bluuebunny/crossref_metadata_2025 huggingface dataset:
Remodeling of intermediate metabolism in the diatom
Phaeodactylum tricornutum
under nitrogen stress
Authors: Levitan Orly , Dinamarca Jorge , Zelzion Ehud , Lun Desmond S. , Guerra L. Tiago , Kim Min Kyung , Kim Joomi , Van Mooy Benjamin A. S. , Bhattacharya Debashish , Falkowski Paul G.
Published: December 2014

Significance

When starved for nutrients, diatoms redirect carbon toward biosynthesis of storage lipids, triacylglycerols (TAGs). We examined how this modification is achieved in the diatom
Phaeodactylum tricornutum.
Under nitrogen stress, the cells cannibalized their photosynthetic apparatus while recycling intracellular nitrogen and redirecting it to synthesize nitrogen assimilation enzymes. Simultaneously, they allocated newly fixed carbon toward lipids. In contrast, a nitrate reductase knocked-down strain shunted ∼40% more carbon toward TAGs than the wild type without losing photosynthetic capacity. Our results show that diatoms can remodel their intermediate metabolism on environmental cues and reveal that a key signal in this remodeling is associated with nitrogen assimilation. This insight informs a strategy of developing a much more efficient pathway to produce algal-based biofuels.
Evolution of the H9N2 influenza genotype that facilitated the genesis of the novel H7N9 virus
Authors: Pu Juan , Wang Shuoguo , Yin Yanbo , Zhang Guozhong , Carter Robert A. , Wang Jinliang , Xu Guanlong , Sun Honglei , Wang Min , Wen Chu , Wei Yandi , Wang Dongdong , Zhu Baoli , Lemmon Gordon , Jiao Yuannian , Duan Susu , Wang Qian , Du Qian , Sun Meng , Bao Jinnan , Sun Yipeng , Zhao Jixun , Zhang Hui , Wu Gang , Liu Jinhua , Webster Robert G.
Published: December 2014

Significance

The emergence of human infection with a novel H7N9 avian influenza reassortant in China raises a pandemic concern. However, it is not fully understood how these H9N2 chicken viruses facilitated the genesis of the novel H7N9 viruses. Here we show that a “fittest” genotype (G57) emerged with changed antigenicity and improved adaptability in chickens. It became predominant in vaccinated farm chickens and caused widespread outbreaks before the H7N9 virus emergence, increasing reassortment between H9N2 and other subtype viruses and finally providing all of their internal genes to the novel H7N9 viruses. The prevalence and variation of H9N2 influenza virus in farmed poultry could provide an important early warning of the emergence of novel reassortants with pandemic potential.
miR-155 augments CD8
+
T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ
c
cytokines
Authors: Ji Yun , Wrzesinski Claudia , Yu Zhiya , Hu Jinhui , Gautam Sanjivan , Hawk Nga V. , Telford William G. , Palmer Douglas C. , Franco Zulmarie , Sukumar Madhusudhanan , Roychoudhuri Rahul , Clever David , Klebanoff Christopher A. , Surh Charles D. , Waldmann Thomas A. , Restifo Nicholas P. , Gattinoni Luca
Published: December 2014

Significance

We describe here a strategy based on microRNA therapeutics to augment the efficacy of T-cell–based therapies without the requirement of toxic maneuvers such as lymphodepletion preconditioning and the administration of high doses of exogenous cytokines. These findings can lead to the development of safer and more effective T-cell–based therapies for the treatment of patients with advanced cancer.
MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs
Authors: Zhao Qingguo , Gregory Carl A. , Lee Ryang Hwa , Reger Roxanne L. , Qin Lizheng , Hai Bo , Park Min Sung , Yoon Nara , Clough Bret , McNeill Eoin , Prockop Darwin J. , Liu Fei
Published: December 2014

Significance

Mesenchymal stem or stromal cells (MSCs) offer great promise as potential therapies for cancers and other diseases. However, applications of MSCs for cancer therapy are hindered by their protumor potential under certain conditions, considerable donor variations, and limited expandability. Here we report generation of induced pluripotent stem cells (iPSC)-derived MSCs with same tumor homing capacity but much less protumor potential using a modified protocol with high derivation efficiency. Starting from iPSCs with almost unlimited expandability, the protocol can be readily scaled up to provide huge amounts of MSCs with uniform biological properties for multicenter evaluation, large animal experiments, and potential clinical trial. Moreover, therapeutic transgenes can be inserted into safe-harbor loci of iPSCs before derivation of MSCs to eliminate insertional mutation and guarantee stable expression of transgenes during prolonged expansion.
Structure of the
Pseudomonas aeruginosa
transamidosome reveals unique aspects of bacterial tRNA-dependent asparagine biosynthesis
Authors: Suzuki Tateki , Nakamura Akiyoshi , Kato Koji , Söll Dieter , Tanaka Isao , Sheppard Kelly , Yao Min
Published: December 2014

Significance

The present structure reveals the architecture of the
Pseudomonas aeruginosa
bacterial-type asparagine-transamidosome, the most common macromolecular assembly required for asparaginyl-tRNA
Asn
formation in bacteria. We show that the presence of an additional GAD domain in the aspartyl-tRNA synthetase, common in most bacteria but missing in the archaeal-type
Thermus thermophilus
transamidosome, results in a complex with a distinct architecture and stoichiometry. Furthermore, our kinetic studies reveal that bacterial transamidosomes have distinct kinetic properties compared with the archaeal complex, with rapid release of the Asn-tRNA
Asn
product, leading to improved turnover by the bacterial-type aspartyl-tRNA synthetase in the complex. Overall, our study provides a structural basis for understanding tRNA-dependent asparagine biosynthesis found in the in majority of bacterial species.
Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity
Authors: Burbage Marianne , Keppler Selina J. , Gasparrini Francesca , Martínez-Martín Nuria , Gaya Mauro , Feest Christoph , Domart Marie-Charlotte , Brakebusch Cord , Collinson Lucy , Bruckbauer Andreas , Batista Facundo D.
Published: December 2014

The small Rho GTPase Cdc42, known to interact with Wiskott–Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-deficient mice are incapable of forming germinal centers or generating plasma B cells upon either viral infection or immunization. Such severe immune deficiency is caused by multiple and profound B cell abnormalities, including early blocks during B cell development; impaired antigen-driven BCR signaling and actin remodeling; defective antigen presentation and in vivo interaction with T cells; and a severe B cell–intrinsic block in plasma cell differentiation. Thus, our study presents a new perspective on Cdc42 as key regulator of B cell physiology.
Hydrophobic interaction between contiguous residues in the S6 transmembrane segment acts as a stimuli integration node in the BK channel
Authors: Carrasquel-Ursulaez Willy , Contreras Gustavo F. , Sepúlveda Romina V. , Aguayo Daniel , González-Nilo Fernando , González Carlos , Latorre Ramón
Published: December 2014

Large-conductance Ca2+- and voltage-activated K+ channel (BK) open probability is enhanced by depolarization, increasing Ca2+ concentration, or both. These stimuli activate modular voltage and Ca2+ sensors that are allosterically coupled to channel gating. Here, we report a point mutation of a phenylalanine (F380A) in the S6 transmembrane helix that, in the absence of internal Ca2+, profoundly hinders channel opening while showing only minor effects on the voltage sensor active–resting equilibrium. Interpretation of these results using an allosteric model suggests that the F380A mutation greatly increases the free energy difference between open and closed states and uncouples Ca2+ binding from voltage sensor activation and voltage sensor activation from channel opening. However, the presence of a bulky and more hydrophobic amino acid in the F380 position (F380W) increases the intrinsic open–closed equilibrium, weakening the coupling between both sensors with the pore domain. Based on these functional experiments and molecular dynamics simulations, we propose that F380 interacts with another S6 hydrophobic residue (L377) in contiguous subunits. This pair forms a hydrophobic ring important in determining the open–closed equilibrium and, like an integration node, participates in the communication between sensors and between the sensors and pore. Moreover, because of its effects on open probabilities, the F380A mutant can be used for detailed voltage sensor experiments in the presence of permeant cations.
Mechanism of activation of the prokaryotic channel ELIC by propylamine: A single-channel study
Authors: Marabelli Alessandro , Lape Remigijus , Sivilotti Lucia
Published: December 2014

Prokaryotic channels, such as Erwinia chrysanthemi ligand-gated ion channel (ELIC) and Gloeobacter violaceus ligand-gated ion channel, give key structural information for the pentameric ligand-gated ion channel family, which includes nicotinic acetylcholine receptors. ELIC, a cationic channel from E. chrysanthemi, is particularly suitable for single-channel recording because of its high conductance. Here, we report on the kinetic properties of ELIC channels expressed in human embryonic kidney 293 cells. Single-channel currents elicited by the full agonist propylamine (0.5–50 mM) in outside-out patches at −60 mV were analyzed by direct maximum likelihood fitting of kinetic schemes to the idealized data. Several mechanisms were tested, and their adequacy was judged by comparing the predictions of the best fit obtained with the observable features of the experimental data. These included open-/shut-time distributions and the time course of macroscopic propylamine-activated currents elicited by fast theta-tube applications (50–600 ms, 1–50 mM, −100 mV). Related eukaryotic channels, such as glycine and nicotinic receptors, when fully liganded open with high efficacy to a single open state, reached via a preopening intermediate. The simplest adequate description of their activation, the “Flip” model, assumes a concerted transition to a single intermediate state at high agonist concentration. In contrast, ELIC open-time distributions at saturating propylamine showed multiple components. Thus, more than one open state must be accessible to the fully liganded channel. The “Primed” model allows opening from multiple fully liganded intermediates. The best fits of this type of model showed that ELIC maximum open probability (99%) is reached when at least two and probably three molecules of agonist have bound to the channel. The overall efficacy with which the fully liganded channel opens was ∼102 (∼20 for α1β glycine channels). The microscopic affinity for the agonist increased as the channel activated, from 7 mM for the resting state to 0.15 mM for the partially activated intermediate state.
Effects of population density and body size on disease ecology of the European lobster in a temperate marine conservation zone
Authors: Davies Charlotte E. , Johnson Andrew F. , Wootton Emma C. , Greenwood Spencer J. , Clark K. Fraser , Vogan Claire L. , Rowley Andrew F.
Published: December 2014

Marine conservation zones (MCZs) are a form of spatial marine management, increasingly popular since the move towards ecosystem-based fisheries management. Implementation, however, is somewhat contentious and as a result of their short history, their effects are still widely unknown and understudied. Here, we investigate the population and health of the European lobster (Homarus gammarus) in the Lundy Island Marine Conservation Zone, Bristol Channel, UK. Using the fished refuge zone (RZ) as a control area, catch per unit effort was calculated for both the no-take zone (NTZ) and RZ and binomial logistic regression models were used to examine the effects of site, sex, landing size, and loss of chelae on the probability of shell disease and injury presence in individuals. Lobsters were also tested for the causative agent of gaffkaemia, Aerococcus viridans var. homari, and white spot syndrome virus (WSSV). The analysis revealed a higher lobster density and larger lobsters in the NTZ compared with the RZ. Shell disease was present in 24% of lobsters and the probability of shell disease occurrence increased notably for individuals over the minimum landing size (MLS) of 90 mm carapace length. Shell disease was also more prevalent in lobsters displaying injury, and in males. Injury was present in 33% of lobsters sampled and prevalence was higher in lobsters in the NTZ compared with the RZ, and in lobsters >MLS. Aerococcus viridans var. homari was detected in <1% of individuals, but WSSV was absent from all sampled lobsters. Overall, the study demonstrates both positive and potentially negative effects of NTZs, methods for effective non-lethal sampling of disease agents, and highlights the need for more comprehensive, long-term monitoring within highly protected MCZs, both before and after implementation.
High-resolution joint symbolic analysis to enhance classification of the cardiorespiratory system in patients with schizophrenia and their relatives
Authors: Schulz Steffen , Haueisen Jens , Bär Karl-Jürgen , Andreas Voss
Published: December 2014

Schizophrenia as a mental illness is one of the most serious in the world. Patients with schizophrenia have an increased cardiac mortality rate, but the reasons for this remain unclear. In addition to other factors, the role of impaired autonomic regulation during acute psychosis has become more evident in different studies applying heart rate (HR) variability analyses. But, until now, respiration and cardiorespiratory regulation, which are important for homeostatic control, have not been considered. In this study, short-term cardiorespiratory couplings (CRCs) of 23 unmedicated patients with paranoid schizophrenia (SZO), 20 of their healthy first-degree relatives (REL) and 20 healthy subjects (CON) matched according to age and sex of SZO and REL were investigated by applying high-resolution joint symbolic dynamics (HRJSD) analysis. We found a significantly (
p
<0.0061) altered HR pattern, respiratory pattern and CRCs in SZO and only marginal alterations for the REL group in comparison with the CON group when we applied HRJSD. These results might be an indication of decreased vagal activity within the brainstem, an altered or suppressed interaction of the brainstem and higher regulatory centres, or panic- and anxiety-related changes in the brainstem associated with the acute psychosis of these patients.
High-resolution genomic surveillance of 2014 ebolavirus using shared subclonal variants
Authors: Emmett Kevin J. , Lee Albert , Khiabanian Hossein , Rabadan Raul
Published: December 2014

Viral outbreaks, such as the 2014 ebolavirus, can spread rapidly and have complex evolutionary dynamics, including coinfection and bulk transmission of multiple viral populations. Genomic surveillance can be hindered when the spread of the outbreak exceeds the evolutionary rate, in which case consensus approaches will have limited resolution. Deep sequencing of infected patients can identify genomic variants present in intrahost populations at subclonal frequencies (i.e. < 50%). Shared subclonal variants (SSVs) can provide additional phylogenetic resolution and inform about disease transmission patterns. Here, we use metrics from population genetics to analyze data from the 2014 ebolavirus outbreak in Sierra Leone and identify phylogenetic signal arising from SSVs. We use methods derived from information theory to measure a lower bound on transmission bottleneck size that is larger than one founder population, yet significantly smaller than the intrahost effective population. Our results demonstrate the important role of shared subclonal variants in genomic surveillance.
Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2
Authors: Wurm Stefanie , Zhang Jisheng , Guinea-Viniegra Juan , García Fernando , Muñoz Javier , Bakiri Latifa , Ezhkova Elena , Wagner Erwin F.
Published: December 2014

Altered epidermal differentiation characterizes numerous skin diseases affecting >25% of the human population. Here we identified Fra-2/AP-1 as a key regulator of terminal epidermal differentiation. Epithelial-restricted, ectopic expression of Fra-2 induced expression of epidermal differentiation genes located within the epidermal differentiation complex (EDC). Moreover, in a papilloma-prone background, a reduced tumor burden was observed due to precocious keratinocyte differentiation by Fra-2 expression. Importantly, loss of Fra-2 in suprabasal keratinocytes is sufficient to cause skin barrier defects due to reduced expression of differentiation genes. Mechanistically, Fra-2 binds and transcriptionally regulates EDC gene promoters, which are co-occupied by the transcriptional repressor Ezh2. Fra-2 remains transcriptionally inactive in nondifferentiated keratinocytes, where it was found monomethylated and dimethylated on Lys104 and interacted with Ezh2. Upon keratinocyte differentiation, Fra-2 is C-terminally phosphorylated on Ser320 and Thr322 by ERK1/2, leading to transcriptional activation. Thus, the induction of epidermal differentiation by Fra-2 is controlled by a dual mechanism involving Ezh2-dependent methylation and activation by ERK1/2-dependent phosphorylation.
Random skin biopsy of patients with intravascular large B‐cell lymphoma associated with thrombocytopenia and coagulation abnormalities: Proposal of a modified biopsy method
Authors: Maekawa Takeo , Komine Mayumi , Murata Satoru , Fukushima Noriyoshi , Ohtsuki Mamitaro
Published: December 2014

Intravascular large B‐cell lymphoma (IVLBCL) is classified as a rare type of non‐Hodgkin's B‐cell lymphoma by the World Health Organization. It is characterized by the presence of lymphoma cells in the lumens of the small vessels of several organs, most notably the skin. Diagnosis of IVLBCL is difficult because of the lack of lymphadenopathy and because lesions need to be histologically confirmed via a biopsy of the affected organs. Random skin biopsy (RSB) of normal‐appearing skin is a useful and apparently safe means of evaluating IVLBCL. However, patients with IVLBCL often exhibit thrombocytopenia, and we describe a case in which a patient with thrombocytopenia experienced hemorrhagic shock and died shortly after RSB. For this reason, we reviewed cases of RSB performed at our hospital and found that the middle adipose tissue contained a higher percentage of atypical lymphoid cells than other layers of the skin. On the basis of our findings, we propose a strategy for the safer performance of RSB in IVLBCL patients with thrombocytopenia and coagulation abnormalities.
Immune complex negatively regulates Toll‐like receptor 9‐mediated immune responses in B cells through the inhibitory Fc‐gamma receptor IIb
Authors: Qian Li , Chen Wenyan , Qin Hongchao , Rui Chenglei , Jia Xiaoqin , Fu Yi , Gong Weijuan , Tian Fang , Ji Mingchun
Published: December 2014

Because inappropriate activation of Toll‐like receptor 9 (TLR9) may induce pathological damage, negative regulation of the TLR9‐triggered immune response has attracted considerable attention. Nonpathogenic immune complex (IC) has been demonstrated to have beneficial therapeutic effects in some kinds of autoimmune diseases. However, the role of IC in the regulation of TLR9‐triggered immune responses and the underlying mechanisms remain unclear. In this study, it was demonstrated that IC stimulation of B cells not only suppresses CpG‐oligodeoxynucleotide (CpG‐ODN)‐induced pro‐inflammatory IL‐6 and IgM κ production, but also attenuates CD40 and CD80 expression. Furthermore, our results suggest that the receptor for the Fc portion of IgG (FcγR) IIb is involved in the suppressive effect of IC on TLR9‐mediated CD40, CD80 and IL‐6 expression. Finally, it was found that IC down‐regulates TLR9 expression in CpG‐ODN activated B cells. Our results provide an outline of a new pathway for the negative regulation of TLR9‐triggered immune responses in B cells via FcγRIIb. A new mechanistic explanation of the therapeutic effect of nonpathogenic IC on inflammatory and autoimmune diseases is also provided.
How Reliable are Parenchymal Tissues for the Evaluation of Carbon Monoxide Poisoning? A Pilot Study
Authors: Casali Michelangelo Bruno , Sironi Luca , Caligara Marina , Blandino Alberto , Circelli Silvia , Schiavi Davide , Cattaneo Cristina
Published: December 2014

Dealing with burnt bodies, the forensic pathologist must first of all answer the question whether the victim was alive at the moment of the fire. This study aims at clarifying whether some human solid tissues may be reliably used for the forensic diagnosis of Co poisoning on burnt bodies providing no collectable blood during the autopsy. From 34 selected cases, both cardiac blood and parenchymal samples were collected to perform CO‐oxymeter, spectrophotometry, and gas chromatography tests: blood CO estimations (blood COHb% and blood[CO]) and parenchymal[CO] values have been compared with special focus on R values. The solid tissues having the best correlations with blood CO amount turned out to be the lung (R 0.84), the liver (R 0.83), the kidney (R 0.79), and the spleen (R 0.92).
Pulmonary artery sarcoma: a rare thoracic tumor frequently misdiagnosed at presentation
Authors: Evison Matthew , Crosbie Philip , Chaturvedi Anshuman , Shah Rajesh , Booton Richard
Published: December 2014

This case illustrates a rare but important differential diagnosis of pulmonary emboli in the field of thoracic oncology, that of pulmonary artery sarcoma. It describes particular clinical features that may raise suspicion of this tumor in cases of suspected pulmonary emboli, and highlights novel radiological modalities and tissue sampling techniques in such cases. Surgical resection, as part of multi‐modality therapy, is the cornerstone of treatment that has seen survival dramatically improve in recent years for patients with this rare cancer.
Comparison of Sinoatrial Conduction Time Measured by Holter method and Premature Stimulation Method
Authors: Kramarz Elżbieta , Piotrowicz Ryszard , Krzyzanowski Krystian , Kramarz Paulina
Published: December 2014

Background

The reliability of noninvasive Holter method for the calculation of sinoatrial conduction time (SACT) has not been confirmed by results of invasive electrophysiological studies of sinus nodal function. The aim of this study was to compare the values of SACT obtained by Holter method with values estimated by premature atrial stimulation method.

Methods

The study population consisted of 61 patients, in whom the 24‐hour ambulatory ECG monitoring had shown the occurrence of atrial premature beats. All these subjects were undergoing electrophysiological study including programmed atrial and ventricular stimulation. The measurements of SACT were obtained using spontaneous atrial premature beats (Holter method) and high right atrial stimulation (Strauss method).

Results

There was a good correlation between measurements of SACT by Holter method and Strauss method (r = 0.79; P < 0.001). There was no significant difference between values of SACT estimated by two compared methods. However, in certain patients, there were appreciable differences and SACT measured using spontaneous premature beats was shorter in 34 and longer in 23 patients than that estimated by the Strauss method. The values of SACT calculated by Holter method and Strauss method were significantly (P < 0.001) higher in patients with sick sinus syndrome than in those without evidence of sinus node dysfunction.

Conclusions

Good correlation between values of SACT obtained by two compared methods suggests that single measurement performed using Holter method may be adequate for reliable calculation of SACT.
Efficacy of theory‐based interventions for young people with type 1 diabetes: A systematic review and meta‐analysis
Authors: Ayling Kieran , Brierley Samantha , Johnson Barbara , Heller Simon , Eiser Christine
Published: December 2014

Purpose

Theory‐based behaviour change interventions have been recommended to improve outcomes for young people with type 1 diabetes. However, theory has exclusively been considered in a simplistic all‐or‐none fashion. We therefore (1) examined the nature and extent of explicit theory use in published interventions involving young people with type 1 diabetes and (2) the relationship between how theory is used and intervention outcomes.

Methods

We conducted systematic searches for randomized controlled trials (RCTs) published between 1999 and 2012. We used a detailed structured framework to code how theory was used and meta‐analytic techniques to examine the relationships between theory use and intervention efficacy.

Results

We identified 34 articles comprising 27 RCTs. Thirty per cent (k = 8) did not use theory in any of the ways assessed. Where present, the most common use of theory was providing evidence that a targeted theoretical construct predicted behaviour (k = 15; 56%). Trials that used theory to some extent had marginally larger pooled effect sizes for both medical and psychological outcomes than those that did not. However, in meta‐regression models, use of theory did not significantly predict intervention outcomes.

Conclusions

Theory is under‐utilized in intervention development for young people with type 1 diabetes. When employed, theory appears to be advantageous, but not necessarily predictive of intervention success. We argue that greater emphasis is needed on choosing appropriate theory, which should then become central to the process of intervention development.

Statement of contribution

What is already known on this subject?

Interventions for young people with type 1 diabetes that explicitly cite a theoretical basis may be more effective than those that do not. Recommendations have been made for theory to be central to the intervention development process in this area.

What does this study add?

Theory use in recent interventions for young people with type 1 diabetes is extremely limited.

Larger positive medical and psychological outcomes are observed in interventions making some use of theory.

Greater use of theory does not necessarily guarantee intervention success.
Coyotaje and Drugs: Two Different Businesses
Authors: IZCARA PALACIOS SIMÓN PEDRO
Published: December 2014

This article, based on a qualitative methodology that includes in‐depth interviews with 85 migrant‐smugglers who operate at the border betweenMexico and theUnitedStates, addresses three research questions: do migrant‐smugglers take part in organised crime? Are criminal groups involved in migrant smuggling? And are migrant‐smugglers engaged in drug trafficking? It concludes that many smugglers have become part of organised crime groups but only after leaving the migrant‐smuggling business; that criminal organisations do not help migrants to cross the border; and that migrant‐smugglers do not carry drugs.
Follicular T helper cells and humoral reactivity in kidney transplant patients
Authors: de Graav G N , Dieterich M , Hesselink D A , Boer K , Clahsen-van Groningen M C , Kraaijeveld R , Litjens N H R , Bouamar R , Vanderlocht J , Tilanus M , Houba I , Boonstra A , Roelen D L , Claas F H J , Betjes M G H , Weimar W , Baan C C
Published: December 2014

Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4POSCXCR5POS T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu.
Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism
Authors: Fritez Nabila , Sobrier Marie‐Laure , Iraqi Hinde , Vié‐Luton Marie‐Pierre , Netchine Irène , El Annas Abdessamad , Pantel Jacques , Collot Nathalie , Rose Sophie , Piterboth William , Legendre Marie , Chraibi Abdelmjid , Amselem Serge , Kadiri Abdelkrim , Hilal Latifa
Published: December 2014

Background/Objectives

Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecular cause. We aimed to document the molecular basis of growth retardation in a Moroccan cohort.

Design/Patients

80 index cases [54 with isolated growth hormone deficiency (IGHD), 26 with combined pituitary hormone deficiency (CPHD)] were screened for molecular defects in GH1 (including LCR‐GH1), GHRHR, GHSR, GHRH, PROP1, POU1F1, HESX1, LHX3, LHX4 and SOX3.

Results

Five different deleterious mutations were identified in 14 patients from eight families. In the IGHD group, three genes were found to be involved: GH1, GHRHR and GHSR. In the CPHD group, PROP1 was the only mutated gene. In addition, two heterozygous variations whose deleterious effect remains to be demonstrated were identified (in GH1 and LHX4), and two polymorphisms (missense variations) were detected (in LHX3 and in GHSR). The prevalence of mutations in this Moroccan GHD cohort was 10% (8/80), 11·1% (6/54) in the IGHD group and 7·7% (2/26) in the CPHD group.

Conclusion

This is the first molecular screening of congenital GHD in a Moroccan population and, like other studies, mutations were preferentially identified in familial cases (75%); mutations in genes such as POU1F1, HESX1, SOX3, LHX3 and LHX4 are extremely rare. The p.R73C PROP1 mutation was the most frequent mutation in CPHD; this should be the first one to screen in this population. Our results should contribute to a better diagnosis and management of this heterogeneous disease condition.
Who owns the trauma? A Kleinian perspective on the dialogue between child protection social workers and the media
Authors: Ben Shlomo Shirley , Levin‐Keini Noga
Published: December 2014

The present paper makes use of the developmental model of movement between mental positions that was formulated by psychoanalyst Melanie Klein, aimed at understanding the dialogue that takes place between the media and social workers in the field of child welfare, centring around incidents of murder within the family. The basic concept in the paper is that when working with children who are victims of abuse and with their parents, and when reporting on them as well, the feeling of personal control is severely undermined, being associated with the loss of the hallowed social value known as ‘unconditional love of a parent for his child’. The paper illustrates these theoretical ideas by describing two cases that took place in Israel and recommendations are made regarding ways of promoting the dialogue between the professions.
A New Model for Catalyzing Translational Science: The Early Stage Investigator Mentored Research Scholar Program in HIV Vaccines
Authors: Adamson Blythe J.S. , Fuchs Jonathan D. , Sopher Carrie J. , Flood Danna M. , Johnson R. Paul , Haynes Barton F. , Kublin James G. ,   The NIAID HIV Vaccine Trials Network
Published: December 2014

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large‐scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.
EXPERT OPINION AND PRODUCT QUALITY: EVIDENCE FROM NEW YORK CITY RESTAURANTS
Authors: Gergaud Olivier , Storchmann Karl , Verardi Vincenzo
Published: December 2014

We analyze whether consumers' quality perception and/or producer investment of New York City restaurants, measured by Zagat scores, responds to newly appearing expert opinion, measured by Michelin scores. Answering this question is of general economic interest as it applies to all markets with information asymmetries. Employing a difference‐in‐differences approach as well as a propensity score matching approach we find significant Michelin treatment effects on food and décor quality. Based on these changes, we find a Michelin‐induced price increase of approximately 30% per Michelin star. To examine whether the improved food and nonfood quality is based on restaurant investments or is merely imagined, we analyze nonfood investments by referring to Wine Spectator wine list awards. Our analysis suggests that Michelin‐reviewed restaurants are significantly more likely to invest in their wine list than others. As a result, Michelin reviewed restaurants are more likely to improve food and nonfood (esp. décor) quality leading to significant price increases. However, while restaurants that increase prices only due to décor and service improvements are more likely to go out of business, food improvements appear to secure a restaurant's survival. (JEL D11, L15, L66)
Should we start evaluating intrathecal IgM production clinically?
Authors: Alvarez E.
Published: December 2014

Click here to view the accompanying paper in this issue.
Calmodulin mutations causing catecholaminergic polymorphic ventricular tachycardia confer opposing functional and biophysical molecular changes
Authors: Søndergaard Mads T. , Sorensen Anders B. , Skov Louise L. , Kjaer‐Sorensen Kasper , Bauer Mikael C. , Nyegaard Mette , Linse Sara , Oxvig Claus , Overgaard Michael T.
Published: December 2014

Calmodulin (CaM) is the central mediator of intracellular Ca2+ signalling in cardiomyocytes, where it conveys the intricate Ca2+ transients to the proteins controlling cardiac contraction. We recently linked two separate mutations in CaM (N53I and N97S) to dominantly inherited catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmic disorder in which exercise or acute emotion can lead to syncope and sudden cardiac death. Given the ubiquitous presence of CaM in all eukaryote cells, it is particular intriguing that carriers of either mutation show no additional symptoms. Here, we investigated the effects of the CaM CPVT mutations in a zebrafish animal model. Three‐day‐old embryos injected with either CaM mRNA showed no detectable pathologies or developmental abnormalities. However, embryos injected with CPVT CaM mRNA displayed increased heart rate compared to wild‐type CaM mRNA under β‐adrenergic stimulation, demonstrating a conserved dominant cardiac specific effect between zebrafish and human carriers of these mutations. Motivated by the highly similar physiological phenotypes, we compared the effects of the N53I and N97S mutations on the biophysical and functional properties of CaM. Surprisingly, the mutations have opposing effects on CaM C‐lobe Ca2+ binding affinity and kinetics, and changes to the CaM N‐lobe Ca2+ binding are minor and specific to the N53I mutation. Furthermore, both mutations induce differential perturbations to structure and stability towards unfolding. Our results suggest different molecular disease mechanisms for the CPVT (N53I and N97S mutations) and strongly support that cardiac contraction is the physiological process most sensitive to CaM integrity.
Mineralization of Alvinella polychaete tubes at hydrothermal vents
Authors: Georgieva M. N. , Little C. T. S. , Ball A. D. , Glover A. G.
Published: December 2014

Alvinellid polychaete worms form multilayered organic tubes in the hottest and most rapidly growing areas of deep‐sea hydrothermal vent chimneys. Over short periods of time, these tubes can become entirely mineralized within this environment. Documenting the nature of this process in terms of the stages of mineralization, as well as the mineral textures and end products that result, is essential for our understanding of the fossilization of polychaetes at hydrothermal vents. Here, we report in detail the full mineralization of Alvinella spp. tubes collected from the East Pacific Rise, determined through the use of a wide range of imaging and analytical techniques. We propose a new model for tube mineralization, whereby mineralization begins as templating of tube layer and sublayer surfaces and results in fully mineralized tubes comprised of multiple concentric, colloform, pyrite bands. Silica appeared to preserve organic tube layers in some samples. Fine‐scale features such as protein fibres, extracellular polymeric substances and two types of filamentous microbial colonies were also found to be well preserved within a subset of the tubes. The fully mineralized Alvinella spp. tubes do not closely resemble known ancient hydrothermal vent tube fossils, corroborating molecular evidence suggesting that the alvinellids are a relatively recent polychaete lineage. We also compare pyrite and silica preservation of organic tissues within hydrothermal vents to soft tissue preservation in sediments and hot springs.
Capital Allocation: Evidence, Analytical Methods, and Assessment Guidance
Authors: Mauboussin Michael J. , Callahan Dan
Published: December 2014

Capital allocation is one of top management's primary responsibilities. Although always important, it is critical today because corporate operating returns on invested capital are at an all‐time high, while recent growth and investment have been modest, and corporate balance sheets in the U.S. have substantial cash.

Yet few senior executives are sufficiently well‐versed in finance theory and methods to allocate capital as effectively as possible. Further, incentive programs that focus on meeting earnings per share often encourage behavior that is not in the best interests of long‐term shareholders.

In this report, the authors begin with the premise that the goal of corporate capital allocation is to build long‐term value per share; and with that view in mind, they examine the main sources and uses of capital by the largest 1,500 U.S. companies during the last 30 years. More specifically, the authors identify the amounts of capital allocated to each of seven important alternatives, including major uses of capital such as M&Amp;A, capital expenditures, R&D, and distributions of capital to investors such as dividends and stock repurchases. And after reviewing the past allocations of capital to each of these alternatives, the authors summarize the academic research on the effects on corporate values of each of these uses of capital.

The authors report that U.S. corporations fund most of their investments internally, and that M&Amp;A and capital expenditures have long been, and continue to be, the largest operating uses of capital, though both capital expenditures and growth in assets have fallen in recent years. At the same time, both corporate cash holdings and distributions to shareholders in the form of dividends and stock buybacks are at record levels. But even with such high payouts, R&D spending as a percentage of revenue by U.S. companies has remained high, and actually increased during the past decade.

Finally, the authors provide a framework that can be used either internally or by outsiders to evaluate the capital allocation practices and effectiveness of a management team. This framework asks management to assess its past performance, provide realistic projections of future returns on invested capital, and evaluate their own incentive programs—all while renewing their commitment to the five principles of thoughtful capital allocation: (1) zero‐based capital allocation; (2) funding of strategies, not projects; (3) no capital rationing; (4) zero tolerance for bad growth; and (5) continuous monitoring of the value of all assets and business, and willingness to take action if and when such values are larger outside than inside the firm.
An Unconventional Conglomerateur: Henry Singleton and Teledyne
Authors: Thorndike William N.
Published: December 2014

Capital allocation involves decisions about raising and returning capital, and about acquiring and selling companies—all of which can have major effects on shareholder value. Rather than judging CEOs by growth in revenues or earnings, the author argues that they should be judged by increases in the per share value of the companies they manage and also in comparison with the returns generated by peer firms and the broader market. Successful CEOs have been able to overcome the “institutional imperative”—the tendency of managers to focus on the sheer size of their enterprises and to avoid doing things that might be seen as unconventional.

In this chapter from his recent book, The Outsiders, which provides accounts of eight remarkably successful and long‐tenured CEOs, the author describes the successful management by Henry Singleton of the conglomerate Teledyne from 1963 to 1990, a period during which the company's shareholders enjoyed annualized returns of over 20%. During the 1960s, the company produced high returns mainly by making large acquisitions funded by new equity issues. During the 1970s and '80s, by contrast, Teledyne used massive share repurchases to return excess capital to shareholders. Thus, Singleton adjusted his capital allocation strategy in response to changes in product and financial markets—and to changes in the perceived difference between market and intrinsic values. When investors provided capital with relatively low required rates of return, as in the 1960s, Singleton was an aggressive buyer investor in a wide range of businesses. But when interest rates were high and equity valuations were low, as in the 1970s and early 1980s, Singleton used share repurchases to create value by reducing investment and limiting growth. The company's shareholders were well rewarded in both environments.
The Icahn Manifesto
Authors: Carlisle Tobias
Published: December 2014

The title of this opening chapter in the author's new book on activist investors refers to Carl Icahn's solution to the “agency” problem faced by the shareholders of public companies in motivating corporate managers and boards to maximize firm value. During the 1960s and '70s, U.S. public companies tended to be run in ways designed to increase their size while minimizing their financial risk, with heavy emphasis on corporate diversification. Icahn successfully challenged corporate managers throughout the 1970s and 1980s by buying blocks of shares in companies he believed were undervalued and then demanding board seats and other changes in corporate governance and management.

This article describes the evolution of Icahn as an investor. Starting by investing in undervalued, closed‐end mutual funds and then shorting shares of the stocks in the underlying portfolio, Icahn was able to get fund managers either to liquidate their funds (giving Icahn an arbitrage profit on his long mutual fund/short underlying stocks position) or take other steps to eliminate the “value gap.” After closing the value gaps within the limited universe of closed‐end mutual funds, Icahn turned his attention to the shares of companies trading for less than his perception of the value of their assets.

As the author goes on to point out, the strategy that Icahn used with such powerful effect can be traced to the influence of the great value investor Benjamin Graham. Graham was a forceful advocate for the use of shareholder activism to bring about change in underperforming—and in that sense undervalued—companies. The first edition of Graham's investing classic, Security Analysis, published in 1934, devoted an entire chapter to the relationship between shareholders and management, which Graham described as “one of the strangest phenomena of American finance.”
Are Certain Dividend Increases Predictable? The Effect of Repeated Dividend Increases on Market Returns
Authors: Michayluk David , Neuhauser Karyn , Walker Scott
Published: December 2014

The authors report the findings of their study of over 400 stocks of public companies that announced at least 20 consecutive increases in their dividends during the period 1999 and 2009. With the assumption that the stock market learns to anticipate future dividend increases from current patterns, the study was designed to answer the question: How many increases does it take for the market to anticipate, and “price in,” the pattern of dividend increases?

The authors report finding that abnormal returns around the first and second announcements of dividend increases are significant and positive, but are much less significant for the third and further increases. They also find that the size of the dividend increases tends to fall with more increases, and that the largest percentage dividend changes occur early in the sequence.
Transarterial chemoembolization aggravated peritumoral fibrosis via hypoxia‐inducible factor‐1α dependent pathway in hepatocellular carcinoma
Authors: Qu Kai , Yan Zhaoyong , Wu Yousheng , Chen Yibing , Qu Ping , Xu Xinsen , Yuan Peng , Huang Xiaojun , Xing Jinliang , Zhang Hongxin , Liu Chang , Zhang Jing
Published: December 2014

Background and Aim

It was commonly accepted that chemotherapeutic cytotoxicity was the main cause for hepatic failure in hepatocellular carcinoma patients after repeated transarterial chemoembolization (TACE). However, the effect of embolization‐induced hypoxia on liver cirrhosis has rarely been concerned.

Methods

Serum levels of alanine aminotransferase, aspartate aminotransferase, and albumin were used to detect liver injury. Hepatic artery ligation was performed in carbon tetrachloride‐induced rat hepatic fibrosis model to mimic the effect of hepatic hypoxia on liver fibrosis after TACE. Sirius Red staining and immunohistochemical analysis of alpha‐smooth muscle actin (α‐SMA) were used to detect the activation of hepatic stellate cells. Moreover, the expression of hypoxia and fibrosis‐related molecules were analyzed at protein and/or mRNA level.

Results

Patients showed a significant increase in alanine aminotransferase and aspartate aminotransferase (P = 0.006), accompanied by a decrease in albumin (P = 0.005) after repeated TACE. Hepatic artery ligation significantly promoted carbon tetrachloride‐induced rat liver fibrosis progression as indicated by Sirius Red and α‐SMA staining, as well as increased expression of hypoxia‐inducible factor (HIF)‐1α, transforming growth factor (TGF)‐β1, and vascular endothelial growth factor (VEGF). Conditioned media of hypoxia‐treated L02 cells induced the expression of Collagen I and α‐SMA in LX‐2 cells, which was inhibited by HIF‐1α small interfering RNA. Finally, HIF‐1α inhibitor LW6 attenuated the hypoxia‐induced fibrosis progression in vivo.

Conclusion

Our data demonstrate that TACE‐induced hepatic hypoxia aggravates the fibrosis progression in peritumoral liver tissue, thus leads to the deterioration of liver function. Intervention of HIF‐1α might be a valuable strategy to optimize the efficacy and reduce the complication of TACE.