromolar affinity CAR T cells demonstrated superior anti-tumor efficacy and safety compared to their nanomolar counterparts. Longitudinal T cell tracking by PET/CT and concurrent cytokine measurement revealed superior expansion and contraction kinetics of micromolar affinity CAR T cells. Therefore, we developed an ICAM-1 specific CAR with broad anti-tumor applicability that utilized a reduced affinity targeting strategy to significantly boost efficacy and safety.
Population dynamics of enteric Salmonella in response to antimicrobial use in beef feedlot cattle
Authors: Ohta Naomi , Norman Keri N. , Norby Bo , Lawhon Sara D. , Vinasco Javier , den Bakker Henk , Loneragan Guy H. , Scott H. Morgan
Published: October 2017

A randomized controlled longitudinal field trial was undertaken to assess the effects of injectable ceftiofur crystalline-free acid (CCFA) versus in-feed chlortetracycline on the temporal dynamics of Salmonella enterica spp. enterica in feedlot cattle. Two replicates of 8 pens (total 176 steers) received one of 4 different regimens. All, or one, out of 11 steers were treated with CCFA on day 0 in 8 pens, with half of the pens later receiving three 5-day regimens of chlortetracycline from day 4 to day 20. Salmonella was isolated from faecal samples and antimicrobial susceptibility was analysed via microbroth dilution. Serotype was determined by whole-genome sequencing. On day 0, mean Salmonella prevalence was 75.0% and the vast majority of isolates were pansusceptible. Both antimicrobials reduced overall prevalence of Salmonella; however, these treatments increased the proportion of multi-drug resistant (MDR) Salmonella from day 4 through day 26, which was the last day of faecal collection. Only six Salmonella serotypes were detected. Salmonella serotype Reading isolates were extensively MDR, suggesting a strong association between serotype and resistance. Our study demonstrates that the selection pressures of a 3rd generation cephalosporin and chlortetracycline during the feeding period contribute to dynamic population shifts between antimicrobial susceptible and resistant Salmonella.