bluuebunny/crossref_metadata_2025 huggingface dataset:
The Genome-Packaging Signal of the Influenza A Virus Genome Comprises a Genome Incorporation Signal and a Genome-Bundling Signal
Authors: Goto Hideo , Muramoto Yukiko , Noda Takeshi , Kawaoka Yoshihiro
Published: August 2013

The influenza A virus genome comprises eight single-stranded negative-sense RNA segments (vRNAs). All eight vRNAs are selectively packaged into each progeny virion via so-called segment-specific genome-packaging signal sequences that are located in the noncoding and terminal coding regions of both the 3′ and the 5′ ends of the vRNAs. However, it remains unclear how these signals ensure that eight different vRNAs are packaged. Here, by using a reverse genetics system, we demonstrated that, in the absence of the other seven vRNAs, a recombinant NP vRNA bearing only a reporter gene flanked by the noncoding NP regions was incorporated into virus-like particles (VLPs) as efficiently as a recombinant NP vRNA bearing the reporter gene flanked by the complete NP packaging signals (i.e., the noncoding sequences and the terminal coding regions). Viruses that comprised a recombinant NP vRNA whose packaging signal was disrupted, and the remaining seven authentic vRNAs, did not undergo multiple cycles of replication; however, a recombinant NP vRNA with only the noncoding regions was readily incorporated into VLPs, suggesting that the packaging signal as currently defined is not necessarily essential for the packaging of the vRNA in which it resides; rather, it is required for the packaging of the full set of vRNAs. We propose that the 3′ and 5′ noncoding regions of each vRNA bear a virion incorporation signal for that vRNA and that the terminal coding regions serve as a bundling signal that ensures the incorporation of the complete set of eight vRNAs into the virion.
Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response
Authors: Yan Dan , Krumm Stefanie A. , Sun Aiming , Steinhauer David A. , Luo Ming , Moore Martin L. , Plemper Richard K.
Published: August 2013

As we are confronted with an increasing number of emerging and reemerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting of host factors required for virus replication presents a tangible approach toward obtaining novel hits with a broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource efficiency and pan-myxovirus activity as the central developmental parameters, we explored coscreening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired coreplication of both viruses, generated suitable firefly and
Renilla
luciferase reporter constructs, respectively, and validated the protocol for up to a 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with a broadened antimyxovirus profile, in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broad-spectrum lead that does not block viral entry but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof of concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para- and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.
Sustained Protein Kinase D Activation Mediates Respiratory Syncytial Virus-Induced Airway Barrier Disruption
Authors: Rezaee Fariba , DeSando Samantha A. , Ivanov Andrei I. , Chapman Timothy J. , Knowlden Sara A. , Beck Lisa A. , Georas Steve N.
Published: August 2013

Understanding the regulation of airway epithelial barrier function is a new frontier in asthma and respiratory viral infections. Despite recent progress, little is known about how respiratory syncytial virus (RSV) acts at mucosal sites, and very little is known about its ability to influence airway epithelial barrier function. Here, we studied the effect of RSV infection on the airway epithelial barrier using model epithelia. 16HBE14o- bronchial epithelial cells were grown on Transwell inserts and infected with RSV strain A2. We analyzed (i) epithelial apical junction complex (AJC) function, measuring transepithelial electrical resistance (TEER) and permeability to fluorescein isothiocyanate (FITC)-conjugated dextran, and (ii) AJC structure using immunofluorescent staining. Cells were pretreated or not with protein kinase D (PKD) inhibitors. UV-irradiated RSV served as a negative control. RSV infection led to a significant reduction in TEER and increase in permeability. Additionally it caused disruption of the AJC and remodeling of the apical actin cytoskeleton. Pretreatment with two structurally unrelated PKD inhibitors markedly attenuated RSV-induced effects. RSV induced phosphorylation of the actin binding protein cortactin in a PKD-dependent manner. UV-inactivated RSV had no effect on AJC function or structure. Our results suggest that RSV-induced airway epithelial barrier disruption involves PKD-dependent actin cytoskeletal remodeling, possibly dependent on cortactin activation. Defining the mechanisms by which RSV disrupts epithelial structure and function should enhance our understanding of the association between respiratory viral infections, airway inflammation, and allergen sensitization. Impaired barrier function may open a potential new therapeutic target for RSV-mediated lung diseases.
Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys
Authors: Amos Joshua D. , Wilks Andrew B. , Fouda Genevieve G. , Smith Shannon D. , Colvin Lisa , Mahlokozera Tatenda , Ho Carrie , Beck Krista , Overman R. Glenn , DeMarco C. Todd , Hodge Terry L. , LaBranche Celia C. , Montefiori David C. , Denny Thomas N. , Liao Hua-Xin , Tomaras Georgia D. , Moody M. Anthony , Permar Sallie R.
Published: August 2013

The design of an effective vaccine to reduce the incidence of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breastfeeding will require identification of protective immune responses that block postnatal virus acquisition. Natural hosts of simian immunodeficiency virus (SIV) sustain nonpathogenic infection and rarely transmit the virus to their infants despite high milk virus RNA loads. This is in contrast to HIV-infected women and SIV-infected rhesus macaques (RhMs), nonnatural hosts which exhibit higher rates of postnatal virus transmission. In this study, we compared the systemic and mucosal B cell responses of lactating, SIV-infected African green monkeys (AGMs), a natural host species, to that of SIV-infected RhMs and HIV-infected women. AGMs did not demonstrate hypergammaglobulinemia or accumulate circulating memory B cells during chronic SIV infection. Moreover, the milk of SIV-infected AGMs contained higher proportions of naive B cells than RhMs. Interestingly, AGMs exhibited robust milk and plasma Env binding antibody responses that were one to two logs higher than those in RhMs and humans and demonstrated autologous neutralizing responses in milk at 1 year postinfection. Furthermore, the plasma and milk Env gp120-binding antibody responses were equivalent to or predominant over Env gp140-binding antibody responses in AGMs, in contrast to that in RhMs and humans. The strong gp120-specific, functional antibody responses in the milk of SIV-infected AGMs may contribute to the rarity of postnatal transmission observed in natural SIV hosts.
Staufen-1 Interacts with the Human Endogenous Retrovirus Family HERV-K(HML-2) Rec and Gag Proteins and Increases Virion Production
Authors: Hanke Kirsten , Hohn Oliver , Liedgens Linda , Fiddeke Katharina , Wamara Jula , Kurth Reinhard , Bannert Norbert
Published: August 2013

The human endogenous retrovirus family HERV-K(HML-2) Rec protein is an RNA transport factor that enhances nuclear export of intron-containing retroviral transcripts. Using the yeast two-hybrid approach, we have newly identified human Staufen-1 as a Rec-interacting protein. The interaction was confirmed by coimmunoprecipitation experiments, and the relevant site in Staufen-1 has been mapped to double-stranded RNA binding domain 4 (RBD4). Staufen-1 is in several aspects functionally related to retroviral RNA transport proteins. It binds mRNAs and targets its ribonuclear cargo to polysomes for efficient translation. We observed an accumulation of Staufen-1 in the nucleus of Rec-expressing cells and colocalization in the nucleoli as well as in the cytoplasm. Overexpression of Staufen-1 resulted in a 5-fold enhancement in nuclear export and/or translation of unspliced HERV-K(HML-2) viral RNAs in the presence of Rec and its Rec-responsive element (RcRE) binding site together with a clear increase in virus production. Staufen-1 was previously shown to interact with the Gag protein of HIV-1, promoting Gag oligomerization and RNA encapsidation. We demonstrate here that Staufen-1 also binds to the Gag protein of HERV-K(HML-2). Under stress conditions, Rec colocalizes with Staufen-1 in stress granules in cells that express viral RNA but not in mRNA-decay-related processing bodies. Our results suggest a new role for Staufen-1 as a cellular Rec and HERV-K(HML-2) Gag cofactor.
Peripheral osteoma of the body of mandible
Authors: Manjunatha B S , Das Nagarajappa , Sutariya Rakesh , Ahmed Tanveer
Published: August 2013

Osteoma is a benign osteogenic neoplasm microscopically consisting of proliferation of cancellous or compact bone. Peripheral osteomas (PO) arise from the periosteum and are quite uncommon in the jaw bones. POs of mandible are considered as rare entity and very few cases have been reported in the literature. The pathogenesis of PO is unclear. Some investigators consider it a true neoplasm, while others believe it as a developmental anomaly, a reactive mechanism due to trauma or infection. The purpose of this article is to present the clinical, radiographic, surgical and histological features of a solitary peripheral osteoma of the mandible in a 43-year-old woman and to review the literature for PO located in the mandible.
Solitary plasmocytoma of the skull
Authors: Gürbüz Mehmet Sabri , Akmil Mehmet Ufuk , Akar Ezgi , Aker Fügen Vardar
Published: August 2013

A 63-year-old man presented with a 4-month history of a slowly growing soft mass at his right parieto-occipital region. Neuroradiological examinations revealed an osteolytic extradural tumour of the skull vault. The outer and inner tables of the skull were partially destroyed by the tumour, but the dura was not involved. The tumour and the invaded bone were totally removed and the skull defect was reconstructed using the outer table of the adjacent intact skull. Histopathological examination confirmed plasmocytoma. Laboratory investigations revealed no systemic myelomatosis. It is very important to differentiate solitary plasmocytoma from systemic myelomatosis since their treatment and prognosis are different. Although the prognosis of solitary plasmocytoma is good, regular follow-up examinations are required for any possibility to progress to systemic myelomatosis.
Cervical pregnancy with massive bleeding after treatment with methotrexate
Authors: Saeng-anan Ubol , Sreshthaputra Opas , Sukpan Kornkanok , Tongsong Theera
Published: August 2013

This report describes a catastrophic bleeding following methotrexate treatment of cervical pregnancy and dramatic response to Bakri surgical obstetric silicone (SOS) balloon tamponade in controlling massive bleeding. A 42-year-old woman was diagnosed for cervical pregnancy with a viable fetus at 12 weeks by transvaginal ultrasound. Conservative treatment with intrafetal potassium chloride injection and systemic methotrexate were instituted. On the sixth day of therapy, catastrophic bleeding lead to hypovolemic shock. After resuscitation and blood transfusion, we attempt to control the bleeding with evacuation and curettage but was unsuccessful. Bakri SOS balloon tamponade was applied with immediate and effective response. Nevertheless, total abdominal hysterectomy was performed. In conclusion, conservative treatment of cervical pregnancy with systemic methotrexate could be catastrophic in some patients. Control of active bleeding with Bakri SOS balloon tamponade may possibly be helpful in case of uncontrolled bleeding in selected cases.
Modern management of acute non-variceal upper gastrointestinal bleeding
Authors: Hegade Vinod S , Sood Ruchit , Mohammed Noor , Moreea Sulleman
Published: August 2013

An acute upper gastrointestinal bleed (AUGIB) often represents a life-threatening event and is recognised universally as a common cause of emergency hospitalisation. Large observational studies have improved our understanding of the disease characteristics and its impact on mortality but despite significant advancement in endoscopic management, mortality remains high, particularly in elderly patients and those with multiple comorbidities. Skilled assessment, risk stratification and prompt resuscitation are essential parts of patient care, with endoscopy playing a key role in the definitive management. A successful outcome partly relies on the clinician's familiarity with current guidelines and recommendations, including the National Institute for Clinical Excellence guidelines published in 2012. Validated risk stratification scores, such as the Blatchford and Rockall score, facilitate early discharge of low-risk patients as well as help in identifying those needing early endoscopic intervention. Major advances in therapeutic endoscopy, including more recently, the development of non-toxic proprietary powders (Hemospray and EndoClot), have resulted in the development of effective treatments of bleeding lesions, reduction in rebleeding rates and the need for emergency surgery. The role of proton-pump inhibitor therapy prior to endoscopy and the level of optimum red cell transfusion in the setting of AUGIB remain fields that require further research.
Monazite ages and pressure–temperature–time paths from anatectites in the southern Ruby Range, Montana, USA: evidence for delamination, ultramafic magmatism, and rapid uplift at ca. 1780 Ma
Authors: Alcock J. , Muller P.D. , Jercinovic M.J.
Published: August 2013

The Wolf Creek ultramafic bodies of the southern Ruby Range, southwest Montana, intruded as high-temperature magma during the late stages of an Early Proterozoic orogeny affecting the Great Falls Tectonic Zone of the western Wyoming craton. Field and petrologic evidence indicate high-temperature metamorphism and deformation uniquely affected metapelitic anatectites adjacent to the ultramafic bodies. Leucosomes are mesoperthite and quartz with garnet. Restite contains sillimanite, garnet, quartz, microcline, and biotite that was partially resorbed by the melt-producing reaction. Late cordierite and sillimanite replace garnet in the migmatites and other pelitic gneiss in the area. Petrogenic grids for the Na2O–CaO–K2O–FeO–MgO–Al2O3–SiO2–H2O (NCKFMASH) system indicate that conditions during anatexis were 750–800 °C, 600–900 MPa. Anatexis occurred during deformation of metapelites and associated rocks adjacent to the larger ultramafic bodies, but crystallization and cooling occurred after deformation, as indicated by the preservation of igneous textures and mesoperthite with undeformed lamellae in the leucosome. Element mapping of monazite using electron-probe micro-analysis (EPMA) identifies four distinct chemical domains of monazite growth during the orogenic event in addition to relict, Archaean to earliest Proterozoic cores. U–Th–Pb dating of the domains establishes two periods of growth of matrix monazite in the paleosome that indicate fabric-forming prograde metamorphism at 1829 ± 17 and 1805 ± 4 Ma (2σ). Coarser, igneous monazites from the leucosome also contain two distinct chemical zones visible in yttrium maps, indicating growth with garnet and then during garnet resorption as decompression led to replacement of garnet by cordierite. The domain ages cannot be statistically distinguished. Together they yield an age of 1782 ± 9 Ma (2σ). The data imply that regional thickening leading to upper amphibolite facies metamorphism occurred prior to 1800 Ma. Thickening was followed after ∼25 Ma by the intrusion of ultramafic magmas, contact anatexis, and then decompression. This sequence is consistent with mantle delamination after orogenic thickening.
Vibration spectrum calculations of isotopic species of hydrogen sulfide using the discrete variable representation (DVR) method
Authors: Yu Ang-yang
Published: August 2013

In this work, a modified three-dimensional discrete variable representation (MDVR3D) program, which could be used to calculate the bound state vibration spectrum of some triatomic molecules is developed. The sine basis functions are chosen to define the DVR for the radial coordinates for this new program. Both the three-dimensional discrete variable representation (DVR3D) program and the MDVR3D program are used to calculate the vibration energy levels of the isotopic species of hydrogen sulfide (H232S, H233S, H234S, D232S, D233S, D234S, T232S, T233S, T234S). The calculated vibration energy levels from the MDVR3D program are consistent with the counterparts from the DVR3D program, which means that they are good procedures for calculating the bound state energy levels of the triatomic molecules and testing the quality of the potential energy surface (PES). The comparison of the experimental and theoretical vibration energy levels for the nine isotopic species of hydrogen sulfide molecule is made and shows good consistency. This work forms the basis for dealing with the rotational spectrum calculations and presents the first theoretical results for D233S, T232S, T233S, and T234S. Future spectrum observations are needed to compare with these new results.
Evidence of social preferences in big brown bats (Eptesicus fuscus)
Authors: Kilgour R.J. , Faure P.A. , Brigham R.M.
Published: August 2013

Among social species, iterative interactions may lead to social preferences among group-mates and often are associated with increased mating opportunities or improved indirect fitness benefits. Although preferential associations have been documented in multiple species, this phenomenon has never been empirically studied in bats—the second largest order of mammals, where many of the 1200+ species live in groups of tens to hundreds of individuals. Given the current understanding of the social behaviour exhibited in this species, we explored the possibility that adult female big brown bats (Eptesicus fuscus (Beauvois, 1796)) show preferential association between group-mates using a pairwise choice design with individuals from a captive colony. Focal individuals were placed in a Y-maze and were given free choice of two familiar conspecifics. We measured the time focal individuals spent in close proximity to each conspecific. Our results indicate that some bats exhibit preferential association between group-mates, as multiple individuals spent significantly more time in close proximity to one conspecific versus another, despite randomizing the position of stimulus bats between trials. Given the frequent and long-term associations between group members of this species, social preferences could play a significant role in the outcomes of their long-term fitness.
Automated forensic soil mineral analysis; testing the potential of lithotyping
Authors: Pirrie Duncan , Rollinson Gavyn K. , Power Matthew R. , Webb Julia
Published: August 2013

In the investigation of serious crimes, soil can be, in some cases, a very valuable class of trace evidence. The complexity of soil is part of the reason why it is useful as trace evidence but is also an inherent problem, as there are many different parameters in a soil sample that could potentially be characterized. The inorganic components of soils are dominated by minerals, along with anthropogenic particulate grains; thus, the analysis of soil mineralogy as the main technique for inorganic forensic soil characterization is recommended. Typical methods that allow the bulk mineralogy to be determined, such as X-ray diffraction (XRD), do not allow the texture of the particles to be characterized. However, automated scanning electron microscopy (SEM) provides both modal mineralogy and also allows particle textures to be characterized. A recent advance in this technique has been the ability to report the modal mineralogy of a sample as ‘lithotypes’, which are defined on the basis of a combination of mineralogy and other parameters, such as grain size and mineral associations. Defined lithotype groups may include monominerallic grains but also, importantly, allow the automated quantification of rock types and other anthropogenic materials. Based on a simulated forensic scenario, the use of lithotyping is evaluated as an aid in the analysis of soil samples. This technique provides additional discrimination when comparing different soil samples.
Cytokine response of primary human myotubes in an in vitro exercise model
Authors: Scheler Mika , Irmler Martin , Lehr Stefan , Hartwig Sonja , Staiger Harald , Al-Hasani Hadi , Beckers Johannes , Hrabé de Angelis Martin , Häring Hans-Ulrich , Weigert Cora
Published: August 2013

Muscle contraction during exercise is a major stimulus for the release of peptides and proteins (myokines) that are supposed to take part in the beneficial adaptation to exercise. We hypothesize that application of an in vitro exercise stimulus as electric pulse stimulation (EPS) to human myotubes enables the investigation of the molecular response to exercise in a clearly defined model. We applied EPS for 24 h to primary human myotubes and studied the whole genome-wide transcriptional response as well as the release of candidate myokines. We observed 183 differentially regulated transcripts with fold changes >1.3. The transcriptional response resembles several properties of the in vivo situation in the skeletal muscle after endurance exercise, namely significant enrichment of pathways associated with interleukin and chemokine signaling, lipid metabolism, and antioxidant defense. Multiplex immunoassays verified the translation of the transcriptional response of several cytokines into high-secretion levels (IL-6, IL-8, CXCL1, LIF, CSF3, IL-1B, and TNF) and the increased secretion of further myokines such as angiopoietin-like 4. Notably, EPS did not induce the release of creatine kinase. Inhibitor studies and immunoblotting revealed the participation of ERK1/2-, JNK-, and NF-κB-dependent pathways in the upregulation of myokines. To conclude, our data highlight the importance of skeletal muscle cells as endocrine cells. This in vitro exercise model is not only suitable to identify exercise-regulated myokines, but it might be applied to primary human myotubes obtained from different muscle biopsy donors to study the molecular mechanisms of the individual response to exercise.
Expression and function of transforming growth factor-β isoforms and cognate receptors in the rat urinary bladder following cyclophosphamide-induced cystitis
Authors: Gonzalez Eric J. , Girard Beatrice M. , Vizzard Margaret A.
Published: August 2013

Numerous proinflammatory cytokines have been implicated in the reorganization of lower urinary tract function following cyclophosphamide (CYP)-induced cystitis. The present study investigated the functional profile of three pleiotropic transforming growth factor-β (TGF-β) isoforms and receptor (TβR) variants in the normal and inflamed (CYP-induced cystitis) rat urinary bladder. Our findings indicate that TGF-β (1, 2, and 3) and TβR (1, 2, and 3) transcript and protein expression were regulated to varying degrees in the urothelium or detrusor smooth muscle following intermediate (48 h; 150 mg/kg ip) or chronic (75 mg/kg ip; once every 3 days for 10 days), but not acute (4 h; 150 mg/kg ip), CYP-induced cystitis. Conscious, open-outlet cystometry was performed to determine whether aberrant TGF-β signaling contributes to urinary bladder dysfunction following intermediate (48 h) CYP-induced cystitis. TβR-1 inhibition with SB505124 (5 μM) significantly (p ≤ 0.001) decreased voiding frequency and increased bladder capacity (2.5-fold), void volume (2.6-fold), and intercontraction intervals (2.5-fold) in CYP-treated (48 h) rats. Taken together, these results provide evidence for 1) the involvement of TGF-β in lower urinary tract neuroplasticity following urinary bladder inflammation, 2) a functional role of TGF-β signaling in the afferent limb of the micturition reflex, and 3) urinary bladder TβR-1 as a viable target to reduce voiding frequency with cystitis.
Complement 3 activates the renal renin-angiotensin system by induction of epithelial-to-mesenchymal transition of the nephrotubulus in mice
Authors: Zhou Xueli , Fukuda Noboru , Matsuda Hiroyuki , Endo Morito , Wang Xiaofei , Saito Kosuke , Ueno Takahiro , Matsumoto Taro , Matsumoto Koichi , Soma Masayoshi , Kobayashi Naohiko , Nishiyama Akira
Published: August 2013

We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.
Intraglomerular inhibition maintains mitral cell response contrast across input frequencies
Authors: Shao Zuoyi , Puche Adam C. , Shipley Michael T.
Published: August 2013

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can “sharpen” MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain “contrast” in MC encoding during sniff-sampled inputs.
Loss of balance during balance beam walking elicits a multifocal theta band electrocortical response
Authors: Sipp Amy R. , Gwin Joseph T. , Makeig Scott , Ferris Daniel P.
Published: August 2013

Determining the neural correlates of loss of balance during walking could lead to improved clinical assessment and treatment for individuals predisposed to falls. We used high-density electroencephalography (EEG) combined with independent component analysis (ICA) to study loss of balance during human walking. We examined 26 healthy young subjects performing heel-to-toe walking on a treadmill-mounted balance beam as well as walking on the treadmill belt (both at 0.22 m/s). ICA identified clusters of electrocortical EEG sources located in or near anterior cingulate, anterior parietal, superior dorsolateral-prefrontal, and medial sensorimotor cortex that exhibited significantly larger mean spectral power in the theta band (4–7 Hz) during walking on the balance beam compared with treadmill walking. Left and right sensorimotor cortex clusters produced significantly less power in the beta band (12–30 Hz) during walking on the balance beam compared with treadmill walking. For each source cluster, we also computed a normalized mean time/frequency spectrogram time locked to the gait cycle during loss of balance (i.e., when subjects stepped off the balance beam). All clusters except the medial sensorimotor cluster exhibited a transient increase in theta band power during loss of balance. Cluster spectrograms demonstrated that the first electrocortical indication of impending loss of balance occurred in the left sensorimotor cortex at the transition from single support to double support prior to stepping off the beam. These findings provide new insight into the neural correlates of walking balance control and could aid future studies on elderly individuals and others with balance impairments.
Acetylcholine enhances excitability by lowering the threshold of spike generation in olfactory receptor cells
Authors: Ohkuma Mahito , Kawai Fusao , Miyachi Ei-ichi
Published: August 2013

Olfactory perception is influenced by behavioral states, presumably via efferent regulation. Using the whole cell version of patch-clamp recording technique, we discovered that acetylcholine, which is released from efferent fibers in the olfactory mucosa, can directly affect the signal encoding in newt olfactory receptor cells (ORCs). Under current-clamp conditions, application of carbachol, an acetylcholine receptor agonist, increased the spike frequency of ORCs and lowered their spike threshold. When a 3-pA current to induce near-threshold depolarization was injected into ORCs, 0.0 spikes/s were generated in control solution and 0.5 spikes/s in the presence of carbachol. By strong stimuli of injection of a 13-pA current into ORCs, 9.1 and 11.0 spikes/s were generated in control and carbachol solutions, respectively. A similar result was observed by bath application of 50 μM acetylcholine. Under voltage-clamp conditions, carbachol increased the peak amplitude of a voltage-gated sodium current by 32% and T-type calcium current by 39%. Atropine, the specific muscarinic receptor antagonist, blocked the enhancement by carbachol of the voltage-gated sodium current and T-type calcium current, suggesting that carbachol increases those currents via the muscarinic receptor rather than via the nicotinic receptor. In contrast, carbachol did not significantly change the amplitude of the L-type calcium current or the delayed rectifier potassium current in the ORCs. Because T-type calcium current is known to lower the threshold in ORCs, we suggest that acetylcholine enhance excitability by lowering the threshold of spike generation in ORCs via the muscarinic receptor.
Differential Induction of Apoptosis and Senescence by the DNA Methyltransferase Inhibitors 5-Azacytidine and 5-Aza-2′-Deoxycytidine in Solid Tumor Cells
Authors: Venturelli Sascha , Berger Alexander , Weiland Timo , Essmann Frank , Waibel Michaela , Nuebling Tina , Häcker Sabine , Schenk Martin , Schulze-Osthoff Klaus , Salih Helmut R. , Fulda Simone , Sipos Bence , Johnstone Ricky W. , Lauer Ulrich M. , Bitzer Michael
Published: August 2013

Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2′-deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies. Therefore, we investigated cell death pathways in vitro in human hepatoma, colon, renal, and lung cancer cells and in vivo in chorioallantoic membrane and xenograft models. Real-time cancer cell monitoring and cytokine profiling revealed a profoundly distinct response pattern to both drugs. 5-aza-dC induced p53-dependent tumor cell senescence and a high number of DNA double-strand breaks. In contrast, 5-aza-CR downregulated p53, induced caspase activation and apoptosis. These individual response patterns of tumor cells could be verified in vivo in chorioallantoic membrane assays and in a hepatoma xenograft model. Although 5-aza-CR and 5-aza-dC are viewed as drugs with similar therapeutic activity, they induce a diverse molecular response in tumor cells. These findings together with other reported differences enable and facilitate a rational design of new combination strategies to further exploit the epigenetic mode of action of these two drugs in different areas of clinical oncology. Mol Cancer Ther; 12(10); 2226–36. ©2013 AACR.
Myeloid TGF-β Responsiveness Promotes Metastases
Authors: Souza-Fonseca-Guimaraes Fernando , Smyth Mark J.
Published: August 2013

Summary: Tumor-induced immune suppression is a major impediment to many potentially effective cancer therapies. TGF-β has previously been described as having both tumor-promoting and tumor-suppressive characteristics. In this issue of Cancer Discovery, Pang and colleagues show that myeloid-specific TGF-β signaling is a critical mediator in tumor metastasis. These findings point to a more specific means to reduce cancer immunosuppression, prevent metastasis, and minimize treatment-related adverse events. Cancer Discov; 3(8); 846–8. ©2013 AACR.

See related article by Pang et al., p. 936
Targeting BRAF in Multiple Myeloma
Authors: O'Donnell Elizabeth , Raje Noopur S.
Published: August 2013

Summary: In multiple myeloma, it is believed that multiple mutations in different pathways deregulate the intrinsic biology of the plasma cell, resulting in a genetically complex heterogeneous disease. Mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway have been identified and represent potential targets for therapy in this disease. BRAF, a serine/threonine kinase, has received considerable attention given the success of targeted therapy in malignant melanoma. Andrulis and colleagues report, for the first time, successful treatment of multiple myeloma with vemurafenib, a BRAF inhibitor, in a patient with a BRAF mutation. Cancer Discov; 3(8); 840–2. ©2013 AACR.

See related article by Andrulis et al., p. 862
Dyslipidemia in Pediatric Systemic Lupus Erythematosus: The Relationship with Disease Activity and Plasma Homocysteine and Cysteine Concentrations
Authors: Ortiz Thaís Tobaruela , Terreri Maria Teresa , Caetano Michelle , Souza Fabíola Suano , D'Almeida Vânia , Sarni Roseli Oselka Saccardo , Hilário Maria Odete Esteves
Published: August 2013

Objective: To evaluate the presence of dyslipidemia and plasma concentrations of homocysteine (Hcy) and cysteine (Cys) in adolescents with juvenile systemic lupus erythematosus (SLE) and relate these findings to disease activity (Systemic Lupus Erythematosus Disease Activity Index, SLEDAI) and cardiovascular risk factors. Methods: A cross-sectional controlled study including 26 female adolescents with SLE and 26 healthy controls was conducted. We evaluated SLEDAI, medications, anthropometric data, dietary intake, lipid profile, proteinuria, Hcy, Cys, folic acid, vitamin B12, and high-sensitivity C-reactive protein levels. Results: Dyslipidemia was observed in 46.2% of the patients and in 19.2% of the controls. The SLE group had a higher Cys concentration and a lower high-density lipoprotein cholesterol concentration compared with the controls. In the multivariate analysis only Hcy was significantly and independently associated with the presence of dyslipidemia in the juvenile SLE group; an increase of 1 μmol/l in the Hcy concentration doubled the chance of dyslipidemia (OR: 2.1; 95% CI: 1.1-4.9; p = 0.030). The Cys concentration was correlated with Hcy, total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations. Conclusion: We observed the presence of cardiovascular risk factors in adolescents with juvenile SLE. The early identification of biochemical alterations allows the development of intervention strategies that may lower the risk of cardiovascular disease.
A New Infant Case of Nakajo-Nishimura Syndrome with a Genetic Mutation in the Immunoproteasome Subunit: An Overlapping Entity with JMP and CANDLE Syndrome Related to PSMB8 Mutations
Authors: Kunimoto Kayo , Kimura Ayako , Uede Koji , Okuda Masumi , Aoyagi Noriyuki , Furukawa Fukumi , Kanazawa Nobuo
Published: August 2013

Nakajo-Nishimura syndrome (NNS) is a very rare hereditary autoinflammatory disorder that generally has its onset in infancy with pernio-like rashes and gradually develops into partial lipodystrophy. A distinct homozygous PSMB8 mutation encoding an immunoproteasome subunit has recently been identified as its genetic cause. Here, we report a new case of a patient with NNS who developed exudative erythemas on his face and extremities at 2 months of age, along with high fever, elevated serum hepatic aminotransferase levels and hepatosplenomegaly. Massive infiltration of inflammatory cells was observed histologically in the dermis and subcutis without apparent leukocytoclastic vasculitis. These symptoms improved with oral corticosteroids but recurred periodically, and a thin angular face with long clubbed fingers gradually developed. Identification of the PSMB8 mutation finalized the diagnosis of NNS at 5 years of age. Understanding a variety of clinicopathological features at the developmental stages is necessary to make an early diagnosis of NNS.
Obesity and Prostate Cancer Incidence and Mortality: A Systematic Review of Prospective Cohort Studies
Authors: Golabek Tomasz , Bukowczan Jakub , Chłosta Piotr , Powroźnik Jan , Dobruch Jakub , Borówka Andrzej
Published: August 2013

Background: There has been a large body of research on obesity and the risk of prostate cancer (PCa) that has been published recently. However, the epidemiological evidence for such an association has not been consistent. This may be attributed to the nature of case-control and retrospective studies, which generally are more prone to biases. Therefore, we conducted a systematic review of prospective cohort studies to assess the association between obesity and the risk of PCa incidence and death. Methods: A search of the PubMed database and references of published studies (from inception until March 2013) was conducted. Twenty-three eligible studies were identified and included in the systematic review. Results: The evidence from the prospective cohort studies linking obesity with PCa incidence has not been consistent. However, cumulative data is compelling for a strong positive association between obesity and fatal PCa. Conclusions: Obesity is a significant diet-related risk factor for fatal PCa. Further well-constructed, large cohort studies on the potential association between obesity and PCa, as well as on underlying mechanisms, are needed.
Exchange of extracellular domains of CCR1 and CCR5 reveals confined functions in CCL5-mediated cell recruitment
Authors: Kramp Birgit K. , Megens Remco T. A. , Sarabi Alisina , Winkler Sabine , Projahn Delia , Weber Christian , Koenen Rory R. , von Hundelshausen Philipp
Published: August 2013

The chemokine CCL5 recruits monocytes into inflamed tissues by triggering primarily CCR1-mediated arrest on endothelial cells, whereas subsequent spreading is dominated by CCR5. The CCL5-induced arrest can be enhanced by heteromer formation with CXCL4. To identify mechanisms for receptor-specific functions, we employed CCL5 mutants and transfectants expressing receptor chimeras carrying transposed extracellular regions. Mutation of the basic 50s cluster of CCL5, a coordinative site for CCL5 surface presentation, reduced CCR5- but not CCR1-mediated arrest and transmigration. Impaired arrest was restored by exchanging the CCR5-N-terminus for that of CCR1, which supported arrest even without the 50s cluster, whereas mutation of the basic 40s cluster essential for proteoglycan binding of CCL5 could not be rescued. The enhancement of CCL5-induced arrest by CXCL4 was mediated by CCR1 requiring its third extracellular loop. The domain exchanges did not affect formation and co-localisation of receptor dimers, indicating a sensing role of the third extracellular loop for hetero-oligomers in an arrest microenvironment. Our data identify confined targetable regions of CCR1 specialised to facilitate CCL5-induced arrest and enhanced responsiveness to the CXCL4-CCL5 heteromer.

Note: The review process for this manuscript was fully handled by G. Y. H. Lip, Editor in Chief.
Plasma Free Fatty Acids and Risk of Heart Failure
Authors: Djoussé Luc , Benkeser David , Arnold Alice , Kizer Jorge R. , Zieman Susan J. , Lemaitre Rozenn N. , Tracy Russell P. , Gottdiener John S. , Mozaffarian Dariush , Siscovick David S. , Mukamal Kenneth J. , Ix Joachim H.
Published: August 2013

Background—

Although plasma free fatty acid (FFA) concentrations have been associated with lipotoxicity, apoptosis, and risk of diabetes mellitus and coronary heart disease, it is unclear whether FFA levels are associated with heart failure (HF).

Methods and Results—

To test the hypothesis that plasma concentration of FFAs is positively associated with incident HF, we prospectively analyzed data on 4248 men and women free of HF at baseline and >65 years old from the Cardiovascular Health Study. FFA concentration was measured in duplicate by the Wako enzymatic method. Incident HF was validated by a centralized Events Committee. We used Cox proportional hazards to estimate the hazard ratio of HF per SD of FFAs. During a median follow-up of 10.5 years, a total of 1286 new cases of HF occurred. In a multivariable model adjusting for clinic site, comorbidity, demographic, anthropometric, and lifestyle factors, each SD (0.2 mEq/L) higher plasma FFA was associated with 12% (95% confidence interval, 6%–19%) higher risk of HF. Controlling for time-varying diabetes mellitus and coronary heart disease did not change the results (hazard ratio per SD, 1.16 [95% confidence interval, 1.09–1.23]).

Conclusions—

A single measure of plasma FFA obtained later in life is associated with a higher risk of HF in older adults. Additional studies are needed to explore biological mechanisms by which FFAs may influence the risk of HF and determine whether FFAs could serve as a novel pharmacological target for HF prevention.
Value of Early Cardiovascular Magnetic Resonance for the Prediction of Adverse Arrhythmic Cardiac Events After a First Noncomplicated ST-Segment–Elevation Myocardial Infarction
Authors: Izquierdo Maite , Ruiz-Granell Ricardo , Bonanad Clara , Chaustre Fabian , Gomez Cristina , Ferrero Angel , Lopez-Lereu Pilar , Monmeneu Jose V. , Nuñez Julio , Chorro F. Javier , Bodi Vicent
Published: August 2013

Background—

Infarct size (IS) determined by cardiac magnetic resonance (CMR) has proven an additional value, on top of left ventricular ejection fraction (LVEF), in prediction of adverse arrhythmic cardiac events (AACEs) in chronic ischemic heart disease. Its value soon after an acute ST-segment–elevation myocardial infarction remains unknown. Our aim was to determine whether early CMR can improve AACE risk prediction after acute ST-segment–elevation myocardial infarction.

Methods and Results—

Patients admitted for a first noncomplicated ST-segment–elevation myocardial infarction were prospectively followed up. A total of 440 patients were included. All of them underwent CMR 1 week after admission. CMR-derived LVEF and IS (grams per meter squared) were quantified. AACEs included postdischarge sudden death, sustained ventricular tachycardia, and ventricular fibrillation either documented on ECG or recorded via an implantable cardioverter-defibrillator. Within a median follow-up of 2 years, 11 AACEs (2.5%) were detected: 5 sudden deaths (1.1%) and 6 spontaneous ventricular tachycardia/ventricular fibrillation. In the whole group, AACEs associated with more depressed LVEF (adjusted hazard ratio [95% confidence interval], 0.90 [0.83–0.97];
P
<0.01) and larger IS (adjusted hazard ratio [95% confidence interval], 1.06 [1.01–1.12];
P
=0.01). According to the corresponding area under the receiver operating characteristic curve, LVEF ≤36% and IS ≥23.5 g/m
2
best predicted AACEs. The vast majority of AACEs (10/11) occurred in patients with simultaneous depressed LVEF ≤36% and IS ≥23.5 g/m
2
(n=39).

Conclusions—

In the era of reperfusion therapies, occurrence of AACEs in patients with an in-hospital noncomplicated first ST-segment–elevation myocardial infarction is low. In this setting, assessment of an early CMR-derived IS could be useful for further optimization of AACE risk prediction.