bluuebunny/crossref_metadata_2025 huggingface dataset:
Colostrogenesis during an induced lactation in dairy cattle
Authors: Stark A. , Wellnitz O. , Dechow C. , Bruckmaier R. , Baumrucker C.
Published: May 2014

Colostrum immunoglobulin G (IgG) is of major importance for the newborn calf because epitheliochorial placentae do not provide transport in utero. The formation of colostrum occurs in the later stages of pregnancy. Our objectives were to induce lactation in non‐pregnant dairy cows and (i) to determine the changes of IgG in serum and mammary secretions during the induction process and (ii) to establish α‐lactalbumin (αLA) and prolactin (Prl) alterations to monitor the changing mammary epithelial tight junction status and development pattern. Estradiol‐17β (E2) and progesterone (P4) injections in a 1–7 days series were combined with a 3‐day injection series (day 21–23) of dexamethasone (DEX). Blood and both front quarter secretion samples were collected daily. Milking started 24 days after the start of the experiment. Results show that the mammary secretory IgG1 was increased at >7 days after the start of steroid injections and depicted a bimodal pattern reaching a high of 16 mg/ml at 21 day compared with 3.2 mg/ml in the serum. There was a small increase in secretory IgG2 that did not correlate with tight junction status, but never reached the serum concentration. The injections of DEX resulted in constriction of tight junctions. Secretory αLA was immediately increased with steroid injections, dropped precipitously after 7 days and then began a steady increase until the start of milking. Changes in serum αLA are related to mammary tight junctions while serum Prl gradually increased from 30 to >60 ng/ml after the steroid injections stopped. These results provide insights into the mechanisms and timing of colostrogenesis during an induced lactation protocol.
Pegylated interferons Lambda‐1a and alfa‐2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells
Authors: Freeman J. , Baglino S. , Friborg J. , Kraft Z. , Gray T. , Hill M. , McPhee F. , Hillson J. , Lopez‐Talavera J. C. , Wind‐Rotolo M.
Published: May 2014

Pegylated interferon‐lambda‐1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa‐2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN‐stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV‐infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN‐λ‐limiting receptor subunit was lower compared with IFN‐α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda‐induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV‐infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP‐10, iTAC, IL‐6, MCP‐1 and MIP‐1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa.
Lower life expectancy among people with an HCV notification: a population‐based linkage study
Authors: Alavi M. , Law M. G. , Grebely J. , Thein H. H. , Walter S. , Amin J. , Dore G. J.
Published: May 2014

Among people with hepatitis C virus (HCV) infection, liver disease‐related deaths have risen over the last 20 years. Life expectancy has not been estimated in this population. HCV notifications (mandatory notification of anti‐HCV‐positive serology since 1991) reported to the New South Wales Health Department from 1992 to 2006 were linked to cause of death data. Abridged life tables were constructed from age‐specific mortality rates. Life expectancy from ages 18–70 years for non‐drug‐related mortality causes was estimated using competing risk methods and compared to the general population of Australia. The cohort comprised 81 644 individuals with an HCV notification, with median follow‐up of 7.6 years. Median age at notification was 34 years [interquartile range (IQR) 28–42] and 63% were male. Between 1992 and 2006, 4607 deaths occurred. Median age at liver‐ and drug‐related death among males was 51 (IQR 45–66) and 36 (IQR 31–42) years, respectively, and among females was 63 (IQR 49–74) and 36 (IQR 30–41) years, respectively. In each year of follow‐up before 2000, 15–21% of deaths were liver‐ and 30–39% were drug‐related. After 2000, liver‐related deaths increased to 20–26% of deaths in each year and drug‐related deaths decreased to 13–19%. Excluding drug‐related causes of death, life expectancy was lowered by an average of 4.2 (SD ± 1.0) and 5.4 (SD ± 0.7) years for males and females, respectively. Among people with an HCV notification, an increasing proportion of deaths are liver‐related. Following removal of drug‐related mortality, life expectancy in this population remained considerably lower, compared with the general population.
Flexibility‐Corotational Formulation of Space Frames with Large Elastic Deformations and Buckling
Authors: Ray Tathagata , Schachter‐Adaros Macarena , Reinhorn Andrei M.
Published: May 2014

While the joints of a frame move in the space with large displacements and rotations, the deformations of the frame member with respect to the imaginary line connecting end joints, known as the chord, remain relatively small but still affect the stress field along the member length. A separation, known also as the corotational formulation, is simple for small displacements and rotations, and for small deformations, while in presence of large geometric changes the kinematic and dynamic interaction between the two systems (rigid and deformational) requires enhanced treatment. An enhanced corotational formulation, based on the flexibility modeling of elastic space frames with large deformations and rotations, expanding the prior developments by the authors, is presented in this article. The enhancements with respect to previous formulations cover: (1) rigid translations and expanded rotations of the chord; (2) a combination of axial and flexural deformations expanded to include torsional and shear influences; (3) a consistent formulation of geometric stiffness matrix; and (4) a rederivation of the formulation in time‐independent incremental form. The entire reformulation enables the application of flexibility‐based solutions to space frames addressing flexural and torsional buckling or postbuckling problems and allows for further integration of material nonlinearity.
Nicotinic receptor subtypes mediating relaxation of the normal human clasp and sling fibers of the upper gastric sphincter
Authors: Ruggieri M. R. , Braverman A. S. , Vegesna A. K. , Miller L. S.
Published: May 2014

Background

Proper function of the gastro‐esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations.

Methods

We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro‐esophageal reflux disease or histologic evidence of Barrett's esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re‐exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re‐exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine.

Key Results

100 μM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro‐beta‐erythroidine is ineffective.

Conclusions & Inferences

Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4, or α4β4 subunits.
Maxillary dentigerous cyst associated with an ectopic third molar in the maxillary sinus: a literature review and report of six consecutive cases
Authors: Sivolella S. , Ricci S. , Busca M. , Stellini E. , Valente M.
Published: May 2014

Dentigerous cysts are benign odontogenic cysts associated with the crowns of deciduous, permanent or supernumerary teeth. When dentigerous cysts surround impacted teeth, they often displace the teeth into ectopic positions; ectopic teeth in the maxilla may be displaced into the maxillary sinus. A review of the literature on this condition is provided, and we report on six consecutive cases of dentigerous cysts associated with an ectopic third molar in the maxillary sinus, focusing on their conservative surgical treatment.
Clinical efficacy of psoralen + sunlight vs. combination of isotretinoin and psoralen + sunlight for the treatment of chronic plaque‐type psoriasis vulgaris: a randomized hospital‐based study
Authors: Gahalaut Pratik , Soodan Puneet Singh , Mishra Nitin , Rastogi Madhur Kant , Soodan Hardev Singh , Chauhan Sandhya
Published: May 2014

Background

Isotretinoin has been used in combination with oral psoralen + UVA (PUVA) and narrowband UVB (NBUVB) for treating psoriasis, especially in women of child‐bearing age. The efficacy of oral psoralen + sun exposure (PUVAsol) is comparable to that of PUVA. This study was planned to compare the efficacy of oral PUVAsol with that of the combination of oral isotretinoin and PUVAsol in patients with chronic plaque psoriasis.

Methods

Forty patients with psoriasis vulgaris were randomized to two groups. Group A (control group) received PUVAsol only. Group B (intervention group) received PUVAsol + isotretinoin (0.5 mg/kg/day). Psoriasis Area Severity Index (PASI) score was recorded at baseline and weeks 4, 8 and 12. Dermatology Life Quality Index was assessed at baseline and 12 weeks. The end point of the study was PASI 75 or 12 weeks, whichever came earlier.

Results

Thirty‐five patients completed the study. There were statistically significant differences between the two study groups for the number of patients achieving the endpoint of PASI 75, PASI scores at the end of 12 weeks, mean duration to achieve PASI 75, number of PUVAsol sessions needed to achieve PASI75 and mean cumulative dosage of 8‐methoxypsoralen needed to achieve PASI 75.

Conclusion

The combination of isotretinoin with PUVAsol is more effective compared with PUVAsol alone for treating chronic plaque psoriasis.
Attitudes Toward Immigration: The Role of Personal Predispositions
Authors: Dinesen Peter Thisted , Klemmensen Robert , Nørgaard Asbjørn Sonne
Published: May 2014

This article examines if deep‐seated psychological differences add to the explanation of attitudes toward immigration. We explore whether the Big Five personality traits matter for immigration attitudes beyond the traditional situational factors of economic and cultural threat and analyze how individuals with different personalities react when confronted with the same situational triggers. Using a Danish survey experiment, we show that different personality traits have different effects on opposition toward immigration. We find that Openness has an unconditional effect on attitudes toward immigration: scoring higher on this trait implies a greater willingness to admit immigrants. Moreover, individuals react differently to economic threat depending on their score on the traits Agreeableness and Conscientiousness. Specifically, individuals scoring low on Agreeableness and individuals scoring high on Conscientiousness are more sensitive to the skill level of immigrants. The results imply that personality is important for attitudes toward immigration, and in the conclusion, we further discuss how the observed conditional and unconditional effects of personality make sense theoretically.
Empirical Innovations in Policy Analysis
Authors: Blume Grant , Scott Tyler , Pirog Maureen
Published: May 2014

In this article we survey the field of policy analysis from two perspectives. First, we discuss recent arguments made for and against the use of random assignment in social experimentation and policy analysis. Second, we argue that data, not methods, are driving policy analysis innovation. We review the benefits and drawbacks of three types of data—administrative data, spatial data, and Big Data—and discuss the role, or potential role, each plays in extant policy analysis. We end with a comment on what we believe are the future directions and areas of growth for the field of policy analysis in coming years.
Advances in Public Opinion and Policy Attitudes Research
Authors: Bachner Jennifer , Hill Kathy Wagner
Published: May 2014

There has been much advancement in the field of public opinion research in the past few years, particularly with respect to the formation of policy attitudes in response to elite rhetoric, the translation of policy information into attitudes, and the biological foundations of policy attitudes. Much of the progress made in these areas of study can be attributed to the increased use of innovative, experimental methods and new data sources. Nonetheless, unresolved issues persist, such as whether there is an identifiable genetic basis of policy attitudes and the extent to which cultural versus partisan orientations drive opinions. This review will discuss both new findings in the field and identify areas that require further research.
Current Trends in Science and Technology Policy Research: An Examination of Published Works from 2010–2012
Authors: Trousset Sarah
Published: May 2014

This essay identifies three notable trends in recent science and technology policy research. By analyzing the keywords listed within published scholarship from 2010–2012, a predominant portion of articles focuses on universities, patenting, and innovation policy models. Scholars have gained some insight into these processes by focusing on how collaborations between the government, universities, and industry impact technological outcomes. However, data and measurement issues have limited research in this area.
Bridging and Bonding Capital in Two‐Mode Collaboration Networks
Authors: Berardo Ramiro
Published: May 2014

Public management and policy scholars have empirically demonstrated that in complex policy arenas, governments depend on the collaboration of policy actors outside their direct control to produce needed goods and services. Government‐sponsored shared‐cost programs are one of the premier mechanisms to foster such cooperation, yet little is known about the inner patterns of participation in such programs and whether they are conditional on specific resource needs that partners may have. In this article, I study the participation of organizations in projects seeking funds from the Cooperative Funding Initiative, a program sponsored by theSouthwestFloridaWaterManagementDistrict that finances projects dealing with the management of water resources. Through the estimation of a series ofExponentialRandomGraphModels in the networks that form when organizations participate in projects (two‐mode networks), I show that centralization around popular organizations results in greater bridging network capital, which facilitates the flow of nonoverlapping information from project to project. I analyze the implications of these findings and discuss how the formation of these bridging structures may enhance the capacity of the program to find innovative solutions to the problems the projects are designed to deal with.
‘Run not before the laws’: Lily's Grammar, the Oxford Bellum grammaticale, and the rules of concord
Authors: McGregor Rachel
Published: May 2014

As the foundational text of humanist education in early modern England, Lily's Latin Grammar taught generations of English learners not only grammatical, but also social and political lessons. The royally prescribed Grammar has often been seen as a vehicle of sovereignty and its rules as instruments of subjection. However, these views are challenged by reading the Grammar alongside the internationally popular fable of the Bellum grammaticale. This didactic tale about a war between the parts of Latin speech endorses concord as the lex suprema of both grammar and society. The political implications of the Bellum grammaticale's emphasis on concord are highlighted most clearly in the Oxford playwright Leonard Hutten's dramatic adaptation of the fable, which concludes with the character Lilius prosecuting two bellicose rulers and presenting his Grammar as a constitution for their realm. When Hutten's play was performed before Queen Elizabeth at Oxford in 1592, she appears to have been offended by its celebration of scholarly authority and determined to defend her legal prerogative. On this occasion, the Grammar was used to place limits on royal authority, offering a new perspective on the ideological function of this iconic text and the rules contained within it.
Estimation of the Marginal Expected Shortfall: the Mean When a Related Variable is Extreme
Authors: Cai Juan-Juan , Einmahl John H. J. , Haan Laurens , Zhou Chen
Published: May 2014

Denote the loss return on the equity of a financial institution as X and that of the entire market as Y. For a given very small value of p > 0, the marginal expected shortfall (MES) is defined as E{X|Y>QY(1−p)}, where Q  Y(1 − p) is the (1 − p)th quantile of the distribution of Y. The MES is an important factor when measuring the systemic risk of financial institutions. For a wide non-parametric class of bivariate distributions, we construct an estimator of the MES and establish the asymptotic normality of the estimator when p ↓ 0, as the sample size n → ∞. Since we are in particular interested in the case p = O(1/n), we use extreme value techniques for deriving the estimator and its asymptotic behaviour. The finite sample performance of the estimator and the relevance of the limit theorem are shown in a detailed simulation study. We also apply our method to estimate the MES of three large US investment banks.
A Virtual Hope Box Smartphone App as an Accessory to Therapy: Proof‐of‐Concept in a Clinical Sample of Veterans
Authors: Bush Nigel E. , Dobscha Steven K. , Crumpton Rosa , Denneson Lauren M. , Hoffman Julia E. , Crain Aysha , Cromer Risa , Kinn Julie T.
Published: May 2014

A “Hope Box” is a therapeutic tool employed by clinicians with patients who are having difficulty coping with negative thoughts and stress, including patients who may be at risk of suicide or nonsuicidal self‐harm. We conducted a proof‐of‐concept test of a “Virtual” Hope Box (VHB)—a smartphone app that delivers patient‐tailored coping tools. Compared with a conventional hope box integrated into VA behavioral health treatment, high‐risk patients and their clinicians used the VHB more regularly and found the VHB beneficial, useful, easy to set up, and said they were likely to use the VHB in the future and recommend the VHB to peers.
Farm Women and Agritourism: Representing a New Rurality
Authors: Wright Wynne , Annes Alexis
Published: May 2014

This article examines how farm women represent rurality and agriculture within the context of farm tourism. We draw upon qualitative data analysis of a farm women's agritourism network in southern France centred on sheep milk production for Roquefort cheese. Through the use of choreography, staging, performances, and their bodies, we found that women represent rurality and agriculture in multiple and seemingly contradictory ways. At times they paint portraits of rural life that reproduce human‐nature and masculine‐feminine binaries affiliated with tradition and cultural heritage. At other times, they choreograph, stage, and perform modernity by accentuating materials, ideals, and roles more accurately articulated as a product of contemporary society. The result is a complex amalgam of agriculture and rural life representations constructed for tourist consumption. We conclude by discussing the opportunities such representations hold for enabling farm women to access cultural influence in agriculture.
Measurement of the time of flight of photons into the skin: influence of site, age and gender, correlation with other skin parameters
Authors: Bernengo J.‐C. , Adhoute H. , Mougin D.
Published: May 2014

Background/purpose

The speed of light (time of flight) into the skin is obviously relied to its structure, and might appear as a tool for non‐invasive investigation of skin physico‐chemical properties, among them aging is of primary importance. Though already published, such time of flight measurements have never been extensively correlated with other well‐documented skin parameters such as localization, the influence of gender and age, the elasticity and roughness, and the water trans‐epidermal diffusion (TEWL).

Methods

A specific practical device was designed to routinely measure the time of flight (TOF) of the light into the human skin ‘in vivo’, in a totally non‐invasive process. This system was tested on volunteers, to relate the TOF parameter to the widely investigated skin properties already mentioned.

An Infra‐red laser at 1064 nm delivered powerful pulses of less than 1 ns duration, sent to the skin surface through a lossless fibre. The light backscattered at a given distance was collected and led onto an Avalanche Photodiode, and the mean TOF was measured on a fast sampling scope. A resolution and a reproducibility of a few picoseconds has been achieved. Experiments were carried out on 100 volunteers of both gender, aged from 18 to 65, on 12 different locations.

Results

No matter age and gender, important variations of TOF according to the localization were observed: On the inner forearm, an increase from wrist to elbow, and much higher values on the forehead and neck, whether orientation parallel or perpendicular to Langer lines did not appear significant. Ageing appeared to increase the TOF on forehead and neck, while this effect could not be confirmed on the forearm. Usual skin parameters such as elasticity, roughness and TEWL have been compared to TOF on the same location for each volunteer: TOF and skin roughness were significantly anti‐correlated, i.e. the TOF got shorter when the Roughness increased, while a striking correlation was observed between TEWL and TOF.

Conclusion

These results assert the dependence of TOF on the nature of the skin upper layers (roughness, water diffusion) and on the dermis layer (ageing), and show the potential capabilities offered by TOF to investigate deeply into the skin structure. They have to be confirmed through further experiments, involving measurements at shorter wavelengths, at which the light path into the skin is much smaller, to get a distribution of the TOF inside the tissue.
MHC class I signaling: new functional perspectives for an old molecule
Authors: Tsai E. W. , Reed E. F.
Published: May 2014

Donor‐specific antibodies are associated with refractory rejection episodes and poor allograft outcomes in solid organ transplantation. Our understanding of antibody‐mediated allograft injury is expanding beyond complement deposition. In fact, unique mechanisms of alloantibodies are advancing our knowledge about transplant vasculopathy and antibody‐mediated rejection. These include direct effects on the endothelium, resulting in the recruitment of leukocytes, chemokine and cytokine production, and stimulation of innate and adaptive alloresponses. These effects will be the focus of the following review.
Cytokine profiles in mouse models of experimental immune thrombocytopenia reveal a lack of inflammation and differences in response to intravenous immunoglobulin depending on the mouse strain
Authors: Leontyev Danila , Neschadim Anton , Branch Donald R.
Published: May 2014

Background

Mouse models of human immune thrombocytopenia (ITP) have been used for years to investigate the mechanism of intravenous immunoglobulin (IVIG) to ameliorate ITP; however, how closely these experimental mouse models mirror the human autoimmune inflammatory disease is unclear. The aim of this study was to assess the cytokine profiles in experimental ITP with and without IVIG treatment.

Study Design and Methods

We examined the production of 23 cytokines that included pro‐ and anti‐inflammatory cytokines, in two different mouse strain models of ITP, BALB/c and C57BL/6J, with and without IVIG treatment.

Results

In contrast to human ITP, in mouse models of ITP generated by passive transfer of an alloantibody we find no evidence of inflammatory disease even when ITP is robust, suggesting that while these models capture the innate response phase of the disease, they may not be capturing the adaptive mechanisms of autoimmune initiation of the disorder. Regardless of the mouse strain examined, interleukin (IL)‐1α, ‐2, ‐6, ‐17, and ‐23; granulocyte‐macrophage–colony‐stimulating factor (GM‐CSF); monocyte chemoattractant protein (MCP)‐1; macrophage inflammatory protein (MIP)‐1β; RANTES; tumor necrosis factor (TNF)‐α; and interferon‐γ remain at negligible levels after ITP induction. IVIG treatment in the absence of ITP induced significant levels of IL‐4, ‐10, ‐11, ‐17, and ‐23; GM‐CSF; MCP‐1; and TNF‐α in BALB/c mice, but only IL‐11 was elevated in C57BL/6J mice. In response to IVIG treatment of ITP, both strains produced IL‐4, ‐10, ‐11, and ‐23; GM‐CSF; MCP‐1; MIP‐1β; and TNF‐α; however, only BALB/c exhibited increased MCP‐3 and RANTES. IL‐11 levels were the highest of any cytokine after IVIG administration, given either alone or as treatment of ITP.

Conclusions

We conclude that mouse models for human ITP do not capture the full range of autoimmune inflammatory mechanisms of this disease. Furthermore, cytokine profiles differ in response to IVIG depending on the mouse strain used.
Influences of low-temperature postdeposition annealing on memory properties of Al/Al2O3/Al-rich Al-O/SiO2/p-Si charge trapping flash memory structures
Authors: Ozaki Shinya , Kato Takashi , Kawae Takeshi , Morimoto Akiharu
Published: May 2014

Charge trapping flash (CTF) memory structure was fabricated on a SiO2/p-Si substrate using Al-rich Al-O as a charge trapping layer. Capacitance–voltage curves of the specimen indicated a large memory window width of 4.8 V with a maximum operation voltage of 7 V due to the charge trapping in the Al-rich Al-O layer. With N2 postdeposition annealing treatment at 350 °C, charge retention characteristics of the CTF memory structure were drastically improved without any serious loss in charge trap density. Furthermore, the proposed structure showed excellent memory characteristics, such as endurance and stable data retention even at 100 °C.
NMR Spectroscopy of Native and in Vitro Tissues Implicates PolyADP Ribose in Biomineralization
Authors: Chow W. Ying , Rajan Rakesh , Muller Karin H. , Reid David G. , Skepper Jeremy N. , Wong Wai Ching , Brooks Roger A. , Green Maggie , Bihan Dominique , Farndale Richard W. , Slatter David A. , Shanahan Catherine M. , Duer Melinda J.
Published: May 2014

Fundamentals of Bone Formation

In vitro models can help guide research for tissue engineering or drug delivery, but the extent to which results from in vitro experiments may mimic in vivo ones will depend on the robustness of the model. For complex tissues like the extracellular matrix or bone, this means matching the chemical organization of the tissue at both the atomic scale and the structural level.

Chow
et al.

(p.
742
) used nuclear magnetic resonance (NMR) spectroscopy to analyze a sample on both these length scales. First an isotope-enriched mouse was produced to enhance the NMR signal. Samples from these mice were then used to study the extracellular matrix of developing bone and the calcification front during fetal bone growth.
Mechanism of Activation of Protein Kinase JAK2 by the Growth Hormone Receptor
Authors: Brooks Andrew J. , Dai Wei , O’Mara Megan L. , Abankwa Daniel , Chhabra Yash , Pelekanos Rebecca A. , Gardon Olivier , Tunny Kathryn A. , Blucher Kristopher M. , Morton Craig J. , Parker Michael W. , Sierecki Emma , Gambin Yann , Gomez Guillermo A. , Alexandrov Kirill , Wilson Ian A. , Doxastakis Manolis , Mark Alan E. , Waters Michael J.
Published: May 2014

Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.
In Situ Imaging of Silicalite-1 Surface Growth Reveals the Mechanism of Crystallization
Authors: Lupulescu Alexandra I. , Rimer Jeffrey D.
Published: May 2014

Crystal Growth

Two main routes for the growth of crystalline species are either via molecule-by-molecule attachment to existing nuclei or via the addition of preformed metastable precursors, but do these mechanisms need to be mutually exclusive?
Lupulescu and Rimer
(p.
729
; see the Perspective by

Dandekar and Doherty

) developed an in situ atomic force microscopy (AFM) technique to study the crystallization of materials under extreme conditions of temperature (25° to 300°C) and alkalinity (up to a pH of 13). The growth of the zeolite silicalite-1 involved both the attachment of metastable precursors and of individual molecules.
Border Control—A Membrane-Linked Interactome of
Arabidopsis
Authors: Jones Alexander M. , Xuan Yuanhu , Xu Meng , Wang Rui-Sheng , Ho Cheng-Hsun , Lalonde Sylvie , You Chang Hun , Sardi Maria I. , Parsa Saman A. , Smith-Valle Erika , Su Tianying , Frazer Keith A. , Pilot Guillaume , Pratelli Réjane , Grossmann Guido , Acharya Biswa R. , Hu Heng-Cheng , Engineer Cawas , Villiers Florent , Ju Chuanli , Takeda Kouji , Su Zhao , Dong Qunfeng , Assmann Sarah M. , Chen Jin , Kwak June M. , Schroeder Julian I. , Albert Reka , Rhee Seung Y. , Frommer Wolf B.
Published: May 2014

Degrees of Separation

Proteins embedded in membranes represent an interesting point of communication between the cell and its environment, but their localization to membranes can make them difficult to study.

Jones
et al.

(p.
711
) found an approach to catalog thousands of interactions involving membrane proteins and membrane-associated signaling machinery—including many previously uncharacterized proteins. With a focus on the model plant
Arabidopsis
, several of the identified interactions fill gaps in important signal transduction chains, while others point to functions for enigmatic unknown proteins.
Stick Insect Genomes Reveal Natural Selection’s Role in Parallel Speciation
Authors: Soria-Carrasco Víctor , Gompert Zachariah , Comeault Aaron A. , Farkas Timothy E. , Parchman Thomas L. , Johnston J. Spencer , Buerkle C. Alex , Feder Jeffrey L. , Bast Jens , Schwander Tanja , Egan Scott P. , Crespi Bernard J. , Nosil Patrik
Published: May 2014

Stick to the Bush

Can the underlying genetic changes driving the divergence of populations into new species be predicted or repeated?Soria-Carrascoet al.(p.738) investigated the genetic changes observed after one generation when stick insect (Timema cristinae) populations were transplanted from their preferred host plants to alternative hosts. Diverged genetic regions were relatively small, with most loci showing divergence in a single population pair. However, the number of loci showing parallel divergence was greater than expected by chance. Thus, selection can drive parallel phenotypic evolution via parallel genetic changes.
Making Hunger Yield
Authors: McClung C. Robertson
Published: May 2014

A combination of approaches to develop crops with improved yields is needed to address the demands of a growing population.
New Tricks for an Old Dimer
Authors: Wells James A. , Kossiakoff Anthony A.
Published: May 2014

The receptor for human growth hormone is poised like scissors to transmit signals across the cell membrane when activated.

[Also see Research Article by

Brooks
et al.

]
Recognizing Foreshocks from the 1 April 2014 Chile Earthquake
Authors: Brodsky Emily E. , Lay Thorne
Published: May 2014

Seismic activity preceding recent large earthquakes, including the 1 April 2014 earthquake in Chile, hints that some large earthquakes may potentially be predictable.
Process of Assay Selection and Optimization for the Study of Case and Control Samples from a Phase IIb Efficacy Trial of a Candidate Tuberculosis Vaccine, MVA85A
Authors: Harris Stephanie A. , Satti Iman , Matsumiya Magali , Stockdale Lisa , Chomka Agnieszka , Tanner Rachel , O'Shea Matthew K. , Manjaly Thomas Zita-Rose , Tameris Michele , Mahomed Hassan , Scriba Thomas J. , Hanekom Willem A. , Fletcher Helen A. , McShane Helen
Published: May 2014

The first phase IIb safety and efficacy trial of a new tuberculosis vaccine since that for BCG was completed in October 2012. BCG-vaccinated South African infants were randomized to receive modified vaccinia virus Ankara, expressing theMycobacterium tuberculosisantigen 85A (MVA85A), or placebo. MVA85A did not significantly boost the protective effect of BCG. Cryopreserved samples provide a unique opportunity for investigating the correlates of the risk of tuberculosis disease in this population. Due to the limited amount of sample available from each infant, preliminary work was necessary to determine which assays and conditions give the most useful information. Peripheral blood mononuclear cells (PBMC) were stimulated with antigen 85A (Ag85A) and purified protein derivative fromM. tuberculosisin anex vivogamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) and a Ki67 proliferation assay. The effects of a 2-h or overnight rest of thawed PBMC on ELISpot responses and cell populations were determined. Both the ELISpot and Ki67 assays detected differences between the MVA85A and placebo groups, and the results correlated well. The cell numbers and ELISpot responses decreased significantly after an overnight rest, and surface flow cytometry showed a significant loss of CD4+and CD8+T cells. Of the infants tested, 50% had a positive ELISpot response to a single pool of flu, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (FEC) peptides. This pilot work has been essential in determining the assays and conditions to be used in the correlate study. Moving forward, PBMC will be rested for 2 h before assay setup. The ELISpot assay, performed in duplicate, will be selected over the Ki67 assay, and further work is needed to evaluate the effect of high FEC responses on vaccine-induced immunity and susceptibility to tuberculosis disease.
Emergence and Prevalence of Non-H
2
S-Producing Salmonella enterica Serovar Senftenberg Isolates Belonging to Novel Sequence Type 1751 in China
Authors: Yi Shengjie , Xie Jing , Liu Nan , Li Peng , Xu Xuebin , Li Hao , Sun Jichao , Wang Jian , Liang Beibei , Yang Chaojie , Wang Xu , Hao Rongzhang , Wang Ligui , Wu Zhihao , Zhang Jianmin , Wang Yong , Huang Liuyu , Sun Yansong , Klena John D. , Meng Jianghong , Qiu Shaofu , Song Hongbin
Published: May 2014

Salmonella enterica
serovar Senftenberg is a common nontyphoidal
Salmonella
serotype which causes human
Salmonella
infections worldwide. In this study, 182
S
. Senftenberg isolates, including 17 atypical non-hydrogen sulfide (H
2
S)-producing isolates, were detected in China from 2005 to 2011. The microbiological and genetic characteristics of the non-H
2
S-producing and selected H
2
S-producing isolates were determined by using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and clustered regularly interspaced short palindromic repeat (CRISPR) analysis. The
phs
operons were amplified and sequenced. The 17 non-H
2
S-producing and 36 H
2
S-producing isolates belonged to 7 sequence types (STs), including 3 new STs, ST1751, ST1757, and ST1758. Fourteen of the 17 non-H
2
S-producing isolates belonged to ST1751 and had very similar PFGE patterns. All 17 non-H
2
S-producing isolates had a nonsense mutation at position 1621 of
phsA
. H
2
S-producing and non-H
2
S-producing
S
. Senftenberg isolates were isolated from the same stool sample from three patients; isolates from the same patients displayed the same antimicrobial susceptibility, ST, and PFGE pattern but could be discriminated based on CRISPR spacers. Non-H
2
S-producing
S
. Senftenberg isolates belonging to ST1751 have been prevalent in Shanghai, China. It is possible that these emerging organisms will disseminate further, because they are difficult to detect. Thus, we should strengthen the surveillance for the spread of this atypical
S
. Senftenberg variant.
Microbial Profiling of Combat Wound Infection through Detection Microarray and Next-Generation Sequencing
Authors: Be Nicholas A. , Allen Jonathan E. , Brown Trevor S. , Gardner Shea N. , McLoughlin Kevin S. , Forsberg Jonathan A. , Kirkup Benjamin C. , Chromy Brett A. , Luciw Paul A. , Elster Eric A. , Jaing Crystal J.
Published: May 2014

Combat wound healing and resolution are highly affected by the resident microbial flora. We therefore sought to achieve comprehensive detection of microbial populations in wounds using novel genomic technologies and bioinformatics analyses. We employed a microarray capable of detecting all sequenced pathogens for interrogation of 124 wound samples from extremity injuries in combat-injured U.S. service members. A subset of samples was also processed via next-generation sequencing and metagenomic analysis. Array analysis detected microbial targets in 51% of all wound samples, with
Acinetobacter baumannii
being the most frequently detected species. Multiple
Pseudomonas
species were also detected in tissue biopsy specimens. Detection of the
Acinetobacter
plasmid pRAY correlated significantly with wound failure, while detection of enteric-associated bacteria was associated significantly with successful healing. Whole-genome sequencing revealed broad microbial biodiversity between samples. The total wound bioburden did not associate significantly with wound outcome, although temporal shifts were observed over the course of treatment. Given that standard microbiological methods do not detect the full range of microbes in each wound, these data emphasize the importance of supplementation with molecular techniques for thorough characterization of wound-associated microbes. Future application of genomic protocols for assessing microbial content could allow application of specialized care through early and rapid identification and management of critical patterns in wound bioburden.
Accuracy of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry for Identification of Clinical Pathogenic Fungi: a Meta-Analysis
Authors: Ling Huazhi , Yuan Zhijie , Shen Jilu , Wang Zhongxin , Xu Yuanhong
Published: May 2014

Fungal infections in the clinic have become increasingly serious. In many cases, the identification of clinically relevant fungi remains time-consuming and may also be unreliable. Matrix-assisted laser desorption ionization–time of flight mass spectroscopy (MALDI-TOF MS) is a newly developed diagnostic tool that is increasingly being employed to rapidly and accurately identify clinical pathogenic microorganisms. The present meta-analysis aimed to systematically evaluate the accuracy of MALDI-TOF MS for the identification of clinical pathogenic fungi. After a rigorous selection process, 33 articles, involving 38 trials and a total of 9,977 fungal isolates, were included in the meta-analysis. The random-effects pooled identification accuracy of MALDI-TOF MS increased from 0.955 (95% confidence interval [CI], 0.939 to 0.969) at the species level to 0.977 (95% CI, 0.955 to 0.993) at the genus level (
P
< 0.001; χ
2
= 15.452). Subgroup analyses were performed at the species level for several categories, including strain, source of strain, system, system database, and modified outcomes, to calculate the accuracy and to investigate heterogeneity. These analyses revealed significant differences between the overall meta-analysis and some of the subanalyses. In parallel, significant differences in heterogeneity among different systems and among different methods for calculating the identification ratios were found by multivariate metaregression, but none of the factors, except for the moderator of outcome, was significantly associated with heterogeneity by univariate metaregression. In summary, the MALDI-TOF MS method is highly accurate for the identification of clinically pathogenic fungi; future studies should analyze the comprehensive capability of this technology for clinical diagnostic microbiology.
Severe Amoebic Placentitis in a Horse Caused by an Acanthamoeba hatchetti Isolate Identified Using Next-Generation Sequencing
Authors: Begg Angela P. , Todhunter Kristen , Donahoe Shannon L. , Krockenberger Mark , Šlapeta Jan
Published: May 2014

A case of amoebic placentitis in a mare from eastern Australia was diagnosed postpartum by histopathological examination of the placenta. The identity of the etiological agent was confirmed as
Acanthamoeba hatchetti
by use of diversity profiling based on a next-generation sequencing approach.
Cell Death-Inducing DFFA-Like Effector b Is Required for Hepatitis C Virus Entry into Hepatocytes
Authors: Wu Xianfang , Lee Emily M. , Hammack Christy , Robotham Jason M. , Basu Mausumi , Lang Jianshe , Brinton Margo A. , Tang Hengli
Published: May 2014

The molecular mechanism of the hepatic tropism of hepatitis C virus (HCV) remains incompletely defined.
In vitro
hepatic differentiation of pluripotent stem cells produces hepatocyte-like cells (HLCs) permissive for HCV infection, providing an opportunity for studying liver development and host determinants of HCV susceptibility. We previously identified the transition stage of HCV permissiveness and now investigate whether a host protein whose expression is induced during this transition stage is important for HCV infection. We suppressed the expression of a liver-specific protein, cell death-inducing DFFA-like effector b (CIDEB), and performed hepatocyte function and HCV infection assays. We also used a variety of cell-based assays to dissect the specific step of the HCV life cycle that potentially requires CIDEB function. We found CIDEB to be an essential cofactor for HCV entry into hepatocytes. Genetic interference with CIDEB in stem cells followed by hepatic differentiation leads to HLCs that are refractory to HCV infection, and infection time course experiments revealed that CIDEB functions in a late step of HCV entry, possibly to facilitate membrane fusion. The role of CIDEB in mediating HCV entry is distinct from those of the well-established receptors, as it is not required for HCV pseudoparticle entry. Finally, HCV infection effectively downregulates CIDEB protein through a posttranscriptional mechanism.

IMPORTANCE
This study identifies a hepatitis C virus (HCV) entry cofactor that is required for HCV infection of hepatocytes and potentially facilitates membrane fusion between viral and host membranes. CIDEB and its interaction with HCV may open up new avenues of investigation of lipid droplets and viral entry.
Influenza A Virus-Induced Degradation of Eukaryotic Translation Initiation Factor 4B Contributes to Viral Replication by Suppressing IFITM3 Protein Expression
Authors: Wang Song , Chi Xiaojuan , Wei Haitao , Chen Yuhai , Chen Zhilong , Huang Shile , Chen Ji-Long
Published: May 2014

Although alteration in host cellular translation machinery occurs in virus-infected cells, the role of such alteration and the precise pathogenic processes are not well understood. Influenza A virus (IAV) infection shuts off host cell gene expression at transcriptional and translational levels. Here, we found that the protein level of eukaryotic translation initiation factor 4B (eIF4B), an integral component of the translation initiation apparatus, was dramatically reduced in A549 cells as well as in the lung, spleen, and thymus of mice infected with IAV. The decrease in eIF4B level was attributed to lysosomal degradation of eIF4B, which was induced by viral NS1 protein. Silencing eIF4B expression in A549 cells significantly promoted IAV replication, and conversely, overexpression of eIF4B markedly inhibited the viral replication. Importantly, we observed that eIF4B knockdown transgenic mice were more susceptible to IAV infection, exhibiting faster weight loss, shorter survival time, and more-severe organ damage. Furthermore, we demonstrated that eIF4B regulated the expression of interferon-induced transmembrane protein 3 (IFITM3), a critical protein involved in immune defense against a variety of RNA viruses, including influenza virus. Taken together, our findings reveal that eIF4B plays an important role in host defense against IAV infection at least by regulating the expression of IFITM3, which restricts viral entry and thereby blocks early stages of viral production. These data also indicate that influenza virus has evolved a strategy to overcome host innate immunity by downregulating eIF4B protein.

IMPORTANCE
Influenza A virus (IAV) infection stimulates the host innate immune system, in part, by inducing interferons (IFNs). Secreted IFNs activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, leading to elevated transcription of a large group of IFN-stimulated genes that have antiviral function. To circumvent the host innate immune response, influenza virus has evolved multiple strategies for suppressing the production of IFNs. Here, we show that IAV infection induces lysosomal degradation of eIF4B protein; and eIF4B inhibits IAV replication by upregulating expression of interferon-induced transmembrane protein 3 (IFITM3), a key protein that protects the host from virus infection. Our finding illustrates a critical role of eIF4B in the host innate immune response and provides novel insights into the complex mechanisms by which influenza virus interacts with its host.