bluuebunny/crossref_metadata_2025 huggingface dataset:
Next‐generation sequencing of a family with a high penetrance of monoclonal gammopathies for the identification of candidate risk alleles
Authors: Bolli Niccolo , Barcella Matteo , Salvi Erika , D'Avila Francesca , Vendramin Antonio , De Philippis Chiara , Munshi Nikhil C. , Avet‐Loiseau Herve , Campbell Peter J. , Mussetti Alberto , Carniti Cristiana , Maura Francesco , Barlassina Cristina , Corradini Paolo , Montefusco Vittorio
Published: May 2017

BACKGROUND

The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele.

METHODS

The authors performed whole‐exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach.

RESULTS

The authors identified gene mutations and single‐nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family.

CONCLUSIONS

To the authors' knowledge, the current study is the first to provide a whole‐exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017;123:3701–3708. © 2017 American Cancer Society
Benzhydryl Ethers of Tartaric Acid Derivatives: Stereochemical Response of a Dynamically Chiral Propeller
Authors: Grajewski Jakub , Mądry Tomasz , Kwit Marcin , Warżajtis Beata , Rychlewska Urszula , Gawroński Jacek
Published: May 2017

The benzhydryl (diphenylmethyl) group is a molecular propeller that can act as a chirality reporter if it is introduced nearby a stereogenic center by making an ether bond. The hydrophobic character of the benzhydryl group allows transformation of insoluble natural tartaric acid derivatives into soluble entities in a nonpolar environment. Electronic circular dichroism spectra, recorded within the short‐wavelength region of the phenyl 1B transitions (190–200 nm) shows strong bisignate Cotton effects. The signs and magnitudes of these Cotton effects are a function of absolute configuration and conformation of the molecule and do not primarily arise from exciton coupling of chiral benzhydryl chromophores. In crystals, the main‐chain conformation is stabilized by intramolecular hydrogen bonds and CH–CO dipolar interactions. The number of the donor NH groups has a pronounced effect on the preferred conformations and inclusion properties of benzhydryl‐(R,R)‐tartaric acid diamides. Evidence is shown for the solvent dependency of the conformations of NH amides of tartaric acid diphenylmethyl ethers.
Spatial autocorrelation reduces model precision and predictive power in deforestation analyses
Authors: Mets Kristjan D. , Armenteras Dolors , Dávalos Liliana M.
Published: May 2017

Generalized linear models are often used to identify covariates of landscape processes and to model land‐use change. Generalized linear models however, overlook the spatial component of land‐use data, and its effects on statistical inference. Spatial autocorrelation may artificially reduce variance in observations, and inflate the effect size of covariates. To uncover the consequences of overlooking this spatial component, we tested both spatially explicit and non‐spatial models of deforestation for Colombia. Parameter estimates, analyses of residual spatial autocorrelation, and Bayesian posterior predictive checks were used to compare model performance. Significant residual correlation showed that non‐spatial models failed to adequately explain the spatial structure of the data. Posterior predictive checks revealed that spatially explicit models had strong predictive power for the entire range of the response variable and only failed to predict outliers, in contrast with non‐spatial models, which lacked predictive power for all response values. The predictive power of non‐spatial models was especially low in regions away from Colombia's center, where about half the observations were clustered. While all analyses consistently identified a core of important covariates of deforestation rates, predictive modeling requires parameter estimates informed by the spatial structure of the data. To inform increasingly important forest and carbon sequestration policy, land‐use models must account for spatial autocorrelation.
Species climatic niche explains drought‐induced die‐off in a Mediterranean woody community
Authors: Sapes Gerard , Serra‐Diaz Josep M. , Lloret Francisco
Published: May 2017

During the last decades, plant die‐off has been reported worldwide as a result of increased frequency and intensity of extreme drought events. From a niche perspective, a species performance should decrease as the climatic conditions defining a drought event differ from those characterizing the species climatic niche (the average conditions experienced by the species). Species distribution models (SDMs) can potentially be used to test the link between species performance and their climatic niche by means of climatic suitability indexes. We studied the remaining green canopy of 18 woody species co‐occurring in a Mediterranean shrubland from the central Iberian Peninsula that experienced a severe die‐off following an extreme drought event. We found that the suitability of the climatic conditions estimated by SDMs strongly declined for all species during the extreme drought event. Species die‐off was significantly explained by the decrease in climatic suitability during the event, estimated as the ratio between the historic and the extreme event climatic suitability. Species with high occupancy levels across the landscape exhibited higher die‐off likely because (1) these species have short life‐span and mortality would be compensated by later high recruitment or (2) populations of rare species may have experienced local adaptation to drier conditions. Our results indicate that extreme drought events can have a negative effect, even in shrubland communities living in arid environments. Also, we develop a new approach that connects population‐level responses to species climatic niches through SDMs, and it can be applied to predict community responses to strong climatic variability, such as drought events.
CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice
Authors: Chitrala Kumaraswamy Naidu , Guan Hongbing , Singh Narendra P. , Busbee Brandon , Gandy Alexa , Mehrpouya‐Bahrami Pegah , Ganewatta Mitra S. , Tang Chuanbing , Chatterjee Saurabh , Nagarkatti Prakash , Nagarkatti Mitzi
Published: May 2017

Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short‐chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT) mice, into EAE‐induced CD44WT mice, led to significant amelioration of EAE. High‐throughput bacterial 16S rRNA gene sequencing, followed by clustering sequences into operational taxonomic units (OTUs) and biochemical analysis, revealed that EAE‐induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE‐induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). Further, data showed a significant change in the abundance of SCFAs, propionic acid, and i‐butyric acid in EAE‐CD44KO compared to EAE‐CD44WT mice. In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota and SCFAs. Furthermore, our studies also demonstrate that the phenotype of gene knock‐out animals may be shaped by gut microbiota.
Chiral Oxazolidine‐Fused N‐Heterocyclic Carbene Complexes of Rhodium and Iridium and Their Utility in the Asymmetric Transfer Hydrogenation of Ketones
Authors: Ramasamy Balasubramaniyam , Kumar Gangwar Manoj , Ghosh Prasenjit
Published: May 2017

The catalytic potential of new N‐heterocyclic carbene ligands, derived from a chiral fused bicyclic ring scaffold with restricted rotation along the C–N bond bearing the chiral auxiliary, has been explored in the transition‐metal‐mediated asymmetric transfer hydrogenation reactions of ketones. In particular, the chiral oxazolidine‐fused N‐heterocyclic carbene precursors (3S)‐3‐R‐6‐methyl‐7‐phenyl‐2,3‐dihydroimidazo[5,1‐b]oxazol‐6‐ium iodide [R = sec‐butyl (1f), i‐butyl (2f), isopropyl (3f)] were synthesized from commercially available optically pure amino acids in a multistep sequence that avoids tedious chiral resolution. The reactions of the chiral imidazolium iodide salts 1f–3f with Ag2O yielded the corresponding silver complexes 1g–3g, which were treated with [(COD)MCl]2 (M = Rh, Ir; COD = 1,5‐cyclooctadiene) to afford the rhodium(I) and iridium(I) complexes (1h–3h and 1i–3i, respectively). The rhodium(I) and iridium(I) complexes conveniently catalyze the asymmetric transfer hydrogenation of acetophenones for a wide variety of substrates ranging from electron‐rich ones such as 4‐methylacetophenone, 3,4‐dimethylacetophenone, 4‐tert‐butylacetophenone, and 4‐(methylthio)acetophenone to electron‐deficient ones such as 4‐bromoacetophenone, 4‐chloroacetophenone, 4‐fluoroacetophenone, 4‐nitroacetophenone, and 3‐fluoroacetophenone in moderate‐to‐good yields (ca. 18–95 %) but with low enantioselectivities (ca. 4–41 % ee).
Protonation of Tetraphenyl‐ and 2,3,4‐Triphenylcyclopentadienone – An NMR and X‐ray Crystallographic Study
Authors: Harrington Laura E. , Britten James F. , Casey Michael , Grealis John , Ortin Yannick , Müller‐Bunz Helge , McGlinchey Michael J.
Published: May 2017

The protonation of 2,3,4,5‐tetraphenylcyclopentadienone (tetracyclone) yields 6,11‐diphenyl‐5H‐benzo[a]fluoren‐5‐one (17) and 2,3,4,5‐tetraphenylcyclopent‐2‐en‐1‐one (18) as the major products. This contrasts with the pyrolysis of tetracyclone, which yields 5,6‐diphenyl‐11H‐benzo[a]fluoren‐11‐one (22), a structural isomer of 17. Mechanisms are presented that rationalize these observations. The protonation of 4‐hydroxy‐2,3,4‐triphenylcyclopent‐2‐en‐1‐none, the precursor to 2,3,4‐triphenylcyclopentadienone, generates 2‐(2′‐oxo‐3′,4′,5′‐triphenylcyclopent‐3′‐enyl)‐3,4,5‐triphenylcyclopenta‐2,4‐dienone (30), which has been unequivocally characterized by X‐ray crystallography. The establishment of the conformation of molecule 30 in the solid state, which correlates with the conformation in solution, provides a rationale for the subsequent formation of the tetrahydro‐pentaphenyl‐as‐indacene‐3,4‐dione (32) upon further protonation.
C3 Sulfenylation of N‐Heteroarenes in Water under Catalyst‐Free Conditions
Authors: Ravi Chitrakar , Joshi Abhisek , Adimurthy Subbarayappa
Published: May 2017

A method for the catalyst‐free C–H sulfenylation of imidazo[1,2‐a]pyridines by using sulfonothioates as an odorless thioarylated reagent in aqueous medium was developed. This protocol was used for a variety of substituted imidazo[1,2‐a]pyridines with broad functional‐group tolerance and was extended to the sulfenylation of indoles and imidazothiazoles. The sulfonothioates were activated exclusively in aqueous medium rather than in an organic solvent, and the feasibility of the process for scale‐up studies was demonstrated.
A cognitive‐behavioral program for parents of children with chronic musculoskeletal pain; A feasibility study
Authors: Wiertz C. , Goossens M. , Spek E.M. , Verbunt J.A.
Published: May 2017

Background

The purpose of the study is to evaluate the feasibility of a newly developed parent program for parents of children with non‐specific chronic musculoskeletal pain. This program is part of the child's interdisciplinary outpatient pain rehabilitation treatment. The goal of the parent program is to change parent's thoughts/behaviour regarding pain with the ultimate intention to further improve their child's functioning. There were two main objectives in the study: First, to evaluate the feasibility of the parent program. Second, to evaluate changing in parental behavioral factors pre‐ and posttreatment.

Methods

Participants were parents of adolescents, who underwent a interdisciplinary outpatient pain program for non‐specific chronic musculoskeletal pain. Parents participated in a parent program as part of their child's treatment. Adolescents reported their level of disability, pain intensity, fear of pain and pain catastrophizing by filling out questionnaires. Parents reported catastrophic thinking about their child's pain, fear of pain and disabilities of their child. In addition, they evaluated the parent program.

Results

Sixty five parents (36 mothers and 29 fathers) of 44 adolescents filled in the baseline questionnaires. Result showed significant and clinically relevant improvements for both parents as well for adolescents. Parents were positive about the content of the parent program, they evaluated the program as supportive and informative.

Conclusion

Adding a parent program to a interdisciplinary outpatient pain program for adolescent with chronic musculoskeletal pain, seems to be feasible in daily life of the parents and results in positive behavioural changes for both parents and adolescents.

Significance

A parent program, designed to change cognition and behaviour of parents of children with chronic musculoskeletal pain is feasible.
Belonging to a majority reduces the immediate need threat from ostracism in individuals with a high need to belong
Authors: Eck Jennifer , Schoel Christiane , Greifeneder Rainer
Published: May 2017

Ostracism—being ignored and excluded—threatens the basic human needs for belonging, self‐esteem, control, and meaningful existence. This work introduces belonging to a majority as a buffer against the immediate negative impact of ostracism on basic needs for individuals with a high need to belong, for whom social groups are especially relevant. Three studies show that for individuals high in the need to belong, need threat was attenuated by membership in a majority group, but not by membership in a minority group (Studies 1 and 3) or a group of unknown size (Study 2). By contrast, individuals low in the need to belong—who place less importance on group membership in general—did not benefit from belonging to a majority group. The general pattern replicated across different manipulations of group membership and social exclusion, with two measures of need threat, and with participants from two different countries.
Contact with bisexual individuals reduces binegativity among heterosexuals and lesbian women and gay men
Authors: Lytle Ashley , Dyar Christina , Levy Sheri R. , London Bonita
Published: May 2017

Although binegativity, the stigmatization of bisexuality, is prevalent among heterosexual and lesbian and gay communities, little research has addressed how the quantity and quality of intergroup contact affect binegativity. Drawing on intergroup contact theory, this study examined contact with and attitudes toward bisexuals among heterosexual undergraduates, heterosexual adults, and lesbians and gay men. Knowing more bisexuals (quantity) predicted more positive attitudes toward and decreased intergroup anxiety with male and female bisexuals. A multilevel structural equation model indicated that contact quality simultaneously predicted higher perceived stability of female bisexuality (but not male bisexuality) and tolerance of and less intergroup anxiety with male and female bisexuals when contact quantity was controlled for. This research suggests that both quantity and quality of contact with bisexuals predicts improved intergroup attitudes. Implications for future research on reducing binegativity are discussed.
Too special to be duped: Need for uniqueness motivates conspiracy beliefs
Authors: Imhoff Roland , Lamberty Pia Karoline
Published: May 2017

Adding to the growing literature on the antecedents of conspiracy beliefs, this paper argues that a small part in motivating the endorsement of such seemingly irrational beliefs is the desire to stick out from the crowd, the need for uniqueness. Across three studies, we establish a modest but robust association between the self‐attributed need for uniqueness and a general conspirational mindset (conspiracy mentality) as well as the endorsement of specific conspiracy beliefs. Following up on previous findings that people high in need for uniqueness resist majority and yield to minority influence, Study 3 experimentally shows that a fictitious conspiracy theory received more support by people high in conspiracy mentality when this theory was said to be supported by only a minority (vs. majority) of survey respondents. Together, these findings support the notion that conspiracy beliefs can be adopted as a means to attain a sense of uniqueness.
Study of the Electrochemical Behavior of Biodiesel Microemulsion
Authors: Moreira Luiz Felipe Pompeu Prado , Beluomini Maísa Azevedo , de Souza João Carlos , Stradiotto Nelson Ramos
Published: May 2017

Microemulsions have become a widely employed technique for the control of biodiesel quality but are still poorly understood as regard to their electrochemical behavior. In this work, we report the fundamental importance associated with the knowledge of electrochemical behavior of microemulsions composed of water in the presence of a supporting electrolyte, soybean biodiesel and propan‐1‐ol as consolute, along with the ferrocyanide–ferricyanide redox system applied as probe. The voltammetric results showed that for different compositions of microemulsions, variation in peak currents and change in system reversibility as well as in the electron transfer process were clearly noted. Furthermore, through the study of the diffusion coefficient, three different types of microemulsions including Oil/Water, Bicontinuous, and Water/Oil were successfully identified. Electrochemical impedance spectroscopy studies were also carried out aiming at obtaining more information regarding the electrode/solution interface. All the studies performed demonstrated that different types of microemulsions were formed upon exerting a direct influence on the electrochemical behavior of the redox probe. These results, in essence, point to the possibility of choosing a more suitable and advantageous microemulsion type for the development of an analytical method, as in the case, for example, of the microemulsions ME‐2 and ME‐3 which presented high voltammetric response in redox probe oxidation.
Effects of nitrogenous wastes on survival of the Barton Springs salamander (Eurycea sosorum)
Authors: Crow Justin C. , Ostrand Kenneth G. , Forstner Michael R.J. , Catalano Matthew , Tomasso Joseph R.
Published: May 2017

The objective of our study was to determine the acute toxicity of 3 common aquatic nitrogenous toxicants to the federally endangered Barton Springs salamander (Eurycea sosorum). Based on our findings, the 96-h median lethal concentrations (96-h LC50) for un-ionized ammonia-N, nitrite-N, and nitrate-N to E. sosorum are 2.0 ± 0.32, 31.7 ± 4.02, and 968.5 ± 150.6 mg/L, respectively. These results establish a benchmark for the tolerance of plethodontid salamanders to these toxicants and indicate that current water quality criteria are adequate for their protection. Environ Toxicol Chem 2017;36:3003–3007. © 2017 SETAC
Survey on the presence of non–dioxine-like PCBs (NDL-PCBs) in loggerhead turtles (Caretta caretta) stranded in south Mediterranean coasts (Sicily, Southern Italy)
Authors: Cammilleri Gaetano , Calvaruso Enza , Pantano Licia , Cascio Giovanni Lo , Randisi Barbara , Macaluso Andrea , Vazzana Mirella , Caracappa Giulia , Giangrosso Giuseppe , Vella Antonio , Ferrantelli Vincenzo
Published: May 2017

A total of 71 loggerhead turtles (Caretta caretta) stranded along the coasts of Sicily (Southern Italy) were examined for non–dioxine like polychlorinated biphenyl (NDL-PCB) levels in muscle and adipose tissue by a gas chromatography-mass spectrometry/mass spectrometry (GC-MS/MS) method. The results revealed 6 high-indicator congener (∑6PCBIND) levels in 45% of the loggerhead turtles examined, with mean values of 980.39 ± 2508.39 ng/g wet weight in adipose tissue and 102.53 ± 238.58 ng/g wet weight in muscle tissue. The hexachloro and heptachloro PCB congeners were the most abundant in both the sample types. The highest NDL-PCB levels were reached in an adipose tissue sample of a loggerhead turtle of 80 kg stranded along the coasts of Termini Imerese (14 183.85 ng/g wet wt). No significant correlation was found between modified Fulton's K values of the loggerhead turtles and PCB contents (S = 47 151, p > 0.05). Furthermore, no significant differences were found between sexes (W = 365, p >  0.05). The PCB levels found in the present study were much higher than those found in the literature. The present study is the first report on the existence of NDL-PCBs in loggerhead turtles stranded in Sicilian coasts confirming C. caretta as a valuable indicator of contaminant exposure in the marine environment because of their specific biological and ecological characteristics. Environ Toxicol Chem 2017;36:2997–3002. © 2017 SETAC
Geomorphological setting of a sacred landscape: Iron age post battle deposition of human remains at Alken Enge, Denmark
Authors: Søe Niels Emil , Odgaard Bent Vad , Hertz Ejvind , Holst Mads K. , Kristiansen Søren M.
Published: May 2017

The Illerup Valley in Denmark contains several large‐scale Iron Age (first to fifth century A.D.) ritual depositions associated with warfare among Germanic groups. The oldest deliberate deposition consisted of human bones and is dated to the first to fifth decade A.D. It is hypothesized that this first deposition initiated a ritual tradition and made the valley sacred to later generations. To understand the choice of the first location, we have reconstructed the landscape setting of the last millennia. Optically stimulated luminescence (OSL) and radiocarbon dating formed the basis of the chronostratigraphy, while sedimentary processes and development were evaluated from profiles and boreholes. We found that the human remains were deposited in a small paleolake Alken Enge, isolated from the large Lake Mossø by a spit system during the last centuries B.C. The spits had prograded across the lake and formed a land bridge between the two sides of the valley with a potential strong connective‐strategic value. The spits were overwashed during storm surges in the period before the first ritual depositions were made, and a conspicuous landform with white sandy beaches must have been clearly visible to the prehistoric community. Thus, it can be speculated that this landscape combination was important for the location of a large ritual.
Great earthquakes and the fall of the Sanxingdui and Jinsha civilizations in central China
Authors: Lin Aiming , Wang Maomao
Published: May 2017

The Bronze Age Sanxingdui civilization, which first developed in the Sichuan Basin of central China, flourished ca. 2200–1500 B.C. and ended suddenly in ca. 1200 B.C. Subsequently, the Jinsha civilization arose in the area around the city of Chengdu, located ∼40 km southwest of the Sanxingdui Site, but it too suddenly disappeared at ca. 500–200 B.C. The reasons for the sudden terminations of these two ancient civilizations are unknown and subject of debate. Here, we present paleoseismic and archeological evidence to show the possibility that the collapse of both civilizations was caused by great earthquakes that occurred along an active fault zone of the Longmen Shan Thrust Belt, which also triggered the 2008 Mw 7.9 Wenchuan earthquake. Field observations, archeological evidence, trench investigations, and radiocarbon dates indicate that: (1) four great earthquakes prior to the 2008 Wenchuan earthquake occurred in the Sichuan Basin within the last 5000 years, with an average recurrence interval of ∼1000 years; (2) the most recent earthquake prior to the 2008 Wenchuan earthquake occurred in the late Tang and early Song dynasties (∼A.D. 800–1000); (3) the penultimate paleoseismic event occurred 400 B.C.–A.D. 200; and (4) the two other strong earthquake events occurred 2800–2000 B.C. and 1600–1200 B.C. Paleoseismic evidence in archaeological contexts suggests that the 1600–1200 B.C. and 400 B.C.–A.D. 200 earthquakes were of sufficient magnitude to have caused numerous deaths and extensive damage to infrastructure and economy. These seismic events coincide with important cultural changes and may have led to the demise of the Sanxingdui and Jinsha civilizations.
Effect of steam hydration on reactivity and strength of cement‐supported calcium sorbents for CO2 capture
Authors: Yu Zhijian , Duan Lunbo , Su Chenglin , Li Yingjie , Anthony Edward John
Published: May 2017

Steam hydration was used to reactivate spent cement‐supported CO2 sorbent pellets for recycle. The effect of steam hydration on the reactivity of sorbents was investigated in a bubbling fluidized reactor. A specially designed impact apparatus was developed to evaluate the strength of the reactivated pellets as well as determine the effect of ‘superheating’. It was found that the reactivity of synthetic pellets was elevated significantly over that of raw limestone after steam hydration. The CaO conversion of spent pellets increased from 0.113 to 0.419 after hydration, whereas that of spent limestone ranged from 0.089 to 0.278. The CaO conversions of hydrated samples calcined under different conditions achieved the identical level, proportional to the degree of hydration. As expected, the mechanical strength of synthetic pellets declined severely after reactivation. Large cracks emerged on hydrated limestone as seen in scanning electron microscope images. By contrast, similar cracks were not observed for synthetic pellets after hydration, although hydration did produce higher porosity than seen with limestone and an increased surface area, which enhanced CO2 capacity and was associated with an increase in strength loss. The breakage rate of superheated, steam‐reactivated limestone‐derived pellets was about half that of hydrated samples. This demonstrates that superheating treatment (which allows the annealing of stacking faults and mechanical strain produced by hydration) could enhance the strength of hydrated pellets. This work demonstrated that combining steam hydration with superheating can both reactivate the spent synthetic pellets and reduce strength decay associated with the hydration process. © 2017 Society of Chemical Industry and John Wiley & Sons, Ltd.
The experience of beauty derived from sorrow
Authors: Ishizu Tomohiro , Zeki Semir
Published: May 2017

We studied the neural mechanisms that are engaged during the experience of beauty derived from sorrow and from joy, two experiences that share a common denominator (beauty) but are linked to opposite emotional valences. Twenty subjects viewed and rerated, in a functional magnetic resonance imaging scanner, 120 images which each had classified into the following four categories: beautiful and sad; beautiful and joyful; neutral; ugly. The medial orbito‐frontal cortex (mOFC) was active during the experience of both types of beauty. Otherwise, the two experiences engaged different parts of the brain: joyful beauty engaged areas linked to positive emotions while sorrowful beauty engaged areas linked to negative experiences. Separate regions of the cerebellum were engaged during experience of the two conditions. A functional connectivity analysis indicated that the activity within the mOFC was modulated by the supplementary motor area/middle cingulate cortex, known to be engaged during empathetic experiences provoked by other peoples' sadness. Hum Brain Mapp 38:4185–4200, 2017. © 2017 Wiley Periodicals, Inc.
Presurgical language fMRI: Mapping of six critical regions
Authors: Benjamin Christopher F. , Walshaw Patricia D. , Hale Kayleigh , Gaillard William D. , Baxter Leslie C. , Berl Madison M. , Polczynska Monika , Noble Stephanie , Alkawadri Rafeed , Hirsch Lawrence J. , Constable R. Todd , Bookheimer Susan Y.
Published: May 2017

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Broca's and Wernicke's areas, although multiple other language‐critical areas are now well‐known. We evaluated whether clinicians could use a novel approach, including clinician‐driven individualized thresholding, to reliably identify six language regions, including Broca's Area, Wernicke's Area (inferior, superior), Exner's Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly thresholded and combined these to identify the six regions. The resulting maps were compared to fixed threshold maps. Clinicians generated maps that overlapped significantly, and were highly consistent, when at least one task came from the same set. Cases diverged when clinicians prioritized different language regions or addressed noise differently. Language laterality closely mirrored Wada data (85% accuracy). Activation consistent with all six language regions was consistently identified. In blind review, three external, independent clinicians rated the individualized fMRI language maps as superior to fixed threshold maps; identified the majority of regions significantly more frequently; and judged language laterality to mirror Wada lateralization more often. These data provide initial validation of a novel, clinician‐based approach to localizing language cortex. They also demonstrate clinical fMRI is superior when analyzed by an experienced clinician and that when fMRI data is of low quality judgments of laterality are unreliable and should be withheld.Hum Brain Mapp 38:4239–4255, 2017. ©2017 Wiley Periodicals, Inc.
Syndecan‐1 limits the progression of liver injury and promotes liver repair in acetaminophen‐induced liver injury in mice
Authors: Nam Eon Jeong , Hayashida Kazutaka , Aquino Rafael S. , Couchman John R. , Kozar Rosemary A. , Liu Jian , Park Pyong Woo
Published: May 2017

Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. Although mechanisms that trigger APAP‐induced liver injury (AILI) are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan‐1, the major cell‐surface HSPG of hepatocytes, in AILI. Ablation of syndecan‐1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times post‐APAP overdose were unaffected by syndecan‐1, suggesting that syndecan‐1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan‐1 null (Sdc1−/−
) mice were traced to a deficiency in protein kinase B (Akt) activation in hepatocytes, which led to a delayed increase in glycogen synthase kinase‐3β (GSK‐3β)‐mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK‐3β and caspases protected mice from AILI. Moreover, administration of purified syndecan‐1, HS, or engineered heparan compounds containing 2‐O‐sulfate groups rescued Sdc1−/−
mice from AILI by potentiating Akt signaling and inhibiting GSK‐3β‐mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N‐acetylcysteine. Conclusion: These results demonstrate that 2‐O‐sulfated domains in syndecan‐1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in AILI. We propose that syndecan‐1 is a critical endogenous factor that controls the balance between prosurvival signaling and apoptosis in hepatocytes in APAP liver disease. (Hepatology 2017;66:1601–1615).
Sofosbuvir and ribavirin in adolescents 12‐17 years old with hepatitis C virus genotype 2 or 3 infection
Authors: Wirth Stefan , Rosenthal Philip , Gonzalez‐Peralta Regino P. , Jonas Maureen M. , Balistreri William F. , Lin Chuan‐Hao , Hardikar Winita , Kersey Kathryn , Massetto Benedetta , Kanwar Bittoo , Brainard Diana M. , Shao Jiang , Svarovskaia Evguenia , Kirby Brian , Arnon Ronen , Murray Karen F. , Schwarz Kathleen B.
Published: May 2017

Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all‐oral combination of sofosbuvir and ribavirin in adolescents aged 12‐17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty‐two patients received sofosbuvir 400 mg once daily and weight‐based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS‐331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty‐three percent of patients were treatment‐naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%‐100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow‐up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS‐331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%‐200%. Conclusion: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102‐1110).
Prevalence and economic burden of extrahepatic manifestations of hepatitis C virus are underestimated but can be improved with therapy
Authors: Reau Nancy , Vekeman Francis , Wu Eric , Bao Yanjun , Gonzalez Yuri Sanchez
Published: May 2017

Despite guideline recommendations, access to hepatitis C virus (HCV) treatment is frequently restricted, with some payers approving therapy for only those with advanced disease or cirrhosis. However, delaying potentially curative treatment until the development of advanced liver disease may have costly consequences in terms of both hepatic complications and extrahepatic manifestations (EHMs) of HCV. Using a large claims database from the United States, we measured the risks and medical costs of 20 EHMs and investigated the role of treatment in different stages of liver fibrosis for mitigating the clinical and economic burden of these EHMs. After adjusting for potential confounders, including comorbid liver disease, patients with HCV had a significantly higher risk for any EHM (adjusted odds ratio, 2.23; P < 0.05) and higher EHM‐related annual medical costs (adjusted medical cost difference, $6,458; P < 0.05) compared to matched patients without HCV. HCV treatment can offset the higher medical costs in patients with HCV by saving ∼$25,000 in all‐cause medical costs per patient per year, with a large proportion attributable to savings in EHM‐related medical costs (adjusted cost difference $12,773, P < 0.05). Finally, additional EHM‐related medical costs could be saved by initiating HCV therapy in early stage fibrosis as opposed to late‐stage fibrosis (adjusted medical cost difference, $10,409; P < 0.05). Conclusion: The clinical and economic burden of EHMs is substantial and can be reduced through viral eradication, especially if treatment is initiated early and not delayed until fibrosis advances. Considering that the wholesale acquisition cost of a 12‐week course of therapy ranges from $55,000 to $147,000, the results of the current study suggest the cost of these treatments could be offset within 3 to 6 years by savings in all‐cause medical costs. (Hepatology Communications 2017;1:439–452)
Circulating tumor DNA profiling reveals clonal evolution and real‐time disease progression in advanced hepatocellular carcinoma
Authors: Cai Zhi‐Xiong , Chen Geng , Zeng Yong‐Yi , Dong Xiu‐Qing , Lin Min‐Jie , Huang Xin‐Hui , Zhang Da , Liu Xiao‐Long , Liu Jing‐Feng
Published: May 2017

Circulating tumor DNA (ctDNA) provides a potential non‐invasive biomarker for cancer diagnosis and prognosis, but whether it could reflect tumor heterogeneity and monitor therapeutic responses in hepatocellular carcinoma (HCC) is unclear. Focusing on 574 cancer genes known to harbor actionable mutations, we identified the mutation repertoire of HCC tissues, and monitored the corresponding ctDNA features in blood samples to evaluate its clinical significance. Analysis of 3 HCC patients' mutation profiles revealed that ctDNA could overcome tumor heterogeneity and provide information of tumor burden and prognosis. Further analysis was conducted on the 4th HCC case with multiple lesion samples and sequential plasma samples. We identified 160 subclonal SNVs in tumor tissues as well as matched peritumor tissues with PBMC as control. 96.9% of this patient's tissue mutations could be also detected in plasma samples. These subclonal SNVs were grouped into 9 clusters according to their trends of cellular prevalence shift in tumor tissues. Two clusters constituted of tumor stem somatic mutations showed circulating levels relating with cancer progression. Analysis of tumor somatic mutations revealed that circulating level of such tumor stem somatic mutations could reflect tumor burden and even predict prognosis earlier than traditional strategies. Furthermore, HCK (p.V174M), identified as a recurrent/metastatic related mutation site, could promote migration and invasion of HCC cells. Taken together, study of mutation profiles in biopsy and plasma samples in HCC patients showed that ctDNA could overcome tumor heterogeneity and real‐time track the therapeutic responses in the longitudinal monitoring.
Less overdiagnosis of kidney cancer? an age‐period‐cohort analysis of incidence trends in 16 populations worldwide
Authors: Znaor Ariana , Laversanne Mathieu , Bray Freddie
Published: May 2017

The increasing rates of kidney cancer incidence, reported in many populations globally, have been attributed both to increasing exposures to environmental risk factors, as well as increasing levels of incidental diagnosis due to widespread use of imaging. To better understand these trends, we examine long‐term cancer registry data worldwide, focusing on the roles of birth cohort and calendar period, proxies for changes in risk factor prevalence and detection practice respectively. We used an augmented version of the Cancer Incidence in Five Continents series to analyze kidney cancer incidence rates 1978‐2007 in 16 geographically representative populations worldwide by sex for ages 30‐74, using age‐period‐cohort (APC) analysis. The full APC model provided the best fit to the data in most studied populations. While kidney cancer incidence rates have been increasing in successive generations born from the early twentieth century in most countries, equivalent period‐specific rises were observed from the late‐1970s, although these have subsequently stabilized in certain European countries (the Czech Republic, Lithuania, Finland, Spain) as well as Japan from the mid‐1990s, and from the mid‐2000s, in Colombia, Costa Rica and Australia. Our results indicate that the effects of both birth cohort and calendar period contribute to the international kidney cancer incidence trends. While cohort‐specific increases may partly reflect the rising trends in obesity prevalence and the need for more effective primary prevention policies, the attenuations in period‐specific increases (observed in 8 of the 16 populations) highlight a possible change in imaging practices that could lead to mitigation of overdiagnosis and overtreatment.
Toward a CRISPR Picture: Use of CRISPR/Cas9 to Model Diseases in Human Stem Cells In Vitro
Authors: Freiermuth Jamie L. , Powell‐Castilla Ian J. , Gallicano G. Ian
Published: May 2017

Human induced pluripotent stem cells (iPSCs) can be differentiated into any cell in the body unlocking enormous research potential. Combined with the recent discovery of CRISPR/Cas9 endonucleases in bacteria and their modification for use in biomedical research, these methods have the potential to revolutionize the field of genetic engineering and open the door to generating in vitro models that more closely resemble the in vivo system than ever before. Use of CRISPR/Cas9 has created a whirlwind within the scientific community in the last few years, as the race to move beyond just disease analysis and toward the goal of gene and cell therapy moves further. This review will detail the CRISPR/Cas9 method and its use in stem cells as well as highlight recent studies that demonstrate its use in creating robust disease models. Finally, recent results and current controversies in the field are reviewed and lingering challenges to further development are explored. J. Cell. Biochem. 119: 62–68, 2018. © 2017 Wiley Periodicals, Inc.
The effect of substrate stiffness on cancer cell volume homeostasis
Authors: Wang Meng , Chai Na , Sha Baoyong , Guo Manyun , Zhuang Jian , Xu Feng , Li Fei
Published: May 2017

Existing studies on the mechanism of cell volume regulation are mainly relevant to ion channels and osmosis in extracellular fluid. Recently, accumulating evidence has shown that cellular mechanical microenvironment also influences the cell volume. Herein, we investigated the regulation of substrate stiffness on the cell volume homeostasis of MCF‐7 cells and their following migration behaviors. We found that cell volume increases with increasing substrate stiffness, which could be affected by blocking the cell membrane anion permeability and dopamine receptor. In addition, the cell migration is significantly inhibited by decreasing the cell volume using tamoxifen and such inhibition effect on migration is enhanced by increasing substrate stiffness. The cell membrane anion permeability might be the linker between cellular mechanical microenvironment and cellular volume homeostasis regulation. This work revealed the regulation of substrate stiffness on cell volume homeostasis for the first time, which would provide a new perspective into the understanding of cancer metastasis and a promising anti‐cancer therapy through regulation of cell volume homeostasis.
Low occurrence of HBsAg but high frequency of transient occult HBV infection in vaccinated and HBIG‐administered infants born to HBsAg positive mothers
Authors: Zhou Shan , Li Tingting , Allain Jean‐Pierre , Zhou Bin , Zhang Yuming , Zhong Mei , Fu Yongshui , Li Chengyao
Published: May 2017

The status of chronic and occult HBV infection (OBI) in neonatal hepatitis B vaccine and immunoglobulin (HBIG) vaccinated infants born to HBsAg+ mothers was investigated at a major hospital in China. Seventy‐seven and 15 blood samples were collected in first or second follow‐up detection from the vaccinated babies aged 3‐36 months born to 43 HBsAg+ or plus 25 HBeAg+ mothers. HBV infection was analyzed between the paired baby and mother by serology and DNA analysis. Among 77 children born to 68 HBsAg+ mothers, 3.9% (3/77) were HBsAg+, and 36.4% (28/77) were HBV DNA+/HBsAg− (OBIs) by a single PCR, respectively. Thirteen of 28 HBV DNA+/HBsAg− samples were conformed by two PCRs or S sequence, which accounted for 16.9% (13/77) of children. Three HBsAg+ and six OBIs were genotyped in consistent with their mother's HBV strains. Of 77 babies’ blood samples, anti‐HBs reactivity varied slightly according to age groups, while passively transmitted anti‐HBc reactivity declined from 100% high reactivity at age 3‐5 months to mostly negative at age ≥12 months. Babies with apparent OBI had higher levels of anti‐HBc and lower levels of anti‐HBs than those without OBI but all eight OBI babies with second follow‐up samples became HBV DNA negative beyond 1 year of age. The vaccinated infants born to HBsAg+ mothers presented the low rate of HBsAg occurrence as vaccination failure and high frequency of viral persistence in the form of transient OBIs since no evidence of active HBV infection occurred beyond 1 year of age.
Development of real‐time RT‐PCR assays for detection of three classes of HHV‐6A gene transcripts
Authors: Ihira Masaru , Urashima Akiko , Miura Hiroki , Hattori Fumihiko , Kawamura Yoshiki , Sugata Ken , Yoshikawa Tetsushi
Published: May 2017

Human herpesvirus 6 (HHV‐6), a member of the betaherpesvirus family, has two distinct species: HHV‐6A and HHV‐6B. HHV‐6B real‐time reverse transcription polymerase chain reaction (RT‐PCR) has been used to distinguish between active and latent viral infection. In this study, we developed a real‐time RT‐PCR assay to detect HHV‐6A‐specific transcripts and evaluated its reliability for analysis of clinical samples. To develop HHV‐6A‐specific real‐time RT‐PCR assays, three different classes of gene transcripts (immediate early: U90; early: U12; and late: U100) were selected as targets. Serial d ilutions of plasmid DNAs containing target sequences and RNAs extracted from HHV‐6A‐infected cells were used to determine assay specificity and sensitivity. Peripheral blood mononuclear cells (PBMCs) collected from patients with either primary or reactivated HHV‐6B infection, and one patient with X‐linked severe combined immunodeficiency (X‐SCID) with HHV‐6A reactivation, were used to evaluate assay reliability. The HHV‐6A‐specific real‐time RT‐PCR assays amplified plasmids containing the target sequences at concentrations between 10 and 1 × 106 copies per reaction. The intra‐assay coefficients of variation were less than 5%. The three classes of HHV‐6A gene transcripts were not detected in any HHV‐6B sample isolated from the patients. In the X‐SCID patient, high copy numbers of HHV‐6A U12 and U100 transcripts were detected in PBMC samples during viremia. Thus, we successfully established highly sensitive and reproducible real‐time RT‐PCR methods targeting three classes of HHV‐6A gene transcripts. This method should be useful for discriminating active HHV‐6A infection from either latent infection or chromosomally integrated HHV‐6A (ciHHV‐6A).