bluuebunny/crossref_metadata_2025 huggingface dataset:
Entrelazando la Ética con las Ciencias Experimentales: una propuesta didáctica para la capacitación de profesores con la serie Breaking Bad
Authors: Cambra Badii Irene , Lorenzo María Gabriela
Published: October 2018

Cada vez es más evidente la necesidad de articular las cuestiones disciplinares con la Naturaleza de la Ciencia, las relaciones entre Ciencia, Tecnología y Sociedad, y la interrogación sobre aspectos éticos de la enseñanza y del conocimiento. Presentamos una investigación-acción a partir de una propuesta en base a la serie Breaking Bad para la capacitación de profesores de ciencias. Los resultados mostraron diferentes formas de concebir la ciencia, el trabajo científico y su enseñanza. Se desataca el surgimiento de situaciones éticamente controversiales en la escuela secundaria. La propuesta promovió el debate y la reflexión sobre una serie de hechos con un amplio impacto social, y, se facilitaron los procesos metacognitivos necesarios para la transformación de las prácticas educativas.
Una tipología de casos para enseñar el modelo de evolución por selección natural
Authors: González Galli Leonardo Martín , Meinardi Elsa Noemí , Pérez Gastón Mariano
Published: October 2018

La enseñanza de todo contenido requiere utilizar casos o ejemplos concretos que sirvan de problemas que den sentido a la construcción de modelos cercanos a los científicos. Existen diversos criterios para la selección de dichos casos. En este trabajo se presentan los fundamentos de una propuesta para la selección de casos para la enseñanza del modelo de evolución por selección natural. Esta propuesta se basa en la interacción entre dichos casos y las concepciones y obstáculos epistemológicos de los estudiantes. Cada categoría de casos propuesta se define por las concepciones y obstáculos cuya explicitación y revisión facilita. Se sugiere también que la toma de conciencia sobre esas concepciones y obstáculos es una condición necesaria el aprendizaje tal como se lo entiende desde el marco teórico de la modelización.
Geometry of antiparallel microtubule bundles regulates relative sliding and stalling by PRC1 and Kif4A
Authors: Wijeratne Sithara , Subramanian Radhika
Published: October 2018

Motor and non-motor crosslinking proteins play critical roles in determining the size and stability of microtubule-based architectures. Currently, we have a limited understanding of how geometrical properties of microtubule arrays, in turn, regulate the output of crosslinking proteins. Here we investigate this problem in the context of microtubule sliding by two interacting proteins: the non-motor crosslinker PRC1 and the kinesin Kif4A. The collective activity of PRC1 and Kif4A also results in their accumulation at microtubule plus-ends (‘end-tag’). Sliding stalls when the end-tags on antiparallel microtubules collide, forming a stable overlap. Interestingly, we find that structural properties of the initial array regulate microtubule organization by PRC1-Kif4A. First, sliding velocity scales with initial microtubule-overlap length. Second, the width of the final overlap scales with microtubule lengths. Our analyses reveal how micron-scale geometrical features of antiparallel microtubules can regulate the activity of nanometer-sized proteins to define the structure and mechanics of microtubule-based architectures.
Acute perturbation of Pet1-neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery
Authors: Dosumu-Johnson Ryan T , Cocoran Andrea E , Chang YoonJeung , Nattie Eugene , Dymecki Susan M
Published: October 2018

Cardiorespiratory recovery from apneas requires dynamic responses of brainstem circuitry. One implicated component is the raphe system ofPet1-expressing (largely serotonergic) neurons, however their precise requirement neonatally for homeostasis is unclear, yet central toward understanding newborn cardiorespiratory control and dysfunction. Here we show that acute in vivo perturbation ofPet1-neuron activity, via triggering cell-autonomously the synthetic inhibitory receptor hM4Di, resulted in altered baseline cardiorespiratory properties and diminished apnea survival. Respiratory more than heart rate recovery was impaired, uncoupling their normal linear relationship. Disordered gasp recovery from the initial apnea distinguished mice that would go on to die during subsequent apneas. Further, the risk likelihood of apnea-related mortality associated with suppression ofPet1neurons was higher for animals with baseline elevated ventilatory equivalents for oxygen. These findings establish thatPet1neurons play an active role in neonatal cardiorespiratory homeostasis and provide mechanistic plausibility for the serotonergic abnormalities associated with SIDS.
LEAFY maintains apical stem cell activity during shoot development in the fern Ceratopteris richardii
Authors: Plackett Andrew RG , Conway Stephanie J , Hewett Hazelton Kristen D , Rabbinowitsch Ester H , Langdale Jane A , Di Stilio Verónica S
Published: October 2018

During land plant evolution, determinate spore-bearing axes (retained in extant bryophytes such as mosses) were progressively transformed into indeterminate branching shoots with specialized reproductive axes that form flowers. The LEAFY transcription factor, which is required for the first zygotic cell division in mosses and primarily for floral meristem identity in flowering plants, may have facilitated developmental innovations during these transitions. Mapping the LEAFY evolutionary trajectory has been challenging, however, because there is no functional overlap between mosses and flowering plants, and no functional data from intervening lineages. Here, we report a transgenic analysis in the fern Ceratopteris richardii that reveals a role for LEAFY in maintaining cell divisions in the apical stem cells of both haploid and diploid phases of the lifecycle. These results support an evolutionary trajectory in which an ancestral LEAFY module that promotes cell proliferation was progressively co-opted, adapted and specialized as novel shoot developmental contexts emerged.
Seven new species ofCichlidogyrusPaperna, 1960 (Monogenea: Dactylogyridae) parasitizing the gills of Congolese cichlids from northern Lake Tanganyika
Authors: Rahmouni Chahrazed , Vanhove Maarten P.M. , Šimková Andrea
Published: October 2018

Seven new species ofCichlidogyrusPaperna, 1960 (Monogenea: Dactylogyridae) isolated from the gills of six cichlid host species belonging to four tribes and sampled from the Congolese coastline of Lake Tanganyika (LT) are described:Cichlidogyrus adkoningsisp. nov. fromCyphotilapia frontosa(tribe Cyphotilapiini);C. koblmuellerisp. nov. fromCardiopharynx schoutedeni(Ectodini);C. habluetzelisp. nov. fromC. schoutedeniandC. frontosa;C. antoinepariselleisp. nov. fromInterochromis loocki(Tropheini);C. masilyaisp. nov. fromPetrochromis orthognathus(Tropheini);C. salzburgerisp. nov. fromP. trewavasae, andC. sergemorandisp. nov. fromTylochromis polylepis(Tylochromini). This study represents the first parasitological examination of cyphotilapiine cichlid hosts. Representatives of the Tanganyikan ectodine, tropheine, and tylochromine cichlids previously sampled from various localities in the lake yielded nine, twelve, and two described species ofCichlidogyrus, respectively. The study further includes a morphological characterization of the male copulatory organ of six undescribed species ofCichlidogyrusfound on the gills of the tropheinesI. loockiandP. orthognathus,and on those ofCallochromis melanostigmaandXenotilapia flavipinnis(both Ectodini). Geographical variation in the monogenean fauna ofI. loockiwas observed. The most closely related cichlid species investigated in this study harbouredCichlidogyrusspp. exhibiting some similarities in their sclerotized structures. Thus, our paper provides additional evidence of the high species richness ofCichlidogyrusand the link with their hosts’s phylogenetic affinities in LT.
Proteorhodopsins dominate the expression of phototrophic mechanisms in seasonal and dynamic marine picoplankton communities
Authors: Sieradzki Ella T. , Fuhrman Jed A. , Rivero-Calle Sara , Gómez-Consarnau Laura
Published: October 2018

The most abundant and ubiquitous microbes in the surface ocean use light as an energy source, capturing it via complex chlorophyll-based photosystems or simple retinal-based rhodopsins. Studies in various ocean regimes compared the abundance of these mechanisms, but few investigated their expression. Here we present the first full seasonal study of abundance and expression of light-harvesting mechanisms (proteorhodopsin, PR; aerobic anoxygenic photosynthesis, AAnP; and oxygenic photosynthesis, PSI) from deep-sequenced metagenomes and metatranscriptomes of marine picoplankton (<1 µm) at three coastal stations of the San Pedro Channel in the Pacific Ocean. We show that, regardless of season or sampling location, the most common phototrophic mechanism in metagenomes of this dynamic region was PR (present in 65–104% of the genomes as estimated by single-copy recA), followed by PSI (5–104%) and AAnP (5–32%). Furthermore, the normalized expression (RNA to DNA ratio) of PR genes was higher than that of oxygenic photosynthesis (average ± standard deviation 26.2 ± 8.4 vs. 11 ± 9.7), and the expression of the AAnP marker gene was significantly lower than both mechanisms (0.013 ± 0.02). We demonstrate that PR expression was dominated by the SAR11-cluster year-round, followed by other Alphaproteobacteria, unknown-environmental clusters and Gammaproteobacteria. This highly dynamic system further allowed us to identify a trend for PR spectral tuning, in which blue-absorbing PR genes dominate in areas with low chlorophyll-aconcentrations (<0.25 µgL−1). This suggests that PR phototrophy is not an accessory function but instead a central mechanism that can regulate photoheterotrophic population dynamics.
Efficacy of nano‐particulated, water‐soluble erlotinib against intracranial metastases of EGFR‐mutant lung cancer
Authors: Kim Dong Ha , Choi Yun Jung , Sung Ki Jung , Yoo Seon‐A , Sung Young Hoon , Kim Jeong Kon , Choi Chang‐Min , Yun Miyong , Lee Eun Yong , Jin Yong Suk , Cook Seungho , Rho Jin Kyung , Lee Jae Cheol
Published: October 2018

Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.
Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis
Authors: Nicholson Katharine , Chan James , Macklin Eric A. , Levine‐Weinberg Mark , Breen Christopher , Bakshi Rachit , Grasso Daniela L. , Wills Anne‐Marie , Jahandideh Samad , Taylor Albert A. , Beaulieu Danielle , Ennist David L. , Andronesi Ovidiu , Ratai Eva‐Maria , Schwarzschild Michael A. , Cudkowicz Merit , Paganoni Sabrina
Published: October 2018

Objective

To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS).

Methods

This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores.

Results

Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions.

Interpretation

Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.
Atherosclerosis in stroke‐related vascular beds and stroke risk: A 3‐D MR vessel wall imaging study
Authors: Li Dongye , Dai Wei , Cai Ying , Han Yongjun , Yao Guoen , Chen Huijun , Yuan Chun , Xiao Lei , Zhao Xihai
Published: October 2018

Objectives

To investigate the characteristics of atherosclerotic plaques in stroke‐related vascular beds and their relationship with stroke using three‐dimensional magnetic resonance (MR) vessel wall imaging.

Methods

Fifty‐two symptomatic patients (mean age: 56.3 ± 13.4 years; 38 males) were enrolled and underwent MR vessel wall imaging for stroke‐related vascular beds including intracranial and extracranial carotid arteries and aortic arch and routine MR imaging for brain. The maximum wall thickness (Max WT) and luminal stenosis of each plaque were measured. The presence/absence of atherosclerotic plaque, intraplaque hemorrhage (IPH), and severe stenosis (stenosis >50%) at each vascular bed and acute ischemic lesion (AIL) were determined. The correlation between Max WT of each vascular bed and AIL was analyzed.

Results

Of 52 patients, 24 (46.2%) had AILs, and 30 (57.7%), 34 (65.4%), and 11 (21.2%) had plaques in intracranial artery, extracranial carotid artery, and aortic arch, respectively. The prevalence of IPH and severe stenosis was 25% and 26.9% for intracranial arteries, 13.5% and 9.6% for extracranial carotid artery, and 3.8% and 0% for aortic arch, respectively. In discriminating AIL, Max WT of intracranial artery had the highest area‐under‐the‐curve (AUC = 0.84), followed by extracranial carotid artery (AUC = 0.83) and aortic arch (AUC = 0.78) after adjusted for confounding factors. The AUC of Max WT combined three stroked‐related vascular beds reached 0.87.

Conclusion

Extracranial carotid arteries have the highest prevalence of plaques and intraplaque hemorrhage and severe stenosis are most frequently seen in intracranial arteries in Asian symptomatic patients. The Max WT combined three stroke‐related vascular beds show stronger predictive value for AIL than each vascular bed alone.
Effects of the putative confession instruction on perceptions of children's true and false statements
Authors: Gongola Jennifer , Scurich Nicholas , Lyon Thomas D.
Published: October 2018

The putative confession (PC) instruction (i.e., “[suspect] told me everything that happened and wants you to tell the truth”) during forensic interviews with children has been shown to increase the accuracy of children's statements, but it is unclear whether adults' perceptions are sensitive to this salutary effect. The present study examined how adults perceive children's true and false responses to the PC instruction. Participants (n = 299) watched videotaped interviews of children and rated the child's credibility and the truthfulness of his/her statements. When viewing children's responses to the PC instruction, true and false statements were rated as equally credible, and there was a decrease in accuracy for identifying false denials as lies. These findings suggest that participants viewed the PC instruction as truth‐inducing. Implications for the forensic use of the PC instruction are discussed.
Active Sites and Mechanism of Oxygen Reduction Reaction Electrocatalysis on Nitrogen‐Doped Carbon Materials
Authors: Singh Santosh K. , Takeyasu Kotaro , Nakamura Junji
Published: October 2018

The oxygen reduction reaction (ORR) is a core reaction for electrochemical energy technologies such as fuel cells and metal–air batteries. ORR catalysts have been limited to platinum, which meets the requirements of high activity and durability. Over the last few decades, a variety of materials have been tested as non‐Pt catalysts, from metal–organic complex molecules to metal‐free catalysts. In particular, nitrogen‐doped graphitic carbon materials, including N‐doped graphene and N‐doped carbon nanotubes, have been extensively studied. However, due to the lack of understanding of the reaction mechanism and conflicting knowledge of the catalytic active sites, carbon‐based catalysts are still under the development stage of achieving a performance similar to Pt‐based catalysts. In addition to the catalytic viewpoint, designing mass transport pathways is required for O2. Recently, the importance of pyridinic N for the creation of active sites for ORR and the requirement of hydrophobicity near the active sites have been reported. Based on the increased knowledge in controlling ORR performances, bottom‐up preparation of N‐doped carbon catalysts, using N‐containing conjugative molecules as the assemblies of the catalysts, is promising. Here, the recent understanding of the active sites and the mechanism of ORRs on N‐doped carbon catalysts are reviewed.
Sundew‐Inspired Simultaneous Actuation and Adhesion/Friction Control for Reversibly Capturing Objects Underwater
Authors: Ma Yanfei , Ma Shuanhong , Yang Wufang , Yu Bo , Pei Xiaowei , Zhou Feng , Liu Weimin
Published: October 2018

The development of intelligent underwater soft actuators by using stimuli‐responsive polymer materials is of immense scientific interest because of its wide application potential. Inspired by the hunting mechanism of sundews in nature, having rosettes of leaves that are sticky and capable of actuating, a novel structural hydrogel actuator made by high mechanical strength hydrogel poly(N‐isopropyl acrylamide‐acrylic acid)/Fe (PNIPAAm/PAAc‐Fe) with asymmetric structures in its two sides is fabricated, which is defined as structural hydrogel film. The as‐prepared hydrogel actuator can demonstrate reversible bending in response to temperature change (below/above the lower critical solution temperature of PNIPAAm) or encountering fast solvent exchange between ethanol and water, along with the switching of surface friction/adhesion force. During responsive bending, the actuator can generate large actuation force of ≈21 mN. Meanwhile, the combination of fast‐responsive bending, switchable surface friction, and strong actuation force endows the actuator excellent capacity to reversibly catch and release objects underwater. Especially, the existing fibrillar hydrogel pillars on actuator makes it possible to be used as a manipulator for realizing precise transportation of small objects underwater. The current actuator shows fantastic actuation capacity similar to natural sundews, and provides inspiration for developing novel soft robotics underwater.
Direct Oxidative Disulfenylation/Cyclization of 2′‐Hydroxyacetophenones with Thiophenols for the Synthesis of 2,2‐Dithio‐Benzofuran‐3(2H)‐Ones
Authors: Hu Biao , Zhang Qiaohe , Zhao Siyun , Wang Yanqin , Xu Li , Yan Shengjiao , Yu Fuchao
Published: October 2018

A direct oxidative disulfenylation/cyclization of 2′‐hydroxyacetophenones with thiophenols mediated by TBAI/K2S2O8 has been successfully developed within this study. The reaction successfully provides an efficient method for the synthesis of functionalized 2,2‐dithio‐benzofuran‐3(2H)‐ones, which exhibits readily available starting materials, a broad substrate scope, excellent yields, and large‐scale applicability. In a single step, two C−S bonds and one C−O bond are simultaneously built on the same sp3 carbon atom under transition‐metal‐free conditions.

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Reaction of Quinoline N‐Oxides and Pyridine N‐Oxides with Arylzinc Reagents: Synthesis of 2‐Arylquinolines and 2‐Arylpyridines
Authors: Li Wei‐Ze , Wang Zhong‐Xia
Published: October 2018

Reaction of quinoline N‐oxides and pyridine N‐oxides with arylzinc reagents under transition‐metal‐free conditions was studied. The reaction was carried out in toluene (for quinoline N‐oxides) or THF (for pyridine N‐oxides) at 100 °C and required 2 equiv. of arylzinc loadings and the presence of 2.5 equiv. of TFAA, affording 2‐arylquinolines and 2‐arylpyridines, respectively, in 24% to 95% yields. Functional groups OMe, F, Cl, Br, CF3, C(O)NH2, COOR and NO2 were tolerated. Mechanistic studies showed that the reaction of quinoline N‐oxides proceeded via a 2‐arylquinolin‐1(2H)‐olate intermediate, and the reaction of pyridine N‐oxides via a 5‐arylpenta‐2,4‐dienal oxime intermediate.
Enantioselective Synthesis of Cyclic α‐Aminophosphonates through N‐Heterocyclic Carbene‐Catalyzed [4+2] Annulation of Enals with α‐Iminophosphonates
Authors: Luo Zhi , Gao Zhong‐Hua , Zhang Chun‐Lin , Chen Kun‐Quan , Ye Song
Published: October 2018

The N‐heterocyclic carbene‐catalyzed [4+2] annulation of enals with α‐iminophosphonates was developed to give the corresponding cyclic α‐aminophosphonates in high yields with excellent enantioselectivities.
Morphological trends in arcade shape and size in Middle Pleistocene Homo
Authors: Stelzer Stefanie , Neubauer Simon , Hublin Jean‐Jacques , Spoor Fred , Gunz Philipp
Published: October 2018

Objectives

Middle Pleistocene fossil hominins, often summarized as Homo heidelbergensis sensu lato, are difficult to interpret due to a fragmentary fossil record and ambiguous combinations of primitive and derived characters. Here, we focus on one aspect of facial shape and analyze shape variation of the dental arcades of these fossils together with other Homo individuals.

Materials and Methods

Three‐dimensional landmark data were collected on computed tomographic scans and surface scans of Middle Pleistocene fossil hominins (n = 8), Homo erectus s.l. (n = 4), Homo antecessor (n = 1), Homo neanderthalensis (n = 13), recent (n = 52) and fossil (n = 19) Homo sapiens. To increase sample size, we used multiple multivariate regression to reconstruct complementary arches for isolated mandibles, and explored size and shape differences among maxillary arcades.

Results

The shape of the dental arcade in H. erectus s.l. and H. antecessor differs markedly from both Neanderthals and H. sapiens. The latter two show subtle but consistent differences in arcade length and width. Shape variation among Middle Pleistocene fossil hominins does not exceed the amount of variation of other species, but includes individuals with more primitive and more derived morphology, all more similar to Neanderthals and H. sapiens than to H. erectus s.l.

Discussion

Although our results cannot reject the hypothesis that the Middle Pleistocene fossil hominins belong to a single species, their shape variation comprises a more primitive morph that represents a likely candidate for the shape of the last common ancestor of Neanderthals and H. sapiens, and a more derived morph resembling Neanderthals. The arcade shape difference between Neanderthals and H. sapiens might be related to different ways to withstand mechanical stress.
Structure and Reactivity of Al−O(H)−Al Moieties in Siloxide Frameworks: Solution and Gas‐Phase Model Studies
Authors: Lokare Kapil Shyam , Braun‐Cula Beatrice , Limberg Christian , Jorewitz Marcel , Kelly John T. , Asmis Knut R. , Leach Stephen , Baldauf Carsten , Goikoetxea Itziar , Sauer Joachim
Published: October 2018

Even though aluminas and aluminosilicates have found widespread application, a consistent molecular understanding of their surface heterogeneity and the behavior of defects resulting from hydroxylation/dehydroxylation remains unclear. Here, we study the well‐defined molecular model compound, [Al3(μ2‐OH)3(THF)3(PhSi(OSiPh2O)3)2], 1, to gain insight into the acid–base reactivity of cyclic trinuclear Al3(μ2‐OH)3 moieties at the atomic level. We find that, like zeolites, they are sufficiently acidic to catalyze the isomerization of olefins. DFT and gas phase vibrational spectroscopy on solvent‐free and deprotonated 1 show that the six‐membered ring structure of its Al3(μ2‐OH)3 core is unstable with respect to deprotonation of one of its hydroxy groups and rearranges into two edge‐sharing four‐membered rings. This renders AlIV−O(H)−AlIV units strong acid sites, and all results together suggest that their acidity is similar to that of zeolitic SiIV−O(H)−AlIV groups.
Deoxygenative Deuteration of Carboxylic Acids with D2O
Authors: Zhang Muliang , Yuan Xiang‐Ai , Zhu Chengjian , Xie Jin
Published: October 2018

We report a general, practical, and scalable means of preparing deuterated aldehydes from aromatic and aliphatic carboxylic acids with D2O as an inexpensive deuterium source. The use of Ph3P as an O‐atom transfer reagent can facilitate the deoxygenation of aromatic acids, while Ph2POEt is a better O‐atom transfer reagent for aliphatic acids. The highly precise deoxygenation of complex carboxylic acids makes this protocol promising for late‐stage deoxygenative deuteration of natural product derivatives and pharmaceutical compounds.
Two validated spectrofluorimeteric and high performance liquid chromatography (HPLC) methods with fluorescence detection for the analysis of a new anti‐hepatitis C drug, daclatasvir hydrochloride, in raw material or tablet form and in biological fluids
Authors: Aboshabana Rasha , Shalan Shereen , Eid Manal , El‐Enany Nahed
Published: October 2018

Two sensitive and accurate methods have been developed for the estimation of daclatasvir (DAC) in its raw material, dosage form and in biological fluids. Method I is based on the measurement of DAC native fluorescence in methanol at 385 nm after excitation at 315 nm. The relationship between fluorescence intensity and concentration was found to be rectilinear over the linearity range (3.0–30.0 ng/ml). There were good per cent recoveries both in the dosage form (99.87 ± 0.84) and in spiked human plasma (99.96 ± 1.54%). Method II utilized reversed‐phase high performance liquid chromatography to estimate the antiviral agent daclatasvir hydrochloride against hepatitis C within 4.0 min on a C18 column (Eurosphere. 100‐5 C18, 150 × 4.6 mm, Germany) using a mobile phase consisting of acetonitrile and 0.1 M sodium dihydrogen phosphate (30:70, v/v) at pH 3.0 and with a fluorescence detector adjusted to 315 nm and 385 nm for excitation and emission respectively. The calibration curve was linear over the range (20.0–200.0 ng/ml) with SD 1.38%, error 0.56%, recovery 99.99 ± 1.30% in tablets, recovery 100.28 ± 1.73% in spiked urine and recovery 99.63 ± 2.72% in spiked plasma.The new developed methods were successfully applied to the assay of the daclatasvir in tablet form and extended to its determination in real plasma, spiked human plasma and urine. The analytical performance of the proposed method was validated according to International Conference on Harmonization (ICH) guidelines. The proposed methods were compared with the results of a comparison method and it was found that there was no significant difference between the methods, as revealed by Student's t‐test and variance ratio F‐test.
Cell‐Nanoparticle Interactions at (Sub)–Nanometer Resolution Analyzed by Electron Microscopy and Correlative Coherent Anti‐Stokes Raman Scattering
Authors: Saarinen Jukka , Gütter Friederike , Lindman Mervi , Agopov Mikael , Fraser‐Miller Sara J. , Scherließ Regina , Jokitalo Eija , Santos Hélder A. , Peltonen Leena , Isomäki Antti , Strachan Clare J.
Published: October 2018

A wide variety of nanoparticles are playing an increasingly important role in drug delivery. Label‐free imaging techniques are especially desirable to follow the cellular uptake and intracellular fate of nanoparticles. The combined correlative use of different techniques, each with unique advantages, facilitates more detailed investigation about such interactions. The synergistic use of correlative coherent anti‐Stokes Raman scattering and electron microscopy (C‐CARS‐EM) imaging offers label‐free, chemically‐specific, and (sub)‐nanometer spatial resolution for studying nanoparticle uptake into cells as demonstrated in the current study. Coherent anti‐Stokes Raman scattering (CARS) microscopy offers chemically‐specific (sub)micron spatial resolution imaging without fluorescent labels while transmission electron microscopy (TEM) offers (sub)‐nanometer scale spatial resolution and thus visualization of precise nanoparticle localization at the sub‐cellular level. This proof‐of‐concept imaging platform with unlabeled drug nanocrystals and macrophage cells revealed good colocalization between the CARS signal and electron dense nanocrystals in TEM images. The correlative TEM images revealed subcellular localization of nanocrystals inside membrane bound vesicles, showing multivesicular body (MVB)−like morphology typical for late endosomes (LEs), endolysosomes, and phagolysosomes. C‐CARS‐EM imaging has much potential to study the interactions between a wide range of nanoparticles and cells with high precision and confidence.
Health‐related quality of life of esophageal cancer patients in daily life after treatment: A multicenter cross‐sectional study in China
Authors: Liu Qian , Zeng Hongmei , Xia Ruyi , Chen Gang , Liu Shuzheng , Zhang Zhiyi , Liu Yuqin , Guo Guizhou , Song Guohui , Zhu Yigong , Wu Xianghong , Song Bingbing , Liao Xianzhen , Chen Yanfang , Wei Wenqiang , Chen Wanqing , Zhuang Guihua
Published: October 2018

Background

The improvement of diagnostic and therapeutic techniques has prolonged the survival time of patients with esophageal cancer. Little is known, however, about their health‐related quality of life (HRQoL) in daily life after treatment.

Methods

Esophageal cancer patients who had been discharged from hospitals more than one year and healthy controls identified by screening were recruited from seven study centers covering eastern, central, and western regions of China. Patients were categorized into severe dysplasia/carcinoma in situ and stages I, II, III, and IV cancer, respectively. The EQ‐5D was employed to assess HRQoL. Multivariate regression analyses were conducted.

Results

A total of 1456 patients and 2179 controls were recruited. After adjusting for potential confounding factors, the likelihood of reporting problems in the five dimensions of patients was 3.8 to 23.1 times higher than controls, whilst the mean EQ‐5D utility score was 0.311 (95% CI, 0.276‐0.346) lower than controls. The mean utility scores of each patient subgroup were 0.158, 0.289, 0.303, 0.296, and 0.505 (95% CIs: 0.108‐0.208, 0.243‐0.336, 0.261‐0.346, 0.244‐0.347, and 0.437‐0.573) lower than controls, respectively. Patients had the greatest impairment in the self‐care dimension compared with controls, followed by the usual activities dimension. Therapeutic regimen, duration of illness, other chronic disease status, age, and marital status also had significant impact on different aspects of HRQoL in patients.

Conclusions

Esophageal cancer significantly impaired patients' HRQoL in daily life after treatment. Advanced cancer stages were associated with larger decrements on health state utility. Utility scores reported here can facilitate further cost‐utility analyses.
Suspicious index in Lyme carditis: Systematic review and proposed new risk score
Authors: Besant Georgia , Wan Douglas , Yeung Cynthia , Blakely Crystal , Branscombe Pamela , Suarez‐Fuster Laiden , Redfearn Damian , Simpson Christopher , Abdollah Hoshiar , Glover Benedict , Baranchuk Adrian
Published: October 2018

Background

Lyme carditis (LC), an early manifestation of Lyme disease that most commonly presents as high‐degree atrioventricular block (AVB), usually resolves with antibiotic treatment. When LC is not identified as the cause of AVB, a permanent pacemaker may be inappropriately implanted in a reversible cardiac conduction disorder.

Hypothesis

The likelihood that a patient's high‐degree AVB is caused by LC can be evaluated by clinical characteristics incorporated into a risk stratification tool.

Methods

A systematic review of all published cases of LC with high‐degree AVB, and five cases from the authors' experience, was conducted. The results informed the development of a new risk stratification tool, the Suspicious Index in LC (SILC) score. The SILC score was then applied to each case included in the review.

Results

Of the 88 cases included, 51 (58%) were high‐risk, 31 (35.2%) intermediate‐risk, and 6 (6.8%) low‐risk for LC according to the SILC score (sensitivity 93.2%). For the subset of 32 cases that reported on all SILC variables, 24 (75%) cases were classified as high‐risk, 8 (25%) intermediate‐risk, and 0 low‐risk (sensitivity 100%). Specificity could not be assessed (no control group). Notably, 6 of the 11 patients who received permanent pacemakers had reversal of AVB with antibiotic treatment.

Conclusion

The SILC risk score and COSTAR mnemonic (constitutional symptoms; outdoor activity; sex = male; tick bite; age < 50; rash = erythema migrans) may help to identify LC in patients presenting with high‐degree AVB, and ultimately, minimize the implantation of unnecessary permanent pacemakers.
Brentuximab vedotin for recurrent Hodgkin lymphoma after allogeneic hematopoietic stem cell transplantation: A report from the EBMT Lymphoma Working Party
Authors: Bazarbachi Ali , Boumendil Ariane , Finel Hervé , Mohty Mohamad , Castagna Luca , Blaise Didier , Peggs Karl S. , Afanasyev Boris , Diez‐Martin J.L. , Corradini Paolo , Michonneau David , Robinson Stephen , Gutiérrez García Gonzalo , Bonifazi Francesca , Yakoub‐Agha Ibrahim , Gülbas Zafer , Bloor Adrian , Delage Jeremy , Esquirol Albert , Malladi Ram , Scheid Christof , El‐Cheikh Jean , Ghesquières Hervé , Montoto Silvia , Dreger Peter , Sureda Anna
Published: October 2018

Background

The treatment of patients with Hodgkin lymphoma (HL) who develop disease progression after undergoing allogeneic stem cell transplantation (allo‐SCT) remains challenging.

Methods

The authors assessed outcomes in 184 adult patients with HL who developed disease recurrence or progression after a matched related or unrelated allo‐SCT at European Society for Blood and Marrow Transplantation–participating centers between 2010 and 2014.

Results

Eighty patients who received brentuximab vedotin (BV) salvage therapy were compared with 104 patients who did not. Patients in the BV group were younger (median age of 30 years vs 34 years) and were more likely to receive pretransplant BV (65% vs 46%) or posttransplant donor lymphocyte infusion (66% vs 33%). The 2 groups otherwise were comparable. Patients in the BV group received a median of 6 doses of posttransplant BV, resulting in a complete remission rate of 29%, a partial response rate of 45%, and a stable disease rate of 26%. Response to BV after allo‐SCT did not appear to be affected by receipt of pretransplant BV. Despite a longer median follow‐up for surviving patients in the BV group (33 months vs 23 months; P<.001), approximately 34% of the original BV cohort were alive and in CR at the time of last follow‐up versus 18% in the group that did not receive BV (P=.003). The use of BV before donor lymphocyte infusion was found to be associated with the highest probability of being alive and in CR (40%) at the time of last follow‐up. Salvage BV appeared to have no effect on chronic graft‐versus‐host disease or 1‐year overall survival from the time of disease recurrence after allo‐SCT (76% vs 67%).

Conclusions

BV is a safe and effective salvage therapy for patients with HL who develop disease recurrence or progression after undergoing allo‐SCT, even after prior exposure to BV.
The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma
Authors: Malempati Suman , Weigel Brenda J. , Chi Yueh‐Yun , Tian Jing , Anderson James R. , Parham David M. , Teot Lisa A. , Rodeberg David A. , Yock Torunn I. , Shulkin Barry L. , Spunt Sheri L. , Meyer William H. , Hawkins Douglas S.
Published: October 2018

Background

The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children’s Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose‐intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin‐like growth factor‐1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone.

Methods

Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval‐compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites.

Results

One hundred sixty‐eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow‐up of 2.9 years, the 3‐year event‐free survival rate was 16% (95% confidence interval, 7%‐25%) with cixutumumab and 18% (95% confidence interval, 2%‐35%) with temozolomide.

Conclusions

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
Overview of PCR
Authors: Kuslich Christine D. , Chui Buena , Yamashiro Carl T.
Published: October 2018

The polymerase chain reaction (PCR) has revolutionized molecular biology and has enabled many other technologies and applications commonly used in research, and is part of many life science products. This unit will cover the basic principles of PCR, including how to carry out PCR in a laboratory that has not used this powerful technique previously. In addition, a number of different applications utilizing the basic PCR technique will be described. © 2018 by John Wiley & Sons, Inc.
Use of flow cytometry in the phenotypic diagnosis of hodgkin's lymphoma
Authors: Grewal Ravnit‐Kaur , Chetty Manogari , Abayomi Emmanuel‐Akinola , Tomuleasa Ciprian , Fromm Jonathan R.
Published: October 2018

Hodgkin's lymphoma (HL) has a unique immunophenotype derived from immunohistochemistry (positive for CD15, CD30, and Pax‐5; negative for CD3, CD20 in most cases, and CD45). The knowledge gained over recent years enables better diagnosis, prognosis, and treatment of HL. Flow cytometry as a tool for the diagnosis of classic HL has not been useful in the past due to the difficulty in isolating Reed–Sternberg cells as they are admixed in a rich inflammatory background which consists mainly of T cells, B cells, eosinophils, histiocytes, and plasma cells. However, in the recent past, several studies have tried to identify Reed–Sternberg cells using flow cytometry on fine needle aspiration or tissue biopsy of lymph nodes to confirm or supplement immunohistochemistry staining in diagnosis. Newer and more sensitive tools such as flow cytometry can be used for diagnosis, technology that may have been difficult in the past for diagnosis of this lymphoma subtype. Using flow cytometry, diagnosis is faster and could lead to point‐of‐care technology especially where we have typical immunophenotype signatures. © 2018 International Clinical Cytometry Society
Profiles of vagal withdrawal to challenging interactions: Links with preschoolers’ conceptual shifting ability
Authors: Scrimin Sara , Patron Elisabetta , Lanfranchi Silvia , Moscardino Ughetta , Palomba Daniela , Mason Lucia
Published: October 2018

The current study investigated profiles of vagal withdrawal in response to a challenging task in preschoolers. Also, the association between those profiles and conceptual shifting ability was assessed. Electrocardiogram of 43 four‐year‐olds was registered during a sequence of games including a win phase and a lose phase, while conceptual shifting ability was assessed via a standardized test. Cluster analyses revealed three profiles of cardiac vagal response to the task. Children in the first cluster displayed significant vagal withdrawal, children in the second cluster showed nonsignificant vagal withdrawal, while children in the third group displayed vagal augmentation to the challenge. These profiles differentiated preschoolers’ conceptual shifting ability. Specifically, children with vagal withdrawal had the best performance in categorization and flexibility tasks and committed fewer perseverative errors compared to children who showed blunted vagal withdrawal or vagal augmentation to the challenge. Implications for theory and practice are discussed.
New beamforming and distributed space‐time coding with selection relaying over Nakagami‐m fading channels
Authors: Shirzadian Gilan Mahsa , Olfat Ali
Published: October 2018

In this paper, a decode‐and‐forward (DF) cooperative network under Nakagami‐m fading is considered. A threshold‐based selection relaying scheme is used to choose the relays for cooperation and the selected relays then employ distributed space‐time coding (DSTC) to retransmit their detected symbols to destination. When employing DSTC, due to decoding errors at DF relays, intersymbol interference (ISI) would be inevitable in these networks. A new beamforming (BF) method, named as bisector alignment, is proposed for mitigating ISI between symbols of DSTC scheme caused by erroneous detection of symbols at relay. It is demonstrated that this scheme by using a simple maximal ratio combining is more power efficient compared with other existing methods. A closed‐form expression for end‐to‐end bit error rate (BER) of the system is derived and the asymptotic behavior analysis of the system illustrates that the threshold‐based selection relaying scheme by employing proper thresholds derived in this paper achieves full diversity order (M + 1)m in a network with M relays and Nakagami shape parameter m. Moreover, we can observe an excellent agreement between analytical and simulation results and the proposed BF achieves more than 3‐dB power gain at BER of 10−3. Based on our results, it can be seen that our proposed scheme is robust to imperfect channel estimation and quantizations.
Public key encryption with conjunctive keyword search secure against keyword guessing attack from lattices
Authors: Mao Yaojun , Fu Xingbing , Guo Chen , Wu Guohua
Published: October 2018

Public key encryption With keyword search (PEKS) enables a cloud server (CS) to get the search trapdoor to identify ciphertext containing the target keyword without decrypting the ciphertext or knowing the target keyword. With the advent of mobile cloud computing, PEKS has ushered in an era of new development opportunities and new challenges. In mobile cloud computing environment, the PEKS schemes demand strict bounded timing response and security. However, traditional PEKS schemes rely on heavy bilinear pairing computations, which causes a delay from the CS to the mobile terminal. Moreover, as computing power increases, PEKS is more vulnerable to suffer from an inherent insecurity known as inside keyword guessing attack, which leaks user data query information. To achieve a secure and efficient searchable encryption scheme in the mobile cloud computing environment, we put forward a lattice‐based searchable encryption scheme that supports conjunctive keyword search. Our scheme achieves higher computational efficiency and is resistant against quantum attacks compared with traditional PEKS schemes. To further enhance security and make our scheme secure against keyword guessing attack, we hide the decryption parameters by outsourcing part of the decryption process to a semitrusted third party called unusual keyword server, so that the CS cannot guess the exact keyword by performing consistency verification.
Molecular mechanisms of long noncoding RNAs‐mediated cancer metastasis
Authors: Li Yajuan , Egranov Sergey D. , Yang Liuqing , Lin Chunru
Published: October 2018

Cancer metastasis is a multistep process that requires cancer cells to leave the primary site, survive in the blood stream, and finally colonize at a distant organ. It is the major cause of cancer morbidity and mortality. The organ‐specific colonization requires close interaction and communication between cancer cells and host organs. Noncoding RNAs represent the majority of the transcriptome, with long noncoding RNAs (lncRNAs) making up a significant proportion. It has been suggested that lncRNAs play a key role in all stages of tumorigenesis and metastasis. This review will provide an overview of how lncRNAs are involved in cancer cell colonization in specific organ sites and the underlying mechanisms as well as therapeutic strategies.