bluuebunny/crossref_metadata_2025 huggingface dataset:
Marine proteorhodopsins rival photosynthesis in solar energy capture
Authors: Gómez-Consarnau Laura , Levine Naomi M. , Cutter Lynda S. , Wang Deli , Seegers Brian , Arístegui Javier , Fuhrman Jed A. , Gasol Josep M. , Sañudo-Wilhelmy Sergio A.
Published: December 2017

All known phototrophic metabolisms on Earth are based on one of three energy-converting pigments: chlorophyll-a, bacteriochlorophyll-a, and retinal, which is the chromophore in rhodopsins [1]. While the contribution of chlorophylls to global energy flows and marine carbon cycling has been studied for decades, the role of retinal-based phototrophy remains largely unexplored [1,2]. We report the first vertical distributions of the three energy-converting pigments measured along a contrasting nutrient gradient through the Mediterranean Sea and the Eastern Atlantic Ocean. The highest proteorhodopsin concentrations were observed above the deep chlorophyll-amaxima, and their geographical distribution tended to be inversely related to that of chlorophyll-a. We further show that proteorhodopsins potentially absorb as much or more light energy than chlorophyll-a–based phototrophy and this energy is sufficient to sustain bacterial basal metabolism. Our results suggest that ubiquitous proteorhodopsin-containing heterotrophs are important contributors to the light energy captured in the sea.
Matrix-corrected mass spectrometry enables sensitive detection of food allergens and reveals widespread soy contamination of processed foods
Authors: Croote Derek , Braslavsky Ido , Quake Stephen R.
Published: December 2017

The frequent use of precautionary food allergen labeling statements such as “may contain” poses challenges to allergic individuals who rely on such labeling to determine whether a food is safe to consume. We developed a multiplexed liquid chromatography-mass spectrometry assay targeting 14 common allergens in order to survey how frequently these precautionary statements indicate allergen contamination and to assess whether variations in precautionary phrasing affect the likelihood of allergen contamination. A survey of 84 foods revealed how scheduled multiple reaction monitoring (MRM) transition interference derived from complex and heterogeneous sample matrices hinders sensitive analyte detection. As a solution, we developed MAtrix-Dependent Interference Correction (MADIC), an approach to sensitively detect trace peptide quantities through interference identification and stringent peptide quality control criteria. Applying this method, we find frequent contamination of soy in breads and corn flour, and observe additional instances of food contamination with tree nuts, wheat, milk, and egg. In some of these cases, the food had no precautionary labeling for the offending allergen. We also find that only 10% of warning labels are indicative of contamination, and that products with “same facility” precautionary labeling are not necessarily less likely to contain trace amounts of allergens than products labeled “may contain.”
A Multifactorial Model of T Cell Expansion and Durable Clinical Benefit in Response to a PD-L1 Inhibitor
Authors: Leiserson Mark DM , Syrgkanis Vasilis , Gilson Amy , Dudik Miroslav , Gillett Sharon , Chayes Jennifer , Borgs Christian , Bajorin Dean F , Rosenberg Jonathan , Funt Samuel , Snyder Alexandra , Mackey Lester
Published: December 2017

Checkpoint inhibitor immunotherapies have had major success in treating patients with late-stage cancers, yet the minority of patients benefit [1]. Mutation load and PD-L1 staining are leading biomarkers associated with response, but each is an imperfect predictor. A key challenge to predicting response is modeling the interaction between the tumor and immune system. We begin to address this challenge with a multifactorial model for response to anti-PD-L1 therapy. We train a model to predict immune response in patients after treatment based on 36 clinical, tumor, and circulating features collected prior to treatment. We analyze data from 21 bladder cancer patients [2] using the elastic net high-dimensional regression procedure [3] and, as training set error is a biased and overly optimistic measure of prediction error, we use leave-one-out cross-validation to obtain unbiased estimates of accuracy on held-out patients. In held-out patients, the model explains 79% of the variance in T cell clonal expansion. This predicted immune response is multifactorial, as the variance explained is at most 23% if clinical, tumor, or circulating features are excluded. Moreover, if patients are triaged according to predicted expansion, only 38% of non-durable clinical benefit (DCB) patients need be treated to ensure that 100% of DCB patients are treated. In contrast, using mutation load or PD-L1 staining alone, one must treat at least 77% of non-DCB patients to ensure that all DCB patients receive treatment. Thus, integrative models of immune response may improve our ability to anticipate clinical benefit of immunotherapy.
Rif1 prolongs the embryonic S phase at the Drosophila mid-blastula transition
Authors: Seller Charles A , O’Farrell Patrick H
Published: December 2017

In preparation for dramatic morphogenetic events of gastrulation, rapid embryonic cell cycles slow at the Mid-Blastula Transition, MBT. In Drosophila melanogaster embryos, downregulation of Cdk1 activity initiates this slowing by delaying replication of satellite sequences and extending S phase. We found that Cdk1 inhibited the chromatin association of Rif1, a candidate repressor of replication. Furthermore, Rif1 bound selectively to satellite sequences following Cdk1 downregulation at the MBT. In the next S phase, Rif1 dissociated from different satellites in an orderly schedule that anticipated their replication. Rif1 lacking potential phosphorylation sites failed to dissociate and dominantly prevented completion of replication. Loss of Rif1 in mutant embryos shortened the post-MBT S phase, and rescued embryonic cell cycles disrupted by depletion of the S phase-promoting kinase, Cdc7. Thus, Drosophila Rif1 mediates the MBT extension of S phase and functionally interacts with S phase promoting kinases to introduce a replication-timing program.
BRUTUS-LIKE proteins moderate the transcriptional response to iron deficiency in roots
Authors: Rodríguez-Celma Jorge , Green Robert T. , Connorton James M. , Kruse Inga , Cui Yan , Ling Hong Qing , Balk Janneke
Published: December 2017

Iron is an essential micronutrient but in excess is toxic inside cells. Under iron deficiency, the expression of iron uptake genes is increased, but it is not known how the transcriptional response is controlled to avoid uptake of too much iron. The hemerythrin E3 ligases BRUTUS (BTS) and BTS-LIKE (BTSL) have previously been identified as negative regulators of the iron deficiency response. Our phylogenetic analysis indicated that BTSL proteins are present in dicotyledonous plants only and form a separate clade from BTS homologs.BTSL1andBTSL2inArabidopsis thalianaare in a network with nearly all iron uptake genes, whereasBTSis in a shoot-specific network.BTSL1andBTSL2are expressed predominantly in the root epidermis and cortex, separate fromBTSin the root stele, shoot and embryos. Mutant analysis identifiedBTSL2as the dominant paralog of the otherwise redundantBTSLgenes. Thebtsldouble mutant had increased protein levels of FIT, the FER-like Iron deficiency-induced Transcription factor, and failed to switch off the transcriptional response upon iron resupply, leading to dramatic iron accumulation in roots and shoots. Protein interaction between the C-terminus of BTSL proteins and FIT indicate that FIT is a direct target for degradation. Taken together, our studies show thatBTSL1andBTSL2control iron uptake in the epidermis and cortex, upstream of BTS in the vasculature and leaves.
Cell-type specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
Authors: Zhang Tongwu , Choi Jiyeon , Kovacs Michael A. , Shi Jianxin , Xu Mai ,   NISC Comparative Sequencing Program,   Melanoma, Meta-Analysis Consortium, Goldstein Alisa M. , Iles Mark M. , Duffy David , MacGregor Stuart , Amundadottir Laufey T. , Law Matthew H. , Loftus Stacie K. , Pavan William J. , Brown Kevin M.
Published: December 2017

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335cis-eQTL SNPs prior to LD-pruning and 4,997 eGenes (FDR<0.05), which are higher numbers than in any GTEx tissue type with a similar sample size. Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were not observed to be eGenes in two types of GTEx skin tissues or TCGA melanoma samples. The melanocyte dataset also identified cell-type specifictrans-eQTLs with a pigmentation-associated SNP for four genes, likely through itscis-regulation ofIRF4, encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched incis-regulatory signatures found in melanocytes as well as melanoma-associated variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for six known GWAS loci including unique genes identified by the melanocyte dataset. Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, andRP11-383H13.1) were associated with melanoma at genome-wide significantP-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.
Statistical Approaches to Decreasing the Discrepancy of Non-detects in qPCR Data
Authors: Sherina Valeriia , McMurray Helene R. , Powers Winslow , Land Hartmut , Love Tanzy M.T. , McCall Matthew N.
Published: December 2017

Quantitative real-time PCR (qPCR) is one of the most widely used methods to measure gene expression. Despite extensive research in qPCR laboratory protocols, normalization, and statistical analysis, little attention has been given to qPCR non-detects – those reactions failing to produce a minimum amount of signal. While most current software replaces these non-detects with a value representing the limit of detection, recent work suggests that this introduces substantial bias in estimation of both absolute and differential expression. Recently developed single imputation procedures, while better than previously used methods, underestimate residual variance, which can lead to anti-conservative inference. We propose to treat non-detects as non-random missing data, model the missing data mechanism, and use this model to impute missing values or obtain direct estimates of relevant model parameters. To account for the uncertainty inherent in the imputation, we propose a multiple imputation procedure, which provides a set of plausible values for each non-detect. In the proposed modeling framework, there are three sources of uncertainty: parameter estimation, the missing data mechanism, and measurement error. All three sources of variability are incorporated in the multiple imputation and direct estimation algorithms. We demonstrate the applicability of these methods on three real qPCR data sets and perform an extensive simulation study to assess model sensitivity to misspecification of the missing data mechanism, to the number of replicates within the sample, and to the overall size of the data set. The proposed methods result in unbiased estimates of the model parameters; therefore, these approaches may be beneficial when estimating both absolute and differential gene expression. The developed methods are implemented in the R/Bioconductor package nondetects. The statistical methods introduced here reduce discrepancies in gene expression values derived from qPCR experiments, providing more confidence in generating scientific hypotheses and performing downstream analysis.
Linked-Read sequencing resolves complex structural variants
Authors: Garcia Sarah , Williams Stephen , Xu Andrew Wei , Herschleb Jill , Marks Patrick , Stafford David , Church Deanna M.
Published: December 2017

Large genomic structural variants (>50bp) are important contributors to disease, yet they remain one of the most difficult types of variation to accurately ascertain, in part because they tend to cluster in duplicated and repetitive regions, but also because the various signals for these events can be challenging to detect with short reads. Clinically, aCGH and karyotype remain the most commonly used assays for genome-wide structural variant (SV) detection, though there is clear potential benefit to an NGS-based assay that accurately detects both SVs and single nucleotide variants. Linked-Read sequencing is a relatively simple, fast, and cost-effective method that is applicable to both genome and targeted assays. Linked-Reads are generated by performing haplotype-level dilution of long input DNA molecules into >1 million barcoded partitions, generating barcoded short reads within those partitions, and then performing short read sequencing in bulk. We performed 30x Linked-Read genome sequencing on a set of 23 samples with known balanced or unbalanced SVs. Twenty-seven of the 29 known events were detected and another event was called as a candidate. Sequence downsampling was performed on a subset to determine the lowest sequence depth required to detect variations. Copy-number variants can be called with as little as 1-2x sequencing depth (5-10Gb) while balanced events require on the order of 10x coverage for variant calls to be made, although specific signal is clearly present at 1-2x sequencing depth. In addition to detecting a full spectrum of variant types with a single test, Linked-Read sequencing provides base-level resolution of breakpoints, enabling complete resolution of even the most complex chromosomal rearrangements.
Teaching data science fundamentals through realistic synthetic clinical cardiovascular data
Authors: Laderas Ted , Vasilevsky Nicole , Pederson Bjorn , Haendel Melissa , McWeeney Shannon , Dorr David A.
Published: December 2017

Objective

Our goal was to create a synthetic dataset and curricular materials to assist in teaching fundamentals of translational data science.

Materials and Methods

A literature review was conducted to extract current cardiovascular risk score logic, data elements, and population characteristics. Then, clinical data elements in the models were pulled from clinical data and transformed to the Observational Medical Outcomes Partnership (OMOP) common data model; genetic data elements were added based on population rates. A hybrid Bayesian network was used to create synthetic data from the logical elements of the risk scores and the underlying population frequencies of the clinical data.

Results

A synthetic dataset of 446,000 patients was created. A two-day curriculum was created based on this synthetic data with exploratory data analysis and machine learning components. The curriculum was offered on two separate occasions; the two groups of learners were given the curriculum and data, and results were tallied, summarized, and compared. Students’ ability to complete the challenge was mixed; more experienced students achieved a range of 70%-85% in balanced accuracy, but many others did not perform better than the baseline model.

Discussion

Overall, students enjoyed the course and dataset, but some struggled to consistently apply machine learning techniques. The curriculum, data set, techniques for generation, and results are available for others to use for their own training.

Conclusion

A realistic synthetic data with clinical and genetic components helps students learn issues in cardiovascular risk scoring, practice data science skills, and compete in a challenge to improve identification of risk.
The soft side of branding: leveraging emotional intelligence
Authors: Hutchins Jennifer , Rodriguez Darlene Xiomara
Published: December 2017

Purpose

The purpose of this paper is to support the need for further research and theory building on emotions in business-to-business (B2B) industries. Specifically, this research conceptualizes emotional intelligence (EI) as an alternative to building brand equity for B2B companies beyond name recognition, product quality and catchy slogans. Additionally, the authors closely analyze social media content marketing by B2Bs as a channel through which to exercise EI with the goal of enhancing brand image and growing brand equity.

Design/methodology/approach

This study takes a conceptual approach, building on current literature to develop a model of functional and emotional paths to B2B brand equity. The study uses content analysis methodology to examine 11 “best in class” B2B companies recognized for their social media content marketing. The analysis reveals the level to which each company demonstrates the collective EI of the firm through content marketing.

Findings

EI is a learned skill that can be an essential behavioral asset. In addition to hard skills such as product development and process refinement, leveraging a firm’s soft skills and collective EI is also a viable route to increasing brand equity. Additionally, B2B companies that are considered the best at content marketing demonstrate EI through their online communication strategies.

Research limitations/implications

This research reveals another avenue through which B2B firms to increase brand equity, but there is a need to empirically validate the model and connections made in this paper.

Practical implications

Leveraging EI in B2B firms through content marketing is a source of or key driver of competitive advantage and increased brand equity.

Originality/value

By providing the history and importance of EI, and by connecting existing knowledge of B2B communications to concepts of improving brand equity, this study offers a unique, extended framework that urges further research to expand this field.
Emotional intelligence and organizational learning at trade shows
Authors: Bettis-Outland Harriette , Guillory Monica D.
Published: December 2017

Purpose

This paper aims to illustrate the interface between emotional intelligence (EI), trust and organizational learning in the context of a trade show environment.

Design/methodology/approach

Theoretical underpinnings of this conceptual study include appraisal theory of emotions. Propositions are presented that suggest positive relationships between antecedent variables, EI and trust, contrasted with the dependent variable, organizational learning.

Findings

Organizational learning is generally considered to be a benign activity, created by the acquisition and dissemination of new information. The outcome of organizational learning is the development of new knowledge that ultimately results in a shared interpretation among members of the organization. This paper suggests that a lack of EI, defined as “the ability to perceive and express emotion, assimilate emotion in thought, understand and reason with emotion, and regulate emotion in the self and others” (Mayer et al., 2000, p. 396), casts doubt on the motives of newly acquired information. Consequently, low levels of EI can inhibit the acceptance of new information, leading to a reduction of learning by the organization.

Originality/value

This paper extends the concept of organizational learning by incorporating EI and trust as antecedents of organizational learning. Previous research suggests a direct relationship between information acquisition, dissemination and organizational learning. This study implies that other factors can intervene after information is acquired, thereby affecting whether newly acquired information is fully incorporated into the organizational learning process.
Trust and duration of buyer-seller relationship in emerging markets
Authors: Dadzie Kofi Q. , Dadzie Charlene A. , Williams Alvin J.
Published: December 2017

Purpose

This study aims to examine how various components of interpersonal trust (affective and cognitive) influence the duration of buyer-seller relationships in the emerging market (EM) context of a heterogeneous market structure dominated by small, fragmented sellers/suppliers.

Design/methodology/approach

The study proposes a hazard model for analyzing duration effects of interpersonal trust in the EM context. The model was validated using data on buying agents provided by 340 cocoa sellers/producers in Ghana, gathered from extensive field interviews.

Findings

Results of the survival analysis reveal a limited but significant positive duration effect of cognitive (ability) trust only. Further analysis of sellers’ duration intentions (intention to remain with a buyer) also reveals a positive impact of affective trust but no impact of cognitive (ability and integrity) trust. Cocoa bean sellers’ evaluation of buying firms’ purchasing agents suggests that buying firms underperform on emotional/affective components of interpersonal trust, and that private firms outperform state buying agents on ability trust as well.

Research limitations/implications

While this study focused on the fragmented nature of sellers in the EM context, and the scope was limited to the sellers’ interpersonal trust perception of the buyer-seller, future research should examine both buyer and seller perceptions to obtain complete insight into the buyer-seller dyad in the EM context. In addition, the results of the duration effects identified in this study may not be generalizable to other EM export commodities, where channels have long been fully privatized. Ghana’s cocoa export marketing system was only recently privatized, and potentially has more sellers at the risk of adopting/switching relationships with their buyers than would be expected in more privatized expert commodity marketing systems.

Practical implications

Managers of export commodity buying firms in EMs can take advantage of the positive duration effects of cognitive trust by constantly improving the capabilities of their purchasing agents throughout the lifetime of their suppliers to sustain their relationship. However, sellers’ intention to switch can be mitigated by formalizing policies that encourage emotional bonds with sellers, especially small-scale producers in highly vulnerable bargaining positions. The aggregate output of small-scale producers could be of strategic importance in the future.

Originality/value

Managers need systematic empirical evidence of the nature of duration effects of interpersonal trust given anecdotal evidence suggesting that managers have a tendency to emphasize cognitive trust over affective/emotional trust. Further, the applicability of such evidence in the EM context is critical given unique conditions such as highly fragmented sellers dealing with relatively large corporations.
Co‐Administration of Low‐Dose Naltrexone and Bupropion Reduces Alcohol Drinking in Alcohol‐Preferring (P) Rats
Authors: Nicholson Emily R. , Dilley Julian E. , Froehlich Janice C.
Published: December 2017

Background

This study examined whether combining naltrexone (NTX) with bupropion (BUP) is more effective in reducing alcohol drinking in alcohol‐preferring (P) rats with a genetic predisposition toward high voluntary alcohol intake than either drug alone.

Methods

Alcohol‐experienced, adult, male, P rats were fed NTX alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 10.0 mg/kg BW, BUP alone in a dose of 20.0 mg/kg BW, NTX (10.0 mg/kg BW) + BUP (10.0 mg/kg BW), or vehicle (VEH) at 1 hour prior to onset of a daily 2‐hour alcohol access period for 5 consecutive days.

Results

When administered alone, neither NTX (10.0 mg/kg BW) nor BUP, in either of 2 doses (10.0 mg/kg BW or 20.0 mg/kg BW), reduced voluntary alcohol intake in P rats. However, NTX combined with BUP (10.0 mg/kg NTX + 10.0 mg/kg BUP) and given as a single medication significantly reduced alcohol consumption throughout prolonged treatment.

Conclusions

Combining low doses of NTX and BUP, each of which is ineffective when given alone, increases the efficacy of the medication. Low drug doses circumvent the problem of negative side effects that can occur with higher doses of either drug. A reduction in side effects can facilitate patient compliance and improve clinical outcomes for alcoholics and heavy drinkers who want to reduce their alcohol intake. The results, together with those from our prior studies, demonstrate the strength of a combinatorial pharmacotherapeutic approach to the treatment of alcohol use disorder.
Associations Between MAOA‐uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males
Authors: Bendre Megha , Comasco Erika , Checknita Dave , Tiihonen Jari , Hodgins Sheilagh , Nilsson Kent W.
Published: December 2017

Background

Epigenetic mechanisms are candidate moderators of the effect of maltreatment on brain and behavior. Interactions between maltreatment and the monoamine oxidase A upstream variable number tandem repeat genotype (MAOA‐uVNTR) are associated with alcohol‐related problems. However, presently it is not known whether DNA methylation moderates this association. The study focused on 53 young adult males and aimed to determine whether MAOA methylation moderated the association of alcohol‐related problems with the interaction of MAOA‐uVNTR and maltreatment, and whether alcohol consumption moderated the association of MAOA methylation with the interaction of MAOA‐uVNTR and maltreatment.

Methods

MAOA‐uVNTR genotypes with ≤ 3 and > 3 repeats were categorized as short (S) and long (L), respectively. Data on maltreatment were obtained retrospectively, using self‐reported questionnaires. DNA methylation of 16 candidate CpGs within part of the MAOA first exon and intron was assessed and grouped based on principal component analyses. Alcohol‐related problems were assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was measured using AUDIT‐C. Moderation effects were assessed and probed using the moderated moderation model and Johnson–Neyman's method, respectively.

Results

Carriers of the S allele, who experienced maltreatment and displayed lower Component 1 (mean of CpGs 13–16 in the first intron) MAOA methylation levels, reported higher AUDIT score in contrast to L‐allele carriers. Carriers of the S allele, who reported higher AUDIT‐C score and experienced maltreatment, displayed lower Component 3 (mean of CpGs 2–6 in the first exon) MAOA methylation levels than L‐allele carriers.

Conclusions

Intronic methylation moderated the association of alcohol‐related problems with the interaction of MAOA‐uVNTR and maltreatment. Alcohol consumption moderated the association of exonic methylation with the interaction of MAOA‐uVNTR and maltreatment. These results suggest that epigenetic factors as well as genotype and maltreatment play a role in the development of alcohol misuse among young adult males.
Monocytes enhance neutrophil‐induced blister formation in an ex vivo model of bullous pemphigoid
Authors: de Graauw E. , Sitaru C. , Horn M. P. , Borradori L. , Yousefi S. , Simon D. , Simon H.‐U.
Published: December 2017

Background

Lesions of bullous pemphigoid (BP), an autoimmune subepidermal blistering disease characterized by the presence of tissue‐bound and circulating autoantibodies to hemidesmosomal antigens, harbor a mixed inflammatory cellular infiltrate. In various models, neutrophils, eosinophils, mast cells, monocytes as well as B and T cells have been shown to be involved in the pathogenesis of BP. However, their interactions with and effective role in blister formation remain uncertain. This study was aimed at investigating the effect of monocyte/neutrophil interaction on blister formation in an ex vivo BP model.

Methods

Skin cryosections were incubated with purified human neutrophils and monocytes, in the presence or absence of BP autoantibodies. Production of reactive oxygen species (ROS), degranulation, mediator release (neutrophil elastase [NE], myeloperoxidase [MPO], matrix metalloproteinase‐9 [MMP‐9]), binding of Fcγ receptor (CD16, CD32, CD64), and cell adhesion (CD18, ICAM‐1) was investigated using appropriate inhibitors. Dermal‐epidermal separation (DES) was assessed by light microscopy and quantified by Fiji software.

Results

Monocytes and neutrophils synergistically interact resulting in a significantly higher DES compared to either monocytes or neutrophils separately (P < .0001). Monocyte/neutrophil‐induced DES was associated with increased ROS production and was dependent on adhesion and FcγRIII binding. Upon stimulation by the granule‐poor fraction of monocyte supernatants, neutrophils increased their release of MMP‐9, thereby also DES at the dermal‐epidermal junction of skin cryosections.

Conclusion

Our observations suggest that the interaction of cells, as shown here for monocytes and neutrophils, enhances mediator release resulting in an increased subepidermal blister formation. Thus, blocking intercellular cross talk promises a new therapeutic approach for blocking tissue damage in BP.
Sudden Anthropology: Phantom Homes
Authors: Walsh Michaela Django
Published: December 2017

This piece reflects on how recursive migratory patterns between Mexico and the United States have affected the geography of an indigenous pueblo in central Mexico, reshaping visions and ideals of home. [migration, Las Vegas, construction, Mexico, indigenous]
Automated refraction is stable 1 week after uncomplicated cataract surgery
Authors: Ostri Christoffer , Holfort Stig K. , Fich Marianne S. , Riise Per
Published: December 2017

Purpose

To compare automated refraction 1 week and 1 month after uncomplicated cataract surgery.

Methods

In this prospective cohort study, we recruited patients in a 2‐month period and included consecutive patients scheduled for bilateral small‐incision phacoemulsification cataract surgery. The exclusion criteria were (i) corneal and/or retinal pathology that could lead to automated refraction miscalculation and (ii) surgery complications. Automated refraction was measured 1 week and 1 month after surgery.

Results

Ninety‐five patients met the in‐ and exclusion criteria and completed follow‐up. The mean refractive shift in spherical equivalent was −0.02 dioptre (D) between 1 week and 1 month after surgery and not statistical significant (p = 0.78, paired t‐test). The magnitude of refractive shift in either myopic or hyperopic direction was neither correlated to age, preoperative corneal astigmatism, axial length nor phacoemulsification energy used during surgery (p > 0.05 for all variables, regression analysis). The refractive target was missed with 1.0 D or more in 11 (12%) patients. In this subgroup, the mean refractive shift in spherical equivalent was 0.49 D between 1 week and 1 month after surgery with a trend towards statistical significance (p = 0.07, paired t‐test). There was no difference in age, preoperative corneal astigmatism, axial length or phacoemulsification energy used during surgery compared to the remainder of the patients (p > 0.05 for all variables, unpaired t‐test).

Conclusion

Automated refraction is stabile 1 week after uncomplicated cataract surgery, but there is a trend towards instability, if the refractive target is missed with 1.0 D or more.
The effect of administration of copper nanoparticles to chickens in their drinking water on the immune and antioxidant status of the blood
Authors: Ognik Katarzyna , Sembratowicz Iwona , Cholewińska Ewelina , Jankowski Jan , Kozłowski Krzysztof , Juśkiewicz Jerzy , Zduńczyk Zenon
Published: December 2017

The aim of this experiment was to determine what dosage of copper (Cu) nanoparticles, added to a standard dietary supplementation with copper sulfate, would improve antioxidant and immune defense in chickens. The experiment was conducted with 126 broiler chickens assigned to seven treatments with three pens per treatment and six broiler chickens per pen. The basal‐diet treatment did not receive Cu nanoparticles (nano‐Cu) and as shown by analyses it was Cu‐deficient (−29% vs. National Research Council (NRC) recommendations; 5.7 vs. 8 mg/kg). Broiler chickens received nano‐Cu (0.5, 1.0 or 1.5 mg/kg body weight per day) via a tube into the crop over three 3‐day periods (days 8–10, 22–24 and 36–38) or three 7‐day periods (days 8–14, 22–28 and 36–42). As a result, in the nano‐Cu‐treated broilers the total experimental Cu intake was from −11% to +96% versus NRC recommendations. At the age of 42 days of broilers, their blood indices were determined. The obtained results showed that correction of the deficient basal diet of chickens with nano‐Cu to a level of copper exceeding the NRC recommendation by 54% increased the antioxidant potential of the organism and inhibited lipid peroxidation. At the dosage of +96% versus NRC, some symptoms of a deterioration in antioxidant status appeared (a decrease in the level of glutathione plus glutathione disulfide and an increase in superoxide dismutase, catalase and ceruloplasmin activity and in lipid hydroperoxide content). Additionally, +7% versus the recommended Cu dietary level was followed by unfavorable results, indicating a deterioration in red blood cell parameters and stimulation of the immune system (an increase in interleukin‐6, immunoglobulin A (IgA), IgM and IgY). To conclude, it was shown that it is possible to simultaneously increase antioxidant and immune defense of chickens by supplementing their diets with nano‐Cu – up to 12 mg per bird during 6 weeks of feeding, that is to a level no more than 7% over the NRC recommendation for growing broiler chickens.
Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts
Authors: Zrzavy Tobias , Machado‐Santos Joana , Christine Sheren , Baumgartner Christoph , Weiner Howard L. , Butovsky Oleg , Lassmann Hans
Published: December 2017

Inflammatory mechanisms, involving granulocytes, T‐cells, B‐cells, macrophages and activated microglia, have been suggested to play a pathogenic role in experimental models of stroke and may be targets for therapeutic intervention. However, knowledge on the inflammatory response in human stroke lesions is limited. Here, we performed a quantitative study on the inflammatory reaction in human ischemic infarct lesions. We found increased numbers of T‐lymphocytes, mainly CD8+ cells, but not of B‐lymphocytes. Their number was very low in comparison to that seen in inflammatory diseases of the central nervous system and they did not show signs of activation. Polymorphonuclear leukocytes were present in meninges and less prominently in the perivascular space in early lesions, but their infiltration into the lesioned tissue was sparse with the exception of a single case. Microglia were lost in the necrotic core of fresh lesions, their number was increased in the surrounding penumbra, apparently due to proliferation. Using TMEM119 as a marker for the resident microglia pool, macrophages in lesions were in part derived from the original microglia pool, depending on the lesion stage. Most microglia and macrophages revealed a pro‐inflammatory activation pattern, expressing molecules involved in phagocytosis, oxidative injury, antigen presentation and iron metabolism and had partially lost the expression of P2RY12, an antigen expressed on homeostatic (“resting”) microglia in rodents. At later lesion stages, the majority of macrophages showed intermediate activation patterns, expressing pro‐inflammatory and anti‐inflammatory markers. Microglia in the normal white matter of controls and stroke patients were already partly activated toward a pro‐inflammatory phenotype. Our data suggest that the direct contribution of lymphocytes and granulocytes to active tissue injury in human ischemic infarct lesions is limited and that stroke therapy that targets pro‐inflammatory microglia and macrophage activation may be effective.
RELN signaling modulates glioblastoma growth and substrate‐dependent migration
Authors: Schulze Markus , Violonchi Christ , Swoboda Stefan , Welz Tobias , Kerkhoff Eugen , Hoja Sabine , Brüggemann Susanne , Simbürger Johann , Reinders Jörg , Riemenschneider Markus J.
Published: December 2017

Glioblastoma (GBM) represents the most common and most malignant type of primary brain tumor and significantly contributes to cancer morbidity and mortality. Invasion into the healthy brain parenchyma is a major feature of glioblastoma aggressiveness. Reelin (RELN) is a large secreted extracellular matrix glycoprotein that regulates neuronal migration and positioning in the developing brain and sustains functionality in the adult brain. We here show that both RELN and its main downstream effector DAB1 are silenced in glioblastoma as compared to non‐neoplastic tissue and mRNA expression is inversely correlated with malignancy grade. Furthermore, RELN expression is positively correlated with patient survival in two large, independent clinically annotated datasets. RELN silencing occurs via promoter hypermethylation as shown by both database mining and bisulfite sequencing of the RELN promoter. Consequently, treatment with 5′‐Azacytidine and trichostatin A induced RELN expression in vitro. On the functional level, we found RELN to regulate glioblastoma cell migration both in a DAB1 (tyrosine phosphorylation)‐dependent and ‐independent fashion, depending on the substrate provided. Moreover, stimulation of RELN signaling strongly reduced proliferation in glioblastoma cells. This phenotype depends on DAB1 stimulation by RELN, as a mutant that lacks all RELN induced tyrosine phosphorylation sites (DAB1‐5F) failed to induce a growth arrest. Proteomic analyzes revealed that these effects are mediated by a reduction in E2F targets and dephosphorylation of ERK1/2. Taken together, our data establish a relevance of RELN signaling in glioblastoma pathology and thereby might unearth novel, yet unrecognized treatment options.
Anti‐Parkinsonian and anti‐dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists
Authors: Arcuri Ludovico , Novello Salvatore , Frassineti Martina , Mercatelli Daniela , Pisanò Clarissa Anna , Morella Ilaria , Fasano Stefania , Journigan Blair V , Meyer Michael E , Polgar Willma E , Brambilla Riccardo , Zaveri Nurulain T , Morari Michele
Published: December 2017

Background and Purpose

We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa‐induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT‐390 and AT‐403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression.

Experimental Approach

Binding affinity and functional efficacy of AT‐390 and AT‐403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti‐Parkinsonian activity was evaluated in 6‐hydroxydopamine hemi‐lesioned rats whereas the anti‐dyskinetic properties were assessed in 6‐hydroxydopamine hemi‐lesioned rats chronically treated with levodopa. The ability of AT‐403 to inhibit the D1 receptor‐induced phosphorylation of striatal ERK was investigated.

Key Results

AT‐390 and AT‐403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT‐403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT‐390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT‐403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT‐403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo.

Conclusions and Implications

NOP receptor stimulation can provide significant albeit mild anti‐dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT‐403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.
Synthesis of novel norsufentanil analogs via a four‐component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity
Authors: Nami Majid , Salehi Peyman , Dabiri Minoo , Bararjanian Morteza , Gharaghani Sajjad , Khoramjouy Mona , Al‐Harrasi Ahmed , Faizi Mehrdad
Published: December 2017

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four‐component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta‐opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure–activity relationship model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil and norsufentanil.
New hydrazide–hydrazones of isonicotinic acid: synthesis, lipophilicity and in vitro antimicrobial screening
Authors: Popiołek Łukasz , Biernasiuk Anna , Berecka Anna , Gumieniczek Anna , Malm Anna , Wujec Monika
Published: December 2017

This study describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide–hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed‐phase thin‐layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram‐positive bacteria, Gram‐negative bacteria and fungi belonging to Candida spp. Some of the synthesized hydrazide–hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents.
Shyness and Trajectories of Functional Network Connectivity Over Early Adolescence
Authors: Sylvester Chad M. , Whalen Diana J. , Belden Andy C. , Sanchez Shana L. , Luby Joan L. , Barch Deanna M.
Published: December 2017

High shyness during early adolescence is associated with impaired peer relationships and risk for psychiatric disorders. Little is known, however, about the relation between shyness and trajectories of brain development over early adolescence. The current study longitudinally examined trajectories of resting‐state functional connectivity (rs‐fc) within four brain networks in 147 adolescents. Subjects underwent functional magnetic resonance imaging at three different time points, at average ages 10.5 (range = 7.8–13.0), 11.7 (range = 9.3–14.1), and 12.9 years (range = 10.1–15.2). Multilevel linear modeling indicated that high shyness was associated with a less steep negative slope of default mode network (DMN) rs‐fc over early adolescence relative to low shyness. Less steep decreases in DMN rs‐fc may relate to increased self‐focus in adolescents with high shyness.
Digital Screen Time Limits and Young Children's Psychological Well‐Being: Evidence From a Population‐Based Study
Authors: Przybylski Andrew K. , Weinstein Netta
Published: December 2017

There is little empirical understanding of how young children's screen engagement links to their well‐being. Data from 19,957 telephone interviews with parents of 2‐ to 5‐year‐olds assessed their children's digital screen use and psychological well‐being in terms of caregiver attachment, resilience, curiosity, and positive affect in the past month. Evidence did not support implementing limits (< 1 or < 2 hr/day) as recommended by the American Academy of Pediatrics, once variability in child ethnicity, age, gender, household income, and caregiver educational attainment were considered. Yet, small parabolic functions linked screen time to attachment and positive affect. Results suggest a critical cost–benefit analysis is needed to determine whether setting firm limits constitutes a judicious use of caregiver and professional resources.
Effective network of deep brain stimulation of subthalamic nucleus with bimodal positron emission tomography/functional magnetic resonance imaging in Parkinson's disease
Authors: Chen Hui‐Min , Sha Zhi‐Qiang , Ma Hui‐Zi , He Yong , Feng Tao
Published: December 2017

Aims

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) has become an effective treatment strategy for patients with Parkinson's disease. However, the biological mechanism underlying DBS treatment remains poorly understood.

Method

In this study, we investigated how STN‐DBS modulated the brain network using a bimodal positron emission tomography (PET)/functional magnetic resonance imaging (fMRI) dataset. We first performed an activation likelihood estimation meta‐analysis of 13 PET/SPECT studies concerning STN‐DBS effects on resting‐state brain activity in Parkinson's disease. Additionally, using a functional connectivity analysis in resting‐state fMRI, we investigated whether these STN‐DBS‐affected regions were functionally connected to constitute an effective network.

Results

The results revealed that STN‐DBS reduced brain activity in the right thalamus, bilateral caudal supplementary area, and the left primary motor cortex, and it increased brain activity in the left thalamus during rest. Second, these STN‐DBS‐affected areas were functionally connected within an STN‐DBS effective network.

Conclusion

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) may deactivate the motor cortex as a remote and network effect, affecting the target and the neighboring subcortical areas. These areas may constitute an effective network of STN‐DBS modulation. Our results shed light on the mechanisms of STN‐DBS treatment from a network perspective and highlight the potential therapeutic benefits of targeted network modulation.