bluuebunny/crossref_metadata_2025 huggingface dataset:
Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation
Authors: Rainer F. , Horvath A. , Sandahl T. D. , Leber B. , Schmerboeck B. , Blesl A. , Groselj‐Strele A. , Stauber R. E. , Fickert P. , Stiegler P. , Møller H. J. , Grønbæk H. , Stadlbauer V.
Published: December 2017

Background

Activated hepatic macrophages play a key role in inflammation and fibrosis progression in chronic liver disease.

Aim

To assess the prognostic value of soluble (s)CD163 and mannose receptor (sMR) in cirrhotic patients and explore associations with markers of intestinal permeability (lactulose‐mannitol ratio, diamine oxidase), bacterial translocation (endotoxin, lipopolysaccharide‐binding protein) and markers of systemic immune activation (interleukin‐6, interleukin‐8, sCD14).

Methods

We prospectively investigated 101 cirrhotic patients (Child‐Pugh class A: n = 72, Child‐Pugh classes B and C: n = 29) and 31 healthy controls. Patients were observed for a median follow‐up of 37 months.

Results

Median plasma levels of sCD163 and soluble mannose receptor were significantly elevated in cirrhotic patients (P < .001) and increased with disease severity (sCD163 in healthy controls = 1.3, Child‐Pugh class A = 4.2, Child‐Pugh classes B and C = 8.4 mg/L; sMR in healthy controls = 15.8, Child‐Pugh class A = 36.5, Child‐Pugh classes B and C = 66.3 μg/dL). A total of 21 patients died during the observation period. Patients with sCD163 levels above 5.9 mg/L showed significantly reduced survival (survival rate after 36 months: 71% versus 98%, P < .001). Patients with soluble mannose receptor levels above 45.5 μg/dL developed significantly more complications of cirrhosis within 12 months (73% versus 9%, P < .001). Furthermore, both variables correlated with the lactulose‐mannitol ratio, diamine oxidase, lipopolysaccharide and interleukin‐8.

Conclusion

Our data demonstrate the prognostic value of sCD163 in predicting long‐term survival in patients with liver cirrhosis and identify soluble mannose receptor as a prognostic marker for occurrence of cirrhosis‐associated complications. The correlation between gut barrier dysfunction and activation of macrophages points towards a link between them.
Distinguishing Polemic From Commentary in Science: Some Guidelines Illustrated With the Case of Sage and Burgio (2017)
Authors: Grimes David Robert , Bishop Dorothy V. M.
Published: December 2017

Exposure to nonionizing radiation used in wireless communication remains a contentious topic in the public mind—while the overwhelming scientific evidence to date suggests that microwave and radio frequencies used in modern communications are safe, public apprehension remains considerable. A recent article in Child Development has caused concern by alleging a causative connection between nonionizing radiation and a host of conditions, including autism and cancer. This commentary outlines why these claims are devoid of merit, and why they should not have been given a scientific veneer of legitimacy. The commentary also outlines some hallmarks of potentially dubious science, with the hope that authors, reviewers, and editors might be better able to avoid suspect scientific claims.
Usefulness of multiple chalk‐based food colorings for inducing better gene silencing by feeding RNA interference in planarians
Authors: Hattori Miki , Miyamoto Mai , Hosoda Kazutaka , Umesono Yoshihiko
Published: December 2017

Planarians have become widely recognized as one of the major animal models for regeneration studies in invertebrates. To induce RNA interference (RNAi) by feeding in planarians, the widely accepted protocol is one in which animals undergo two or three feedings of food containing double‐stranded RNA (dsRNA) plus visible food coloring (e.g., blood) for confirmation of feeding by individual animals. However, one possible problem is that incorporated food coloring is often retained within the gut for several days, which makes it difficult to confirm the success of each round of dsRNA feeding based on the difference of the color density within the gut before and after feeding. As a consequence, the difference of appetite levels among individuals undergoing dsRNA feeding leads to phenotypic variability among them due to insufficient knockdown. In our attempts to overcome this problem, we have developed a novel method for achieving robust confirmation of the success of dsRNA feeding in individuals fed multiple times by means of including a combination of three different colored chalks (pink, yellow and blue) as food coloring. Notably, we found that this method is superior to the conventional method for positively marking individuals that actively consumed the dsRNA‐containing food during four times of once‐daily feeding. Using these selected animals, we obtained stable and sufficiently strong RNAi‐induced phenotypes. We termed this improved multi‐colored chalk‐spiked method of feeding RNAi “Candi” and propose its benefits for gene function analysis in planarians.
Sistem Kenaikan Pangkat dan Kepuasan Kerja : Satu Kajian Kes Ke atas Perkhidmatan Awam Persekutuan Di Malaysia
Authors: Chin Mohammad , Syed Khalid Wafa Syed Azizi Wafa , Hassan Ramraini Ali
Published: December 2017

This research is a case study exploring the relationship between the promotion system and job satisfaction among federal civil servants in federal departments and agencies in Malaysia. The samples involved in this study are government officers serving in federal departments and agencies in the state of Sabah, Malaysia.  A quantitative method was used in this study. A total of 700 questionnaires were distributed among federal civil servants in grades 41 to grades 54. A total of 420 questionnaires were returned but after screening only 380 questionnaires were found useable and analysed in the study. Questionnaires were distributed to respondents based on purposive sampling methods. A significant positive relationship was found between the promotion system and job satisfaction. This study will contribute knowledge through the empirical data obtained as well as gaining a better understanding of the relationship between the promotion system and the level of job satisfaction among federal public servants in Malaysia. From a practical perspective, the findings of this study can be used by policy makers, managers and researchers who are interested in improving the policy of human resource management within the public sector in Malaysia.
On the Utility of Crystal Plasticity Modeling to Uncover the Individual Roles of Microdeformation Mechanisms on the Work Hardening Response of Fe-23Mn-0.5C TWIP Steel in the Presence of Hydrogen
Authors: Bal B. , Koyama M. , Canadinc D. , Gerstein G. , Maier H. J. , Tsuzaki K.
Published: December 2017

This paper presents a combined experimental and theoretical analysis focusing on the individual roles of microdeformation mechanisms that are simultaneously active during the deformation of twinning-induced plasticity (TWIP) steels in the presence of hydrogen. Deformation responses of hydrogen-free and hydrogen-charged TWIP steels were examined with the aid of thorough electron microscopy. Specifically, hydrogen charging promoted twinning over slip–twin interactions and reduced ductility. Based on the experimental findings, a mechanism-based microscale fracture model was proposed, and incorporated into a visco-plastic self-consistent (VPSC) model to account for the stress–strain response in the presence of hydrogen. In addition, slip-twin and slip–grain boundary interactions in TWIP steels were also incorporated into VPSC, in order to capture the deformation response of the material in the presence of hydrogen. The simulation results not only verify the success of the proposed hydrogen embrittlement (HE) mechanism for TWIP steels, but also open a venue for the utility of these superior materials in the presence of hydrogen.
Three-Dimensional Wear Prediction of Four-Degrees-of-Freedom Parallel Mechanism With Clearance Spherical Joint and Flexible Moving Platform
Authors: Wang Gengxiang , Liu Hongzhao
Published: December 2017

Three-dimensional (3D) wear of the clearance spherical joint in four-degrees-of-freedom (DOF) parallel mechanism is predicted based on Archard's wear model. The flexible moving platform is treated as thin plate element based on absolute nodal coordinate formulation (ANCF). The tangent frame is introduced to formulate the constraint equation of universal joint. One of the spherical joints is treated as clearance joint. The normal and tangential contact forces are calculated based on Flores contact force model and modified Coulomb friction model. In order to predict 3D wear, the normal contact force, tangential contact velocity, and eccentricity vector are decomposed in the global coordinate system. Simulation results show that 3D wear occurred in three directions are not uniform each other.
Host susceptibility to snake fungal disease is highly dispersed across phylogenetic and functional trait space
Authors: Burbrink Frank T. , Lorch Jeffrey M. , Lips Karen R.
Published: December 2017

Snake fungal disease is expected to infect many more species than known.
Denial of service to same-sex and interracial couples: Evidence from a national survey experiment
Authors: Powell Brian , Schnabel Landon , Apgar Lauren
Published: December 2017

Americans’ views on service refusal vary by several factors but not by whether it is for religious or nonreligious reasons.
Saturn's rings are solar system newcomers
Authors: Voosen Paul
Published: December 2017

Cassini data point to a cataclysmic collision in the past few hundred million years
Blockade harms Qatari science
Authors: Kaiser Jocelyn
Published: December 2017

Rift with neighbors has strangled collaborations and shut Qatari researchers out of regional meetings
Cosmic convergence
Authors: Cho Adrian
Published: December 2017

The merger of two neutron stars captivated thousands of observers and fulfilled
multiple astrophysical predictions
Loss of
AvrSr50
by somatic exchange in stem rust leads to virulence for
Sr50
resistance in wheat
Authors: Chen Jiapeng , Upadhyaya Narayana M. , Ortiz Diana , Sperschneider Jana , Li Feng , Bouton Clement , Breen Susan , Dong Chongmei , Xu Bo , Zhang Xiaoxiao , Mago Rohit , Newell Kim , Xia Xiaodi , Bernoux Maud , Taylor Jennifer M. , Steffenson Brian , Jin Yue , Zhang Peng , Kanyuka Kostya , Figueroa Melania , Ellis Jeffrey G. , Park Robert F. , Dodds Peter N.
Published: December 2017

Fungal effectors of wheat stem rust

The fungal pathogen Ug99 (named for its identification in Uganda in 1999) threatens wheat crops worldwide. Ug99 can kill entire fields of wheat and is undeterred by many of the disease-resistance genes that otherwise protect wheat crops. Two papers describe two peptides secreted by the fungus as it attacks the wheat (see the Perspective by Moscou and van Esse). Chen
et al.
show that fungal AvrSr50 binds to the plant's immune receptor Sr50, and Salcedo
et al.
show that fungal AvrSr35 binds to Sr35. Successful binding activates the plant's immune defenses. Removing or inactivating these Avr effectors leaves the plant defenseless and susceptible to disease.

Science
, this issue p.
1607
, p.
1604
; see also p.
1541
Recurrent infection progressively disables host protection against intestinal inflammation
Authors: Yang Won Ho , Heithoff Douglas M. , Aziz Peter V. , Sperandio Markus , Nizet Victor , Mahan Michael J. , Marth Jamey D.
Published: December 2017

Minor infections cause big problems

Pathogenic infection has been implicated in the chronic inflammation seen in inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn's disease. Yang
et al.
show that recurrent, low-level, and fully resolving
Salmonella enterica
Typhimurium (ST) infections can precipitate severe colonic inflammation in mice. ST-induced TLR4 activation resulted in increased neuraminidase 3 (Neu3) production and activity in the duodenum. This led to intestinal alkaline phosphatase (IAP) desialylation and degradation. IAP deficiency caused a marked increase in commensal bacteria-generated lipopolysaccharide-phosphate in the colon, provoking inflammation. Treatment with calf IAP or the antiviral drug zanamivir (which inhibits Neu3 activity) prevented this inflammatory cascade. This pathway may serve as an effective target for future human IBD therapies.

Science
, this issue p.
eaao5610
A New World of plants
Authors: Givnish Thomas J.
Published: December 2017

A searchable database collates information on all known vascular plants in the Americas
The secret life of Hedy Lamarr
Bombshell: The Hedy Lamarr Story
Alexandra Dean, director
Reframed Pictures, 2017
Authors: Blackburn Renée
Published: December 2017

A new documentary reveals the underappreciated intellectual contributions of the 1940s film star
Cellular Stoichiometry of Methyl-Accepting Chemotaxis Proteins in Sinorhizobium meliloti
Authors: Zatakia Hardik M. , Arapov Timofey D. , Meier Veronika M. , Scharf Birgit E.
Published: December 2017

The chemosensory system in
Sinorhizobium meliloti
has several important deviations from the widely studied enterobacterial paradigm. To better understand the differences between the two systems and how they are optimally tuned, we determined the cellular stoichiometry of the methyl-accepting chemotaxis proteins (MCPs) and the histidine kinase CheA in
S. meliloti
. Quantitative immunoblotting was used to determine the total amount of MCPs and CheA per cell in
S. meliloti
. The MCPs are present in the cell in high abundance (McpV), low abundance (IcpA, McpU, McpX, and McpW), and very low abundance (McpY and McpZ), whereas McpT was below the detection limit. The approximate cellular ratio of these three receptor groups is 300:30:1. The chemoreceptor-to-CheA ratio is 23.5:1, highly similar to that seen in
Bacillus subtilis
(23:1) and about 10 times higher than that in
Escherichia coli
(3.4:1). Different from
E. coli
, the high-abundance receptors in
S. meliloti
are lacking the carboxy-terminal NWETF pentapeptide that binds the CheR methyltransferase and CheB methylesterase. Using transcriptional
lacZ
fusions, we showed that chemoreceptors are positively controlled by the master regulators of motility, VisNR and Rem. In addition, FlbT, a class IIA transcriptional regulator of flagellins, also positively regulates the expression of most chemoreceptors except for McpT and McpY, identifying chemoreceptors as class III genes. Taken together, these results demonstrate that the chemosensory complex and the adaptation system in
S. meliloti
deviates significantly from the established enterobacterial paradigm but shares some similarities with
B. subtilis
.

IMPORTANCE
The symbiotic soil bacterium
Sinorhizobium meliloti
is of great agricultural importance because of its nitrogen-fixing properties, which enhances growth of its plant symbiont, alfalfa. Chemotaxis provides a competitive advantage for bacteria to sense their environment and interact with their eukaryotic hosts. For a better understanding of the role of chemotaxis in these processes, detailed knowledge on the regulation and composition of the chemosensory machinery is essential. Here, we show that chemoreceptor gene expression in
S. meliloti
is controlled through the main transcriptional regulators of motility. Chemoreceptor abundance is much lower in
S. meliloti
than in
Escherichia coli
and
Bacillus subtilis
. Moreover, the chemoreceptor-to-kinase CheA ratio is different from that of
E. coli
but similar to that of
B. subtilis
.
Deficiency of the IRE1α-Autophagy Axis Enhances the Antitumor Effects of the Oncolytic Virus M1
Authors: Li Kai , Hu Cheng , Xing Fan , Gao Mingshi , Liang Jiankai , Xiao Xiao , Cai Jing , Tan Yaqian , Hu Jun , Zhu Wenbo , Yin Wei , Li Yuan , Chen Wenli , Lu Bingzheng , Mai Jialuo , Qiu Pengxin , Su Xingwen , Yan Guangmei , Zhang Haipeng , Lin Yuan
Published: December 2017

Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancer cells. M1 is a naturally occurring alphavirus (
Togaviridae
) which shows potent oncolytic activities against many cancers. Accumulation of unfolded proteins during virus replication leads to a transcriptional/translational response known as the unfolded protein response (UPR), which might counteract the antitumor effect of the oncolytic virus. In this report, we show that either pharmacological or biological inhibition of IRE1α or PERK, but not ATF6, substantially increases the oncolytic effects of the M1 virus. Moreover, inhibition of IRE1α blocks M1 virus-induced autophagy, which restricts the antitumor effects of the M1 virus through degradation of viral protein, in glioma cells. In addition, IRE1α suppression significantly increases the oncolytic effect of M1 virus in an orthotopic glioma model. From a molecular pathology study, we found that IRE1α is expressed at lower levels in higher-grade gliomas, suggesting greater antitumor efficacy of the oncolytic virus M1. Taken together, these findings illustrate a defensive mechanism of glioma cells against the oncolytic virus M1 and identify possible approaches to enhance the oncolytic viral protein accumulation and the subsequent lysis of tumor cells.

IMPORTANCE
Although oncolytic virotherapy is showing great promise in clinical applications, not all patients are benefiting. Identifying inhibitory signals in refractory cancer cells for each oncolytic virus would provide a good chance to increase the therapeutic effect. Here we describe that infection with the oncolytic virus M1 triggers the unfolded protein response (UPR) and subsequent autophagy, while blocking the UPR-autophagy axis significantly potentiates the antitumor efficacy of M1
in vitro
and
in vivo
. A survey of cancer tissue banks revealed that IRE1α, a key element in the UPR pathway, is commonly downregulated in higher-grade human gliomas, suggesting favorable prospects for the application of M1. Our work provides a potential predictor and target for enhancement of the therapeutic effectiveness of the M1 virus. We predict that the mechanism-based combination therapy will promote cancer virotherapy in the future.
Identification of a Conserved Interface of Human Immunodeficiency Virus Type 1 and Feline Immunodeficiency Virus Vifs with Cullin 5
Authors: Gu Qinyong , Zhang Zeli , Gertzen Christoph G. W. , Häussinger Dieter , Gohlke Holger , Münk Carsten
Published: December 2017

Members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC3 [A3]) family of DNA cytidine deaminases are intrinsic restriction factors against retroviruses. In felids such as the domestic cat (
Felis catus
), the A3 genes encode the A3Z2, A3Z3, and A3Z2Z3 antiviral cytidine deaminases. Only A3Z3 and A3Z2Z3 inhibit viral infectivity factor (Vif)-deficient feline immunodeficiency virus (FIV). The FIV Vif protein interacts with Cullin (CUL), Elongin B (ELOB), and Elongin C (ELOC) to form an E3 ubiquitination complex to induce the degradation of feline A3s. However, the functional domains in FIV Vif for the interaction with Cullin are poorly understood. Here, we found that the expression of dominant negative CUL5 prevented the degradation of feline A3s by FIV Vif, while dominant negative CUL2 had no influence on the degradation of A3. In coimmunoprecipitation assays, FIV Vif bound to CUL5 but not CUL2. To identify the CUL5 interaction site in FIV Vif, the conserved amino acids from positions 47 to 160 of FIV Vif were mutated, but these mutations did not impair the binding of Vif to CUL5. By focusing on a potential zinc-binding motif (K175-C161-C184-C187) of FIV Vif, we found a conserved hydrophobic region (174IR175) that is important for the CUL5 interaction. Mutation of this region also impaired the FIV Vif-induced degradation of feline A3s. Based on a structural model of the FIV Vif-CUL5 interaction, the 52LW53 region in CUL5 was identified as mediating binding to FIV Vif. By comparing our results to the human immunodeficiency virus type 1 (HIV-1) Vif-CUL5 interaction surface (120IR121, a hydrophobic region that is localized in the zinc-binding motif), we suggest that the CUL5 interaction surface in the diverse HIV-1 and FIV Vifs is evolutionarily conserved, indicating a strong structural constraint. However, the FIV Vif-CUL5 interaction is zinc independent, which contrasts with the zinc dependence of HIV-1 Vif.

IMPORTANCE
Feline immunodeficiency virus (FIV), which is similar to human immunodeficiency virus type 1 (HIV-1), replicates in its natural host in T cells and macrophages that express the antiviral restriction factor APOBEC3 (A3). To escape A3s, FIV and HIV induce the degradation of these proteins by building a ubiquitin ligase complex using the viral protein Vif to connect to cellular proteins, including Cullin 5. Here, we identified the protein residues that regulate this interaction in FIV Vif and Cullin 5. While our structural model suggests that the diverse FIV and HIV-1 Vifs use conserved residues for Cullin 5 binding, FIV Vif binds Cullin 5 independently of zinc, in contrast to HIV-1 Vif.
The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling
Authors: Chiang Cindy , Pauli Eva-Katharina , Biryukov Jennifer , Feister Katharina F. , Meng Melissa , White Elizabeth A. , Münger Karl , Howley Peter M. , Meyers Craig , Gack Michaela U.
Published: December 2017

Retinoic acid-inducible gene I (RIG-I) is a key pattern recognition receptor that senses viral RNA and interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade that results in the production of type I interferons (IFNs). This signaling axis is initiated by K63-linked ubiquitination of RIG-I mediated by the E3 ubiquitin ligase TRIM25, which promotes the interaction of RIG-I with MAVS. USP15 was recently identified as an upstream regulator of TRIM25, stabilizing the enzyme through removal of degradative K48-linked polyubiquitin, ultimately promoting RIG-I-dependent cytokine responses. Here, we show that the E6 oncoprotein of human papillomavirus type 16 (HPV16) as well as of other HPV types form a complex with TRIM25 and USP15 in human cells. In the presence of E6, the K48-linked ubiquitination of TRIM25 was markedly increased, and in line with this, TRIM25 degradation was enhanced. Our results further showed that E6 inhibited the TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS. HPV16 E6, but not E7, suppressed the RIG-I-mediated induction of IFN-β, chemokines, and IFN-stimulated genes (ISGs). Finally, CRISPR-Cas9 gene targeting in human keratinocytes showed that the TRIM25-RIG-I-MAVS triad is important for eliciting an antiviral immune response to HPV16 infection. Our study thus identifies a novel immune escape mechanism that is conserved among different HPV strains and further indicates that the RIG-I signaling pathway plays an important role in the innate immune response to HPV infection.

IMPORTANCE
Persistent infection and tumorigenesis by HPVs are known to require viral manipulation of a variety of cellular processes, including those involved in innate immune responses. Here, we show that the HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection, providing evidence that RIG-I, whose role in sensing RNA virus infections has been well characterized, also plays a crucial role in the antiviral host response to small DNA viruses of the
Papillomaviridae
family.
Asian Elephant T Cell Responses to Elephant Endotheliotropic Herpesvirus
Authors: Fuery Angela , Leen Ann M. , Peng Rongsheng , Wong Matthew C. , Liu Hao , Ling Paul D.
Published: December 2017

Elephant endotheliotropic herpesvirus (EEHV) can cause lethal hemorrhagic disease in juvenile Asian elephants, an endangered species. One hypothesis to explain this vulnerability of some juvenile elephants is that they fail to mount an effective T cell response to the virus. To our knowledge, there have been no studies of Asian elephant T cell responses to EEHV. To address this deficiency, we validated the gamma interferon (IFN-γ) enzyme-linked immunospot assay for tracking antigen-directed T cell activity by monitoring rabies-specific responses in vaccinated elephants. In addition, we generated monoclonal antibodies to Asian elephant CD4 and CD8 to facilitate phenotypic T cell profiling. Using these tools, we screened healthy elephants with a history of EEHV infection for reactivity against nine EEHV proteins whose counterparts in other herpesviruses are known to induce T cell responses in their natural hosts. We identified glycoprotein B (gB) and the putative regulatory protein E40 as the most immunogenic T cell targets (IFN-γ responses in five of seven elephants), followed by the major capsid protein (IFN-γ responses in three of seven elephants). We also observed that IFN-γ responses were largely from CD4
+
T cells. We detected no activity against the predicted major immediate early (E44) and large tegument (E34) proteins, both immunodominant T cell targets in humans latently infected with cytomegalovirus. These studies identified EEHV-specific T cells in Asian elephants for the first time, lending insight into the T cell priming that might be required to protect against EEHV disease, and will guide the design of effective vaccine strategies.

IMPORTANCE
Endangered Asian elephants are facing many threats, including lethal hemorrhagic disease from elephant endotheliotropic herpesvirus (EEHV). EEHV usually establishes chronic, benign infections in mature Asian elephants but can be lethal to juvenile elephants in captivity and the wild. It is the leading cause of death in captive Asian elephants in North America and Europe. Despite the availability of sensitive tests and protocols for treating EEHV-associated illness, these measures are not always effective. The best line of defense would be a preventative vaccine. We interrogated normal healthy elephants previously infected with EEHV for T cell responses to nine EEHV proteins predicted to induce cellular immune responses. Three proteins elicited IFN-γ responses, suggesting their potential usefulness as vaccine candidates. Our work is the first to describe T cell responses to a member of the proposed fourth subfamily of mammalian herpesviruses, the
Deltaherpesvirinae
, within a host species in the clade Afrotheria. An EEHV vaccine would greatly contribute to the health care of Asian and African elephants that are also susceptible to this disease.
Selecting a risk assessment tool to use in practice:a 10-point guide
Authors: Fazel Seena , Wolf Achim
Published: December 2017

With the increase in the number of risk assessment tools and clinical algorithms in many areas of science and medicine, this Perspective article provides an overview of research findings that can assist in informing the choice of an instrument for practical use. We take the example of violence risk assessment tools in criminal justice and forensic psychiatry, where there are more than 200 such instruments and their use is typically mandated. We outline 10 key questions that researchers, clinicians and other professionals should ask when deciding what tool to use, which are also relevant for public policy and commissioners of services. These questions are based on two elements: research underpinning the external validation, and derivation or development of a particular instrument. We also recommend some guidelines for reporting drawn from consensus guidelines for research in prognostic models.
Moral case deliberation
Authors: Tan Daniel Y B , ter Meulen Bastiaan C , Molewijk Albert , Widdershoven Guy
Published: December 2017

Ethical dilemmas in general are characterised by a choice between two mutually excluding options neither of which is satisfactory, because there always will be a form of moral damage. Within the context of medicine several ethics support services have been developed to support healthcare professionals in dealing with ethical dilemmas, including moral case deliberation. In this article, we describe how moral case deliberation works in daily practice, illustrated with a case example from the neurology ward. The article is meant as an introduction to moral case deliberation according to the dilemma method. We show its relevance to the clinic and the context needed to put it into practice.
Different strategies to kill the host presented byMetarhizium anisopliaeandBeauveria bassiana
Authors: Rustiguel Cynthia Barbosa , Fernández-Bravo María , Guimarães Luis Henrique Souza , Quesada-Moraga Enrique
Published: December 2017

Studies conducted over the last decades have shown the potential of entomopathogenic fungi for the biocontrol of some insect pests. Entomopathogenic fungi infect their host through the cuticle, so they do not need to be ingested to be effective. These fungi also secrete secondary metabolites and proteins that are toxic to insect pests. In this context, we analyzed the pathogenicity of Metarhizium anisopliae (Metschn.) strains IBCB 384 and IBCB 425 and Beauveria bassiana (Bals.-Criv.) Vuill. strains E 1764 and E 3158 against Galleria mellonella (Linn.) larvae, during pre-invasion and post-invasion phases. The results showed M. anisopliae, especially strain IBCB 384, was most virulent in the pre-invasion phase against G. mellonella, whereas B. bassiana, especially strain E 1764, was most virulent in the post-invasion phase. During in vivo development and in the production of toxic serum, B. bassiana E 3158 was the most virulent. Different fungal growth (or toxin) strategies were observed for studied strains. Metarhizium anisopliae IBCB 425 prioritizes the growth strategy, whereas strain IBCB 384 and B. bassiana strains E 1764 and E 3158 have a toxic strategy. All strains have pathogenicity against G. mellonella, indicating their possible use for biocontrol.
Static Mapping of Applications on Heterogeneous Multi-Core Platforms Combining Logic-Based Benders Decomposition with Integer Linear Programming
Authors: Emeretlis Andreas , Theodoridis George , Alefragis Panayiotis , Voros Nikolaos
Published: December 2017

The proper mapping of an application on a multi-core platform and the scheduling of its tasks are key elements to achieve the maximum performance. In this article, a novel hybrid approach based on integrating the Logic-Based Benders Decomposition (LBBD) principle with a pure Integer Linear Programming (ILP) model is introduced for mapping applications described by Directed Acyclic Graphs (DAGs) on platforms consisting of heterogeneous cores. The LBBD approach combines two optimization techniques with complementary strengths, namely ILP and Constraint Programming (CP), and is employed as a cut generation scheme. The generated constraints are utilized by the ILP model to cut possible assignment combinations aiming at improving the solution or proving the optimality of the best-found one. The introduced approach was applied both on synthetic DAGs and on DAGs derived from real applications. Through the proposed approach, many problems were optimally solved that could not be solved by any of the above methods (ILP, LBBD) alone within a time limit of 2 hours, while the overall solution time was also significantly decreased. Specifically, the hybrid method exhibited speedups equal to 4.2× for the synthetic instances and 10× for the real-application DAGs over the LBBD approach and two orders of magnitude over the ILP model.
Hardware-Enabled Pharmaceutical Supply Chain Security
Authors: Yang Kun , Shen Haoting , Forte Domenic , Bhunia Swarup , Tehranipoor Mark
Published: December 2017

The pharmaceutical supply chain is the pathway through which prescription and over-the-counter (OTC) drugs are delivered from manufacturing sites to patients. Technological innovations, price fluctuations of raw materials, as well as tax, regulatory, and market demands are driving change and making the pharmaceutical supply chain more complex. Traditional supply chain management methods struggle to protect the pharmaceutical supply chain, maintain its integrity, enhance customer confidence, and aid regulators in tracking medicines. To develop effective measures that secure the pharmaceutical supply chain, it is important that the community is aware of the state-of-the-art capabilities available to the supply chain owners and participants. In this article, we will be presenting a survey of existing hardware-enabled pharmaceutical supply chain security schemes and their limitations. We also highlight the current challenges and point out future research directions. This survey should be of interest to government agencies, pharmaceutical companies, hospitals and pharmacies, and all others involved in the provenance and authenticity of medicines and the integrity of the pharmaceutical supply chain.
Excitation conduction in Auerbach's plexus of rabbit small intestine.
Authors: Yokoyama S , Ozaki T , Kajitsuka T
Published: December 2017

Excitation conduction in Auerbach's plexus of the rabbit small intestine was investigated by analyzing its evoked potentials as the response to a single electrical stimulus given to this plexus. When the conduction distance was 1 mm, two spike waves were recorded. Conduction velocities of nerve impulses were 0.3-0.5 m/s, and chronaxie was 0.06-0.11 ms. When the distance between stimulating and recording electrodes was further increased, evoked potential waves became multiple and small, until beyond 15 mm in the longitudinal direction and beyond 3 mm in the circular direction they could no longer be recorded. Evoked potentials recorded at a distance greater than 2 mm were reduced in their amplitude, and some potential waves were abolished after repeated stimulation with high frequency above 50/s, and also after hexamethonium application and lack of oxygen. It was concluded that in Auerbach's plexus nerve impulses spread through multiple pathways, conducting mainly on the longitudinal axis of the small intestine, and that some impulses make synaptaic transmission at ganglia.
Glucose-stimulated and La3+-nondisplaceable Ca2+ pool in pancreatic islets.
Authors: Bloom G D , Hellman B , Sehlin J , Täljedal I
Published: December 2017

To study intracellular pools of calcium tissue specimens from noninbred ob/ob mice were labeled with 45Ca2+ and subsequently washed with La3+. D-glucose, 20 mM, enhanced the labeling of the La3+-nondisplaceable calcium in pancreatic islets but not in pieces of exocrine pancreas or liver. The disappearance of 45Ca2+ from labeled islets was accelerated by the ionophore, X-537A, but not by dibutyryl cyclic AMP, theophylline, or pentobarbital. On fractionation of 45Ca2+-labeled islets, the greatest radioactivity per unit of protein occured in a fraction rich in insulin secretory granules. The radioactivity of this fraction was higher after the islets had been loaded with 45Ca2+ in the presence of 20 mM glucose as compared to 3 mM glucose. It is concluded that the secretory granules make up a considerable part of the glucose-sensitive calcium store in the beta-cells.
Prostaglandins in adrenergic transmission of isolated perfused rat pancreas.
Authors: Hamamdzić M , Malik K U
Published: December 2017

In the isolated, perfused rat pancreas, prostaglandins (PGs) E1 and E2 1-5 ng/ml, reduced the vasoconstrictor responses to periarterial nerve stimulation and variably affected those to injected norepinephrine. Prostaglandin F2alpha had no consistent effect on the vasoconstrictor responses to both adrenergic stimuli. Stimulation of adrenergic nerves or administration of norepinephrine released a PGE-like substance from the perfused pancreas which was abolished by inhibitors of PG synthesis, acetylsalicylic acid, indomethacin, meclofenamate, and eicosa-5,8,11,14-tetraynoic acid. The latter three agents did not potentiate, but rather reduced the vasoconstrictor responses to both adrenergic stimuli. Arachidonic acid that was converted by the pancreas into PGE2 and PGF2alpha inhibited the vasoconstrictor responses to adrenergic stimuli. The latter effect of arachidonic acid was not altered by the simultaneous infusion of PG synthetase inhibitors. Although these results, which could be attributed to a direct effect of inhibitors of PG synthesis and arachidonic acid on adrenergic neuroeffector junction, fail to establish the role of endogenous PGs in modulating adrenergic responses in rat pancreatic vessels, they emphasize the differences in the effect of PGE1 and PGE2 on adrenergic responses in various vascular beds of the rat.
Changes in protein and nucleic acid synthesis in rat gastric mucosa after pentagastrin.
Authors: Enochs M R , Johnson L R
Published: December 2017

The trophic effects of gastrin on gastrointestinal tissues have been shown to be physiologically important. This study was designed to investigate the sequence of changes in macromolecular synthesis in the rat gastric mucosa following a single dose of pentagastrin. The earliest response was an increase at 1-2 h of poly (A) messenger RNA (mRNA). This increase dropped after 4 h but remained slightly elevated even 12 h after pentagastrin. By 6 h there was a large increase in protein synthesis that lasted until 12 h. Accompanying this rise in protein synthesis was a large increase in ribosomal (rRNA) and transfer RNA (tRNA), which peaked at 12 h. The changes in both fractions of RNA and protein were over by 18 h. No significant increase in secreted protein was noted, but there was a slight, transient decrease at 1 h. Pentagastrin stimulated all forms of RNA, but the largest increase was seen in the rRNA fraction. After multiple doses, parallel increases in rRNA and tRNA were seen. The stimulation of protein synthesis could be abolished by actinomycin D, and was, therefore, RNA dependent.
Suppression of pineal multiunit response to flash after habenular lesion in quail.
Authors: Herbuté S , Baylé J D
Published: December 2017

Habenular nuclei were completely destroyed in male photostimulated and nonphotostimulated quail (Coturnix coturnix japonica). Lesion of the nuclei habenulae led to a markedly increased pineal multiunit activity (MUA) pattern in both long and short daily photoperiods compared to control values. Intact, as well as habenular lesioned birds, showed a lower level of pineal MUA under long-day rearing than under short-day rearing. The decrease in pineal firing rates found in controls under repetitive flash-light stimulations was suppressed in quail bearing habenular lesions. Data are compared to results obtained in sympathectomized and blinded birds. It is suggested that some acute photic information might reach the pineal organ through retinal receptors and habenular pathways. However chronic influence of lighting on pineal MUA, mediated by the retina, does not seem to involve habenular or cervical sympathetic pathways in quail.
Oscillatory changes in muscle lipoprotein lipase activity of fed and starved rats.
Authors: Kotlar T J , Borensztajn J
Published: December 2017

Lipoprotein lipase activity was measured at short time intervals in cardiac and skeletal muscles of normal and streptozotocin-treated diabetic rats fed ad libitum or deprived of food. In normal animals fed ad libitum, lipoprotein lipase activities of heart, diaphragm, soleus, and fast-twitch red fibers of the quadriceps muscle showed rhythmic oscillations that appeared to coincide with the nocturnal feeding habits of the animals. During the day (7 A.M. to 7 P.M.), when food consumption by the rats was greatly reduced, lipoprotein lipase activity in all muscles increased, followed by a decline to basal levels during the night. Similar oscillatory changes in lipoprotein lipase activity were observed in the muscles of diabetic rats fed ad libitum. In normal rats deprived of food, however, the oscillatory changes in muscle lipoprotein lipase activity were not abolished and persisted for at least 48 h. In diabetic rats starved during a 48-h period, the oscillatory changes in muscle lipoprotein lipase activity were markedly altered. In all animals, muscle lipoprotein lipase activities were not correlated to plasma glucagon levels.
Synthesis of macromolecules by intestinal cells incubated with ammonia.
Authors: Topping D C , Visek W J
Published: December 2017

Mucosal cells isolated from the small intestine of chicks and rats were incubated with concentrations of ammonia normally found in the intestinal tract of mammals and birds. NH4Cl added to the incubation medium increased glucose metabolism in cells from both species. Ammonia stimulated incorporation of precursors into RNA and decarboxylation of orotic acid by cells isolated from chickens, but an increase in incorporation of precursors into DNA was not observed in cells from either species. Cultured embryonic chicken duodena showed increased incorporation of orotate into RNA with NH4Cl added to the medium. Rats immunized against jack bean urease showed lower urease activity per gram of dry intestinal content, lower intestinal weight, lower mucosal cell, and total gut protein and less protein per unit weight of DNA in the mucosal cell fraction. The results are compatible with the conclusion that ammonia PRODUCED IN THE INTESTINE BY BACTERIAL UREASES CAUSES SIGNIFICANT CHANGES IN THE CONTENT OF RNA and protein in intestine cells.
Effect of synthetic C-terminal fragments of hGH on insulin release by isolated islets.
Authors: Weerasinghe C , Bornstein J
Published: December 2017

Synthetic fragments representing the C-terminal end of the growth hormone molecule have been tested for their direct in vitro effects on insulin release by isolated rat islets of Langerhans. hGH 177-191 caused a dose-related potentiation of glucose-induced insulin release, whereas the peptide by itself caused no stimulation of insulin release from the islets. The rate curves constructed for insulin secretion as a function of extracellular glucose concentration showed that the Km for glucose is not altered in the presence of the peptide, but that the Vmax of secretion is increased. Significant potentiation of insulin release by the peptide was seen only at high extracellular concentrations of glucose. Measurement of cAMP levels in islets showed that the peptide caused no significant alteration of cAMP levels while still potentiating insulin release. It was therefore concluded that the mechanism of potentiation of insulin release by the peptide may be independent of the changes in cAMP levels in islets. hGH 172-191, too, caused potentiation of glucose-stimulated insulin release from islets, whereas hGH 179-191 was not active in this report.
In vitro and in vivo inhibition of renin by fatty acids.
Authors: Kotchen T A , Welch W J , Talwalkar R T
Published: December 2017

Circulating neutral lipids inhibit the in vitro renin reaction. To identify the inhibitor(s), free fatty acids were added to human renin and homologous substrate. Capric, lauric, palmitoleic, linoleic, and arachidonic acids each inhibited the rate of angiotensin I production in vitro (P less than 0.01). Inhibition by polysaturated fatty acids (linoleic and arachidonic) was less (P less than 0.01) after catalytic hydrogenation of the double bonds. To evaluate an in vivo effect of renin inhibition intra-arterial blood pressure responses to infusions of renin and angiotensin II (5.0 microgram) were measured in anephric rats (n = 6) before and after infusion of linoleic acid (10 mg iv). Mean increase of blood pressure to angiotensin II before (75 mmHg +/- 9) and after (90 +/- 12) linoleic acid did not differ (P greater than 0.05). However, the pressor response to renin after linoleic acid (18 +/- 3) was less (P less than 0.00)) than that before (102 +/- 13). In summary, several fatty acids inhibit the in vitro renin reaction, and in part inhibition is dependent on unsaturation. Linoleic acid also inhibits the in vivo pressor response to renin. These results suggest that fatty acids may modify the measurement of plasma renin activity and may also affect angiotensin production in vivo.
Influence of intrinsic nerves on electromyogram of cat colon in vitro.
Authors: Christensen J , Anuras S , Arthur C
Published: December 2017

The electromyogram of the circular muscle layer of the cat colon was studied in vitro in superfused strips of muscle. Records exhibited electrical slow waves and migrating spike bursts, as described previously. Both the neurotoxin, tetrodotoxin, and the local anesthetic lidocaine, (P less than 0.05) prolonged the duration of migrating spike bursts, but migrating spike bursts were not affected by the adrenergic alpha-antagonist, phenoxybenzamine, nor by the adrenergic beta-antagonist, propranolol. Also, physostigmine and atropine did not affect them. Large concentrations of catecholamines did abolish them. This suggests that the migrating spike burst represents periodic release of the muscle from the tonic influence of nonadrenergic inhibitory nerves in the intramural plexuses. Slow-wave frequency and the congruence of slow waves were not affected (P greater than 0.05) by the antagonists listed above, nor by cholinergic and adrenergic agonists. This suggests that the slow waves are not importantly controlled by intrinsic nerves.
Relative rates of gastric emptying of glucose vs. fat in rats fed nonliquid meals.
Authors: Trout D L , Putney J D , Conway E S
Published: December 2017

Sprague-Dawley rats were briefly starved, fed various test meals, and killed at measured intervals, and the average fractional emptying (disappearance from stomach) rates for glucose (Kgl) and for fat (Kfat) were determined. The Kgl/Kfat ratio was calculated as a measure of the degree to which the stomach emptied glucose preferentially to fat. The size of the meal affected this ratio, which was 7.6 for a small (0.5 g) meal and 2.4 for a large (2.0 g) meal of a nutritionally complete diet. When test meals contained one of two levels of fat (0.4 and 0.1 g) and of glucose (1.2 and 0.3 g), the high level of fat depressed Kgl and Kgl/Kfat, whereas the high level of glucose depressed Kgl and particularly Kfat and, therefore, raised Kgl/Kfat. Kgl/Kfat was also affected by strain of rat and was reduced almost to 1.0 by mixing the meal into a viscous gel of xanthan gum. In the absence of this gel, the percentage of water existing in stomach contents shortly after the test meals varied between 53 and 79% and was suspected of influencing Kgl/Kfat.
Insulin secretion in fetal and newborn sheep.
Authors: Philipps A F , Carson B S , Meschia G , Battaglia F C
Published: December 2017

The relationships between arterial plasma insulin, glucose, and fructose concentrations during the fed and fasted state were studied in seven fetal lambs and their mothers. A significant correlation between insulin and glucose concentration was noted in all fetal lambs and in their mothers. Fetal sensitivity to glucose, as measured by the slopes of the insulin-response curves, was equal to that of the adult although the fetal response was shifted to the left of the maternal. Glucose infusion in four fetal lambs caused significant insulin elevations but no early insulin response (phase I). Maternal fasting caused no alteration in glucose-induced response in the fetus. Similar glucose infusions in newborn and 1-mo-old lambs demonstrated significant early-phase insulin secretion. Basal insulin to glucose ratios were consistent with an adult pattern as early as 3 days after birth.