bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelets are efficient and protective depots for storage, distribution, and delivery of lysosomal enzyme in mice with Hurler Syndrome
Authors: Dai Mei , Han Jingfen , El-Amouri Salim S. , Brady Roscoe O. , Pan Dao
Published: February 2014

Significance

The therapeutic potential of hematopoietic stem cell (HSC)-mediated gene therapy has been demonstrated in clinical trials, and yet the dilemma of the need for high transgene frequency to maximize expression while concurrently minimizing the associated increased risk of oncogenesis remains unresolved. Use of megakaryocytes (MKs)/platelets for transgene expression may take advantage of their rapid turnover and protective storage in platelets and reduce the risk of activating oncogenes in HSC. Here, we demonstrate that the MK/platelet lineage is capable of generating/storing a fully functional lysosomal enzyme and leads to highly efficient, continuous, and versatile transport/distribution of enzyme into the circulation and major diseased organs. This study provides proof of concept of MK/platelet as a depot for efficient production, delivery, and effective distribution of lysosomal enzymes.
Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer
Authors: Monk Brian C. , Tomasiak Thomas M. , Keniya Mikhail V. , Huschmann Franziska U. , Tyndall Joel D. A. , O’Connell Joseph D. , Cannon Richard D. , McDonald Jeffrey G. , Rodriguez Andrew , Finer-Moore Janet S. , Stroud Robert M.
Published: February 2014

Significance

The absence in the Protein Data Bank of full-length structures of bitopic membrane proteins with one transmembrane helix, probably because of difficulties with ordered crystallization, has limited understanding of how single-transmembrane helices orient enzymes and sensors at the bilayer surface. X-ray crystal structures of full-length yeast lanosterol 14α-demethylase, a cytochrome P450, show how a helix spanning a single transmembrane may lead to constraints on the orientation of the putative substrate entry portal from within the bilayer. The crystal structures also locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding the drug resistance associated with orthologs of the enzyme found in fungal pathogens.
Light responses of primate and other mammalian cones
Authors: Cao Li-Hui , Luo Dong-Gen , Yau King-Wai
Published: February 2014

Significance

We aimed to solve a longstanding conundrum about the light response of primate cones. Unlike those of lower vertebrates, the primate cones’ response to light has long been reported as being biphasic. This surprise has also raised a yet-unanswered question about the requisite signal processing in the retina. More recently, human paired-flash electroretinographic data have challenged the biphasic waveform of the primate cone response. Our suction-pipette recordings from single primate cones now show directly that the light responses of primate and other mammalian cones are in fact very predominantly monophasic, much like those in invertebrates.
Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging
Authors: Eberlin Livia S. , Tibshirani Robert J. , Zhang Jialing , Longacre Teri A. , Berry Gerald J. , Bingham David B. , Norton Jeffrey A. , Zare Richard N. , Poultsides George A.
Published: February 2014

Significance

Complete resection of a tumor is associated with an improved prognosis for most types of solid malignancies. In gastric-cancer surgery, surgical-margin evaluation is commonly performed intraoperatively by histopathologic evaluation of frozen sections. However, frozen-section results are subjective and can be unreliable in up to 30% of patients undergoing resection of gastrointestinal cancers. We used desorption electrospray ionization mass spectrometric imaging (DESI-MSI) and the statistical method of least absolute shrinkage and selection operator (Lasso) to classify tissue as cancer or normal based on molecular information obtained from tissue and also to select those mass-spectra features most indicative of disease state. The results obtained using margin samples from nine gastric-cancer operations suggest that DESI-MSI/Lasso may be a valuable tool for routine intraoperative assessment of surgical margins during gastric-cancer surgery.
Dopamine dependency for acquisition and performance of Pavlovian conditioned response
Authors: Darvas Martin , Wunsch Amanda M. , Gibbs Jeffrey T. , Palmiter Richard D.
Published: February 2014

Significance

Dopaminergic signaling is critical for many reward-related processes, including learning associations between stimuli and rewards (“Pavlovian learning”). Behavioral responses to reward-associated stimuli have been described as being initially directed either at the stimulus itself (“sign tracking”) or at the location of reward delivery (“goal tracking”). Although other studies have demonstrated that dopaminergic signaling is crucial for sign tracking, its role for goal-tracking behavior is less clear. Our approach uses genetic manipulations that allow determining whether dopamine is required for learning goal tracking and also which dopaminergic projections are most relevant for this behavior. Moreover, we report that instrumental learning can facilitate Pavlovian learning in mice that are impaired in Pavlovian learning but not in instrumental learning.
Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance
Authors: Chatzigeorgiou Antonios , Seijkens Tom , Zarzycka Barbara , Engel David , Poggi Marjorie , van den Berg Susan , van den Berg Sjoerd , Soehnlein Oliver , Winkels Holger , Beckers Linda , Lievens Dirk , Driessen Ann , Kusters Pascal , Biessen Erik , Garcia-Martin Ruben , Klotzsche-von Ameln Anne , Gijbels Marion , Noelle Randolph , Boon Louis , Hackeng Tilman , Schulte Klaus-Martin , Xu Aimin , Vriend Gert , Nabuurs Sander , Chung Kyoung-Jin , Willems van Dijk Ko , Rensen Patrick C. N. , Gerdes Norbert , de Winther Menno , Block Norman L. , Schally Andrew V. , Weber Christian , Bornstein Stefan R. , Nicolaes Gerry , Chavakis Triantafyllos , Lutgens Esther
Published: February 2014

Significance

Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.
Inducible and titratable silencing ofCaenorhabditis elegansneurons in vivo with histamine-gated chloride channels
Authors: Pokala Navin , Liu Qiang , Gordus Andrew , Bargmann Cornelia I.
Published: February 2014

Significance

Inducible silencing of neurons is a powerful method for studying the functions of neural circuits. We describe a system for inducible silencing ofCaenorhabditis elegansneurons, based on transgenicC. elegansnematodes engineered to produce the inhibitoryDrosophilahistamine-gated chloride channel (HisCl1) in specific neurons. The activity of HisCl1-expressing neurons is acutely and reversibly silenced by exogenous histamine, whichC. elegansabsorbs from the media. In addition to completely silencing neurons, the histamine-HisCl1 system can be used to titrate neural activity, demonstrating quantitative relationships between neural activity and behavior. The histamine-HisCl1 system is complementary to other methods of monitoring and manipulating neuronal activity, providing opportunities for combinatorial control of circuits.
2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft-specific CD8+ T cell responses
Authors: Liu Danya , Krummey Scott M. , Badell I. Raul , Wagener Maylene , Schneeweis Lumelle A. , Stetsko Dawn K. , Suchard Suzanne J. , Nadler Steven G. , Ford Mandy L.
Published: February 2014

Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8+ T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8+ T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti–CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8+ T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8+ T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8+ effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8+ T cell responses.
Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation
Authors: Mehlhop-Williams Erin R. , Bevan Michael J.
Published: February 2014

A hallmark of immunological memory is the ability of previously primed T cells to undergo rapid recall responses upon antigen reencounter. Classic work has suggested that memory T cells proliferate in response to lower doses of antigen than naive T cells and with reduced requirements for co-stimulation. In contrast to this premise, we observed that naive but not memory T cells proliferate in vivo in response to limited antigen presentation. To reconcile these observations, we tested the antigen threshold requirement for cell cycle entry in naive and central memory CD8+ T cells. Although both naive and memory T cells detect low dose antigen, only naive T cells activate cell cycle effectors. Direct comparison of TCR signaling on a single cell basis indicated that central memory T cells do not activate Zap70, induce cMyc expression, or degrade p27 in response to antigen levels that activate these functions in naive T cells. The reduced sensitivity of memory T cells may result from both decreased surface TCR expression and increased expression of protein tyrosine phosphatases as compared with naive T cells. Our data describe a novel aspect of memory T cell antigen threshold sensitivity that may critically regulate recall expansion.
The TCR ligand-inducible expression of CD73 marks γδ lineage commitment and a metastable intermediate in effector specification
Authors: Coffey Francis , Lee Sang-Yun , Buus Terkild B. , Lauritsen Jens-Peter Holst , Wong Gladys W. , Joachims Michelle L. , Thompson Linda F. , Zúñiga-Pflücker Juan Carlos , Kappes Dietmar J. , Wiest David L.
Published: February 2014

Numerous studies indicate that γδ T cell receptor (γδTCR) expression alone does not reliably mark commitment of early thymic progenitors to the γδ fate. This raises the possibility that the γδTCR is unable to intrinsically specify fate and instead requires additional environmental factors, including TCR–ligand engagement. We use single cell progenitor assays to reveal that ligand acts instructionally to direct adoption of the γδ fate. Moreover, we identify CD73 as a TCR ligand-induced cell surface protein that distinguishes γδTCR-expressing CD4−CD8− progenitors that have committed to the γδ fate from those that have not yet done so. Indeed, unlike CD73− γδTCR+ progenitors, which largely adopt the αβ fate upon separation from the intrathymic selecting environment, those that express CD73 remain CD4−CD8− and committed to the γδ fate. CD73 is expressed by >90% of peripheral γδ cells, suggesting this is a common occurrence during development. Moreover, CD73 induction appears to mark a metastable intermediate stage before acquisition of effector function, suggesting that γδ lineage and effector fate are specified sequentially. These findings have important implications for the role of ligand in γδ lineage commitment and its relationship to the specification of effector fate.
Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells
Authors: Avalos Ana M. , Bilate Angelina M. , Witte Martin D. , Tai Albert K. , He Jiang , Frushicheva Maria P. , Thill Peter D. , Meyer-Wentrup Friederike , Theile Christopher S. , Chakraborty Arup K. , Zhuang Xiaowei , Ploegh Hidde L.
Published: February 2014

Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR. By altering length and valency of epitope-bearing synthetic peptides, we examined the properties of ligands required for optimal OB1 B cell activation. Monovalent engagement of the BCR with an epitope-bearing 17-mer synthetic peptide readily activated OB1 B cells. Dimers of the minimal peptide epitope oriented in an N to N configuration were more stimulatory than their C to C counterparts. Although shorter length correlated with less activation, a monomeric 8-mer peptide epitope behaved as a weak agonist that blocked responses to cell-bound peptide antigen, a blockade which could not be reversed by CD40 ligation. The 8-mer not only delivered a suboptimal signal, which blocked subsequent responses to OVA, anti-IgG, and anti-kappa, but also competed for binding with OVA. Our results show that fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition.
On Where Things Could Be
Authors: Russell Jeffrey Sanford
Published: February 2014

Some philosophers respond to Leibniz’s “shift” argument against absolute space by appealing to antihaecceitism about possible worlds, using David Lewis’s counterpart theory. But separated from Lewis’s distinctive system, it is difficult to understand what this doctrine amounts to or how it bears on the Leibnizian argument. In fact, the best way of making sense of the relevant kind of antihaecceitism concedes the main point of the Leibnizian argument, pressing us to consider alternative spatiotemporal metaphysics.
Dwindling Confirmation
Authors: Roche William , Shogenji Tomoji
Published: February 2014

We show that as a chain of confirmation becomes longer, confirmation dwindles under screening-off. For example, if E confirms H1, H1 confirms H2, and H1 screens off E from H2, then the degree to which E confirms H2 is less than the degree to which E confirms H1. Although there are many measures of confirmation, our result holds on any measure that satisfies the Weak Law of Likelihood. We apply our result to testimony cases, relate it to the Data-Processing Inequality in information theory, and extend it in two respects so that it covers a broader range of cases.
ARTS: automated randomization of multiple traits for study design
Authors: Maienschein-Cline Mark , Lei Zhengdeng , Gardeux Vincent , Abbasi Taimur , Machado Roberto F. , Gordeuk Victor , Desai Ankit A. , Saraf Santosh , Bahroos Neil , Lussier Yves
Published: February 2014

Summary: Collecting data from large studies on high-throughput platforms, such as microarray or next-generation sequencing, typically requires processing samples in batches. There are often systematic but unpredictable biases from batch-to-batch, so proper randomization of biologically relevant traits across batches is crucial for distinguishing true biological differences from experimental artifacts. When a large number of traits are biologically relevant, as is common for clinical studies of patients with varying sex, age, genotype and medical background, proper randomization can be extremely difficult to prepare by hand, especially because traits may affect biological inferences, such as differential expression, in a combinatorial manner. Here we present ARTS (automated randomization of multiple traits for study design), which aids researchers in study design by automatically optimizing batch assignment for any number of samples, any number of traits and any batch size.

Availability and implementation: ARTS is implemented in Perl and is available at github.com/mmaiensc/ARTS. ARTS is also available in the Galaxy Tool Shed, and can be used at the Galaxy installation hosted by the UIC Center for Research Informatics (CRI) at galaxy.cri.uic.edu.

Contact:  mmaiensc@uic.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage
Authors: Das Benu Brata , Huang Shar-yin N. , Murai Junko , Rehman Ishita , Amé Jean-Christophe , Sengupta Souvik , Das Subhendu K. , Majumdar Papiya , Zhang Hongliang , Biard Denis , Majumder Hemanta K. , Schreiber Valérie , Pommier Yves
Published: February 2014

Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3′-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1–PARP1 complexes, in turn recruit X-ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1.
DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues
Authors: DeNizio Jamie E. , Elsässer Simon J. , Black Ben E.
Published: February 2014

Histone chaperones are a diverse class of proteins that facilitate chromatin assembly. Their ability to stabilize highly abundant histone proteins in the cellular environment prevents non-specific interactions and promotes nucleosome formation, but the various mechanisms for doing so are not well understood. We now focus on the dynamic features of the DAXX histone chaperone that have been elusive from previous structural studies. Using hydrogen/deuterium exchange coupled to mass spectrometry (H/DX-MS), we elucidate the concerted binding-folding of DAXX with histone variants H3.3/H4 and H3.2/H4 and find that high local stability at the variant-specific recognition residues rationalizes its known selectivity for H3.3. We show that the DAXX histone binding domain is largely disordered in solution and that formation of the H3.3/H4/DAXX complex induces folding and dramatic global stabilization of both histone and chaperone. Thus, DAXX uses a novel strategy as a molecular chaperone that paradoxically couples its own folding to substrate recognition and binding. Further, we propose a model for the chromatin assembly reaction it mediates, including a stepwise folding pathway that helps explain the fidelity of DAXX in associating with the H3.3 variant, despite an extensive and nearly identical binding surface on its counterparts, H3.1 and H3.2.
Improved search heuristics find 20 000 new alignments between human and mouse genomes
Authors: Frith Martin C. , Noé Laurent
Published: February 2014

Sequence similarity search is a fundamental way of analyzing nucleotide sequences. Despite decades of research, this is not a solved problem because there exist many similarities that are not found by current methods. Search methods are typically based on a seed-and-extend approach, which has many variants (e.g. spaced seeds, transition seeds), and it remains unclear how to optimize this approach. This study designs and tests seeding methods for inter-mammal and inter-insect genome comparison. By considering substitution patterns of real genomes, we design sets of multiple complementary transition seeds, which have better performance (sensitivity per run time) than previous seeding strategies. Often the best seed patterns have more transition positions than those used previously. We also point out that recent computer memory sizes (e.g. 60 GB) make it feasible to use multiple (e.g. eight) seeds for whole mammal genomes. Interestingly, the most sensitive settings achieve diminishing returns for human–dog and melanogaster–pseudoobscura comparisons, but not for human–mouse, which suggests that we still miss many human–mouse alignments. Our optimized heuristics find ∼20 000 new human–mouse alignments that are missing from the standard UCSC alignments. We tabulate seed patterns and parameters that work well so they can be used in future research.
Resuscitation with Lipid Emulsion
Authors: Fettiplace Michael R. , Akpa Belinda S. , Ripper Richard , Zider Brian , Lang Jason , Rubinstein Israel , Weinberg Guy
Published: February 2014

Background:

Recent publications have questioned the validity of the “lipid sink” theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model.

Methods:

Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic–pharmacodynamic model parameterized using previously published laboratory data.

Results:

Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both lipid emulsion–treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately.

Conclusion:

Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect.
Beneficial Effects of Nitric Oxide on Outcomes after Cardiac Arrest and Cardiopulmonary Resuscitation in Hypothermia-treated Mice
Authors: Kida Kotaro , Shirozu Kazuhiro , Yu Binglan , Mandeville Joseph B. , Bloch Kenneth D. , Ichinose Fumito
Published: February 2014

Background:

Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Although nitric oxide prevents organ injury induced by ischemia and reperfusion, role of nitric oxide during TH after CPR remains unclear. In this article, the authors examined the impact of endogenous nitric oxide synthesis on the beneficial effects of hypothermia after CA/CPR. The authors also examined whether or not inhaled nitric oxide during hypothermia further improves outcomes after CA/CPR in mice treated with TH.

Methods:

Wild-type mice and mice deficient for nitric oxide synthase 3 (NOS3−/−) were subjected to CA at 37°C and then resuscitated with chest compression. Body temperature was maintained at 37°C (normothermia) or reduced to 33°C (TH) for 24 h after resuscitation. Mice breathed air or air mixed with nitric oxide at 10, 20, 40, 60, or 80 ppm during hypothermia. To evaluate brain injury and cerebral blood flow, magnetic resonance imaging was performed in wild-type mice after CA/CPR.

Results:

Hypothermia up-regulated the NOS3-dependent signaling in the brain (n = 6 to 7). Deficiency of NOS3 abolished the beneficial effects of hypothermia after CA/CPR (n = 5 to 6). Breathing nitric oxide at 40 ppm improved survival rate in hypothermia-treated NOS3−/− mice (n = 6) after CA/CPR compared with NOS3−/− mice that were treated with hypothermia alone (n = 6; P < 0.05). Breathing nitric oxide at 40 (n = 9) or 60 (n = 9) ppm markedly improved survival rates in TH-treated wild-type mice (n = 51) (both P < 0.05 vs. TH-treated wild-type mice). Inhaled nitric oxide during TH (n = 7) prevented brain injury compared with TH alone (n = 7) without affecting cerebral blood flow after CA/CPR (n = 6).

Conclusions:

NOS3 is required for the beneficial effects of TH. Inhaled nitric oxide during TH remains beneficial and further improves outcomes after CA/CPR. Nitric oxide breathing exerts protective effects after CA/CPR even when TH is ineffective due to impaired endogenous nitric oxide production.
Potassium channels in cell cycle and cell proliferation
Authors: Urrego Diana , Tomczak Adam P. , Zahed Farrah , Stühmer Walter , Pardo Luis A.
Published: February 2014

Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression.
Remodelling of Ca2+transport in cancer: how it contributes to cancer hallmarks?
Authors: Prevarskaya Natalia , Ouadid-Ahidouch Halima , Skryma Roman , Shuba Yaroslav
Published: February 2014

Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca2+signalling is determined by the concerted action of a molecular Ca2+-handling toolkit which includes: active energy-dependent Ca2+transporters, Ca2+-permeable ion channels, Ca2+-binding and storage proteins, Ca2+-dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca2+-handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca2+concentrations or spatio-temporal patterns of Ca2+signalling become distorted. This causes deregulation of Ca2+-dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca2+homeostasis remodelling in cancer cells as well as in identification of the key Ca2+-transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca2+transport-targeting tools for cancer diagnosis and treatment.
Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment
Authors: Andersen Anne Poder , Moreira José M. A. , Pedersen Stine Falsig
Published: February 2014

Major changes in intra- and extracellular pH homoeostasis are shared features of most solid tumours. These changes stem in large part from the metabolic shift of most cancer cells towards glycolytic metabolism and other processes associated with net acid production. In combination with oncogenic signalling and impact from factors in the tumour microenvironment, this upregulates acid-extruding plasma membrane transport proteins which maintain intracellular pH normal or even more alkaline compared with that of normal cells, while in turn acidifying the external microenvironment. Mounting evidence strongly indicates that this contributes significantly to cancer development by favouring e.g. cancer cell migration, invasion and chemotherapy resistance. Finally, while still under-explored, it seems likely that non-cancer cells in the tumour microenvironment also exhibit altered pH regulation and that this may contribute to their malignant properties. Thus, the physical tumour microenvironment and the cancer and stromal cells within it undergo important reciprocal interactions which modulate the tumour pH profile, in turn severely impacting on the course of cancer progression. Here, we summarize recent knowledge of tumour metabolism and the tumour microenvironment, placing it in the context of tumour pH regulation, and discuss how interfering with these properties may be exploited clinically.
The chemistry, physiology and pathology of pH in cancer
Authors: Swietach Pawel , Vaughan-Jones Richard D. , Harris Adrian L. , Hulikova Alzbeta
Published: February 2014

Cell survival is conditional on the maintenance of a favourable acid–base balance (pH). Owing to intensive respiratory CO2and lactic acid production, cancer cells are exposed continuously to large acid–base fluxes, which would disturb pH if uncorrected. The large cellular reservoir of H+-binding sites can buffer pH changes but, on its own, is inadequate to regulate intracellular pH. To stabilize intracellular pH at a favourable level, cells control trans-membrane traffic of H+-ions (or their chemical equivalents, e.g.) using specialized transporter proteins sensitive to pH. In poorly perfused tumours, additional diffusion-reaction mechanisms, involving carbonic anhydrase (CA) enzymes, fine-tune control extracellular pH. The ability of H+-ions to change the ionization state of proteins underlies the exquisite pH sensitivity of cellular behaviour, including key processes in cancer formation and metastasis (proliferation, cell cycle, transformation, migration). Elevated metabolism, weakened cell-to-capillary diffusive coupling, and adaptations involving H+/H+-equivalent transporters and extracellular-facing CAs give cancer cells the means to manipulate micro-environmental acidity, a cancer hallmark. Through genetic instability, the cellular apparatus for regulating and sensing pH is able to adapt to extracellular acidity, driving disease progression. The therapeutic potential of disturbing this sequence by targeting H+/H+-equivalent transporters, buffering or CAs is being investigated, using monoclonal antibodies and small-molecule inhibitors.
Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation
Authors: Fraser Scott P. , Ozerlat-Gunduz Iley , Brackenbury William J. , Fitzgerald Elizabeth M. , Campbell Thomas M. , Coombes R. Charles , Djamgoz Mustafa B. A.
Published: February 2014

Although ion channels are increasingly being discovered in cancer cellsin vitroandin vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na+channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer.
Ureibacillus defluvii sp. nov., isolated from a thermophilic microbial fuel cell
Authors: Zhou Shungui , Tang Jia , Qin Dongxing , Lu Qin , Yang Guiqin
Published: February 2014

A thermophilic bacterium, designated DX-1T, was isolated from the anode biofilm of a microbial fuel cell (MFC). Cells of strain DX-1T were oxidase-positive, catalase-positive and Gram-staining-negative. The strain was found to be rod-shaped and non-motile and to produce subterminal spores. The strain was able to grow with NaCl at concentrations ranging from 0 to 6 %, at temperatures of 25–60 °C (optimum 55 °C) and pH 6.0–8.0 (optimum pH 7.0). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain DX-1T formed a cluster with

Ureibacillus thermosphaericus

DSM 10633T (96.9 % 16S rRNA sequence similarity),

Ureibacillus composti

DSM 17951T (95.8 %),

Ureibacillus thermophilus

DSM 17952T (95.7 %) and

Ureibacillus terrenus

DSM 12654T (95.3 %). The G+C content of the genomic DNA was 40.4 mol%. The major quinone was MK-7, the peptidoglycan type was l-Lys←d-Asp, and the major cellular fatty acids (>5 %) were iso-C16 : 0 and iso-C14 : 0. The polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol and phospholipids of unknown composition. Based on phenotypic characteristics, chemotaxonomic features and results of phylogenetic analyses, the strain was determined to represent a distinct novel species of the genus

Ureibacillus

, and the name proposed for the novel species is Ureibacillus defluvii sp. nov., with type strain DX-1T ( = CGMCC 1.12358T = KCTC 33127T).
FgIlv5 is required for branched-chain amino acid biosynthesis and full virulence in Fusarium graminearum
Authors: Liu Xin , Wang Jian , Xu Jianhong , Shi Jianrong
Published: February 2014

In this study, we characterized FgIlv5, a homologue of the Saccharomyces cerevisiae keto-acid reductoisomerase (KARI) from the important wheat head scab fungus Fusarium graminearum. KARI is a key enzyme in the branched-chain amino acid (BCAA, including leucine, isoleucine and valine) biosynthetic pathway that exists in a variety of organisms from bacteria to fungi and higher plants, but not in mammals. The FgILV5 deletion mutant ΔFgIlv5-4 failed to grow when the culture medium was nutritionally limited for BCAAs. When grown on potato-dextrose agar plates, ΔFgIlv5-4 exhibited a significant decrease in aerial hyphae formation and red pigmentation. Conidia formation was also blocked in ΔFgIlv5-4. Exogenous addition of 1 mM isoleucine and valine was able to rescue the defects of mycelial growth and conidial morphogenesis. Cellular stress assays showed that ΔFgIlv5-4 was more sensitive to osmotic and oxidative stresses than the wild-type strain. In addition, virulence of ΔFgIlv5-4 was dramatically reduced on wheat heads, and a low level of deoxynivalenol production was detected in ΔFgIlv5-4 in wheat kernels. The results of this study indicate that FgIlv5 is involved in valine and isoleucine biosynthesis and is required for full virulence in F. graminearum.
Vegetative and Sperm Cell-Specific Aquaporins of Arabidopsis Highlight the Vacuolar Equipment of Pollen and Contribute to Plant Reproduction
Authors: Wudick Michael M. , Luu Doan-Trung , Tournaire-Roux Colette , Sakamoto Wataru , Maurel Christophe
Published: February 2014

The water and nutrient status of pollen is crucial to plant reproduction. Pollen grains of Arabidopsis (Arabidopsis thaliana) contain a large vegetative cell and two smaller sperm cells. Pollen grains express AtTIP1;3 and AtTIP5;1, two members of the Tonoplast Intrinsic Protein subfamily of aquaporins. To address the spatial and temporal expression pattern of the two homologs, C-terminal fusions of AtTIP1;3 and AtTIP5;1 with green fluorescent protein and mCherry, respectively, were expressed in transgenic Arabidopsis under the control of their native promoter. Confocal laser scanning microscopy revealed that AtTIP1;3 and AtTIP5;1 are specific for the vacuoles of the vegetative and sperm cells, respectively. The tonoplast localization of AtTIP5;1 was established by reference to fluorescent protein markers for the mitochondria and vacuoles of sperm and vegetative cells and is at variance with the claim that AtTIP5;1 is localized in vegetative cell mitochondria. AtTIP1;3-green fluorescent protein and AtTIP5;1-mCherry showed concomitant expression, from first pollen mitosis up to pollen tube penetration in the ovule, thereby revealing the dynamics of vacuole morphology in maturating and germinating pollen. Transfer DNA insertion mutants for either AtTIP1;3 or AtTIP5;1 showed no apparent growth phenotype and had no significant defect in male transmission of the mutated alleles. By contrast, a double knockout displayed an abnormal rate of barren siliques, this phenotype being more pronounced under limited water or nutrient supply. The overall data indicate that vacuoles of vegetative and sperm cells functionally interact and contribute to male fertility in adverse environmental conditions.
Revisiting the Evolutionary History and Roles of Protein Phosphatases with Kelch-Like Domains in Plants
Authors: Maselli Gustavo A. , Slamovits Claudio H. , Bianchi Javier I. , Vilarrasa-Blasi Josep , Caño-Delgado Ana I. , Mora-García Santiago
Published: February 2014

Protein phosphatases with Kelch-like domains (PPKL) are members of the phosphoprotein phosphatases family present only in plants and alveolates. PPKL have been described as positive effectors of brassinosteroid (BR) signaling in plants. Most of the evidence supporting this role has been gathered using one of the four homologs in Arabidopsis (Arabidopsis thaliana), BRASSINOSTEROID-INSENSITIVE1 SUPPRESSOR (BSU1). We reappraised the roles of the other three members of the family, BSL1, BSL2, and BSL3, through phylogenetic, functional, and genetic analyses. We show that BSL1 and BSL2/BSL3 belong to two ancient evolutionary clades that have been highly conserved in land plants. In contrast, BSU1-type genes are exclusively found in the Brassicaceae and display a remarkable sequence divergence, even among closely related species. Simultaneous loss of function of the close paralogs BSL2 and BSL3 brings about a peculiar array of phenotypic alterations, but with marginal effects on BR signaling; loss of function of BSL1 is, in turn, phenotypically silent. Still, the products of these three genes account for the bulk of PPKL-related activity in Arabidopsis and together have an essential role in the early stages of development that BSU1 is unable to supplement. Our results underline the functional relevance of BSL phosphatases in plants and suggest that BSL2/BSL3 and BSU1 may have contrasting effects on BR signaling. Given that BSU1-type genes have likely undergone a functional shift and are phylogenetically restricted, we caution that inferences based on these genes to the whole family or to other species may be misleading.
Methyl 3-phenylisoxazole-5-carboxylate
Authors: Wang Li , Li Ya-jun , Li Yao-dong , Zhang Wei , Xu Rui
Published: February 2014

In the title compound, C11H9NO3, the dihedral angle between the isoxazole and phenyl rings is 19.79 (12), while the ester group is inclined to the isoxazole group by 12.14 (6)°. In the crystal, molecules are linked by C—H...O hydrogen bonds, forming layers lying parallel to (010).
Bis(dicyclohexylammonium) sulfate dihydrate
Authors: Ndoye Daouda , Sow Mouhamadou M. , Diop Libasse
Published: February 2014

In the title dihydrate salt, 2C12H24N+·SO42−·2H2O, the cation possesses twofold rotational symmetry, with the N atom situated on the twofold axis. The sulfate anion has fourfold roto-inversion symmetry, with the S atom located on the -4 axis. In the crystal, the components are linkedviaammonium–sulfate N—H...O and water–sulfate O—H...O hydrogen bonds, forming a three-dimensional network.
N′-[(E)-Furan-2-ylmethylidene]-4-hydroxybenzohydrazide
Authors: Datta Riya , Ramya V. , Sithambaresan M. , Kurup M. R. Prathapachandra
Published: February 2014

The title compound, C12H10N2O3, exists in theEconformation. The five-membered ring and the phenyl rings form dihedral angles of 36.73 (10) and 12.22 (10)°, respectively, with the central C(=O)N2C unit. The crystal packing is dominated by strong N—H...O and O—H...N hydrogen bonds. Together with weaker C—H...O interactions, these establish a three-dimensional supramolecular network.
3-Anilino-5,5-dimethylcyclohex-2-enone
Authors: Boulebd Houssem , Bouraiou Abdelmalek , Bouacida Sofiane , Merazig Hocine , Belfaitah Ali
Published: February 2014

In the title molecule, C14H17NO, the 5,5-dimethylcyclohex-2-enone moiety is attached to an aniline group, the dihedral angle subtended [54.43 (3)°] indicating a significant twist. The hexaneone ring has a half-chair conformation with the C atom bearing two methyl groups lying 0.6384 (8) Å above the plane of the five remaining atoms (r.m.s. deviation = 0.0107 Å). The crystal packing can be described as alternating layers parallel to (-101), which are consolidated by N—H...O hydrogen bonds and C—H...π interactions.
4-Cyano-3-fluorophenyl 4-(hexadecyloxy)benzoate
Authors: Usha M. K. , Srinivas H. T. , Kant Rajni , Gupta Vivek K. , Revannasiddaiah D.
Published: February 2014

In the title compound, C30H40FNO3, the dihedral angle between the benzene rings is 57.76 (7)°. The alkyl chain adopts an all-transconformation. In the crystal, molecules are linked by pairs of C—H...O hydrogen bonds, forming inversion dimers.
Bis[5-(pyridin-2-yl-κN)tetrazolido-κN1]copper(II)
Authors: Li Jian-Quan , Mu Dan , Fan Meng-Bao
Published: February 2014

In the title complex, [Cu(C6H4N5)2], the CuIIion lies on an inversion center and is coordinated by two chelating 5-(pyridin-2-yl)tetrazolide ligands in a slightly distorted square-planar coordination geometry. In the crystal, π–π stacking interactions, with centroid–centroid distances in the range 3.4301 (14)–3.4387 (13) Å, link the complex molecules along [101].
Bis(acetato-κO)bis(thiourea-κS)cobalt(II)
Authors: Lutz Martin
Published: February 2014

The title compound, [Co(CH3COO)2(CH4N2S)2], is isotypic with the corresponding ZnIIcomplex. The metal atom is in a distorted tetrahedral coordination environment with the two S atoms from two thiourea ligands and two O atoms from two acetate anions as the coordinating atoms. All H atoms of the thiourea ligands are involved in N—H...O and N—H...S hydrogen bonds, leading to a three-dimensional network.
Ethyl 4,9-dimethyl-9H-carbazole-3-carboxylate
Authors: Öncüoğlu Serkan , Dilek Nefise , Çaylak Delibaş Nagihan , Ergün Yavuz , Hökelek Tuncer
Published: February 2014

In the title compound, C17H17NO2, the carbazole skeleton includes an ethoxycarbonyl group at the 3-position. The indole three-ring system is almost planar [maximum deviation = 0.065 (2) Å], and the ethyl ester group is inclined to its mean plane by 15.48 (2)°. In the crystal, there are π–π stacking interactions between parallel benzene rings and between parallel benzene and pyrrole rings of adjacent molecules [centroid–centroid distances = 3.9473 (8) and 3.7758 (8) Å, respectively]. Weak C—H...π interactions are also present.
(E)-13-(2-Bromophenyl)micheliolide
Authors: Penthala Narsimha Reddy , Bommagani Shobanbabu , Janganati Venumadhav , Parkin Sean , Crooks Peter A.
Published: February 2014

The title compound, C21H23BrO3[systematic name: (3E,3aS,6Z,9R,9aS,9bS)-3-(2-bromobenzylidene)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] was prepared by the reaction of 1-bromo-2-iodobenzene with micheliolide [systematic name: (3aS,R,9aS,9bS,Z)-9-hydroxy-6,9-dimethyl-3-methylene-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] under Heck reaction conditions. The title compound exhibits intramolecular O—H...O hydrogen bonding between the hydroxy group and the lactone ring O atom, forming a ring of graph-set motifS(6). The 2-bromophenyl group istransto the lactone ring, indicating that this is theEisomer (geometry of the exocyclic C=C bond). The dihedral angle between the benzene ring of the 2-bromophenyl moiety and the mean plane of the lactone ring is 51.68 (7)°.
Cyclohexylammonium nitrate
Authors: Bagabas Abdulaziz A. , Aboud Mohamed F. A. , Shemsi Ahsan M. , Addurihem Emad S. , Al-Othman Zeid A. , Chidan Kumar C. S. , Fun Hoong-Kun
Published: February 2014

In the title salt, C6H14N+·NO3−, the cyclohexyl ring adopts a chair conformation. The ammonium group occupies an equatorial position and the crystal struture is stabilized by intermolecular N—H...O hydrogen-bonding interactions, resulting in a three-dimensional network.
Negotiating crisis in the social media environment
Authors: Pang Augustine , Begam Binte Abul Hassan Nasrath , Chee Yang Chong Aaron
Published: February 2014

Purpose

– The aim of this paper is to examine how crises can be triggered online, how different social media tools escalate crises, and how issues gain credibility when they transit to mainstream media.

Design/methodology/approach

– This exploratory study uses the multiple case study method to analyze five crises, generated online, throughout their life-cycles, in order to build analytic generalizations (Yin).

Findings

– Crises are often triggered online when stakeholders are empowered by social media platforms to air their grievances. YouTube and Twitter have been used to raise issues through its large user base and the lack of gatekeeping. Facebook and blogs escalate crises beyond the immediate stakeholder groups. These crises are covered by mainstream media because of their newsworthiness. As a result, the crises gain credibility offline. Mainstream media coverage ceases when traditional news elements are no longer present.

Research limitations/implications

– If crises are increasingly generated online, this study aims to apply a framework to manage the impact on organizations.

Practical implications

– How practitioners can use different new media tools to counter crises online and manage the transition of crises to mainstream media.

Originality/value

– This is one of the first few studies that analyses how organizational crises originate online, gain traction and get escalated onto mainstream media. Understanding what causes crises to trigger online and gain legitimacy offline will enable practitioners to engage in effective crisis management strategies.