bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: bipolar disorder as the first manifestation of CADASIL
Authors: Park Soyeon , Park Boram , Koh Min Kyung , Joo Yeon Ho
Published: June 2014

Background

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease, clinically characterized by variable manifestations of migraine, recurrent transient ischemic attack or lacunar strokes, cognitive decline, and mood disturbances. However, manic episodes have rarely been documented as an initial symptom of CADASIL and bipolar disorder presenting as the first manifestation in CADASIL has not been reported previously from evaluations by psychiatrists or psychological testing by psychologists.

Case presentation

A 53 year old woman developed symptoms of mania in her 50s leading to a personality change involving a continuously labile mood and irritability over a number of years. Neuropsychological testing revealed an intact memory, but impairment in attention and executive function. In the Rorschach test, she showed a high level of cognitive rigidity. Magnetic resonance imaging findings were very consistent with a diagnosis of CADASIL, which was confirmed by genetic testing for NOTCH3 mutations. Atypical antipsychotics proved to be helpful in treating her manic symptoms and for behavior control.

Conclusion

We present a novel case of CADASIL that first presented as bipolar disorder. We contend that when patients show a late onset personality change or chronically irritable mood that deteriorates over many years, an organic cause such as CADASIL must be considered. Further studies are needed to better understand the exact impacts of cerebral tissue lesions and psychiatric symptoms in CADASIL patients.
Tuning oxygen impurities and microstructure of nanocrystalline silicon photovoltaic materials through hydrogen dilution
Authors: Wen Chao , Xu Hao , He Wei , Li Zhengping , Shen Wenzhong
Published: June 2014

As a great promising material for third-generation thin-film photovoltaic cells, hydrogenated nanocrystalline silicon (nc-Si:H) thin films have a complex mixed-phase structure, which determines its defectful nature and easy residing of oxygen impurities. We have performed a detailed investigation on the microstructure properties and oxygen impurities in the nc-Si:H thin films prepared under different hydrogen dilution ratio treatment by the plasma-enhanced chemical vapor deposition (PECVD) process. X-ray diffraction, transmission electron microscopy, Raman spectroscopy, and optical transmission spectroscopy have been utilized to fully characterize the microstructure properties of the nc-Si:H films. The oxygen and hydrogen contents have been obtained from infrared absorption spectroscopy. And the configuration state of oxygen impurities on the surface of the films has been confirmed by X-ray photoelectron spectroscopy, indicating that the films were well oxidized in the form of SiO2. The correlation between the hydrogen content and the volume fraction of grain boundaries derived from the Raman measurements shows that the majority of the incorporated hydrogen is localized inside the grain boundaries. Furthermore, with the detailed information on the bonding configurations acquired from the infrared absorption spectroscopy, a full explanation has been provided for the mechanism of the varying microstructure evolution and oxygen impurities based on the two models of ion bombardment effect and hydrogen-induced annealing effect.
Effects of environmental conditions on inducing charge structures of thunderstorms over Eastern India
Authors: Pawar Sunil Dnyandeo , Gopalakrishnan Venkatachalam , Murugavel Palani , Sinkevich Andrei , Lal Deen Mani
Published: June 2014

It is well known that environmental conditions like convective instability, aerosol loading, and availability of moisture content affect the polarity of charge structures of thunderstorms. The electrical characteristics of thunderstorms observed during the pre-monsoon season of year 2009, over Eastern India were studied to identify the effects of different environmental conditions on charge structures of thunderstorms occurring over this region. Electric field and Maxwell current data suggest that at least one of these thunderstorms had an inverted charge structure. Doppler RADAR, radiosonde, and Moderate Resolution Imaging Spectroradiometer (MODIS) Aerosol Optical Depth (AOD) data have been used to compare the microphysical and dynamical characteristics of these thunderstorms. The thermo dynamical structure observed by radiosonde during the day on which an inverted polarity thunderstorm was observed showed very high CAPE in the mixed-phase region compared to other thunderstorm days. Furthermore, the AOD peaked 1 day before this thunderstorm. The back trajectories of winds also suggest that the aerosols might have been transported from a desert region on that day. It has been proposed that the large ice nuclei concentration can produce dominant positive charge in the lower portion of the mixed-phase region by maintaining ice saturation.
Fractalkine (CX3CL1), GM‐CSF and VEGF‐a levels are reduced by statins in adult patients
Authors: Cimato Thomas R , Palka Beth A
Published: June 2014

Background

Fractalkine (CX3CL1) promotes migration and adhesion of lymphocytes and monocytes to inflamed tissues. Prior studies show a role for CX3CL1 in atherosclerosis. The relationship between inflammatory cytokines, cholesterol, and CX3CL1 levels in human subjects without known coronary artery disease is not well characterized. The goal of our study was to assess baseline CX3CL1 levels, and after modulation of cholesterol levels by statins to determine if CX3CL1 is linked to cholesterol levels or inflammatory stimuli.

Methods

We performed a blinded, randomized hypothesis generating study in human subjects without known coronary artery disease treated sequentially with three statins of differing potencies. Fractalkine (CX3CL1), GM‐CSF, VEGF‐A, other chemokines, and lipid levels were measured. Mechanistic studies of CX3CL1 induction by LDL cholesterol and TNFα in cultured human endothelial cells were performed using real‐time PCR.

Results

Therapy with statins reduced total and LDL cholesterol levels as expected. CX3CL1 levels were significantly reduced from no statin control levels (89.9 ± 18.5 pg/mL) after treatment with atorvastatin (60.0 ± 7.8 pg/mL), pravastatin (54.2 ± 7.0 pg/mL) and rosuvastatin (65.6 ± 7.3 pg/mL) (χ2(2) = 17.4, p ≤ 0.001). Cholesterol is not a known regulator of CX3CL1. We found GM‐CSF (r2 = 0.524; p < 0.005) and VEGF‐A (r2 = 0.4; p < 0.005) levels were highly and positively correlated with CX3CL1. Total (r2 = 0.086) and LDL cholesterol (r2 = 0.059) levels weakly correlated with CX3CL1 levels. Finally, we tested whether LDL cholesterol could induce CX3CL1, GM‐CSF, and VEGF‐A in human endothelial cells, versus TNFα. LDL cholesterol alone resulted in small, non‐significant increases in CX3CL1 and GM‐CSF, while TNFα resulted in > 10‐fold induction.

Conclusions

Our findings suggest that while statins suppress CX3CL1 levels, inflammatory cytokines may be the major regulator of CX3CL1 levels rather than cholesterol itself. Additional studies in a larger patient population are needed to confirm these findings, determine if CX3CL1 levels reflect inflammation levels, and potentially add to standard risk factors in prediction of atherosclerotic disease events.
Cardiovascular medication burden in dementia disorders: a nationwide study of 19,743 dementia patients in the Swedish Dementia Registry
Authors: Cermakova Pavla , Fereshtehnejad Seyed-Mohammad , Johnell Kristina , Winblad Bengt , Eriksdotter Maria , Religa Dorota
Published: June 2014

Introduction

Administration of several cardiovascular drugs has an effect on dementia. We aimed to investigate whether there are differences in the use of cardiovascular medication between different dementia disorders.

Methods

We obtained information about dementia patients from the Swedish Dementia Registry. Patients were diagnosed with one of these dementia disorders: Alzheimer’s disease (n = 8,139), mixed dementia (n = 5,203), vascular dementia (n = 4,982), Lewy body dementia (n = 605), frontotemporal dementia (n = 409) and Parkinson’s disease dementia (n = 405). Multivariate logistic regression analysis was performed to investigate the association between use of cardiovascular medication and dementia disorders, after adjustment for age, gender, living alone, cognitive status and total number of drugs (a proxy for overall co-morbidity).

Results

Seventy percent of all the dementia patients used cardiovascular medication. Use of cardiovascular drugs is common in patients with vascular and mixed dementia. Male gender, higher age, slightly better cognitive status and living with another person was associated with use of cardiovascular medication.

Conclusions

Cardiovascular medication is used extensively across dementia disorders and particularly in vascular and mixed dementia. Future research should investigate the tolerability and effectiveness of these drugs in the different dementia disorders.
Coagulopathy following major trauma hemorrhage: lytic, lethal and a lack of fibrinogen
Authors: Davenport Ross
Published: June 2014

Trauma-induced coagulopathy (TIC) is present soon after injury and is associated with increased transfusion requirements and worse outcomes. The pathophysiological mechanisms, which result in the widespread derangements of hemostasis following major trauma hemorrhage, are as yet not fully defined. Profound activation of fibrinolytic pathways and fibrinogen depletion appear to be fundamental processes in the development of TIC and offer potential therapeutic targets. Collaborative and multi-disciplinary scientific study is thus a research priority in order to characterize the primary drivers of TIC and develop targeted and efficacious treatment strategies.
Rescue bedside laparotomy in the intensive care unit in patients too unstable for transport to the operating room
Authors: Schreiber Joerg , Nierhaus Axel , Vettorazzi Eik , Braune Stephan A , Frings Daniel P , Vashist Yogesh , Izbicki Jakob R , Kluge Stefan
Published: June 2014

Introduction

The prognoses of critically ill patients with a requirement for emergency laparotomy and severe respiratory and/or hemodynamic instability precluding transport to the operating room (OR) are often fatal without surgery. Attempting emergency surgery at the bedside might equally result in an adverse outcome. However, risk factors and predictors that could support clinical decision making have not been identified so far. This study describes the clinical characteristics, indicative pathophysiology and outcomes in patients undergoing resuscitative laparotomy in the intensive care unit (ICU).

Methods

This was a retrospective observational study of all critically ill adult patients undergoing resuscitative laparotomy in the ICUs of a German university hospital from January 2005 to July 2013. Clinical characteristics, risk factors, and treatments were compared between survivors and non-survivors. The primary endpoint was 28-day survival.

Results

A total of 41 patients with a median age of 64 (21 to 83) were included. The most frequent reasons for ICU admission were sepsis, pneumonia, and pancreatic surgery. All patients were mechanically ventilated, receiving vasopressors, and were in multiple organ failure. Twenty-nine patients (70.7%) were on renal replacement therapy and two patients (4.9%) on extracorporeal membrane oxygenation. The main reasons for surgery were suspected intra-abdominal bleeding (39.0%), suspected intestinal ischemia (24.4%) or abdominal compartment syndrome (24.4%). Twenty-eight-day, ICU and hospital mortalities were 75.6%, 80.5%, and 82.9%, respectively. In six out of ten patients (60%) who survived surgery for more than 28 days, bedside laparotomy was rated as a life-saving procedure by an interdisciplinary group of the investigators.

Conclusions

These findings suggest that in selected critically ill patients with a vital indication for emergency laparotomy and severe cardiopulmonary instability precluding transport to the OR, a bedside resuscitative laparotomy in the ICU can be considered as a rescue procedure, even though very high mortality is to be expected.
A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases
Authors: Janols Helena , Bergenfelz Caroline , Allaoui Roni , Larsson Anna-Maria , Rydén Lisa , Björnsson Sven , Janciauskiene Sabina , Wullt Marlene , Bredberg Anders , Leandersson Karin
Published: June 2014

The causative microorganisms dictate the type of MDSC generated in sepsis patients, and a large proportion of PMN-MDSCs in gram-positive sepsis includes immunosuppressive myeloid blasts. MDSCs constitute a heterogeneous population of immature myeloid cells that potently suppress immune responses. They were identified originally in cancer patients and have since been reported to occur also in chronic inflammation, autoimmunity, and even bacterial infections. Human MDSCs are commonly divided into Mo-MDSCs and granulocytic (PMN-MDSCs) subtypes. To what extent the bona fide cancer MDSCs are representative of the proposed MDSCs found in other diseases is not well known. PMN-MDSCs have been found previously to be enriched among LDGs in density gradient-centrifuged blood. In this study, we analyzed potential MDSCs in sepsis patients with different causative microorganisms, using total peripheral blood compared with density gradient-centrifuged blood. We found a high frequency of typical CD14+HLA-DRlow Mo-MDSCs in all sepsis patients, whereas the typical PMN-MDSCs, as well as a prominent CD14low PMN-MDSC-like population, appeared preferentially in gram-positive cases. The CD14low PMN-MDSC variant was demonstrated to suppress T cell proliferation in vitro via a ROS-dependent mechanism, to display an increased IL-10:TNF-α ratio, and to present with signs of immaturity: blast morphology and low cytokine levels. We conclude that a spectrum of cells with MDSC features is enriched in sepsis and that the microbial origin of sepsis contributes to the substantial interindividual patient variation in the MDSC pattern.
Pancreatic β-Cell–specific Ablation of TASK-1 Channels Augments Glucose-stimulated Calcium Entry and Insulin Secretion, Improving Glucose Tolerance
Authors: Dadi Prasanna K. , Vierra Nicholas C. , Jacobson David A.
Published: June 2014

Calcium entry through voltage-dependent Ca2+ channels (VDCCs) is required for pancreatic β-cell insulin secretion. The 2-pore-domain acid-sensitive potassium channel (TASK-1) regulates neuronal excitability and VDCC activation by hyperpolarizing the plasma membrane potential (Δψp); however, a role for pancreatic β-cell TASK-1 channels is unknown. Here we examined the influence of TASK-1 channel activity on the β-cell Δψp and insulin secretion during secretagogue stimulation. TASK-1 channels were found to be highly expressed in human and rodent islets and localized to the plasma membrane of β-cells. TASK-1–like currents of mouse and human β-cells were blocked by the potent TASK-1 channel inhibitor, A1899 (250nM). Although inhibition of TASK-1 currents did not influence the β-cell Δψp in the presence of low (2mM) glucose, A1899 significantly enhanced glucose-stimulated (14mM) Δψp depolarization of human and mouse β-cells. TASK-1 inhibition also resulted in greater secretagogue-stimulated Ca2+ influx in both human and mouse islets. Moreover, conditional ablation of mouse β-cell TASK-1 channels reduced K2P currents, increased glucose-stimulated Δψp depolarization, and augmented secretagogue-stimulated Ca2+ influx. The Δψp depolarization caused by TASK-1 inhibition resulted in a transient increase in glucose-stimulated mouse β-cell action potential (AP) firing frequency. However, secretagogue-stimulated β-cell AP duration eventually increased in the presence of A1899 as well as in β-cells without TASK-1, causing a decrease in AP firing frequency. Ablation or inhibition of mouse β-cell TASK-1 channels also significantly enhanced glucose-stimulated insulin secretion, which improved glucose tolerance. Conversely, TASK-1 ablation did not perturb β-cell Δψp, Ca2+ influx, or insulin secretion under low-glucose conditions (2mM). These results reveal a glucose-dependent role for β-cell TASK-1 channels of limiting glucose-stimulated Δψp depolarization and insulin secretion, which modulates glucose homeostasis.
A Rapid Cytoplasmic Mechanism for PI3 Kinase Regulation by the Nuclear Thyroid Hormone Receptor, TRβ, and Genetic Evidence for Its Role in the Maturation of Mouse Hippocampal Synapses In Vivo
Authors: Martin Negin P. , Marron Fernandez de Velasco Ezequiel , Mizuno Fengxia , Scappini Erica L. , Gloss Bernd , Erxleben Christian , Williams Jason G. , Stapleton Heather M. , Gentile Saverio , Armstrong David L.
Published: June 2014

Several rapid physiological effects of thyroid hormone on mammalian cells in vitro have been shown to be mediated by the phosphatidylinositol 3-kinase (PI3K), but the molecular mechanism of PI3K regulation by nuclear zinc finger receptor proteins for thyroid hormone and its relevance to brain development in vivo have not been elucidated. Here we show that, in the absence of hormone, the thyroid hormone receptor TRβ forms a cytoplasmic complex with the p85 subunit of PI3K and the Src family tyrosine kinase, Lyn, which depends on two canonical phosphotyrosine motifs in the second zinc finger of TRβ that are not conserved in TRα. When hormone is added, TRβ dissociates and moves to the nucleus, and phosphatidylinositol (3, 4, 5)-trisphosphate production goes up rapidly. Mutating either tyrosine to a phenylalanine prevents rapid signaling through PI3K but does not prevent the hormone-dependent transcription of genes with a thyroid hormone response element. When the rapid signaling mechanism was blocked chronically throughout development in mice by a targeted point mutation in both alleles of Thrb, circulating hormone levels, TRβ expression, and direct gene regulation by TRβ in the pituitary and liver were all unaffected. However, the mutation significantly impaired maturation and plasticity of the Schaffer collateral synapses on CA1 pyramidal neurons in the postnatal hippocampus. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases.
Biochemical and Cell Biological Properties of the Human Prohormone Convertase 1/3 Ser357Gly Mutation: A PC1/3 Hypermorph
Authors: Blanco Elias H. , Peinado Juan R. , Martín Martín G. , Lindberg Iris
Published: June 2014

Satiety and appetite signaling are accomplished by circulating peptide hormones. These peptide hormones require processing from larger precursors to become bioactive, often by the proprotein convertase 1/3 (PC1/3). Several subcellular maturation steps are necessary for PC1/3 to achieve its optimal enzymatic activity. Certain PC1/3 variants found in the general population slightly attenuate its enzymatic activity and are associated with obesity and diabetes. However, mutations that increase PC1/3 activity and/or affect its specificity could also have physiological consequences. We here present data showing that the known human Ser357Gly PC1/3 mutant (PC1/3S357G) represents a PC1/3 hypermorph. Conditioned media from human embryonic kidney-293 cells transfected with PC1/3WT and PC1/3S357G were collected and enzymatic activity characterized. PC1/3S357G exhibited a lower calcium dependence; a higher pH optimum (neutral); and a higher resistance to peptide inhibitors than the wild-type enzyme. PC1/3S357G exhibited increased cleavage to the C-terminally truncated form, and kinetic parameters of the full-length and truncated mutant enzymes were also altered. Lastly, the S357G mutation broadened the specificity of the enzyme; we detected PC2-like specificity on the substrate proCART, the precursor of the cocaine- and amphetamine regulated transcript neuropeptide known to be associated with obesity. The production of another anorexigenic peptide normally synthesized only by PC2, αMSH, was increased when proopiomelanocortin was coexpressed with PC1/3S357G. Considering the aberrant enzymatic profile of PC1/3S357G, we hypothesize that this enzyme possesses unusual processing activity that may significantly change the profile of circulating peptide hormones.
Regulation of GLUT Transporters by Flavonoids in Androgen-Sensitive and -Insensitive Prostate Cancer Cells
Authors: Gonzalez-Menendez Pedro , Hevia David , Rodriguez-Garcia Aida , Mayo Juan C. , Sainz Rosa M.
Published: June 2014

Cancer cells show different metabolic requirements from normal cells. In prostate cancer, particularly, glycolytic metabolism differs in androgen-responsive and nonresponsive cells. In addition, some natural compounds with antiproliferative activities are able to modify glucose entry into cells by either modulating glucose transporter (GLUT) expression or by altering glucose binding. The aim of this work was to study the regulation of some GLUTs (GLUT1 and GLUT4) in both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells by 4 structurally different flavonoids (ie, genistein, phloretin, apigenin, and daidzein). Glucose uptake was measured using nonradiolabeled 2-deoxyglucose. The evaluation of protein levels as well as subcellular distribution of GLUT1/4 were analyzed by Western blot and immunocytochemistry, respectively. Androgen-insensitive LNCaP-R and androgen-sensitive PC-3-AR cells were used to study the effect of androgen signaling. Additionally, a docking simulation was employed to compare interactions between flavonoids and XylE, a bacterial homolog of GLUT1 to -4. Results show for the first time the presence of functionally relevant GLUT4 in prostate cancer cells. Furthermore, differences in GLUT1 and GLUT4 levels and glucose uptake were found, without differences on subcellular distribution, after incubation with flavonoids. Docking simulation showed that all compounds interact with the same location of transporters. More importantly, differences between androgen-sensitive and -insensitive prostate cancer cells were found in both GLUT protein levels and glucose uptake. Thus, phenotypic characteristics of prostate cancer cells are responsible for the different effects of these flavonoids in glucose uptake and in GLUT expression rather than their structural differences, with the most effective in reducing cell growth being the highest in modifying glucose uptake and GLUT levels.
Shape and position of the node and notochord along the bilateral plane of symmetry are regulated by cell–extracellular matrix interactions
Authors: Pulina Maria , Liang Dong , Astrof Sophie
Published: June 2014

The node and notochord (and their equivalents in other species) are essential signaling centers, positioned along the plane of bilateral symmetry in developing vertebrate embryos. However, genes and mechanisms regulating morphogenesis of these structures and their placement along the embryonic midline are not well understood. In this work, we provide the first evidence that the position of the node and the notochord along the bilateral plane of symmetry are under genetic control and are regulated by integrin α5β1 and fibronectin in mice. We found that the shape of the node is often inverted in integrin α5-null and fibronectin-null mutants, and that the positioning of node and the notochord is often skewed away from the perceived plane of embryonic bilateral of symmetry. Our studies also show that the shape and position of the notochord are dependent on the shape and embryonic placement of the node. Our studies suggest that fibronectin regulates the shape of the node by affecting apico-basal polarity of the nodal cells. Taken together, our data indicate that cell–extracellular matrix interactions mediated by integrin α5β1 and fibronectin regulate the geometry of the node as well as the placement of the node and notochord along the plane of bilateral symmetry in the mammalian embryo.
Fission yeast mtr1p regulates interphase microtubule cortical dwell-time
Authors: Carlier-Grynkorn Frédérique , Ji Liang , Fraisier Vincent , Lombard Berangère , Dingli Florent , Loew Damarys , Paoletti Anne , Ronot Xavier , Tran Phong T.
Published: June 2014

The microtubule cytoskeleton plays important roles in cell polarity, motility and division. Microtubules inherently undergo dynamic instability, stochastically switching between phases of growth and shrinkage. In cells, some microtubule-associated proteins (MAPs) and molecular motors can further modulate microtubule dynamics. We present here the fission yeast mtr1+, a new regulator of microtubule dynamics that appears to be not a MAP or a motor. mtr1-deletion (mtr1Δ) primarily results in longer microtubule dwell-time at the cell tip cortex, suggesting that mtr1p acts directly or indirectly as a destabilizer of microtubules. mtr1p is antagonistic to mal3p, the ortholog of mammalian EB1, which stabilizes microtubules. mal3Δ results in short microtubules, but can be partially rescued by mtr1Δ, as the double mutant mal3Δ mtr1Δ exhibits longer microtubules than mal3Δ single mutant. By sequence homology, mtr1p is predicted to be a component of the ribosomal quality control complex. Intriguingly, deletion of a predicted ribosomal gene, rps1801, also resulted in longer microtubule dwell-time similar to mtr1Δ. The double-mutant mal3Δ rps1801Δ also exhibits longer microtubules than mal3Δ single mutant alone. Our study suggests a possible involvement of mtr1p and the ribosome complex in modulating microtubule dynamics.
RhoJ interacts with the GIT-PIX complex and regulates focal adhesion disassembly
Authors: Wilson Eleanor , Leszczynska Katarzyna , Poulter Natalie S. , Edelmann Francesca , Salisbury Victoria A. , Noy Peter J. , Bacon Andrea , Rappoport Joshua Z. , Heath John K. , Bicknell Roy , Heath Victoria L.
Published: June 2014

RhoJ is a RhoGTPase expressed in endothelial cells and tumour cells which regulates cell motility, invasion, endothelial tube formation and focal adhesion numbers. This study aimed to further delineate the molecular function of RhoJ. Using timelapse microscopy RhoJ was found to regulate focal adhesion disassembly; siRNA-mediated knockdown of RhoJ increased focal adhesion disassembly time, while expression of an active mutant (daRhoJ) decreased it. Further, daRhoJ co-precipitated with the GIT-PIX complex, a regulator of focal adhesion disassembly. An interaction between daRhoJ and GIT1 was confirmed using yeast-2-hybrid, which depended on the Spa homology domain of GIT1. GIT1, GIT2, β-PIX and RhoJ all co-localised in focal adhesions and depended on each other for their recruitment to focal adhesions. Functionally, the GIT-PIX complex regulated endothelial tube formation, with knockdown of GIT1/2 or β-PIX phenocopying RhoJ knockdown. RhoJ knockout mice showed reduced tumour growth and diminished tumour vessel density, identifying a role for RhoJ in mediating tumour angiogenesis. These studies give novel insight into the molecular function of RhoJ in regulating cell motility and tumour vessel formation.
Recruitment of septin cytoskeletal proteins by Botulinum toxin A protease determines its remarkable stability
Authors: Vagin Olga , Tokhtaeva Elmira , Garay Patton E. , Souda Puneet , Bassilian Sara , Whitelegge Julian P. , Lewis Ramilla , Sachs George , Wheeler Larry , Aoki Roger , Fernandez-Salas Ester
Published: June 2014

Proteolytic cleavage of synaptosomal-associated protein 25 by the light chain of Botulinum neurotoxin type A (LCA), resulting in a blockade of neurotransmitter release, persists for several months in motor neurons. The L428A/L429A mutation in LCA is known to significantly shorten both proteolytic and neuroparalytic effects of the neurotoxin in mice. To elucidate the cellular mechanism for LCA longevity, we studied the effects of L428A/L429A mutation on the interactome, localization, and stability of LCA expressed in cultured neuronal cells. Mass spectrometry analysis of the LCA interactome showed that the mutation prevented the interaction of LCA with septins. The wild type LCA was concentrated in plasma membrane-associated clusters, co-localizing with septins-2 and septin-7, which accumulated in these clusters only in the presence of LCA. The L428A/L429A mutation decreased co-clustering of LCA and septins and accelerated proteasomal and non-proteasomal degradation of LCA. Similarly, the impairment of septin oligomerization by forchlorfenuron or silencing of septin-2 prevented LCA interaction and clustering with septins and increased LCA degradation. Therefore, the dileucine-mediated LCA-septin co-clustering is crucial for the long-lasting stabilization of LCA-related proteolytic and presumably neuroparalytic activity.
Rassf5 and Ndr kinases act in a novel pathway regulating neuronal polarity through Par3 phosphorylation
Authors: Yang Rui , Kong Eryan , Jin Jing , Hergovich Alexander , Püschel Andreas W.
Published: June 2014

The morphology and polarized growth of cells depend on pathways that control the asymmetric distribution of regulatory factors. The evolutionarily conserved Ndr kinases play important roles in cell polarity and morphogenesis in yeast and invertebrates but it is unclear if they perform a similar function in mammalian cells. Here we analyze the function of mammalian Ndr1 and 2 in the establishment of polarity in neurons. We show that they act downstream of the tumor suppressor Rassf5 and upstream of the polarity protein Par3. Rassf5 and Ndr1/2 are required during the polarization of hippocampal neurons to prevent the formation of supernumerary axons. Mechanistically, the Ndr kinases act by phosphorylating Par3 at Ser383 to inhibit the interaction with dynein. Thereby they polarize the distribution of Par3 and reinforce axon specification. Our results identify a novel Rassf5/Ndr/Par3 signaling cascade that regulates the transport of Par3 during the establishment of neuronal. Their role in neuronal polarity suggests that Ndr kinases perform a conserved function as regulators of cell polarity.
Reconstitution of human rRNA gene transcription in mouse cells by complete SL1 complex
Authors: Murano Kensaku , Okuwaki Mitsuru , Momose Fumitaka , Kumakura Michiko , Ueshima Shuhei , Newbold Robert F. , Nagata Kyosuke
Published: June 2014

An important characteristic of transcription of a ribosomal RNA gene (rDNA) mediated by DNA-dependent RNA polymerase (Pol) I is its stringent species-specificity. SL1/TIF-IB is a key complex for species-specificity, but its functional complex has not been reconstituted. We established a novel and highly sensitive monitoring system for Pol I transcription to reconstitute the SL1 activity, in which a transcript harboring a reporter gene synthesized by Pol I is amplified and converted to translatable mRNA by the influenza virus RNA-dependent RNA polymerase. Using this monitoring system, we reconstituted Pol I transcription from the human rDNA promoter in mouse cells by expressing four human TBP-associated factors (TAFI) in the SL1 complex. The reconstituted SL1 also re-activated human rDNA transcription in mouse A9 cells carrying an inactive human chromosome 21, which contains the rDNA cluster. Chimeric SL1 complexes containing human and mouse TAFIs can be formed, but these complexes are inactive for human rDNA transcription. We conclude that four human TAFIs are necessary and sufficient to overcome the barrier of species-specificity for human rDNA transcription in mouse cells.
Dynamics of theToxoplasma gondiiinner membrane complex
Authors: Ouologuem Dinkorma T. , Roos David S.
Published: June 2014

Unlike most cells, protozoa in the phylum apicomplexa divide by a distinctive process in which multiple daughters are assembled within the mother (schizogony, endodyogeny), using scaffolding known as the Inner Membrane Complex. The ‘IMC’ underlies the plasma membrane during interphase, but new daughters develop in the cytoplasm, as cytoskeletal filaments associate with flattened membrane cisternae (alveolae), which elongate rapidly to encapsulate subcellular organelles. Newly assembled daughters acquire their plasma membrane as they emerge from the mother, leaving behind vestiges of the maternal cell. While the maternal plasma membrane remains intact throughout this process, the maternal IMC disappears – is it degraded, or recycled to form the daughter IMC? Exploiting fluorescently tagged IMC markers, we have used live cell imaging, fluorescence photobleaching-recovery, and mEos2 photoactivation to monitor the dynamics of IMC biogenesis and turnover during Toxoplasma gondii tachyzoite replication. These studies reveal that formation of the T. gondii IMC involves two distinct steps: de novo assembly during daughter IMC elongation within the mother cell, followed by recycling of maternal IMC membranes after the emergence of daughters from the mother cell.
Myosin VI mediates the movement of NHE3 down the microvillus in intestinal epithelial cells
Authors: Chen Tiane , Hubbard Ann , Murtazina Rakhilya , Price Jennifer , Yang Jianbo , Cha Boyoung , Sarker Rafiquel , Donowitz Mark
Published: June 2014

The intestinal brush border (BB) Na+/H+ exchanger, NHE3, is acutely regulated through changes in its endocytosis/exocytosis. Myosin VI, a minus-end directed motor, has been implicated in endocytosis at the inter-microvillar (MV) cleft and vesicle remodeling in the terminal web. We asked if myosin VI also regulates NHE3 movement down MV. Basal NHE3 activity and surface amount, determined by BCECF/fluorometry and biotinylation, respectively, were increased in myosin VI knock-down (KD) Caco-2/Bbe cells. Carbachol (CCH) and forskolin (FSK) stimulated NHE3 endocytosis in control but not in myosin VI KD cells. Importantly, immuno-EM results showed NHE3 preferentially localized in the basal half of MV in control but in the distal half of myosin VI KD cells. Dynasore duplicated some aspects of myosin VI KD: it increased basal surface NHE3 activity and prevented FSK-induced NHE3 endocytosis; but NHE3's distribution along the MV was intermediate in dynasore-treated as compared to either myosin VI KD or untreated cells. We conclude that myosin VI is required for basal and stimulated endocytosis of NHE3 in intestinal cells and suggest that myosin VI also moves NHE3 down MV.
A nuclear ubiquitin-proteasomal pathway targets inner nuclear membrane protein Asi2 for degradation
Authors: Boban Mirta , Pantazopoulou Marina , Schick Anna , Ljungdahl Per O. , Foisner Roland
Published: June 2014

The nuclear envelope consists of inner and outer nuclear membranes. While the outer membrane is an extension of the endoplasmic reticulum, the inner nuclear membrane represents a unique membranous environment containing specific proteins. The mechanisms of integral inner nuclear membrane protein degradation are unknown. Here we investigated the turnover of Asi2, an integral INM protein in Saccharomyces cerevisiae. We report that Asi2 is degraded by the proteasome and independent of the vacuole exhibiting a half-life of ≈ 45 min. Asi2 exhibits enhanced stability in mutants lacking the E2 ubiquitin conjugating enzymes Ubc6 or Ubc7, or the E3 ubiquitin ligase Doa10. Consistently, Asi2 is post-translationally modified by poly-ubiquitylation in a Ubc7- and Doa10-dependent manner. Importantly Asi2 degradation is significantly reduced in a sts1-2 mutant that fails to accumulate proteasomes in the nucleus, indicating that Asi2 is degraded in the nucleus. Our results reveal a molecular pathway that affects the stability of integral proteins of the inner nuclear membrane and indicate that Asi2 is subject to protein quality control in the nucleus.
State-to-State Reaction Dynamics in Collision of Deuterium Molecule with Excited-State Nitrogen Atom
Authors: Lü Rui , Chu Tian-shu , Chang Zhi-shang , Zhang Wen-qing
Published: June 2014

The collision dynamics of deuterium molecule with excited-state nitrogen atom has been investigated at a state-to-state dynamic level by using the real wave packet method. The energy-dependent behavior of the differential and integral cross sections, especially from the reactant quantum states of v = 0, j = 0 to the product quantum states of j′ = 0–7, v′ = 0–5, is presented and discussed for total energies up to 0.4 eV. The present study predicted noninverted vibrational populations and inverted rotational populations in product rovibrational distributions. Comparison of the theoretical total differential cross section with the previous experimental measurement has also been presented and discussed.
Research Note—Influence Techniques in Phishing Attacks: An Examination of Vulnerability and Resistance
Authors: Wright Ryan T. , Jensen Matthew L. , Thatcher Jason Bennett , Dinger Michael , Marett Kent
Published: June 2014

Phishing is a major threat to individuals and organizations. Along with billions of dollars lost annually, phishing attacks have led to significant data breaches, loss of corporate secrets, and espionage. Despite the significant threat, potential phishing targets have little theoretical or practical guidance on which phishing tactics are most dangerous and require heightened caution. The current study extends persuasion and motivation theory to postulate why certain influence techniques are especially dangerous when used in phishing attacks. We evaluated our hypotheses using a large field experiment that involved sending phishing messages to more than 2,600 participants. Results indicated a disparity in levels of danger presented by different influence techniques used in phishing attacks. Specifically, participants were less vulnerable to phishing influence techniques that relied on fictitious prior shared experience and were more vulnerable to techniques offering a high level of self-determination. By extending persuasion and motivation theory to explain the relative efficacy of phishers' influence techniques, this work clarifies significant vulnerabilities and lays the foundation for individuals and organizations to combat phishing through awareness and training efforts.
Excessive focus on patients ignores disabled rehabilitation professionals
Authors: Marno Carly
Published: June 2014

The therapy world is fast-paced, forward-thinking, and ever-developing new strategies, treatments and approaches to patient care. It strives to improve quality of life for patients (Chartered Society of Physiotherapy, 2002; College of Occupational Therapists, 2010). In fact, it could be argued that the entire focus of the forward drive of our professions is patient-centred. But this poses a rather interesting question. In our pursuit of the perfect treatment, are we leaving some of our own behind? Are we neglecting the therapists who attempt to strive alongside us in preference of the possible achievement of the end goal? If the answer is yes, perhaps we must ask ourselves if the achievement of the end goal justifies the means used.
A language full of life
Authors: Rajkumar Kimcha
Published: June 2014

With Latin or ancient Greek options for the compulsory Foreign Languages component of the new curriculum, we get advice on why and how you could pick and teach a classic.
Use shape and balance to begin your gym plan
Authors: Donohoe Tom
Published: June 2014

With careful planning gymnastics can provide challenge and reward for children of all abilities. Start with a warm up and then move on to the ‘show mat’
Is it time to introduce a spirit of adventure?
Authors: Aitken Elizabeth
Published: June 2014

Learning outside the classroom has immense value on all sorts of levels and does not need to be fraught with risks. In fact, with a sensible policy, it is easy to do.
Disgust c . 1600
Authors: Robinson Benedict
Published: June 2014

This article traces a history of disgust from the moment the word is first attested in English. It tracks the grammar of disgust and its relationship to an emerging socioaesthetics of taste in an urban scene. And it explores some of the literary texts that take disgust as their subject: Ben Jonson’s Poetaster and “On the Famous Voyage,” Edmund Spenser’s Faerie Queene , with reference to William Shakespeare’s Measure for Measure . The largest claim is that in the early modern period a rhetorical theory of the passions that treats them as situated social events decisively shaped the forms of literary production with results that are still with us today.
“That Darker, Though Truer Aspect of Things”: Melville’s Failed Romances
Authors: Lamm Zachary
Published: June 2014

This essay explores ways in which Herman Melville’s romances, including Pierre and Moby-Dick , simultaneously utilize and undermine the conventions of the romance as defined by Nathaniel Hawthorne. The visionary work of the romance is undercut by Melville’s skepticism toward fantasy, resulting from his perception of the inescapability of material culture.
Antonin Artaud and Freud’s “Family Romance”: The Transgressive Sublime
Authors: Engelbert Lynn Hughey
Published: June 2014

Freud’s family romance and Romantic idealism conjoined in Antonin Artaud’s work such that repetition and transference became accompanied by a Romantic quest for a strange and more sublime aesthetic order. This was both a psychological system and a philosophical perspective that negatively and energetically influenced his radical and existential forms of self-identification.
Irreverently Unromantic: A Rhetorical Path to Sophistic Poetics in the Poetry of Bob Hicok
Authors: Hendrickson Brian
Published: June 2014

Rhetorical analysis of Bob Hicok’s earliest and most recent poems reveals how the poet modifies the terms of the central problem in contemporary poetry—Romantic irony—by employing an irreverent poetics I describe as sophistic to highlight its rhetorical tendencies while differentiating it from the inverted Platonism of Romantic irony.
Love across Borders in Hadji Murad : Variations on a Cross-Cultural Motif in Tolstoy, Stendhal, and D. H. Lawrence
Authors: Foster John Burt
Published: June 2014

Tolstoy’s concise, highly suggestive short novel Hadji Murad (posthumously published in 1912) emphasizes war but also includes two distinct depictions of erotic attachment across the Russian/Muslim border. If Stendhal was a theorist of love before becoming a novelist, and if Lawrence’s love novels became increasingly expository, Tolstoy represents a third alternative: his best thinking about love takes place in narrative. As Isaiah Berlin noted in a different context, he was a Heraclitean fox, splendidly attentive to varied details, rather than a hedgehog expounding one big idea. Hadji Murad ’s first key set of scenes gives parallel accounts of Nicholas I’s and the imam Shamil’s love lives, which undermine sharp distinctions between Christian monogamy and Muslim polygamy. Another group of scenes shows the responses of Murad and the Russian army officer Butler to Marya Dmitrievna, the lower-class mistress of another officer. These scenes of erotic attraction explore potential disruptions in boundaries between cultures and classes alike only to drop the possibility when this war-torn novel ends in brutal tragedy. Further comparison with Stendhal and Lawrence addresses Fabrizio and Clélia in The Charterhouse of Parma and love conflict in “The Princess.” In highlighting each novelist’s fascination with love across borders, these situations bring out Tolstoy’s relative restraint in an intertextual series where treatment of this motif led to operatic grand passion or intimacy gone horribly awry. The essay ends by reflecting on love across borders in Tolstoy's earlier fiction and its implications for What Is Art?
Transnational Activist: Magda Mortal and the American Popular Revolutionary Alliance (APRA), 1926–1950
Authors: García-Bryce Iñigo
Published: June 2014

In March of 1929, die young Peruvian poet and political activist Magda Portal departed from die Yucatan in Mexico to give a series of lectures in Cuba, Puerto Rico, the Dominican Republic, and Colombia. She traveled as an emissary of the Alianza Popular Revolucionaria Americana (American Popular Revolutionary Alliance, APRA), a recendy founded political organization that sought to transform Latin America by creating a united front against foreign imperialism. On July 14, in Santo Domingo she gave a lecture titled “Latin America Confronted by Imperialism,” at “the largest theater in town” to an audience of about 200. Her presence as an intelligent, energetic, and beautiful woman, standing on stages normally reserved to men, enhanced the power of her words, and she was well aware of the striking effect on audiences of seeing a woman in the traditionally male role of political orator
History, Memory, and Utopia in the Missionaries' Creation of the Indigenous Movement in Brazil (1967–1988)
Authors: Belleau Jean-Philippe
Published: June 2014

On April 17, 1974, and die two days following, a gathering of 16 indigenous participants from nine different indigenous societies was held in Diamantino, Mato Grosso, Brazil. During the three days, vernacular narratives, trivial announcements, and critiques of the government and local ranchers were presented—without any of the participants significantly engaging with one another. Only one primary source on this event, a short, typed document, is available today. The historicity of this “Assembly of Indigenous Chiefs” is granted by both the anthropological and the historical situations of the participating communities. For the first time, individuals from indigenous societies that did not share ethnic borders or history met to advance indigenous rights; for the first time also, these individuals were granted political representation (of their groups), a notion largely foreign to indigenous political traditions. There was a conscious effort to draw chiefs from as many communities as possible and to establish a large, pan-Indian movement.
Of Signatures and Status: Andrés Sánchez Gallque and Contemporary Painters in Early Colonial Quito
Authors: Webster Susan V.
Published: June 2014

The 1599 portrait Don Francisco de Arobe and His Sons, Pedro and Domingo by Andean artist Andres Sanchez Gallque (Figure 1) is one of the most frequently cited and reproduced paintings in the modern literature on colonial South America. The painting has been extensively praised, parsed, and interpreted by twentieth- and twenty-first-century authors, and heralded as the first signed South American portrait. “Remarkable” is the adjective most frequently employed to describe this work: modern authors express surprise and delight not only with the persuasive illusionistic power of the painting, the mesmerizing appearance of its subjects, and the artist's impressive mastery of the genre, but with the fact that the artist chose to sign and date his work, including a specific reference to his Andean identity.
Rachel: The Union Catalog of the European Network of Judaica and Hebraica Libraries
Authors: Musnik Noémie
Published: June 2014

The union catalog Rachel was launched in 2004 by four Parisian private libraries with significant holdings in Judaica and Hebraica. Further developed by the Réseau Européen des Bibliothèques Judaica et Hebraica (REBJH; European Network of Judaica and Hebraica Libraries), Rachel moves forward the network’s mission to promote the preservation and increase the use of the recorded heritage of the Jewish people in Europe and around the world. The article reviews the history of the REBJH and its founding members, analyses cataloging practices of member institutions of Rachel, and describes user services provided by this union catalog.
Be-tzelem Elohim — In the Image of God: Identifying Essential Jewish LGBTQ Books for Jewish Libraries
Authors: Stahl Sheryl , Kushner Joel
Published: June 2014

The authors take as a given that all libraries should include books on Lesbian, Gay, Bi-sexual, Transgender and Queer (LGBTQ) issues. This article discusses the challenges of collection development in this area and the factors that necessitate LGBTQ Jewish materials' inclusion in Jewish academic, school, synagogue, and community libraries. The article makes recommendations for a range of Jewish libraries on what essential books and movies on this topic are.
Scatter of the Literature, 2008-2013
Authors: Bergson Steven
Published: June 2014

This article reviews studies related to the field of Judaica librarianship published in a variety of publications.