bluuebunny/crossref_metadata_2025 huggingface dataset:
Temperature thresholds of physically dormant seeds and plant functional response to fire: variation among species and relative impact of climate change
Authors: Ooi Mark K. J. , Denham Andrew J. , Santana Victor M. , Auld Tony D.
Published: February 2014

Variation in dormancy thresholds among species is rarely studied but may provide a basis to better understand the mechanisms controlling population persistence. Incorporating dormancy‐breaking temperature thresholds into existing trait frameworks could improve predictions regarding seed bank persistence, and subsequently species resilience in response to fire, climate change and anthropogenic management. A key ecological strategy for many species from fire‐prone ecosystems is the possession of a long‐lived seed bank, ensuring recovery after fire. Physical dormancy is dominant in these ecosystems and maintaining this dormancy is directly linked to seed bank persistence. We identified a suite of seed‐related factors relevant to maintaining populations in fire‐prone regions for 14 co‐occurring physically dormant species. We measured variation in initial levels of dormancy and then applied experimental heating treatments, based on current seasonal temperatures and those occurring during fires, to seeds of all study species. Additionally, higher seasonal temperature treatments were applied to assess response of seeds to temperatures projected under future climate scenarios. Levels of germination response and mortality were determined to assess how tightly germination response was bound to either fire or seasonal cues. Six species were found to have dormancy cues bound to temperatures that only occur during fires (80°C and above) and were grouped as having obligate pyrogenic dormancy release. The remaining species, classified as having facultative pyrogenic dormancy, had lower temperature dormancy thresholds and committed at least 30% of seeds to germinate after summer‐temperature treatments. Evidence from this study supports including dormancy‐breaking temperature thresholds as an attribute for identifying functional types. High temperature thresholds for breaking dormancy, found in our obligate pyrogenic group, appear to be a fire‐adapted trait, while we predict that species in the facultative group are most at risk to increased seed bank decay resulting from elevated soil temperatures under projected climate change.
New insights into the role of the aryl hydrocarbon receptor in the function of CD11c+ cells during respiratory viral infection
Authors: Jin Guang‐Bi , Winans Bethany , Martin Kyle C. , Lawrence B. Paige
Published: February 2014

The aryl hydrocarbon receptor (AHR) has garnered considerable attention as a modulator of CD4+ cell lineage development and function. It also regulates antiviral CD8+ T‐cell responses, but via indirect mechanisms that have yet to be determined. Here, we show that during acute influenza virus infection, AHR activation skews dendritic‐cell (DC) subsets in the lung‐draining lymph nodes, such that there are fewer conventional CD103+ DCs and CD11b+ DCs. Sorting DC subsets reveals AHR activation reduces immunostimulatory function of CD103+ DCs in the mediastinal lymph nodes, and decreases their frequency in the lung. DNA‐binding domain Ahr mutants demonstrate that alterations in DC subsets require the ligand‐activated AHR to contain its inherent DNA‐binding domain. To evaluate the intrinsic role of AHR in DCs, conditional knockouts were created using Cre‐LoxP technology, which revealed that AHR in CD11c+ cells plays a key role in controlling the acquisition of effector CD8+ T cells in the infected lung. However, AHR within other leukocyte lineages contributes to diminished naïve CD8+ T‐cell activation in the draining lymphoid nodes. These findings indicate DCs are among the direct targets of AHR ligands in vivo, and AHR signaling modifies host responses to a common respiratory pathogen by affecting the complex interplay of multiple cell types.
Cross‐presenting dendritic cells are required for control of Leishmania major infection
Authors: Ashok Devika , Schuster Steffen , Ronet Catherine , Rosa Muriel , Mack Vanessa , Lavanchy Christine , Marraco Silvia F. , Fasel Nicolas , Murphy Kenneth M. , Tacchini‐Cottier Fabienne , Acha‐Orbea Hans
Published: February 2014

Leishmania major infection induces self‐healing cutaneous lesions in C57BL/6 mice. Both IL‐12 and IFN‐γ are essential for the control of infection. We infected Jun dimerization protein p21SNFT (Batf3−/−) mice (C57BL/6 background) that lack the major IL‐12 producing and cross‐presenting CD8α+ and CD103+ DC subsets. Batf3−/− mice displayed enhanced susceptibility with larger lesions and higher parasite burden. Additionally, cells from draining lymph nodes of infected Batf3−/− mice secreted less IFN‐γ, but more Th2‐ and Th17‐type cytokines, mirrored by increased serum IgE and Leishmania‐specific immunoglobulin 1 (Th2 indicating). Importantly, CD8α+ DCs isolated from lymph nodes of L. major‐infected mice induced significantly more IFN‐γ secretion by L. major‐stimulated immune T cells than CD103+ DCs. We next developed CD11c‐diptheria toxin receptor: Batf3−/− mixed bone marrow chimeras to determine when the DCs are important for the control of infection. Mice depleted of Batf‐3‐dependent DCs from day 17 or wild‐type mice depleted of cross‐presenting DCs from 17–19 days after infection maintained significantly larger lesions similar to mice whose Batf‐3‐dependent DCs were depleted from the onset of infection. Thus, we have identified a crucial role for Batf‐3‐dependent DCs in protection against L. major.
Self‐Assembly of a Mixed‐Valent Co32 Ring
Authors: Bai Yue‐Ling , Bao Xiaoli , Zhu Shourong , Fang Jianhui , Shao Min , Shi Haiyan
Published: February 2014

Solvothermal reaction of CoCl2·6H2O with H3tci [H3tci = tris(2‐carboxyethyl)isocyanurate] in H2O/CH3COCH3 in the presence of triethylamine gave rise to a mixed‐valent thirty‐two nuclear cobalt cluster, namely, [CoII16CoIII16(μ4‐O)16(tci)16(H2O)12]·40H2O (1). Crystal structural analysis showed that four octanuclear [CoII4CoIII4(μ4‐O)4]12+ units were bridged by the carbonyl oxygen atoms of the tci3– ligands to give a Co32 ring. Magnetic studies confirmed the paramagnetic nature of this cluster, and cyclic voltammetry showed an irreversible oxidation at 1.0 V versus saturated calomel electrode.
Cationic derivative of polyprenol, a potential component of liposomal drug carriers, does not alter renal function in rats
Authors: Gawrys Olga , Olszyński Krzysztof Hubert , Gawarecka Katarzyna , Swiezewska Ewa , Chojnacki Tadeusz , Masnyk Marek , Chmielewski Marek , Kompanowska‐Jezierska Elżbieta
Published: February 2014

Potential toxicity of a cationic derivative of polyprenol (APren‐7) with lipofecting activity was examined, especially its influence on renal haemodynamics and function, in order to conduct further investigation of its suitability as a component of liposomal drug carriers. Sprague–Dawley rats received daily injections (0.5 mL, s.c.) of liposomes comprised of 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE) and APren‐7 (LP); classic liposomes composed of DOPE only (L); water solvent (W). After 4 weeks rats were anaesthetised and a wide spectrum of functional parameters were measured. These included mean arterial blood pressure (MBP), total renal blood flow (RBF), renal cortical, outer and inner medullary blood flow (CBF, OMBF, IMBF, respectively), diuresis, and sodium and solute excretion. Most parameters did not significantly differ between treated and control groups. A lower OMBF/IMBF ratio in liposome‐treated groups (L: 1.0 ± 0.1; LP: 1.1 ± 0.1 vs. W: 1.9 ± 0.3, p < 0.05) might be an early sign of renal function impairment, however, since the lowering occurred in both L and LP groups, there was no reason to suspect that APren‐7 had any untoward influence on renal haemodynamics or excretion. The present results did not reveal toxic effects of APren‐7 in experimental rats, indicating that it could be suitable as a component of liposomal drug carriers.

Practical applications: Many currently used drugs have severe side effects, which present a serious problem in the treatment of numerous diseases. Searching for compounds augmenting efficacy of drugs to reduce their dosage seems to be a promising strategy. This can be accomplished by facilitating the bioavailability of the drug, e.g. by improving penetration of biological membranes or delivery to the areas distant from the lumen of blood vessels and in particular instances by improving drug stability. The cationic derivative of polyprenol APren‐7 has lipofecting properties. In this study we found APren‐7 to be harmless to the experimental animals. Newly designed liposomal carriers could find application not only in the pharmaceutical and cosmetics industry but also in biological laboratories and in molecular medicine.
Enantioselective Syntheses of Bicyclic Lactams Based on Iridium‐Catalyzed Asymmetric Allylic Substitution and Heck Cyclization
Authors: Satyanarayana Gedu , Helmchen Günter
Published: February 2014

A sequence of reactions that include an iridium‐catalyzed regio‐ and enantioselective allylic amination, the formation of an amide, a ruthenium‐catalyzed ring‐closing metathesis, and an intramolecular Heck reaction allows for the preparation of [3,3,1]‐ and [4,3,1]‐bicyclic amides. The target compounds have a nitrogen atom at the bridgehead, a nonplanar amide moiety, and a stereogenic center at the one‐carbon bridge.
Spark production by abrasion of titanium alloys in golf club heads
Authors: Arulmoli Janahan , Vu Bryant , Sung Ming‐Je , Mohamed Farghalli A. , Earthman James C.
Published: February 2014

The objective of the present study was to determine whether golf clubs that have titanium (Ti) alloy surfaces can produce sparks when abraded under normal swing conditions. In the present work, sparks are defined as moving particles that emit radiant energy due to the process of combustion on its surface. Two three‐irons and a three‐wood containing a Ti alloy in the head as well as two three‐irons and a three‐wood that only contain stainless steel in the head were included in the study. The impact events during abrasion testing were recorded using a high‐speed video camera, and abrasion damage was determined using stereometric analysis of scanning electron microscopy images. The findings reveal that Ti alloy faceplates that extend to the sole of the club can produce a number of Ti alloy particles when abraded under swing conditions. The particles then combust for a sufficient duration to potentially ignite a neighboring fuel source such as dry foliage and grasses. Abraded Ti alloy microparticles up to 500 µm in diameter were observed to burn for nearly 1 s, allowing ample time for fuel ignition. By contrast, no sparks were produced by stainless steel club heads when tested under the same conditions. Copyright © 2014 John Wiley & Sons, Ltd.
Compressive strength of fly‐ash‐based geopolymer concrete at elevated temperatures
Authors: Shaikh F. U. A. , Vimonsatit V.
Published: February 2014

This paper presents the compressive strength of fly‐ash‐based geopolymer concretes at elevated temperatures of 200, 400, 600 and 800 °C. The source material used in the geopolymer concrete in this study is low‐calcium fly ash according to ASTM C618 class F classification and is activated by sodium silicate (Na2SiO3) and sodium hydroxide (NaOH) solutions. The effects of molarities of NaOH, coarse aggregate sizes, duration of steam curing and extra added water on the compressive strength of geopolymer concrete at elevated temperatures are also presented. The results show that the fly‐ash‐based geopolymer concretes exhibited steady loss of its original compressive strength at all elevated temperatures up to 400 °C regardless of molarities and coarse aggregate sizes. At 600 °C, all geopolymer concretes exhibited increase of compressive strength relative to 400 °C. However, it is lower than that measured at ambient temperature. Similar behaviour is also observed at 800 °C, where the compressive strength of all geopolymer concretes are lower than that at ambient temperature, with only exception of geopolymer concrete containing 10 m NaOH. The compressive strength in the latter increased at 600 and 800 °C. The geopolymer concretes containing higher molarity of NaOH solution (e.g. 13 and 16 m) exhibit greater loss of compressive strength at 800 °C than that of 10 m NaOH. The geopolymer concrete containing smaller size coarse aggregate retains most of the original compressive strength of geopolymer concrete at elevated temperatures. The addition of extra water adversely affects the compressive strength of geopolymer concretes at all elevated temperatures. However, the extended steam curing improves the compressive strength at elevated temperatures. The Eurocode EN1994:2005 to predict the compressive strength of fly‐ash‐based geopolymer concretes at elevated temperatures agrees well with the measured values up to 400 °C. Copyright © 2014 John Wiley & Sons, Ltd.
RU_CAGeochem, a database and sample repository for Central American volcanic rocks at Rutgers University
Authors: Carr Michael J. , Feigenson Mark D. , Bolge Louise L. , Walker James A. , Gazel Esteban
Published: February 2014

The Rutgers University Central American geochemical dataset focuses on the active volcanoes related to the Cocos‐Caribbean convergent plate boundary that extends from Guatemala to Costa Rica in Central America. The RU prefix signifies that the data and samples are primarily from the long‐term Central American research project started at Dartmouth College in 1970 and continued at Rutgers University from 1974 to the present. The database is decidedly uneven because of the impressive improvement of analytical techniques over the span of data collection. Further complications arose because most of the sampling and analysis were part of the educational process for many different undergraduate and graduate students using different types of instruments. This note presents, as a reasonably coherent whole, geochemical data and metadata for about 1400 samples collected by at least 40 students and colleagues. Many unpublished Sr, Nd, and Pb isotopic ratios are included here but most of the new data are metadata that provide greatly improved descriptions of the tectonic settings, locations, and status of the samples as well as estimates of data quality.
Blocking of irrelevant memories by posterior alpha activity boosts memory encoding
Authors: Park Hyojin , Lee Dong Soo , Kang Eunjoo , Kang Hyejin , Hahm Jarang , Kim June Sic , Chung Chun Kee , Jensen Ole
Published: February 2014

In our daily lives, we are confronted with a large amount of information. Because only a small fraction can be encoded in long‐term memory, the brain must rely on powerful mechanisms to filter out irrelevant information. To understand the neuronal mechanisms underlying the gating of information into long‐term memory, we employed a paradigm where the encoding was directed by a “Remember” or a “No‐Remember” cue. We found that posterior alpha activity increased prior to the “No‐Remember” stimuli, whereas it decreased prior to the “Remember” stimuli. The sources were localized in the parietal cortex included in the dorsal attention network. Subjects with a larger cue‐modulation of the alpha activity had better memory for the to‐be‐remembered items. Interestingly, alpha activity reflecting successful inhibition following the “No‐Remember” cue was observed in the frontal midline structures suggesting preparatory inhibition was mediated by anterior parts of the dorsal attention network. During the presentation of the memory items, there was more gamma activity for the “Remember” compared to the “No‐Remember” items in the same regions. Importantly, the anticipatory alpha power during cue predicted the gamma power during item. Our findings suggest that top‐down controlled alpha activity reflects attentional inhibition of sensory processing in the dorsal attention network, which then finally gates information to long‐term memory. This gating is achieved by inhibiting the processing of visual information reflected by neuronal synchronization in the gamma band. In conclusion, the functional architecture revealed by region‐specific changes in the alpha activity reflects attentional modulation which has consequences for long‐term memory encoding. Hum Brain Mapp 35:3972–3987, 2013. © 2013 Wiley Periodicals, Inc.
Behavioral and neural correlates of imagined walking and walking‐while‐talking in the elderly
Authors: Blumen Helena M. , Holtzer Roee , Brown Lucy L. , Gazes Yunglin , Verghese Joe
Published: February 2014

Cognition is important for locomotion and gait decline increases the risk for morbidity, mortality, cognitive decline, and dementia. Yet, the neural correlates of gait are not well established, because most neuroimaging methods cannot image the brain during locomotion. Imagined gait protocols overcome this limitation. This study examined the behavioral and neural correlates of a new imagined gait protocol that involved imagined walking (iW), imagined talking (iT), and imagined walking‐while‐talking (iWWT). In Experiment 1, 82 cognitively‐healthy older adults (M = 80.45) walked (W), iW, walked while talking (WWT) and iWWT. Real and imagined walking task times were strongly correlated, particularly real and imagined dual‐task times (WWT and iWWT). In Experiment 2, 33 cognitively‐healthy older adults (M = 73.03) iW, iT, and iWWT during functional magnetic resonance imaging. A multivariate Ordinal Trend (OrT) Covariance analysis identified a pattern of brain regions that: (1) varied as a function of imagery task difficulty (iW, iT and iWWT), (2) involved cerebellar, precuneus, supplementary motor and other prefrontal regions, and (3) were associated with kinesthetic imagery ratings and behavioral performance during actual WWT. This is the first study to compare the behavioral and neural correlates of imagined gait in single and dual‐task situations, an issue that is particularly relevant to elderly populations. These initial findings encourage further research and development of this imagined gait protocol as a tool for improving gait and cognition among the elderly. Hum Brain Mapp 35:4090–4104, 2014. © 2014 Wiley Periodicals, Inc.
High-Fat Diet Triggers Mallory-Denk Body Formation Through Misfolding and Crosslinking of Excess Keratin 8
Authors: Kucukoglu Ozlem , Guldiken Nurdan , Chen Yu , Usachov Valentyn , El-Heliebi Amin , Haybaeck Johannes , Denk Helmut , Trautwein Christian , Strnad Pavel
Published: February 2014

Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated keratins 8/18 (K8/K18). MDBs are characteristic of alcoholic and nonalcoholic steatohepatitis (NASH) and discriminate between the relatively benign simple steatosis and the more aggressive NASH. Given the emerging evidence for a genetic predisposition to MDB formation and NASH development in general, we studied whether high-fat (HF) diet triggers MDB formation and liver injury in susceptible animals. Mice were fed a high-fat (HF) or low-fat (LF) diet plus a cofactor for MDB development, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Additionally, we fed nontransgenic and K8 overexpressing mice (K8tg) with the HF diet. The presence of MDB and extent of liver injury was evaluated using biochemical markers, histological staining, and immunofluorescence microscopy. In DDC-fed animals, an HF diet resulted in greater liver injury and up-regulation of inflammation-related genes. As a potential mechanism, K8/K18 accumulation and increased ecto-5′-nucleotidase (CD73) levels were noted. In the genetically susceptible K8tg mice, HF diet triggered hepatocellular injury, ballooning, apoptosis, inflammation, and MDB development by way of 1) decreased expression of the major stress-inducible chaperone Hsp72 with appearance of misfolded keratins; 2) elevated levels of the transglutaminase 2 (TG2); 3) increased K8 phosphorylation at S74 with subsequent TG2-mediated crosslinking of phosphorylated K8; and 4) higher production of the MDB-modifier gene CD73.

Conclusion :

Our data demonstrate that HF diet triggers aggregate formation and development of liver injury in susceptible individuals through misfolding and crosslinking of excess K8. (Hepatology 2014;60:169–178)
Blockade of Cd47-Mediated Cathepsin S/Protease-Activated Receptor 2 Signaling Provides a Therapeutic Target for Hepatocellular Carcinoma
Authors: Lee Terence Kin-Wah , Cheung Vincent Chi-Ho , Lu Ping , Lau Eunice Yuen Ting , Ma Stephanie , Tang Kwan Ho , Tong Man , Lo Jessica , Ng Irene Oi Lin
Published: February 2014

Identification of therapeutic targets against tumor-initiating cells (TICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched a TIC population capable of tumor initiation and self-renewal by serial passages of hepatospheres with chemotherapeutic agents. In chemoresistant hepatospheres, CD47 was found to be up-regulated, when compared with differentiated progenies. CD47 is preferentially expressed in liver TICs, which contributed to tumor initiation, self-renewal, and metastasis and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed stem/progenitor cell characteristics. CD47+ hepatocellular carcinoma (HCC) cells preferentially secreted cathepsin S (CTSS), which regulates liver TICs through the CTSS/protease-activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino approach suppressed growth of HCC

in vivo

and exerted a chemosensitization effect through blockade of CTSS/PAR2 signaling.

Conclusion:

These data suggest that CD47 may be an attractive therapeutic target for HCC therapy. (Hepatology 2014;60:179–191)
Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis
Authors: Wunsch Ewa , Trottier Jocelyn , Milkiewicz Malgorzata , Raszeja-Wyszomirska Joanna , Hirschfield Gideon M. , Barbier Olivier , Milkiewicz Piotr
Published: February 2014

Ursodeoxycholic acid (UDCA) is no longer recommended for management of adult patients with primary sclerosing cholangitis (PSC). We undertook a prospective evaluation of UDCA withdrawal in a group of consecutive patients with PSC. Twenty six patients, all treated with UDCA (dose range: 10-15 mg/kg/day) were included. Paired blood samples for liver biochemistry, bile acids, and fibroblast growth factor 19 (FGF19) were collected before UDCA withdrawal and 3 months later. Liquid chromatography/tandem mass spectrometry was used for quantification of 29 plasma bile acid metabolites. Pruritus and health-related quality of life (HRQoL) were assessed with a 10-point numeric rating scale, the Medical Outcomes Study Short Form-36 (SF-36), and PBC-40 questionnaires. UDCA withdrawal resulted in a significant deterioration in liver biochemistry (increase of alkaline phosphatase of 75.6%; P < 0.0001; gamma-glutamyl transpeptidase of 117.9%, P < 0.0001; bilirubin of 50.0%, P < 0.001; alanine aminotransferase of 63.9%, P < 0.005; and aspartate aminotransferase of 45.0%, P < 0.005) and increase of Mayo Risk Score for PSC (change from baseline of +0.5 point; P < 0.003). Bile acid analysis revealed a significant decrease in lithocholic acid and its derivatives after UDCA withdrawal, but no effect on concentrations of primary bile acids aside from an increased accumulation of their taurine conjugates. After UDCA removal cholestatic parameters, taurine species of cholic acid and chenodeoxycholic acid correlated with serum FGF19 levels. No significant effect on HRQoL after UDCA withdrawal was observed; however, 42% of patients reported a deterioration in their pruritus. Conclusion: At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites. A proportion of patients report increased pruritus, but other short-term markers of quality of life are unaffected. (Hepatology 2014;60:931–940)
Prepubertal stress and hippocampal function: Sex‐specific effects
Authors: Brydges Nichola M. , Wood Emma R. , Holmes Megan C. , Hall Jeremy
Published: February 2014

The chances of developing psychiatric disorders in adulthood are increased when stress is experienced early in life. In particular, stress experienced in the childhood or ‘prepubertal' phase is associated with the later development of disorders such as depression, anxiety, post‐traumatic stress disorder, and psychosis. Relatively little is known about the biological basis of this effect, but one hypothesis is that prepubertal stress produces long‐lasting changes in brain development, particularly in stress sensitive regions such as the hippocampus, leaving an individual vulnerable to disorders in adulthood. In this study, we used an animal model of prepubertal stress to investigate the hypothesis that prepubertal stress induces alterations in hippocampal function in adulthood. Male and female rats were exposed to a brief, variable prepubertal stress protocol (postnatal days 25–27), and their performance in two distinct hippocampal‐dependent tasks (contextual fear and spatial navigation) was compared with controls in adulthood. Prepubertal stress significantly impaired contextual fear responses in males and enhanced performance in spatial navigation in females. These results demonstrate that exposure to a brief period of stress in the prepubertal phase alters hippocampal‐dependent behaviors in adulthood in a sex‐specific manner. © 2014 Wiley Periodicals, Inc.
Efficacy of cryotherapy associated with laser therapy for decreasing severity of melphalan‐induced oral mucositis during hematological stem‐cell transplantation: a prospective clinical study
Authors: de Paula Eduardo Fernanda , Bezinelli Leticia Mello , da Graça Lopes Roberta Marques , Nascimento Sobrinho Jairo Jose , Hamerschlak Nelson , Correa Luciana
Published: February 2014

Melphalan followed by hematopoietic stem‐cell transplantation (HSCT) is the standard treatment for multiple myeloma and other hematopoietic neoplasms. However, high doses of melphalan cause severe oral mucositis (OM). The objective was to verify the efficacy of cryotherapy plus laser therapy on reduction of OM severity. HSCT patients undergoing melphalan chemotherapy (n = 71) were randomly divided into two groups according to OM treatment: oral cryotherapy performed with ice chips for 1 h 35 min followed by low‐level laser therapy (InGaAIP, 660 nm, 40 mW, 6 J/cm2) (n = 54) and laser therapy alone with the same protocol (n = 17). A control group (n = 33) was composed of HSCT patients treated with melphalan who received no specific treatment for OM. OM scores and clinical information were collected from D0 to D + 11. The cryotherapy/laser therapy group showed the lowest OM scores (maximum Grade I) and the lowest mean number of days (8 days) with OM in comparison with the other groups (p < 0.001). OM Grades III and IV were present with high frequency only in the control group. The association of cryotherapy with laser therapy was effective in reducing OM severity in HSCT patients who underwent melphalan conditioning. Copyright © 2014 John Wiley & Sons, Ltd.
Biweekly THP‐COP therapy for newly diagnosed peripheral T‐cell lymphoma patients
Authors: Tomita Naoto , Kodama Fumio , Tsuyama Naoko , Sakata Seiji , Takeuchi Kengo , Ishibashi Daisuke , Koyama Satoshi , Ishii Yoshimi , Yamamoto Wataru , Takasaki Hirotaka , Hagihara Maki , Kuwabara Hideyuki , Tanaka Masatsugu , Hashimoto Chizuko , Yamazaki Etsuko , Koharazawa Hideyuki , Fujimaki Katsumichi , Sakai Rika , Fujisawa Shin , Ishigatsubo Yoshiaki
Published: February 2014

Pirarubicin tetrahydropyranyl adriamycin (THP‐ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin‐resistant cell lines. We performed a phase II study of biweekly THP‐COP [50 mg/m2 pirarubicin, 750 mg/m2 cyclophosphamide, 1.4 mg/m2 vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1–5] in patients with peripheral T‐cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T‐cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP‐COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow‐up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3‐year progression‐free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP‐COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP‐COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485). Copyright © 2014 John Wiley & Sons, Ltd.
Spatial variability in streambed hydraulic conductivity of contrasting stream morphologies: channel bend and straight channel
Authors: Sebok E. , Duque C. , Engesgaard P. , Boegh E.
Published: February 2014

Streambed hydraulic conductivity is one of the main factors controlling variability in surface water‐groundwater interactions, but only few studies aim at quantifying its spatial and temporal variability in different stream morphologies. Streambed horizontal hydraulic conductivities (Kh) were therefore determined from in‐stream slug tests, vertical hydraulic conductivities (Kv) were calculated with in‐stream permeameter tests and hydraulic heads were measured to obtain vertical head gradients at eight transects, each comprising five test locations, in a groundwater‐dominated stream. Seasonal small‐scale measurements were taken in December 2011 and August 2012, both in a straight stream channel with homogeneous elevation and downstream of a channel meander with heterogeneous elevation. All streambed attributes showed large spatial variability. Kh values were the highest at the depositional inner bend of the stream, whereas high Kv values were observed at the erosional outer bend and near the middle of the channel. Calculated Kv values were related to the thickness of the organic streambed sediment layer and also showed higher temporal variability than Kh because of sedimentation and scouring processes affecting the upper layers of the streambed. Test locations at the channel bend showed a more heterogeneous distribution of streambed properties than test locations in the straight channel, whereas within the channel bend, higher spatial variability in streambed attributes was observed across the stream than along the stream channel. Copyright © 2014 John Wiley & Sons, Ltd.
Involvement of Working Memory in Longitudinal Development of Number–Magnitude Skills
Authors: Kolkman Meijke E. , Kroesbergen Evelyn H. , Leseman Paul P. M.
Published: February 2014

The ability to connect numbers and magnitudes is an important prerequisite for math learning, here referred to as number–magnitude skills. It has been proposed that working memory plays an important role in constructing these connections. The aim of the current study was to examine if working memory accounts for constructing these connections by testing whether development of number–magnitude skills can be explained by different components of working memory. Number–magnitude skills and working memory skills of 69 children were assessed at age 5, 5.5 and 6. Different results were found for different components of working memory. Whereas no effects were found for the visuospatial sketchpad and phonological loop in development of number–magnitude skills, the central executive predicted variance in intercept and slope of number–magnitude skills. The results of this study provide longitudinal evidence for the involvement of general cognitive skills (i.e. working memory) in the development of number–magnitudes connections. Copyright © 2014 John Wiley & Sons, Ltd.
Variation in promptness of presentation among 10,297 patients subsequently diagnosed with one of 18 cancers: Evidence from a National Audit of Cancer Diagnosis in Primary Care
Authors: Keeble Stuart , Abel Gary A. , Saunders Catherine L. , McPhail Sean , Walter Fiona M. , Neal Richard D. , Rubin Gregory P. , Lyratzopoulos Georgios
Published: February 2014

Cancer awareness public campaigns aim to shorten the interval between symptom onset and presentation to a doctor (the ‘patient interval’). Appreciating variation in promptness of presentation can help to better target awareness campaigns. We explored variation in patient intervals recorded in consultations with general practitioners among 10,297 English patients subsequently diagnosed with one of 18 cancers (bladder, brain, breast, colorectal, endometrial, leukaemia, lung, lymphoma, melanoma, multiple myeloma, oesophageal, oro‐pharyngeal, ovarian, pancreatic, prostate, renal, stomach, and unknown primary) using data from of the National Audit of Cancer Diagnosis in Primary Care (2009–2010). Proportions of patients with ‘prompt’/‘non‐prompt’ presentation (0–14 or 15+ days from symptom onset, respectively) were described and respective odds ratios were calculated by multivariable logistic regression. The overall median recorded patient interval was 10 days (IQR 0–38). Of all patients, 56% presented promptly. Prompt presentation was more frequent among older or housebound patients (p < 0.001). Prompt presentation was most frequent for bladder and renal cancer (74% and 70%, respectively); and least frequent for oro‐pharyngeal and oesophageal cancer (34% and 39%, respectively, p <.001). Using lung cancer as reference, the adjusted odds ratios of non‐prompt presentation were 2.26 (95% confidence interval 1.57–3.25) and 0.42 (0.34–0.52) for oro‐pharyngeal and bladder cancer, respectively. Sensitivity analyses produced similar findings. Routinely recorded patient interval data reveal considerable variation in the promptness of presentation. These findings can help to prioritise public awareness initiatives and research focusing on symptoms of cancers associated with greater risk of non‐prompt presentation, such as oro‐pharyngeal and oesophageal cancer.
MiR‐200c suppresses TGF‐β signaling and counteracts trastuzumab resistance and metastasis by targeting ZNF217 and ZEB1 in breast cancer
Authors: Bai Wen‐Dong , Ye Xing‐Ming , Zhang Meng‐Yao , Zhu Hua‐Yu , Xi Wen‐Jin , Huang Xun , Zhao Jiao , Gu Bin , Zheng Guo‐Xu , Yang An‐Gang , Jia Lin‐Tao
Published: February 2014

Resistance to trastuzumab and concomitantly distal metastasis are leading causes of mortality in HER2‐positive breast cancers, the molecular basis of which remains largely unknown. Here, we generated trastuzumab‐resistant breast cancer cells with increased tumorigenicity and invasiveness compared with parental cells, and observed robust epithelial–mesenchymal transition (EMT) and consistently elevated TGF‐β signaling in these cells. MiR‐200c, which was the most significantly downregulated miRNA in trastuzumab‐resistant cells, restored trastuzumab sensitivity and suppressed invasion of breast cancer cells by concurrently targeting ZNF217, a transcriptional activator of TGF‐β, and ZEB1, a known mediator of TGF‐β signaling. Given the reported backward inhibition of miR‐200c by ZEB1, ZNF217 also exerts a feedback suppression of miR‐200c via TGF‐β/ZEB1 signaling. Restoration of miR‐200c, silencing of ZEB1 or ZNF217 or blockade of TGF‐β signaling increased trastuzumab sensitivity and suppressed invasiveness of breast cancer cells. Therefore, our study unraveled nested regulatory circuits of miR‐200c/ZEB1 and miR‐200c/ZNF217/TGF‐β/ZEB1 in synergistically promoting trastuzumab resistance and metastasis of breast cancer cells. These findings provide novel insights into the common role of EMT and related molecular machinery in mediating the malignant phenotypes of breast cancers.
Early detection of CIN3 and cervical cancer during long‐term follow‐up using HPV/Pap smear co‐testing and risk‐adapted follow‐up in a locally organised screening programme
Authors: Luyten Alexander , Buttmann‐Schweiger Nina , Luyten Katrin , Mauritz Claudia , Reinecke‐Lüthge Axel , Pietralla Martina , Meijer Chris J.L.M. , Petry Karl Ulrich
Published: February 2014

We evaluated compliance with human papillomavirus (HPV) testing and risk‐adapted patient pathways and monitored changes in high‐grade cervical disease during long‐term follow‐up. Women aged >30 years attending routine screening for cervical cancer were managed according to results from first‐round screening tests (cytology and high‐risk HPV; Hybrid Capture 2). Between February 2006 and January 2011, 19,795 of 19,947 women agreed to participate, of whom 4,067 proceeded to a second screening round 5 years after recruitment. Predefined endpoints were compliance, grade 3 cervical intraepithelial neoplasia or cancer (CIN3+), new HPV infection, HPV persistence and abnormal smears in round 2. A total of 765 of 19,795 women (3.9%) in round 1 and 41 of 4,067 (1.0%) in round 2 were referred for colposcopy. Compliance rates with colposcopy were 93.1 and 92.7%, respectively, while histological assessment was performed in 680 of 712 (95.5%) and 36 of 38 (94.7%), respectively. CIN3+ rates were 172 of 19,795 (0.87%; 95% confidence intervals: 0.7–1.0) in round 1 and 2 of 4,064 (0.05%; 95% confidence intervals: 0.006–0.2) in round 2; the difference was statistically significant (Fisher's exact test, p < 0.001). After 5 years, the incidence of new HPV infection was 124 of 3,906 (3.2%) and HPV persistence was observed in 22 of 161 (13.7%). Locally organised HPV/cytology co‐testing is feasible and acceptable to women. Risk‐adapted management rapidly detected a high rate of prevalent CIN3+, while the subsequent long‐term risk of new high‐grade cervical disease was surprisingly low. It remains unclear if this phenomenon is explained by CIN3 mostly occurring early in life or by modifying the natural course of HPV infection with colposcopy and histological assessment.
Recent Advances in Magic‐Angle Spinning Solid‐State NMR of Proteins
Authors: Ladizhansky Vladimir
Published: February 2014

Magic‐angle spinning (MAS) solid‐state NMR (SSNMR) spectroscopy is emerging as an important technique for the determination of three‐dimensional structures of biological molecules and for the characterization of their dynamics. While there is an established suite of MAS SSNMR experiments for protein structure determination in small‐ and medium‐sized proteins, these methods face many challenges in large systems. In this review, recent progress in MAS NMR spectroscopy is discussed, specifically focusing on the emerging developments aimed at improving the sensitivity and resolution of SSNMR that are likely to determine its future applications. These developments include sample preparation and isotopic labeling strategies, fast MAS, proton detection, and paramagnetic NMR spectroscopy.
Mands for information using “who?” and “which?” in the presence of establishing and abolishing operations
Authors: Shillingsburg M. Alice , Bowen Crystal N. , Valentino Amber L. , Pierce Laura E.
Published: February 2014

Treatments designed to teach mands for information have included prompting and differential reinforcement, as well as procedures to manipulate the relevant establishing operation (EO). However, previous studies have not included relevant abolishing operation (AO) conditions to ensure that the mand is under relevant antecedent control. Data on listener responses (i.e., use of the information) are also absent in the literature. The current study shows differential responding under EO and AO conditions and reports listener responses that demonstrate use of the provided information. Three participants, diagnosed with an autism spectrum disorder, learned to mand for information using “who?” and “which?” questions exclusively under EO conditions. In addition, each participant responded to the information provided to access a preferred item. Generalization of the “which?” mand for information was also demonstrated across novel stimuli.
In vivo study of endometriosis in mice by photoacoustic microscopy
Authors: Ding Yichen , Zhang Mingzhu , Lang Jinghe , Leng Jinhua , Ren Qiushi , Yang Jie , Li Changhui
Published: February 2014

Endometriosis (EM) impacts the healthcare and the quality of life for women of reproductive age. However, there is no reliable noninvasive diagnosis method for either animal study or clinical use. In this work, a novel imaging method, photoacoustic microscopy (PAM) was employed to study the EM on the mouse model. Our results demonstrated the PAM noninvasively provided the high contrast and 3D imaging of subcutaneously implanted EM tissue in the nude mouse in vivo. The statistical study also indicated PAM had high sensitivity and specificity in the diagnosis of EM in this animal study. In addition, we also discussed the potential clinical application for PAM in the diagnosis of EM. (© 2014 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim)
Relaxin Augments BMP-2–Induced Osteoblast Differentiation and Bone Formation
Authors: Moon Jung-Sun , Kim Sun-Hun , Oh Sin-Hye , Jeong Yong-Wook , Kang Jee-Hae , Park Jong-Chun , Son Hye-Ju , Bae Suk , Park Byung-Il , Kim Min-Seok , Koh Jeong-Tae , Ko Hyun-Mi
Published: February 2014

Relaxin (Rln), a polypeptide hormone of the insulin superfamily, is an ovarian peptide hormone that is involved in a diverse range of physiological and pathological reactions. In this study, we investigated the effect of Rln on bone morphogenetic protein 2 (BMP-2)-induced osteoblast differentiation and bone formation. Expression of Rln receptors was examined in the primary mouse bone marrow stem cells (BMSCs) and mouse embryonic fibroblast cell line C3H/10T1/2 cells by RT-PCR and Western blot during BMP-2–induced osteoblast differentiation. The effect of Rln on osteoblast differentiation and mineralization was evaluated by measuring the alkaline phosphatase activity, osteocalcin production, and Alizarin red S staining. For the in vivo evaluation, BMP-2 and/or Rln were administered with type I collagen into the back of mice, and after 3 weeks, bone formation was analyzed by micro–computed tomography (µCT). Western blot was performed to determine the effect of Rln on osteoblast differentiation-related signaling pathway. Expression of Rxfp 1 in BMSCs and C3H/10T1/2 cells was significantly increased by BMP-2. In vitro, Rln augmented BMP-2–induced alkaline phosphatase expression, osteocalcin production, and matrix mineralization in BMSCs and C3H/10T1/2 cells. In addition, in vivo administration of Rln enhanced BMP-2–induced bone formation in a dose-dependent manner. Interestingly, Rln synergistically increased and sustained BMP-2–induced Smad, p38, and transforming growth factor-β activated kinase (TAK) 1 phosphorylation. BMP-2–induced Runx 2 expression and activity were also significantly augmented by Rln. These results show that Rln enhanced synergistically BMP-2–induced osteoblast differentiation and bone formation through its receptor, Rxfp 1, by augmenting and sustaining BMP-2–induced Smad and p38 phosphorylation, which upregulate Runx 2 expression and activity. These results suggest that Rln might be useful for therapeutic application in destructive bone diseases. © 2014 American Society for Bone and Mineral Research.
Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta
Authors: Jacobsen Christina M , Barber Lauren A , Ayturk Ugur M , Roberts Heather J , Deal Lauren E , Schwartz Marissa A , Weis MaryAnn , Eyre David , Zurakowski David , Robling Alexander G , Warman Matthew L
Published: February 2014

The cell surface receptor low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and bone strength. Heterozygous missense mutations in LRP5 cause autosomal dominant high bone mass (HBM) in humans by reducing binding to LRP5 by endogenous inhibitors, such as sclerostin (SOST). Mice heterozygous for a knockin allele (Lrp5p.A214V) that is orthologous to a human HBM-causing mutation have increased bone mass and strength. Osteogenesis imperfecta (OI) is a skeletal fragility disorder predominantly caused by mutations that affect type I collagen. We tested whether the LRP5 pathway can be used to improve bone properties in animal models of OI. First, we mated Lrp5+/p.A214V mice to Col1a2+/p.G610C mice, which model human type IV OI. We found that Col1a2+/p.G610C;Lrp5+/p.A214V offspring had significantly increased bone mass and strength compared to Col1a2+/p.G610C;Lrp5+/+ littermates. The improved bone properties were not a result of altered mRNA expression of type I collagen or its chaperones, nor were they due to changes in mutant type I collagen secretion. Second, we treated Col1a2+/p.G610C mice with a monoclonal antibody that inhibits sclerostin activity (Scl-Ab). We found that antibody-treated mice had significantly increased bone mass and strength compared to vehicle-treated littermates. These findings indicate increasing bone formation, even without altering bone collagen composition, may benefit patients with OI. © 2014 American Society for Bone and Mineral Research.
METTL21C Is a Potential Pleiotropic Gene for Osteoporosis and Sarcopenia Acting Through the Modulation of the NF-κB Signaling Pathway
Authors: Huang Jian , Hsu Yi-Hsiang , Mo Chenglin , Abreu Eduardo , Kiel Douglas P , Bonewald Lynda F , Brotto Marco , Karasik David
Published: February 2014

Sarcopenia and osteoporosis are important public health problems that occur concurrently. A bivariate genome-wide association study (GWAS) identified METTL21c as a suggestive pleiotropic gene for both bone and muscle. The METTL21 family of proteins methylates chaperones involved in the etiology of both myopathy and inclusion body myositis with Paget's disease. To validate these GWAS results, Mettl21c mRNA expression was reduced with siRNA in a mouse myogenic C2C12 cell line and the mouse osteocyte-like cell line MLO-Y4. At day 3, as C2C12 myoblasts start to differentiate into myotubes, a significant reduction in the number of myocytes aligning/organizing for fusion was observed in the siRNA-treated cells. At day 5, both fewer and smaller myotubes were observed in the siRNA-treated cells as confirmed by histomorphometric analyses and immunostaining with myosin heavy chain (MHC) antibody, which only stains myocytes/myotubes but not myoblasts. Intracellular calcium (Ca2+) measurements of the siRNA-treated myotubes showed a decrease in maximal amplitude peak response to caffeine, suggesting that less Ca2+ is available for release due to the partial silencing of Mettl21c, correlating with impaired myogenesis. In siRNA-treated MLO-Y4 cells, 48 hours after treatment with dexamethasone there was a significant increase in cell death, suggesting a role of Mettl21c in osteocyte survival. To investigate the molecular signaling machinery induced by the partial silencing of Mettl21c, we used a real-time PCR gene array to monitor the activity of 10 signaling pathways. We discovered that Mettl21c knockdown modulated only the NF-κB signaling pathway (ie, Birc3, Ccl5, and Tnf). These results suggest that Mettl21c might exert its bone-muscle pleiotropic function via the regulation of the NF-κB signaling pathway, which is critical for bone and muscle homeostasis. These studies also provide rationale for cellular and molecular validation of GWAS, and warrant additional in vitro and in vivo studies to advance our understanding of role of METTL21C in musculoskeletal biology. © 2014 American Society for Bone and Mineral Research