bluuebunny/crossref_metadata_2025 huggingface dataset:
Linking the spatial distribution of bed load transport to morphological change during high‐flow events in a shallow braided river
Authors: Williams R. D. , Rennie C. D. , Brasington J. , Hicks D. M. , Vericat D.
Published: February 2015

This paper provides novel observations linking the connections between spatially distributed bed load transport pathways, hydraulic patterns, and morphological change in a shallow, gravel bed braided river. These observations shed light on the mechanics of braiding processes and illustrate the potential to quantify coupled material fluxes using remotely sensed methods. The paper focuses upon a 300 m long segment of the Rees River, New Zealand, and utilizes spatially dense observations from a mobile acoustic Doppler current profiler (aDcp) to map depth, velocity, and channel topography through a sequence of high‐flow events. Apparent bed load velocity is estimated from the bias in aDcp bottom tracking and mapped to indicate bed load transport pathways. Terrestrial laser scanning (TLS) of exposed bar surfaces is fused with the aDcp surveys to generate spatially continuous digital elevation models, which quantify morphological change through the sequence of events. Results map spatially distributed bed load pathways that were likely to link zones of erosion and deposition. The coherence between the channel thalweg, zone of maximum hydraulic forcing, and maximum apparent bed load pathways varied. This suggests that, in places, local sediment supply sources exerted a strong control on the distribution of bed load, distinct from hydraulic forcing. The principal braiding mechanisms observed were channel choking, leading to subsequent bifurcation. Results show the connection between sediment sources, pathways, and sinks and their influence on channel morphology and flow path directions. The methodology of coupling spatially dense aDcp surveys with TLS has considerable potential to understand connections between processes and morphological change in dynamic fluvial settings.
Permafrost thaw and soil moisture driving CO2 and CH4 release from upland tundra
Authors: Natali Susan M. , Schuur Edward A. G. , Mauritz Marguerite , Schade John D. , Celis Gerardo , Crummer Kathryn G. , Johnston Catherine , Krapek John , Pegoraro Elaine , Salmon Verity G. , Webb Elizabeth E.
Published: February 2015

As permafrost degrades, the amount of organic soil carbon (C) that thaws during the growing season will increase, but decomposition may be limited by saturated soil conditions common in high‐latitude ecosystems. However, in some areas, soil drying is expected to accompany permafrost thaw as a result of increased water drainage, which may enhance C release to the atmosphere. We examined the effects of ecosystem warming, permafrost thaw, and soil moisture changes on C balance in an upland tundra ecosystem. This study was conducted at a water table drawdown experiment, established in 2011 and located within the Carbon in Permafrost Experimental Heating Research project, an ecosystem warming and permafrost thawing experiment in Alaska. Warming and drying increased cumulative growing season ecosystem respiration by ~20% over 3 years of this experiment. Warming caused an almost twofold increase in decomposition of a common substrate in surface soil (0–10 cm) across all years, and drying caused a twofold increase in decomposition (0–20 cm) relative to control after 3 years of drying. Decomposition of older C increased in the dried and in the combined warmed + dried plots based on soil pore space 14CO2. Although upland tundra systems have been considered CH4 sinks, warming and ground thaw significantly increased CH4 emission rates. Water table depth was positively correlated with monthly respiration and negatively correlated with CH4 emission rates. These results demonstrate that warming and drying may increase loss of old permafrost C from tundra ecosystems, but the form and magnitude of C released to the atmosphere will be driven by changes in soil moisture.
Mechanisms for convection triggering by cold pools
Authors: Torri Giuseppe , Kuang Zhiming , Tian Yang
Published: February 2015

Cold pools are fundamental ingredients of deep convection. They contribute to organizing the subcloud layer and are considered key elements in triggering convective cells. It was long known that this could happenmechanically, through lifting by the cold pools' fronts. More recently, it has been suggested that convection could also be triggeredthermodynamically, by accumulation of moisture around the edges of cold pools. A method based on Lagrangian tracking is here proposed to disentangle the signatures of both forcings and quantify their importance in a given environment. Results from a simulation of radiative‐convective equilibrium over the ocean show that parcels reach their level of free convection through a combination of both forcings, each being dominant at different stages of the ascent. Mechanical forcing is an important player in lifting parcels from the surface, whereas thermodynamic forcing reduces the inhibition encountered by parcels before they reach their level of free convection.
Programmable “Semismart” Sensor: Relevance to Monitoring Antipsychotics
Authors: Kim Eunkyoung , Chocron Sheryl E. , Ben‐Yoav Hadar , Winkler Thomas E. , Liu Yi , Glassman Matthew , Wolfram Christopher , Kelly Deanna L. , Ghodssi Reza , Payne Gregory F.
Published: February 2015

Mental health disorders are complex and poorly understood but would benefit from real‐time chemical analysis capable of assessing a patient's current status, personalizing a therapeutic action, and monitoring compliance. Here, an electrochemical sensor is reported for detecting the antipsychotic drug clozapine which is one of the most effective but under‐utilized drugs for managing schizophrenia. This sensor employs a composite film of multiwalled carbon nanotubes (CNTs) embedded within a matrix of the aminopolysaccharide chitosan. Chitosan allows programmable assembly of the composite film at an electrode address while the CNTs confer electrocatalytic activities that displace interfering serum peaks from the voltage region where clozapine oxidation occurs. Using differential pulse voltammetry, high sensitivities (limit of detection 0.05 × 10–6m) are demonstrated for clozapine analysis in buffer. In serum, clozapine sensitivity is reduced by an order of magnitude but still sufficient for clinical analysis. Finally, the detection of clozapine from the serum of a schizophrenia patient is demonstrated without the need for serum pretreatment. In the long term, it is envisioned that the CNT‐chitosan coated electrode could be integrated within a small array of other sensor types to enhance information‐extraction to allow mental health disorders to be better managed and better understood.
Bioinspired Stimuli‐Responsive and Antifreeze‐Secreting Anti‐Icing Coatings
Authors: Sun Xiaoda , Damle Viraj G. , Liu Shanliangzi , Rykaczewski Konrad
Published: February 2015

The detrimental impacts of icing on transportation and power industries are well‐known. Inspired by natural systems that secrete a functional liquid in response to stimuli, this work introduces an anti‐icing coating that responds to surface icing by releasing antifreeze liquid. It consists of an outer porous superhydrophobic epidermis and a wick‐like underlying dermis that is infused with antifreeze liquid. The functionality of the new coating is validated through condensation frosting, simulated freezing fog, and freezing rain experiments. In the tested conditions, the introduced anti‐icing skin delays onset of frost, rime, and glaze accumulation at least ten times longer than anti‐icing superhydrophobic and lubricant impregnated surfaces. Furthermore, the coating delays onset of glaze formation ten times longer than surfaces flooded with a thin film of antifreeze. In each of the icing scenarios, the fundamental mechanisms responsible for antifreeze release and their relation to required antifreeze replenishment rates are described.
A Dehydrogenative Diels–Alder Reaction of Prenyl Derivatives with 2,3‐Dichloro‐5,6‐dicyanobenzoquinone
Authors: Feng Hong‐Xia , Wang Yuan‐Yuan , Chen Jie , Zhou Ling
Published: February 2015

An efficient dehydrogenative Diels–Alder (DHDA) reaction of prenyl derivatives with 2,3‐dichloro‐5,6‐dicyanobenzoquinone (DDQ) has been developed under mild conditions, leading to a series of cyclohexene derivatives with good to excellent yields and excellent diastereoselectivity.

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French firefighter mortality: Analysis over a 30‐year period
Authors: Amadeo Brice , Marchand Jean‐Luc , Moisan Frédéric , Donnadieu Stéphane , Coureau Gaëlle , Mathoulin‐Pélissier Simone , Lembeye Christian , Imbernon Ellen , Brochard Patrick
Published: February 2015

Objective

To explore mortality of French professional male firefighters.

Methods

Standardized mortality ratios (SMR) were calculated for 10,829 professional male firefighters employed in 1979 and compared with the French male population between 1979–2008. Firefighters were identified from 89 French administrative departments (93% of population).

Results

One thousand six hundred forty two deaths were identified, representing significantly lower all‐cause mortality than in the general population (SMR = 0.81; 95%CI: 0.77–0.85). SMR increased with age and was not different from 1 for firefighters >70 years. No significant excess of mortality was observed for any specific cause, but a greater number of deaths than expected were found for various digestive neoplasms (rectum/anus, pancreas, buccal‐pharynx, stomach, liver, and larynx).

Conclusion

We observed lower all and leading‐cause mortality likely due to the healthy worker effect in this cohort, with diseases of the respiratory system considerably lower (SMR = 0.57). Non‐significant excesses for digestive neoplasms are notable, but should not be over‐interpreted at this stage. Am. J. Ind. Med. 58:437–443, 2015. © 2015 Wiley Periodicals, Inc.
Microcephaly, ectodermal dysplasia, multiple skeletal anomalies and distinctive facial appearance: Delineation of cerebro‐dermato‐osseous‐dysplasia
Authors: Castori Marco , Pascolini Giulia , Parisi Valentina , Sana Maria Elena , Novelli Antonio , Nürnberg Peter , Iascone Maria , Grammatico Paola
Published: February 2015

In 1980, a novel multiple malformation syndrome has been described in a 17‐year‐old woman with micro‐ and turricephaly, intellectual disability, distinctive facial appearance, congenital atrichia, and multiple skeletal anomalies mainly affecting the limbs. Four further sporadic patients and a couple of affected sibs are also reported with a broad clinical variability. Here, we describe a 4‐year‐old girl strikingly resembling the original report. Phenotype comparison identified a recurrent pattern of multisystem features involving the central nervous system, and skin and bones in five sporadic patients (including ours), while the two sibs and a further sporadic case show significant phenotypic divergence. Marked clinical variability within the same entity versus syndrome splitting is discussed and the term “cerebro‐dermato‐osseous dysplasia” is introduced to define this condition. © 2015 Wiley Periodicals, Inc.
Beare–Stevenson syndrome: Two new patients, including a novel finding of tracheal cartilaginous sleeve
Authors: Wenger Tara L. , Bhoj Elizabeth J. , Wetmore Ralph F. , Mennuti Michael T. , Bartlett Scott P. , Mollen Thomas J. , McDonald‐McGinn Donna M. , Zackai Elaine H.
Published: February 2015

Beare–Stevenson syndrome (BSS) is a rare FGFR2‐associated craniosynostosis syndrome with a higher rate of sudden unexplained death than related conditions such as Apert, Pfeiffer, and Crouzon syndromes. BSS presents with craniosynostosis, cutis gyrata, and significant developmental delay in most patients who survive infancy. There have only been 21 reported patients with BSS, which limits prognostication for clinicians and likely does not capture the full extent of the phenotype. Here we report on two additional patients with molecularly confirmed BSS, one each with p.Ser372Tyr and p.Tyr375Cys mutations in FGFR2. Cloverleaf skull was identified prenatally in one patient, with initial concern for Crouzon syndrome. Prenatal 3D ultrasound was performed, but cutis gyrata was only visible on retrospective examination following the clinical diagnosis of BSS after birth. Due to phenotypic overlap with Crouzon syndrome, but worse prognosis, we recommend consideration of prenatal 3D ultrasound and mutation testing for patients with suspected Crouzon to allow for prenatal diagnosis of BSS and to enable appropriate genetic counseling and postnatal care. One of our patients was noted to have a tracheal cartilaginous sleeve, which if present could explain sudden death. Of note, tracheal cartilaginous sleeves have been reported in other FGFR2‐related craniosynostosis syndromes, and are associated with 90% risk of death by two years of age without tracheostomy. Tracheal cartilaginous sleeves are often only found incidentally at autopsy as they are difficult to diagnose without direct visualization of the trachea. This association and our experience suggests that BSS patients be evaluated for tracheal cartilaginous sleeve to prevent airway compromise. © 2015 Wiley Periodicals, Inc.
Mutations in PIGL in a patient with Mabry syndrome
Authors: Fujiwara Ikuma , Murakami Yoshiko , Niihori Tetsuya , Kanno Junko , Hakoda Akiko , Sakamoto Osamu , Okamoto Nobuhiko , Funayama Ryo , Nagashima Takeshi , Nakayama Keiko , Kinoshita Taroh , Kure Shigeo , Matsubara Yoichi , Aoki Yoko
Published: February 2015

Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI)‐anchor biosynthesis pathway) in patients with HPMRS. We performed whole‐exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13‐bp deletion in exon 1 (c.36_48del) and a two‐base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13‐bp deletion was inherited from the father, and the two‐base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA‐tag at the C‐ or N‐terminus in PIGL‐deficient CHO cells only partially restored the surface expression of GPI‐anchored proteins (GPI‐APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS. © 2015 Wiley Periodicals, Inc.
Interstitial deletion 5q14.3q21.3 associated with lethal epilepsy
Authors: Yang Yong‐jia , Yao Xu , Guo Jihong , Zhao Rui , He Xin‐yu , Zhao Liu , Tu Ming , Zhu Yi‐min
Published: February 2015

The 5q14.3 deletion syndrome is a heterogeneous disorder with remarkable phenotypic diversity ranging from severe to mild manifestation. In this paper, we report on a patient with 5q14.3 q21.3 deletion who exhibited the severe phenotype and died at 5.5 months. This patient can be classified as having sudden unexplained death in epilepsy (SUDEP) [Tomson et al., 2008]. The deleted region (21.02 Mb, Chr.5: 88, 047, 621–109,072,596 × 1 dn), which included MEF2C and EFNA5, was a 16.5 Mb sequence that overlapped with previously reported deletions in a patient with the mild phenotype. This study further demonstrated the complexity of clinical cytogenetic correlation of the 5q14.3 deletion. © 2015 Wiley Periodicals, Inc.
Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy
Authors: Long Pamela A. , Evans Jared M. , Olson Timothy M.
Published: February 2015

Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non‐syndromic dilated cardiomyopathy in a one‐month‐old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis‐diagnosis are common owing to its rarity and age‐dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care. © 2015 Wiley Periodicals, Inc.
Thiamine responsive megaloblastic anemia syndrome: A novel homozygous SLC19A2 gene mutation identified
Authors: Mikstiene Violeta , Songailiene Jurgita , Byckova Jekaterina , Rutkauskiene Giedre , Jasinskiene Edita , Verkauskiene Rasa , Lesinskas Eugenijus , Utkus Algirdas
Published: February 2015

Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease – megaloblastic anemia, early onset deafness, and non‐type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania – a 3‐year‐old boy born to a non‐consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis – novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition. © 2015 Wiley Periodicals, Inc.
Neonatal pulmonary arterial hypertension and Noonan syndrome: Two fatal cases with a specific RAF1 mutation
Authors: Hopper Rachel K. , Feinstein Jeffrey A. , Manning Melanie A. , Benitz William , Hudgins Louanne
Published: February 2015

Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf‐1 kinase, part of the Ras/mitogen‐activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf‐1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation. © 2015 Wiley Periodicals, Inc.
A Mixed Ionic and Electronic Conducting Dual‐Phase Membrane with High Oxygen Permeability
Authors: Fang Wei , Liang Fangyi , Cao Zhengwen , Steinbach Frank , Feldhoff Armin
Published: February 2015

To combine good chemical stability and high oxygen permeability, a mixed ionic‐electronic conducting (MIEC) 75 wt % Ce0.85Gd0.1Cu0.05O2−δ‐25 wt % La0.6Ca0.4FeO3−δ (CGCO‐LCF) dual‐phase membrane based on a MIEC–MIEC composite has been developed. Copper doping into Ce0.9Gd0.1O2−δ (CGO) oxide enhances both ionic and electronic conductivity, which then leads to a change from ionic conduction to mixed conduction at elevated temperatures. For the first time we demonstrate that an intergranular film with 2–10 nm thickness containing Ce, Ca, Gd, La, and Fe has been formed between the CGCO grains in the CGCO‐LCF one‐pot dual‐phase membrane. A high oxygen permeation flux of 0.70 mL min−1 cm−2 is obtained by the CGCO‐LCF one‐pot dual‐phase membrane with 0.5 mm thickness at 950 °C using pure CO2 as the sweep gas, and the membrane shows excellent stability in the presence of CO2 even at lower temperatures (800 °C) during long‐term operation.
Temperaturgesteuerte bidirektionale Enantioselektivität eines dynamischen Katalysators für asymmetrische Hydrierungen
Authors: Storch Golo , Trapp Oliver
Published: February 2015

Asymmetrische Katalyse mit enantiomerenreinen Katalysatoren ist eine der weitverbreitetsten Methoden zur Herstellung enantiomerenreiner Verbindungen. Die selektive Synthese beider enantiomerenreiner Produkte erfordert dabei die aufwändige Synthese beider enantiomerenreiner Katalysatoren oder alternativ die Enantiomerentrennung racemischer Produkte. Wir stellen einen stereodynamisch flexiblen diastereomeren Rhodium(I)‐Katalysator für die asymmetrische Hydrierung prochiraler (Z)‐α‐Acetamidozimtsäure‐ und α‐substituierter Acrylsäurederivate vor, der seine Enantioselektivität in Abhängigkeit der Temperatur ändert und somit selektiv beide Enantiomere in hoher Ausbeute liefert. Derselbe axial‐chirale Rhodium(I)‐Katalysator bildet (R)‐Phenylalaninderivate mit Enantiomerenverhältnissen bis zu 87:13 (R/S) bei niedriger Temperatur und bis zu 3:97 (R/S) des entsprechenden S‐Enantiomers nach Reäquilibrierung des Katalysators bei erhöhter Temperatur.
Enantioselective Synthesis of Macrocyclic Heterobiaryl Derivatives of Molecular Asymmetry by Molybdenum‐Catalyzed Asymmetric Ring‐Closing Metathesis
Authors: Okayama Yoichi , Tsuji Satoru , Toyomori Yuka , Mori Atsunori , Arae Sachie , Wu Wei‐Yi , Takahashi Tamotsu , Ogasawara Masamichi
Published: February 2015

Winding vine‐shaped molecular asymmetry is induced by enantioselective ring‐closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E‐selective ring‐closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96 % ee.
Electro‐assembly of a Chromophore–Catalyst Bilayer for Water Oxidation and Photocatalytic Water Splitting
Authors: Ashford Dennis L. , Sherman Benjamin D. , Binstead Robert A. , Templeton Joseph L. , Meyer Thomas J.
Published: February 2015

The use of electropolymerization to prepare electrocatalytically and photocatalytically active electrodes for water oxidation is described. Electropolymerization of the catalyst RuII(bda)(4‐vinylpyridine)2 (bda=2,2′‐bipyridine‐6,6′‐dicarboxylate) on planar electrodes results in films containing semirigid polymer networks. In these films there is a change in the water oxidation mechanism compared to the solution analogue from bimolecular to single‐site. Electro‐assembly construction of a chromophore–catalyst structure on mesoporous, nanoparticle TiO2 films provides the basis for a dye‐sensitized photoelectrosynthesis cell (DSPEC) for sustained water splitting in a pH 7 phosphate buffer solution. Photogenerated oxygen was measured in real‐time by use of a two‐electrode cell design.
Temperature‐Controlled Bidirectional Enantioselectivity in a Dynamic Catalyst for Asymmetric Hydrogenation
Authors: Storch Golo , Trapp Oliver
Published: February 2015

Asymmetric catalysis using enantiomerically pure catalysts is one of the most widely used methods for the preparation of enantiomerically pure compounds. The separate synthesis of both enantiomerically pure compounds requires tedious and time‐consuming preparation of both enantiomerically pure catalysts or chiral separation of the racemic products. Here, we report a stereochemically flexible diastereomeric rhodium(I) catalyst for asymmetric hydrogenations of prochiral (Z)‐α‐acetamidocinnamates and α‐substituted acrylates, which changes its enantioselectivity depending on the temperature to produce each enantiomerically pure compound in high yield with constant high enantioselectivity over time. The same axially chiral rhodium(I) catalyst produces (R)‐phenylalanine derivatives in enantiomeric ratios of up to 87:13 (R/S) at low temperature and up to 3:97 (R/S) of the corresponding S enantiomers after re‐equilibration of the same catalyst at elevated temperature.
OH‐Directed Alkynylation of 2‐Vinylphenols with Ethynyl Benziodoxolones: A Fast Access to Terminal 1,3‐Enynes
Authors: Finkbeiner Peter , Kloeckner Ulrich , Nachtsheim Boris J.
Published: February 2015

The first direct alkynylation of 2‐vinylphenols was developed. The rationally optimized hypervalent iodine reagent TIPS‐EBX* in combination with [(Cp*RhCl2)2] as a CH‐activating transition metal catalyst enables the construction of a variety of highly substituted 1,3‐enynes in high yields of up to 98 %. This novel CH activation method shows excellent chemoselectivity and exclusive (Z)‐stereoselectivity, and it is also remarkably mild and tolerates a variety of functional groups. Furthermore, synthetic modifications of the resulting 1,3‐enynes were demonstrated. To our knowledge, this is the first example for an OH‐directed CH alkynylation with hypervalent iodine reagents.
Adult Primary Central Nervous System Vasculitis Treatment and Course: Analysis of One Hundred Sixty‐Three Patients
Authors: Salvarani Carlo , Brown Robert D. , Christianson Teresa J. H. , Huston John , Giannini Caterina , Miller Dylan V. , Hunder Gene G.
Published: February 2015

Objective

To describe the treatment and outcomes of patients with primary central nervous system (CNS) vasculitis.

Methods

We retrospectively studied a cohort of 163 consecutive patients with primary CNS vasculitis who were seen at the Mayo Clinic over a 29‐year period. We analyzed treatments, treatment responses, and factors predictive of outcomes.

Results

A favorable response was observed in 85% of patients treated with prednisone alone and in 80% of patients treated with prednisone and cyclophosphamide. Relapses were observed in 27% of patients, and 25% of patients had discontinued therapy by the time of the last followup visit. Treatment with prednisone alone was associated with more frequent relapses (odds ratio [OR] 2.90), while large vessel involvement (OR 6.14) and cerebral infarcts at the time of diagnosis (OR 3.32) were associated with a poor response to treatment. Prominent gadolinium‐enhanced cerebral lesions or meninges were linked with continued treatment at the last followup encounter (OR 2.28). Higher disability scores at the last followup visit were associated with increasing age at the time of diagnosis (OR 1.44) and cerebral infarctions (OR 3.74), while lower disability scores were associated with gadolinium‐enhanced cerebral lesions or meninges (OR 0.35) and cerebral amyloid angiopathy (OR 0.24). Increased mortality was associated with increasing age at diagnosis (hazard ratio [HR] 1.39), diagnosis by angiography (HR 3.28), cerebral infarction (HR 4.44), and large vessel involvement (HR 4.98), while reduced mortality was associated with gadolinium‐enhanced cerebral lesions or meninges (HR 0.20).

Conclusion

The majority of patients with primary CNS vasculitis responded to treatment. Recognition of findings at diagnosis that predict the course or outcome may aid in decision‐making regarding therapy.
The Relationship of Autophagy Defects to Cartilage Damage During Joint Aging in a Mouse Model
Authors: Caramés Beatriz , Olmer Merissa , Kiosses William B. , Lotz Martin K.
Published: February 2015

Objective

Aging is a main risk factor for osteo arthritis (OA), the most prevalent musculoskeletal disorder. Defects in autophagy, an essential cellular homeostasis mechanism, have recently been observed in OA articular cartilage. The objectives of this study were to establish the constitutive level of autophagy activation in normal cartilage and to monitor the temporal relationship between changes in autophagy and aging‐related degradation of cartilage in a mouse model.

Methods

In GFP‐LC3–transgenic mice, green fluo rescent protein (GFP)–light chain 3 (LC3) is ubiquitously expressed, and the accumulation of GFP puncta, repre senting autophagosomes, was quantified by confocal microscopy as a measure of autophagy activation. Expression of the autophagy proteins autophagy‐related protein 5 (ATG‐5) and microtubule‐associated protein 1 light chain 3 (LC3) was analyzed by immunohistochemistry. Cartilage cellularity, apoptotic cell death, and cartilage structural damage and changes in synovium and bone were examined by histology and immunohistochemistry.

Results

Basal autophagy activation was detected in liver and knee articular cartilage from young (6‐month‐old) mice, with higher levels in cartilage than in liver in the same animals. In 28‐month‐old mice, there was a statistically significant reduction in the total number of autophagic vesicles per cell (P < 0.01) and in the total area of vesicles per cell (P < 0.01) in the articular cartilage as compared to that from young 6‐month‐old mice. With increasing age, the expression of ATG‐5 and LC3 decreased, and this was followed by a reduction in cartilage cellularity and an increase in the apoptosis marker poly(ADP‐ribose) polymerase p85. Cartilage structural damage progressed in an age‐dependent manner subsequent to the autophagy changes.

Conclusion

Autophagy is constitutively activated in normal cartilage. This is compromised with aging and precedes cartilage cell death and structural damage.
Calcitonin Gene‐Related Peptide–Expressing Sensory Neurons and Spinal Microglial Reactivity Contribute to Pain States in Collagen‐Induced Arthritis
Authors: Nieto Francisco R. , Clark Anna K. , Grist John , Chapman Victoria , Malcangio Marzia
Published: February 2015

Objective

To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagen‐induced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs.

Methods

Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin gene‐related peptide (CGRP) antagonist (CGRP8–37) from day 11 to day 18 postimmunization on CIA‐induced hypersensitivity. During CIA development, CGRP and p‐ERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with Fluoro‐Gold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached.

Results

CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased p‐ERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP8–37 attenuated established mechanical hypersensitivity and reduced spinal microgliosis.

Conclusion

Sensory neuron–derived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients.
Efficacy and Safety of Anti–Interleukin‐20 Monoclonal Antibody in Patients With Rheumatoid Arthritis: A Randomized Phase IIa Trial
Authors: Šenolt Ladislav , Leszczynski Piotr , Dokoupilová Eva , Göthberg Marie , Valencia Xavier , Hansen Brian Bekker , Cañete Juan D.
Published: February 2015

Objective

Interleukin‐20 (IL‐20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109‐0012, a selective anti–IL‐20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy.

Methods

Sixty‐seven patients with RA were enrolled and randomized (2:1) to receive NNC0109‐0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double‐blind, 12‐week trial with a 13‐week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C‐reactive protein level (DAS28‐CRP) from baseline to week 12.

Results

In patients treated with NNC0109‐0012, the primary end point, improvement in the DAS28‐CRP at week 12, was achieved (estimated difference −0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference −1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109‐0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109‐0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109‐0012 were observed.

Conclusion

In this phase IIa trial, treatment with NNC0109‐0012 (anti–IL‐20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109‐0012 administration.
Lubricin/Proteoglycan 4 Binding to CD44 Receptor: A Mechanism of the Suppression of Proinflammatory Cytokine–Induced Synoviocyte Proliferation by Lubricin
Authors: Al‐Sharif Afnan , Jamal Maha , Zhang Ling X. , Larson Katherine , Schmidt Tannin A. , Jay Gregory D. , Elsaid Khaled A.
Published: February 2015

Objective

To evaluate the binding of recombinant human proteoglycan 4 (rhPRG4) to CD44 receptor and its consequences on cytokine‐induced synoviocyte proliferation.

Methods

The binding of rhPRG4 to CD44 and competition with high molecular weight (HMW) hyaluronic acid (HA) was evaluated using a direct enzyme‐linked immunosorbent assay (ELISA) and surface plasmon resonance. Sialidase A and O‐glycosidase digestion of rhPRG4 was performed, and CD44 binding was evaluated using ELISA. Rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS) were stimulated with interleukin‐1β (IL‐1β) or tumor necrosis factor α (TNFα) for 48 hours in the presence or absence of rhPRG4 or HMW HA at 20, 40, and 80 μg/ml, and cell proliferation was measured. The contribution of CD44 was assessed by coincubation with a CD44 antibody (IM7). The antiproliferative effect of rhPRG4 was investigated following treatment of PRG4–/– mouse synoviocytes with IL‐1β or TNFα in the presence or absence of IM7.

Results

Recombinant human PRG4 bound CD44 and interfered with the binding of HMW HA to CD44. Removal of sialic acid and O‐glycosylations significantly increased CD44 binding by rhPRG4 (P < 0.001). Both rhPRG4 and HMW HA at 40 and 80 μg/ml significantly suppressed IL‐1β–induced proliferation of RA FLS (P < 0.05). Recombinant human PRG4 at 20, 40, and 80 μg/ml significantly suppressed TNFα‐induced RA FLS proliferation (P < 0.05). CD44 neutralization reversed the effect of rhPRG4 on IL‐1β– and TNFα‐stimulated RA FLS and the effect of HMW HA on IL‐1β–stimulated RA FLS. Recombinant human PRG4 inhibited cytokine‐induced proliferation of PRG4–/– synoviocytes, which could be prevented by blocking CD44.

Conclusion

PRG4 (lubricin) is a novel putative ligand for CD44 and may control synoviocyte overgrowth in inflammatory arthropathies via a CD44‐mediated mechanism.
Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjögren's Syndrome
Authors: Jousse‐Joulin Sandrine , Devauchelle‐Pensec Valérie , Cornec Divi , Marhadour Thierry , Bressollette Luc , Gestin Simon , Pers Jacques Olivier , Nowak Emmanuel , Saraux Alain
Published: February 2015

Objective

To evaluate changes in salivary gland echostructure and vascularization after rituximab treatment in patients with primary Sjögren's syndrome (SS).

Methods

Twenty‐eight patients with primary SS included in the multicenter, randomized, double‐blind, placebo‐controlled Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS) trial underwent salivary gland ultrasonography before the first placebo or rituximab infusion and then 6 months later. Trial inclusion criteria were scores of ≥50 mm on at least 2 of 4 visual analog scales (VAS) evaluating dryness, pain, fatigue, and global disease; and recent‐onset (<10 years) biologically active primary SS and/or systemic primary SS. Patients were randomly assigned (1:1) to rituximab (1 gm at weeks 0 and 2) or placebo. Ultrasonography of both parotid and submandibular glands was performed to assess echostructure (using a semiquantitative score of 0–4, with improvement defined as a ≥1‐point decrease), size of each gland, and vascularization based on the resistive index of the transverse facial artery of the parotid gland before and after lemon juice stimulation.

Results

Of the 28 patients, 5 (18%; 3 in the placebo group and 2 in the rituximab group) had clinically detectable bilateral parotid gland enlargement at baseline. Parotid parenchyma echostructure improved in 50% of the rituximab‐treated patients versus 7% of the placebo‐treated patients (P = 0.03). In the submandibular glands, echostructure also improved in a larger proportion of rituximab‐treated patients, although the difference was not significant (36% versus 7% of placebo‐treated patients; P = 0.16). Gland sizes and resistive index remained unchanged.

Conclusion

Ultrasonography showed improved salivary gland echostructure in patients with primary SS receiving rituximab, with no changes in salivary gland size or vascularization, 6 months after the first infusion.
Evaluating the retrieval effectiveness of web search engines using a representative query sample
Authors: Lewandowski Dirk
Published: February 2015

Search engine retrieval effectiveness studies are usually small scale, using only limited query samples. Furthermore, queries are selected by the researchers. We address these issues by taking a random representative sample of 1,000 informational and 1,000 navigational queries from a major German search engine and comparing Google's and Bing's results based on this sample. Jurors were found through crowdsourcing, and data were collected using specialized software, the Relevance Assessment Tool (RAT). We found that although Google outperforms Bing in both query types, the difference in the performance for informational queries was rather low. However, for navigational queries, Google found the correct answer in 95.3% of cases, whereas Bing only found the correct answer 76.6% of the time. We conclude that search engine performance on navigational queries is of great importance, because users in this case can clearly identify queries that have returned correct results. So, performance on this query type may contribute to explaining user satisfaction with search engines.
Learning from Elitist Jerks: Creating high‐quality knowledge resources from ongoing conversations
Authors: Bullard Julia , Howison James
Published: February 2015

Online‐community management is commonly presented as the facilitation of conversation and contributions, especially converting readers to contributors. However, the goal of many discussion communities is to produce a high‐quality knowledge resource, whether to improve external task performance or to increase reputation and site traffic. What do moderation practices look like when the community is focused on the creation of a useable knowledge resource rather than facilitating an inclusive conversation? Under what conditions is this style of moderation likely to be successful? We present a case study from online gaming—Elitist Jerks—in which aggressive moderation is used to transform a conversational medium into a high‐quality knowledge resource, using the strategy of open censorship. We present a content analysis of moderator comments regarding censored messages. Our analysis revealed differences in types of contributor mistakes and the severity of moderator actions: infractions that interfered with both conversation and resource quality were punished harshly, whereas a set of infractions that supported conversation but undermined resource quality were more respectfully removed. We describe a set of conditions under which moderators should intervene in the conversion of conversation to knowledge resource rather than the conversion of lurkers to contributors.
Some properties and applications of cumulative Kullback–Leibler information
Authors: Crescenzo Antonio Di , Longobardi Maria
Published: February 2015

The cumulative Kullback–Leibler information has been proposed recently as a suitable extension of Kullback–Leibler information to the cumulative distribution function. In this paper, we obtain various results on such a measure, with reference to its relation with other information measures and notions of reliability theory. We also provide some lower and upper bounds. A dynamic version of the cumulative Kullback–Leibler information is then proposed for past lifetimes. Furthermore, we investigate its monotonicity property, which is related to some new concepts of relative aging. Moreover, we propose an application to the failure of nanocomponents. Finally, in order to provide an application in image analysis, we introduce the empirical cumulative Kullback–Leibler information and prove an asymptotic result. Copyright © 2015 John Wiley & Sons, Ltd.
Pharmacokinetic modeling of tranexamic acid for patients undergoing cardiac surgery with normal renal function and model simulations for patients with renal impairment
Authors: Yang Qi Joy , Jerath Angela , Bies Robert R. , Wąsowicz Marcin , Pang K. Sandy
Published: February 2015

Tranexamic acid (TXA), an effective anti‐fibrinolytic agent that is cleared by glomerular filtration, is used widely for cardiopulmonary bypass (CPB) surgery. However, an effective dosing regimen has not been fully developed in patients with renal impairment. The aims of this study were to characterize the inter‐patient variability associated with pharmacokinetic parameters and to recommend a new dosing adjustment based on the BART dosing regimen for CPB patients with chronic renal dysfunction (CRD). Recently published data on CPB patients with normal renal function (n = 15) were re‐examined with a two‐compartment model using the ADAPT5® and NONMEMVII® to identify covariates that explain inter‐patient variability and to ascertain whether sampling strategies might affect parameter estimation. A series of simulations was performed to adjust the BART dosing regimen for CPB patients with renal impairment. Based on the two‐compartmental model, the number of samples obtained after discontinuation of TXA infusion was found not to be critical in parameter estimation (p > 0.05). Both body weight and creatinine clearance were identified as significant covariates (p < 0.005). Simulations showed significantly higher than normal TXA concentrations in CRD patients who received the standard dosing regimen in the BART trial. Adjustment of the maintenance infusion rate based on the percent reduction in renal clearance resulted in predicted plasma TXA concentrations that were safe and therapeutic (~100 mg·L−1). Our proposed dosing regimen, with consideration of renal function, is predicted to maintain effective target plasma concentrations below those associated with toxicity for patients with renal failure for CPB. Copyright © 2015 John Wiley & Sons, Ltd.
Effects of Maternal and Lactational Exposure to 2‐Hydroxy‐4‐Methoxybenzone on Development and Reproductive Organs in Male and Female Rat Offspring
Authors: Nakamura Noriko , Inselman Amy L. , White Gene A. , Chang Ching‐Wei , Trbojevich Raul A. , Sephr Estatira , Voris Kristie L. , Patton Ralph E. , Bryant Matthew S. , Harrouk Wafa , McIntyre Barry S. , Foster Paul M.D. , Hansen Deborah K.
Published: February 2015

BACKGROUND

2‐Hydroxy‐4‐methoxybenzophenone (HMB) is an ultraviolet (UV) absorbing compound used in many cosmetic products as a UV‐protecting agent and in plastics for preventing UV‐induced photodecomposition. HMB has been detected in over 95% of randomly collected human urine samples from adults and from premature infants, and it may have estrogenic potential.

METHODS

To determine the effects of maternal and lactational exposure to HMB on development and reproductive organs of offspring, time‐mated female Harlan Sprague‐Dawley rats were dosed with 0, 1000, 3000, 10,000, 25,000, or 50,000 ppm HMB (seven to eight per group) added to chow from gestation day 6 until weaning on postnatal day (PND) 23.

RESULTS AND CONCLUSION

Exposure to HMB was associated with reduced body and organ weights in female and male offspring. No significant differences were observed in the number of implantation sites/litter, mean resorptions/litter, % litters with resorptions, number and weights of live fetuses, or sex ratios between the control and HMB dose groups. Normalized anogenital distance in male pups at PND 23 was decreased in the highest dose group. Spermatocyte development was impaired in testes of male offspring in the highest dose group. In females, follicular development was delayed in the highest dose group. However, by evaluating levels of the compound in rat serum, the doses at which adverse events occurred are much higher than usual human exposure levels. Thus, exposure to less than 10,000 ppm HMB does not appear to be associated with adverse effects on the reproductive system in rats