bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes
Authors: Cojohari Olesea , Peppenelli Megan A. , Chan Gary C.
Published: May 2016

Human cytomegalovirus (HCMV) is a pervasive herpesvirus responsible for significant morbidity and mortality among immunodeficient/naive hosts. Following a primary HCMV infection, circulating blood monocytes mediate the systemic spread of the virus. Extending the short 48-h life span of monocytes is critical to the viral dissemination process, as these blood-borne cells are nonpermissive for virus replication until they are fully differentiated into macrophages. Here, we show that HCMV glycoprotein gB binding to cellular epidermal growth factor receptor (EGFR) during HCMV entry initiated a rapid (within 15 min) activation of the apoptosis suppressor Akt, which was maintained through 72 h. The virus-induced activation of Akt was more robust than that with the normal myeloid growth factor macrophage colony-stimulating factor (M-CSF) and was essential for infected monocytes to bypass the 48-h viability checkpoint. Activation of phosphoinositide 3-kinase (PI3K) following EGFR engagement by HCMV mediated the phosphorylation of Akt. Moreover, HCMV entry drove a switch away from the PI3K p110δ isoform, which was required for the viability of uninfected monocytes, to the p110β isoform in order to facilitate the Akt-dependent prosurvival state within infected cells. Simultaneously, in contrast to M-CSF, HCMV promoted a rapid increase in SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) expression, leading to signaling through a noncanonical Akt activation pathway. To ensure maximum Akt activity, HCMV also induced an early phosphorylation-dependent inactivation of the negative regulator phosphatase and tensin homolog. Overall, our data indicate that HCMV hijacks the upstream Akt signaling network to induce a nontraditional activation of Akt and subsequently a prosurvival decision at the 48-h cell fate checkpoint, a vital step for HCMV's dissemination and persistence strategy.

IMPORTANCEHCMV is found throughout the world with a prevalence of 55 to 100% within the human population. HCMV infection is generally asymptomatic in immunocompetent or naive individuals but is a significant cause of morbidity and mortality among the immunocompromised. Widespread organ inflammation is associated with symptomatic infections, which is a direct consequence of the viral dissemination strategy. Inflammatory peripheral blood monocytes facilitate the spread of HCMV. However, HCMV must subvert the naturally short life span of monocytes. In this work, we demonstrate that HCMV induces the activation of Akt, an antiapoptotic protein, in a manner distinct from that of normal myeloid growth factors. Moreover, we decipher how HCMV dysregulates the upstream Akt signaling network during viral entry to promote an Akt-dependent prosurvival state following infection. Delineation of the virus-specific mechanisms that regulate cellular prosurvival pathways in order to drive the survival of HCMV-infected monocytes is important to identifying new anti-HCMV therapeutic targets.
Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly
Authors: Blazevic Janja , Rouha Harald , Bradt Victoria , Heinz Franz X. , Stiasny Karin
Published: May 2016

The structural proteins of flaviviruses carry a unique set of transmembrane domains (TMDs) at their C termini that are derived from the mode of viral polyprotein processing. They function as internal signal and stop-transfer sequences during protein translation, but possible additional roles in protein interactions required during assembly and maturation of viral particles are ill defined. To shed light on the role of TMDs in these processes, we engineered a set of tick-borne encephalitis virus mutants in which these structural elements were replaced in different combinations by the homologous sequences of a distantly related flavivirus (Japanese encephalitis virus). The effects of these modifications were analyzed with respect to protein synthesis, viral particle secretion, specific infectivity, and acidic-pH-induced maturation processes. We provide evidence that interactions involving the double-membrane anchor of the envelope protein E (a unique feature compared to other viral fusion proteins) contribute substantially to particle assembly, stability, and maturation. Disturbances of the inter- and intra-TMD interactions of E resulted in the secretion of a larger proportion of capsidless subviral particles at the expense of whole virions, suggesting a possible role in the still incompletely understood mechanism of capsid integration during virus budding. In contrast, the TMD initially anchoring the C protein to the endoplasmic reticulum membrane does not appear to take part in envelope protein interactions. We also show that E TMDs are involved in the envelope protein rearrangements that are triggered by acidic pH in the
trans
-Golgi network and represent a hallmark of virus maturation.

IMPORTANCE
The assembly of flaviviruses occurs in the endoplasmic reticulum and leads to the formation of immature, noninfectious particles composed of an RNA-containing capsid surrounded by a lipid membrane, with the two integrated envelope proteins, prM and E, arranged in an icosahedral lattice. The mechanism by which the capsid is formed and integrated into the budding viral envelope is currently unknown. We provide evidence that the transmembrane domains (TMDs) of E are essential for the formation of capsid-containing particles and that disturbances of these interactions lead to the preferential formation of capsidless subviral particles at the expense of whole virions. E TMD interactions also appear to be essential for the envelope protein rearrangements required for virus maturation and for the generation of infectious virions. Our data thus provide new insights into the biological functions of E TMDs and extend their role during viral polyprotein processing to additional functions in particle assembly and maturation.
Unexpected Interfarm Transmission Dynamics during a Highly Pathogenic Avian Influenza Epidemic
Authors: Fusaro Alice , Tassoni Luca , Milani Adelaide , Hughes Joseph , Salviato Annalisa , Murcia Pablo R. , Massi Paola , Zamperin Gianpiero , Bonfanti Lebana , Marangon Stefano , Cattoli Giovanni , Monne Isabella
Published: May 2016

Next-generation sequencing technology is now being increasingly applied to study the within- and between-host population dynamics of viruses. However, information on avian influenza virus evolution and transmission during a naturally occurring epidemic is still limited. Here, we use deep-sequencing data obtained from clinical samples collected from five industrial holdings and a backyard farm infected during the 2013 highly pathogenic avian influenza (HPAI) H7N7 epidemic in Italy to unravel (i) the epidemic virus population diversity, (ii) the evolution of virus pathogenicity, and (iii) the pathways of viral transmission between different holdings and sheds. We show a high level of genetic diversity of the HPAI H7N7 viruses within a single farm as a consequence of separate bottlenecks and founder effects. In particular, we identified the cocirculation in the index case of two viral strains showing a different insertion at the hemagglutinin cleavage site, as well as nine nucleotide differences at the consensus level and 92 minority variants. To assess interfarm transmission, we combined epidemiological and genetic data and identified the index case as the major source of the virus, suggesting the spread of different viral haplotypes from the index farm to the other industrial holdings, probably at different time points. Our results revealed interfarm transmission dynamics that the epidemiological data alone could not unravel and demonstrated that delay in the disease detection and stamping out was the major cause of the emergence and the spread of the HPAI strain.

IMPORTANCE
The within- and between-host evolutionary dynamics of a highly pathogenic avian influenza (HPAI) strain during a naturally occurring epidemic is currently poorly understood. Here, we perform for the first time an in-depth sequence analysis of all the samples collected during a HPAI epidemic and demonstrate the importance to complement outbreak investigations with genetic data to reconstruct the transmission dynamics of the viruses and to evaluate the within- and between-farm genetic diversity of the viral population. We show that the evolutionary transition from the low pathogenic form to the highly pathogenic form occurred within the first infected flock, where we identified haplotypes with hemagglutinin cleavage site of different lengths. We also identify the index case as the major source of virus, indicating that prompt application of depopulation measures is essential to limit virus spread to other farms.
Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase
Authors: Cheng Fan , He Meilan , Jung Jae U. , Lu Chun , Gao Shou-Jiang
Published: May 2016

The host intracellular antiviral restriction factors inhibit viral infection and replication. The 5′-AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. Activated AMPK inhibits the replication of numerous RNA viruses but enhances the entry of vaccinia virus. However, the role of AMPK in herpesvirus infection is unclear. In this study, we showed that the constitutive AMPK activity restricted Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in primary human umbilical vein endothelial cells while KSHV infection did not markedly affect the endogenous AMPK activity. Knockdown of the AMPKα1 considerably enhanced the expression of viral lytic genes and the production of infectious virions, while overexpression of a constitutively active AMPK had the opposite effects. Accordingly, an AMPK inhibitor, compound C, augmented viral lytic gene expressions and virion productions but an AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), suppressed both. Furthermore, a common diabetes drug, metformin, which carries an AMPK-agonistic activity, drastically inhibited the expression of viral lytic genes and the production of infectious virions, suggesting the use of metformin as a therapeutic agent for KSHV infection and replication. Together, these results identify the host AMPK as a KSHV restriction factor that can serve as a potential therapeutic target.

IMPORTANCE
Host cells encode specific proteins to restrict viral infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. In this study, we have identified 5′-AMP-activated protein kinase (AMPK), a cellular energy sensor, as a restriction factor of KSHV lytic replication during primary infection. Activation of AMPK suppresses, while inhibition of AMPK enhances, KSHV lytic replication by regulating the expression of viral genes. AICAR and metformin, both of which are AMPK agonists currently used in clinics for the treatment of conditions associated with metabolic disorders, inhibit KSHV lytic replication. Thus, our work has identified AMPK as a potential therapeutic target and AICAR and metformin as potential therapeutic agents for KSHV-associated cancers.
Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses
Authors: Verhalen Brandy , Starrett Gabriel J. , Harris Reuben S. , Jiang Mengxi
Published: May 2016

The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis.

IMPORTANCE
Polyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virus-induced tumorigenesis.
Influence of CT utilisation on patient flow in the emergency department: a retrospective 1-year cohort study
Authors: Li Chao-Jui , Syue Yuan-Jhen , Lin Yan-Ren , Cheng Hsien-Hung , Cheng Fu-Jen , Tsai Tsung-Cheng , Chen Kuan-Fu , Lee Chien-Hung
Published: May 2016

Objective

CT, an important diagnostic tool in the emergency department (ED), might increase the ED length of stay (LOS). Considering the issue of ED overcrowding, it is important to evaluate whether CT use delays or facilitates patient disposition in the ED.

Design

A retrospective 1-year cohort study.

Setting

5 EDs within the same healthcare system dispersed nationwide in Taiwan.

Participants

All adult non-trauma patients who visited the 5 EDs from 1 July 2011 to 30 June 2012.

Interventions

Patients were grouped by whether or not they underwent a CT scan (CT and non-CT groups, respectively).

Primary and secondary outcome measures

The ED LOS and hospital LOS between patients who had and had not undergone CT scans were compared by stratifying different dispositions and diagnoses.

Results

CT use prolonged patient ED LOS among those who were directly discharged from the ED. Among patients admitted to the observation unit and then discharged, patients diagnosed with nervous system disease had shorter ED LOS if they underwent a CT scan. CT use facilitated patient admission to the general ward. CT use also accelerated patients' admission to the intensive care unit (ICU) for patients with nervous system disease, neoplasm and digestive disease. Finally, patients admitted to the general wards had shorter hospital LOS if they underwent CT scans in the ED.

Conclusions

CT use did not seem to have delayed patient disposition in ED. While CT use facilitated patient disposition if they were finally hospitalised, it mildly prolonged ED LOS in cases of patients discharged from the ED.
Management of transition cows in dairy practice
Authors: Atkinson Owen
Published: May 2016

The calving period is a high‐risk time for dairy cows. Common disorders that can occur include milk fever, clinical ketosis, displaced abomasa, mastitis, metritis and endometritis, all of which reduce subsequent fertility. The higher the milk yield potential of the cow, the greater the challenge, and as many of the diseases are interlinked, cows often suffer multiple disorders. This article discusses a number of preventive strategies centred around transition cow management that have the potential to reduce the incidence of disease at this important time, and thus improve animal welfare.
Medical humanities: a closer look at learning
Authors: Patterson A , Sharek D , Hennessy M , Phillips M , Schofield S
Published: May 2016

The inclusion of medical humanities with medical curricula is a question that has been the focus of attention for many within the evolving field. This study addressed the question from a medical education perspective and aimed to investigate what students at Trinity College Dublin learned from participating in a short medical humanities student-selected module in their first year of an undergraduate medical programme. A total of 156 students provided a written reflection on a memorable event that occurred during their student-selected module. The reflections were analysed using the Reflection Evaluation for Learners' Enhanced Competencies Tool (REFLECT) and through qualitative thematic analysis of the written reflections. Evidence of learning from the REFLECT quantitative analysis showed that 50% of students displayed higher levels of reflection when describing their experience. The reflection content analysis supported the heterogeneous nature of learning outcome for students, with evidence to support the idea that the module provided opportunities for students to explore their beliefs, ideas and feelings regarding a range of areas outside their current experience or world view, to consider the views of others that they may have not previously been aware of, to reflect on their current views, and to consider their future professional practice.
The impact of a 48-h fast on SIRT1 and GCN5 in human skeletal muscle
Authors: Edgett Brittany A. , Scribbans Trisha D. , Raleigh James P. , Matusiak Jennifer B.L. , Boonstra Kristen , Simpson Craig A. , Perry Christopher G.R. , Quadrilatero Joe , Gurd Brendon J.
Published: May 2016

The present study examined the impact of a 48 h fast on the expression and activation status of SIRT1 and GCN5, the relationship between SIRT1/GCN5 and the gene expression of PGC-1α, and the PGC-1α target PDK4 in the skeletal muscle of 10 lean healthy men (age, 22.0 ± 1.5 years; peak oxygen uptake, 47.2 ± 6.7 mL/(min·kg)). Muscle biopsies and blood samples were collected 1 h postprandial (Fed) and following 48 h of fasting (Fasted). Plasma insulin (Fed, 80.8 ± 47.9 pmol/L; Fasted, not detected) and glucose (Fed, 4.36 ± 0.86; Fasted, 3.74 ± 0.25 mmol/L, p = 0.08) decreased, confirming participant adherence to fasting. Gene expression of PGC-1α decreased (p < 0.05, –24%), while SIRT1 and PDK4 increased (p < 0.05, +11% and +1023%, respectively), and GCN5 remained unchanged. No changes were observed for whole-muscle protein expression of SIRT1, GCN5, PGC-1α, or COX IV. Phosphorylation of SIRT1, AMPKα, ACC, p38 MAPK, and PKA substrates as well as nuclear acetylation status was also unaltered. Additionally, nuclear SIRT1 activity, GCN5, and PGC-1α content remained unchanged. Preliminary findings derived from regression analysis demonstrate that changes in nuclear GCN5 and SIRT1 activity/phosphorylation may contribute to the control of PGC-1α, but not PDK4, messenger RNA expression following fasting. Collectively, and in contrast with previous animal studies, our data are inconsistent with the altered activation status of SIRT1 and GCN5 in response to 48 h of fasting in human skeletal muscle.
Improving plant biomass estimation in the field using partial least squares regression and ridge regression
Authors: Ohsowski Brian M. , Dunfield Kari E. , Klironomos John N. , Hart Miranda M.
Published: May 2016

Estimating primary productivity over time is challenging for plant ecologists. The most accurate biomass measurements require destructive sampling and weighing. This is often not possible for manipulative studies that involve repeated measures over time, or for studies in protected areas. Estimates of aboveground plant biomass using allometric equations or linear regression on single plant traits have been used, but tend to have poor predictability both within and across systems, or are limited to specific plant taxa. Here we estimate aboveground plant biomass using multiple collinear plant traits to generate a standard curve specific to the site of interest. Partial least squares regression (PLS) and ridge regression (RR), addressing predictor collinearity, are robust, highly accurate statistical methods to estimate plant biomass across gross differences in plant morphology and growth habit.
State Estimation and Forecasting of the Ski-Slope Model Using an Improved Shadowing Filter
Authors: Mat Daud Auni Aslah
Published: May 2016

In this paper, we present the application of the gradient descent of indeterminism (GDI) shadowing filter to a chaotic system, that is the ski-slope model. The paper focuses on the quality of the estimated states and their usability for forecasting. One main problem is that the existing GDI shadowing filter fails to provide stability to the convergence of the root mean square error and the last point error of the ski-slope model. Furthermore, there are unexpected cases in which the better state estimates give worse forecasts than the worse state estimates. We investigate these unexpected cases in particular and show how the presence of the humps contributes to them. However, the results show that the GDI shadowing filter can successfully be applied to the ski-slope model with only slight modification, that is, by introducing the adaptive step-size to ensure the convergence of indeterminism. We investigate its advantages over fixed step-size and how it can improve the performance of our shadowing filter.
Bifurcation Complexity from Orbit-Flip Homoclinic Orbit of Weak Type
Authors: Lu Qiuying , Naudot Vincent
Published: May 2016

In this paper, we study the unfolding of a three-dimensional vector field having an orbit-flip homoclinic orbit of weak type. Such a homoclinic orbit is a degenerate version of the so-called orbit-flip homoclinic orbit. We show the existence of inclination-flip homoclinic orbits of arbitrary higher order bifurcating from the unperturbed system. Our strategy consists of using the local moving coordinates method and blow up in the parameter space. In addition, the numerical existence of the orbit-flip homoclinic orbit of weak type is presented based on the truncated Taylor expansion and the numerical computation for both the strong stable manifold and unstable manifold.
Fast and Direct Polygonization for Gray-Scale Images Using Digital Straightness and Exponential Averaging
Authors: Pratihar Sanjoy , Bhowmick Partha
Published: May 2016

Although there exist various algorithms for polygonization of objects present in a digital image, most of them cannot directly be applied on a gray-scale image without resorting to edge map computation, thinning, etc. Hence, with the aim of applying polygonization directly on a gray-scale image, we propose here an improved algorithm. It is based on a novel proposition of exponential averaging of estimated edge strengths, which is used to extract (thinned) digitally straight edges directly from a gray-scale image. These straight edges are subsequently used as input for a fast polygonization based on simple primitive operations in the integer domain. Procedural advantages and implementation details of the proposed method are explained in this paper to adjudge its fitness in the context of polygonization. Experimental results have been furnished to demonstrate the usefulness, efficiency, and robustness of the proposed technique.
Photochemical hydrogen evolution using Sn-porphyrin as photosensitizer and a series of Cobaloximes as catalysts
Authors: Landrou Georgios , Panagiotopoulos Athanassios A. , Ladomenou Kalliopi , Coutsolelos Athanassios G.
Published: May 2016

Herein, we report a photochemical hydrogen evolution system consisting of various cobalt based catalysts, a metallated Sn porphyrin as photosensitizer and a triethanolamine as a sacrificial electron donor in acetonitrile/H2O (1:1) solution. Since a tin metallated porphyrin is used for the first time as photosensitizer in this type of systems, a systematic study was performed in order to elucidate the best conditions for H[Formula: see text]production. Upon visible irradiation hydrogen production was detected with the best result obtained at pH 7 with a TON of 150, after 100 h in the presence of catalyst 1. Moreover, when TiO2 nanoparticles were added at the catalytic system 2 the hydrogen production was increased from 53 TON to 131 TON, under the same experimental conditions.
Microstructure evolution in multilayer c-TiAlN/TiN coatings during spinodal decomposition — A phase-field study
Authors: Zhou Jingjing , Zhang Lijun , Chen Li , Wu Hong , Du Yong
Published: May 2016

By means of the combined model, i.e., the phase-field model with finite interface dissipation in combination with the modified Cahn–Hilliard model, together with the materials parameters comprehensively verified in monolithic c-TiAlN coatings, the microstructure evolution in multilayer c-Ti[Formula: see text]Al[Formula: see text]N/TiN coatings annealed at [Formula: see text]C was quantitatively simulated by directly comparing with the experimental data. The sharp interface between c-TiN and c-Ti[Formula: see text]Al[Formula: see text]N layers in the as-deposited state was found to change into a diffuse one, which can act as highly effective obstacles against dislocation motion. Moreover, the simulations indicate that the spinodal decomposition occurs in the Ti[Formula: see text]Al[Formula: see text]N layer and the decomposed layer becomes thinner, which is in good agreement with the experimental observation. In addition, the effect of modulation period and modulation ratio on microstructure evolution in c-Ti[Formula: see text]Al[Formula: see text]N/TiN coating was further studied. The relatively smaller modulation period can generate more layers in the real scale of coatings, which can help to strengthen the coatings due to refinement of grains and restriction of dislocations. As for the modulation ratio, when the value decreases from 5:1 to 1:1, Ti atoms in the decomposed layer disappear faster. A further extension into a larger-sized simulation was also performed.
Non-linear mechanical analogue of quantum Rabi oscillations in coherent output coupler for atoms in Bose-Einstein condensate
Authors: Kosevich Yuriy A.
Published: May 2016

The analogies between coherent matter waves in Bose–Einstein condensates of atomic gases and coherent photons have been discussed in connection with possible realization of an “atom laser”. Theoretical discussions of the atom laser have considered the case in which atoms are fed into and coupled out of the condensate continuously. Here, we discuss the analogy between the output coupler for the trapped coherent matter waves and collective non-linear energy transfer in a system of three-coupled mechanical oscillators (pendulums) with variable parameters. One pendulum in the system is weakly coupled through a spring with the pair of pendulums, which are tightly bound through a common string. We show that self-sustained oscillations of the energy distribution between the weakly coupled and tightly bound subsystems can occur. In our simulations, the coherent fraction of the total mechanical energy of the system, which is periodically transferred to the weakly linked subsystem, can be of the order of 1/1000 and even smaller. These periodic oscillations in vibrational energy distribution can be considered as mechanical analogue, with a similar time evolution, of the quantum Rabi oscillations in the populations of the trapped and untrapped (out-coupled) states in the coherent output coupler for atoms in the Bose–Einstein condensate. The described effects can be used for the coherent control of the transfer of mechanical energy on the micro- and nano-scales.
Improving Resource Efficiency at Scale with Heracles
Authors: Lo David , Cheng Liqun , Govindaraju Rama , Ranganathan Parthasarathy , Kozyrakis Christos
Published: May 2016

User-facing, latency-sensitive services, such as websearch, underutilize their computing resources during daily periods of low traffic. Reusing those resources for other tasks is rarely done in production services since the contention for shared resources can cause latency spikes that violate the service-level objectives of latency-sensitive tasks. The resulting under-utilization hurts both the affordability and energy efficiency of large-scale datacenters. With the slowdown in technology scaling caused by the sunsetting of Moore’s law, it becomes important to address this opportunity.

We present Heracles, a feedback-based controller that enables the safe colocation of best-effort tasks alongside a latency-critical service. Heracles dynamically manages multiple hardware and software isolation mechanisms, such as CPU, memory, and network isolation, to ensure that the latency-sensitive job meets latency targets while maximizing the resources given to best-effort tasks. We evaluate Heracles using production latency-critical and batch workloads from Google and demonstrate average server utilizations of 90% without latency violations across all the load and colocation scenarios that we evaluated.
Development and Applications of Liquid Sample Desorption Electrospray Ionization Mass Spectrometry
Authors: Zheng Qiuling , Chen Hao
Published: May 2016

Desorption electrospray ionization mass spectrometry (DESI-MS) is a recent advance in the field of analytical chemistry. This review surveys the development of liquid sample DESI-MS (LS-DESI-MS), a variant form of DESI-MS that focuses on fast analysis of liquid samples, and its novel analy-tical applications in bioanalysis, proteomics, and reaction kinetics. Due to the capability of directly ionizing liquid samples, liquid sample DESI (LS-DESI) has been successfully used to couple MS with various analytical techniques, such as microfluidics, microextraction, electrochemistry, and chromatography. This review also covers these hyphenated techniques. In addition, several closely related ionization methods, including transmission mode DESI, thermally assisted DESI, and continuous flow–extractive DESI, are briefly discussed. The capabilities of LS-DESI extend and/or complement the utilities of traditional DESI and electrospray ionization and will find extensive and valuable analytical application in the future.
Mechanisms of Mitotic Spindle Assembly
Authors: Petry Sabine
Published: May 2016

Life depends on cell proliferation and the accurate segregation of chromosomes, which are mediated by the microtubule (MT)-based mitotic spindle and ∼200 essential MT-associated proteins. Yet, a mechanistic understanding of how the mitotic spindle is assembled and achieves chromosome segregation is still missing. This is mostly due to the density of MTs in the spindle, which presumably precludes their direct observation. Recent insight has been gained into the molecular building plan of the metaphase spindle using bulk and single-molecule measurements combined with computational modeling. MT nucleation was uncovered as a key principle of spindle assembly, and mechanistic details about MT nucleation pathways and their coordination are starting to be revealed. Lastly, advances in studying spindle assembly can be applied to address the molecular mechanisms of how the spindle segregates chromosomes.
CRISPR/Cas9 in Genome Editing and Beyond
Authors: Wang Haifeng , La Russa Marie , Qi Lei S.
Published: May 2016

The Cas9 protein (CRISPR-associated protein 9), derived from type II CRISPR (clustered regularly interspaced short palindromic repeats) bacterial immune systems, is emerging as a powerful tool for engineering the genome in diverse organisms. As an RNA-guided DNA endonuclease, Cas9 can be easily programmed to target new sites by altering its guide RNA sequence, and its development as a tool has made sequence-specific gene editing several magnitudes easier. The nuclease-deactivated form of Cas9 further provides a versatile RNA-guided DNA-targeting platform for regulating and imaging the genome, as well as for rewriting the epigenetic status, all in a sequence-specific manner. With all of these advances, we have just begun to explore the possible applications of Cas9 in biomedical research and therapeutics. In this review, we describe the current models of Cas9 function and the structural and biochemical studies that support it. We focus on the applications of Cas9 for genome editing, regulation, and imaging, discuss other possible applications and some technical considerations, and highlight the many advantages that CRISPR/Cas9 technology offers.
Cell Geometry: How Cells Count and Measure Size
Authors: Marshall Wallace F
Published: May 2016

The cell represents a highly organized state of living matter in which numerous geometrical parameters are under dynamic regulation in order to match the form of a cell with its function. Cells appear capable of regulating not only the total quantity of their internal organelles, but also the size and number of those organelles. The regulation of three parameters, size, number, and total quantity, can in principle be accomplished by regulating the production or growth of organelles, their degradation or disassembly, and their partitioning among daughter cells during division. Any or all of these steps could in principle be under regulation. But if organelle assembly or disassembly is regulated by number or size, how would the cell know how many copies of an organelle it has, or how big they are?
Single-Molecule FRET Spectroscopy and the Polymer Physics of Unfolded and Intrinsically Disordered Proteins
Authors: Schuler Benjamin , Soranno Andrea , Hofmann Hagen , Nettels Daniel
Published: May 2016

The properties of unfolded proteins have long been of interest because of their importance to the protein folding process. Recently, the surprising prevalence of unstructured regions or entirely disordered proteins under physiological conditions has led to the realization that such intrinsically disordered proteins can be functional even in the absence of a folded structure. However, owing to their broad conformational distributions, many of the properties of unstructured proteins are difficult to describe with the established concepts of structural biology. We have thus seen a reemergence of polymer physics as a versatile framework for understanding their structure and dynamics. An important driving force for these developments has been single-molecule spectroscopy, as it allows structural heterogeneity, intramolecular distance distributions, and dynamics to be quantified over a wide range of timescales and solution conditions. Polymer concepts provide an important basis for relating the physical properties of unstructured proteins to folding and function.
Lewis Acid Zeolites for Biomass Conversion: Perspectives and Challenges on Reactivity, Synthesis, and Stability
Authors: Luo Helen Y. , Lewis Jennifer D. , Román-Leshkov Yuriy
Published: May 2016

Zeolites containing Sn, Ti, Zr, Hf, Nb, or Ta heteroatoms are versatile catalysts for the activation and conversion of oxygenated molecules owing to the unique Lewis acid character of their tetrahedral metal sites. Through fluoride-mediated synthesis, hydrophobic Lewis acid zeolites can behave as water-tolerant catalysts, which has resulted in a recent surge of experimental and computational studies in the field of biomass conversion. However, many open questions still surround these materials, especially relating to the nature of their active sites. This lack of fundamental understanding is exemplified by the many dissonant results that have been described in recent literature reports. In this review, we use a molecular-based approach to provide insight into the relationship between the structure of the metal center and its reactivity toward different substrates, with the ultimate goal of providing a robust framework to understand the properties that have the strongest influence on catalytic performance for the conversion of oxygenates.
Evolution of Gene Regulation in Humans
Authors: Reilly Steven K. , Noonan James P.
Published: May 2016

As a species, we possess unique biological features that distinguish us from other primates. Here, we review recent efforts to identify changes in gene regulation that drove the evolution of novel human phenotypes. We discuss genotype-directed comparisons of human and nonhuman primate genomes to identify human-specific genetic changes that may encode new regulatory functions. We also review phenotype-directed approaches, which use comparisons of gene expression or regulatory function in homologous human and nonhuman primate cells and tissues to identify changes in expression levels or regulatory activity that may be due to genetic changes in humans. Together, these studies are beginning to reveal the landscape of regulatory innovation in human evolution and point to specific regulatory changes for further study. Finally, we highlight two novel strategies to model human-specific regulatory functions in vivo: primate induced pluripotent stem cells and the generation of humanized mice by genome editing.
Neoliberalism, Post-Communism, and the Law
Authors: Bugarič Bojan
Published: May 2016

Neoliberalism represents the revival of economic liberalism that has been taking place since the late 1970s. Its main premise is that the market is morally and practically superior to government and any form of political control intended to improve on market outcomes. Central and Eastern European countries (CEEs) were global leaders in the adoption of neoliberal ideas and policies during the 1990s and 2000s. Almost all CEEs adopted neoliberal ideas and policies at a dramatic rate and are now among the most open economies in Europe. This was particularly true during the early transition period, when neoliberalism emerged as a virtually unchallenged ideology strongly dominating the course of economic and political reforms in the region. CEEs largely followed the script written by the authors of the Washington consensus and implemented monetary stabilization, economic liberalization, and a grand-scale privatization of the largely state-owned economy. This article traces the role of law during the first 25 years of transition and its relationship with neoliberal policies and institutions that were put in place in CEEs. It does so chronologically, through three different periods of transition, which also represent the quite different roles that the law assumed in the process.
Metal Additive Manufacturing: A Review of Mechanical Properties
Authors: Lewandowski John J. , Seifi Mohsen
Published: May 2016

This article reviews published data on the mechanical properties of additively manufactured metallic materials. The additive manufacturing techniques utilized to generate samples covered in this review include powder bed fusion (e.g., EBM, SLM, DMLS) and directed energy deposition (e.g., LENS, EBF3). Although only a limited number of metallic alloy systems are currently available for additive manufacturing (e.g., Ti-6Al-4V, TiAl, stainless steel, Inconel 625/718, and Al-Si-10Mg), the bulk of the published mechanical properties information has been generated on Ti-6Al-4V. However, summary tables for published mechanical properties and/or key figures are included for each of the alloys listed above, grouped by the additive technique used to generate the data. Published values for mechanical properties obtained from hardness, tension/compression, fracture toughness, fatigue crack growth, and high cycle fatigue are included for as-built, heat-treated, and/or HIP conditions, when available. The effects of test orientation/build direction on properties, when available, are also provided, along with discussion of the potential source(s) (e.g., texture, microstructure changes, defects) of anisotropy in properties. Recommendations for additional work are also provided.
Multiscale Modeling of Powder Bed–Based Additive Manufacturing
Authors: Markl Matthias , Körner Carolin
Published: May 2016

Powder bed fusion processes are additive manufacturing technologies that are expected to induce the third industrial revolution. Components are built up layer by layer in a powder bed by selectively melting confined areas, according to sliced 3D model data. This technique allows for manufacturing of highly complex geometries hardly machinable with conventional technologies. However, the underlying physical phenomena are sparsely understood and difficult to observe during processing. Therefore, an intensive and expensive trial-and-error principle is applied to produce components with the desired dimensional accuracy, material characteristics, and mechanical properties. This review presents numerical modeling approaches on multiple length scales and timescales to describe different aspects of powder bed fusion processes. In combination with tailored experiments, the numerical results enlarge the process understanding of the underlying physical mechanisms and support the development of suitable process strategies and component topologies.
Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens
Authors: Santajit Sirijan , Indrawattana Nitaya
Published: May 2016

The ESKAPE pathogens (Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) are the leading cause of nosocomial infections throughout the world. Most of them are multidrug resistant isolates, which is one of the greatest challenges in clinical practice. Multidrug resistance is amongst the top three threats to global public health and is usually caused by excessive drug usage or prescription, inappropriate use of antimicrobials, and substandard pharmaceuticals. Understanding the resistance mechanisms of these bacteria is crucial for the development of novel antimicrobial agents or other alternative tools to combat these public health challenges. Greater mechanistic understanding would also aid in the prediction of underlying or even unknown mechanisms of resistance, which could be applied to other emerging multidrug resistant pathogens. In this review, we summarize the known antimicrobial resistance mechanisms of ESKAPE pathogens.
Pancreatic Pseudocyst Pleural Fistula in Gallstone Pancreatitis
Authors: Abdalla Sala , Nikolopoulos Ioannis , Kerwat Rajab
Published: May 2016

Extra-abdominal complications of pancreatitis such as pancreaticopleural fistulae are rare. A pancreaticopleural fistula occurs when inflammation of the pancreas and pancreatic ductal disruption lead to leakage of secretions through a fistulous tract into the thorax. The underlying aetiology in the majority of cases is alcohol-induced chronic pancreatitis. The diagnosis is often delayed given that the majority of patients present with pulmonary symptoms and frequently have large, persistent pleural effusions. The diagnosis is confirmed through imaging and the detection of significantly elevated amylase levels in the pleural exudate. Treatment options include somatostatin analogues, thoracocentesis, endoscopic retrograde cholangiopancreatography (ERCP) with pancreatic duct stenting, and surgery. The authors present a case of pancreatic pseudocyst pleural fistula in a woman with gallstone pancreatitis presenting with recurrent pneumonias and bilateral pleural effusions.
Citizen Sensing for Improved Urban Environmental Monitoring
Authors: Jiang Qijun , Kresin Frank , Bregt Arnold K. , Kooistra Lammert , Pareschi Emma , van Putten Edith , Volten Hester , Wesseling Joost
Published: May 2016

Citizen science is increasingly being used in diverse research domains. With the emergence and rapid development of sensor technologies, citizens potentially have more powerful tools to collect data and generate information to understand their living environment. Although sensor technologies are developing fast, citizen sensing has not been widely implemented yet and published studies are only a few. In this paper, we analyse the practical experiences from an implementation of citizen sensing for urban environment monitoring. A bottom-up model in which citizens develop and use sensors for environmental monitoring is described and assessed. The paper focuses on a case study of Amsterdam Smart Citizens Lab using NO2sensors for air quality monitoring. We found that the bottom-up citizen sensing is still challenging but can be successful with open cooperation and effective use of online and offline facilities. Based on the assessment, suggestions are proposed for further implementations and research.
Altered Expression of TLR2 and TLR4 on Peripheral CD14+ Blood Monocytes in Children with Urinary Tract Infection
Authors: Karananou Panagiota , Fleva Alexandra , Tramma Despoina , Alataki Anastasia , Pavlitou-Tsiontsi Aikaterini , Emporiadou-Peticopoulou Maria , Papadopoulou-Alataki Efimia
Published: May 2016

Urinary tract infection (UTI) is the second most common bacterial infection, after otitis media, in infants and children. The mechanisms of disease susceptibility and the role of immunity in the pathogenesis of UTI in children have been evaluated. In recent years, Toll-Like Receptors (TLRs) have been recognized as specific components of the innate immune system constituting important mediators in host immune recognition. The aim of the present study was to determine ΤLR2 and TLR4 expression during the acute phase of UTI in infants and children by measuring the CD14/TLR2 and CD14/TLR4 expression on monocytes. We also attempted to compare the TLRs expression with the immunological status of the patients to healthy children. The study group consisted of 60 children (36 females and 24 males) and the control group included 60 age-matched pediatric subjects (27 females and 33 males). In our study, no antibody deficiency was found either in the children with UTI or in healthy subjects. There might be a connection between low IgA, IgG, and IgG subclasses serum levels and UTI as there was a statistically significant difference between patients and healthy children. A higher expression of CD14/TLR2 was revealed in patients (90,07%) compared to controls (85,48%) as well as CD14/TLR4 in patients (90,53%) compared to controls (87,25%) (statistically significant difference,p<0,05). The results of this study could provide new understanding of UTIs’ pathogenesis in children.
A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle
Authors: Mackenzie R. W. A. , Watt P.
Published: May 2016

Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control.