bluuebunny/crossref_metadata_2025 huggingface dataset:
Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release
Authors: Tagliatti Erica , Bello Oscar D. , Mendonça Philipe R. F. , Kotzadimitriou Dimitrios , Nicholson Elizabeth , Coleman Jeff , Timofeeva Yulia , Rothman James E. , Krishnakumar Shyam S. , Volynski Kirill E.
Published: March 2019

Synaptotagmin1 (Syt1) synchronises neurotransmitter release to action potentials acting as the fast Ca2+ release sensor and as the inhibitor (clamp) of spontaneous and delayed asynchronous release. Whilst the Syt1 Ca2+ activation mechanism has been well characterised, how Syt1 clamps transmitter release remains enigmatic. Here we show that C2B domain-dependent oligomerisation provides the molecular basis for the Syt1 clamping function. This follows from the investigation of a designed mutation (F349A), which selectively destabilises Syt1 oligomerisation. Using combination of fluorescence imaging and electrophysiology in neocortical synapses we show that Syt1F349A is more efficient than wild type Syt1 (Syt1WT) in triggering synchronous transmitter release but fails to clamp spontaneous and Synaptotagmin7 (Syt7)-mediated asynchronous release components both in rescue (Syt1−/− knock-out background) and dominant-interference (Syt1+/+ background) conditions. Thus we conclude that Ca2+-sensitive Syt1 oligomers, acting as an exocytosis clamp, are critical for maintaining the balance among the different modes of neurotransmitter release.
Crosstalk and Ultrasensitivity in Protein Degradation Pathways
Authors: Mallela Abhishek , Nariya Maulik K. , Deeds Eric J.
Published: March 2019

Protein turnover is vital to protein homeostasis within the cell. Many proteins are degraded efficiently only after they have been post-translationally “tagged” with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Over three decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not holdin vivowhere protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key to ultimately developing a global picture of protein homeostasis.
Patterns and potential drivers of intraspecific variability in the body elemental composition of a terrestrial consumer, the snowshoe hare (Lepus americanus)
Authors: Rizzuto Matteo , Leroux Shawn J. , Wal Eric Vander , Wiersma Yolanda F. , Heckford Travis R. , Balluffi-Fry Juliana
Published: March 2019

Intraspecific variability in ecological traits is widespread in nature. Recent evidence, mostly from aquatic ecosystems, shows individuals differing at the most fundamental level, that of their chemical composition. Age, sex, or body size may be key drivers of intraspecific variability in the body concentrations of carbon (C), nitrogen (N), and phosphorus (P). However, we still have a rudimentary understanding of the patterns and drivers of intraspecific variability in chemical composition of terrestrial consumers, particularly vertebrates.

Here, we investigate the whole-body chemical composition of snowshoe hareLepus americanus, providing one of the few studies of patterns of stoichiometric variability and its potential drivers for a terrestrial vertebrate. Based on snowshoe hare ecology, we expected higher P and N concentrations in females, as well as in larger and older individuals.

We obtained whole-body C, N, and P concentrations and C:N, C:P, N:P ratios from a sample of 50 snowshoe hares. We then used general linear models to test for evidence of a relationship between age, sex, or body size and stoichiometric variability in hares.

We found considerable variation in the C, N, and P concentrations and elemental ratios within our sample. Contrary to our predictions, we found evidence of N content decreasing with age. As expected, we found evidence of P content increasing with body size. As well, we found no support for a relationship between sex and N or P content, nor for variability in C content and any of our predictor variables.

Despite finding considerable stoichiometric variability in our sample, we found no substantial support for age, sex, or body size to relate to this variation. The weak relationship between body N concentration and age may suggest varying nutritional requirements of individuals at different ages. Conversely, P’s weak relationship to body size appears in line with recent evidence of the potential importance of P in terrestrial systems. Snowshoe hares are a keystone herbivore in the boreal forest of North America. The substantial stoichiometric variability we find in our sample could have important implications for nutrient dynamics in both boreal and adjacent ecosystems.
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Authors: Díaz Osterman Carlos J. , Ozmadenci Duygu , Kleinschmidt Elizabeth G. , Taylor Kristin N. , Barrie Allison M. , Jiang Shulin , Bean Lisa M. , Sulzmaier Florian J. , Jean Christine , Tancioni Isabelle , Anderson Kristen , Uryu Sean , Cordasco Edward A. , Li Jian , Chen Xiao Lei , Fu Guo , Ojalill Marjaana , Rappu Pekka , Heino Jyrki , Mark Adam M. , Xu Guorong , Fisch Kathleen M. , Kolev Vihren N. , Weaver David T. , Pachter Jonathan A. , Győrffy Balázs , McHale Michael T. , Connolly Denise C. , Molinolo Alfredo , Stupack Dwayne G. , Schlaepfer David D.
Published: March 2019

Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-β-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encodingKRAS,MYCandFAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosisin vitroandin vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/β-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.

Graphical Summary

Key Points

High grade serous ovarian carcinoma tumors containPTK2(FAK) 8q24.3 gains associated with prognostic differences.

KMF, a new murine ovarian cancer model withK-Ras,Myc, andFAK gene gains and intrinsic platinum resistance.

FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.

FAK facilitates a β-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.

FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.
Feature overlap modulates rapid semantic but not lexical integration of novel associations by means of fast mapping
Authors: Zaiser Ann-Kathrin , Meyer Patric , Bader Regine
Published: March 2019

There is evidence that rapid integration of novel associations into cortical networks is possible if associations are acquired through a learning procedure called fast mapping (FM). FM requires precise visual discrimination of sometimes highly similar pictures of a previously unknown and a known item, and linking an unfamiliar label to the unknown item. In order to shed light on the mechanisms underlying learning through FM, we manipulated feature overlap between the two items as potential modulating factor. In Experiment 1, we found that labels of the unknown items generally evoked instantaneous lexical competition when encoded through FM, indicating rapid integration into lexical networks. In Experiment 2, we observed semantic priming immediately after FM encoding but only if the items shared many features. This indicates that whereas feature overlap leaves item-level lexical integration unaffected, it might mediate semantic integration of arbitrary picture-label associations, which could explain contradictory findings in the literature.

Highlights

We examined cortical integration of associations using implicit memory measures.

Fast mapping enables immediate integration of associations into cortical networks.

Semantic integration requires the discrimination between items sharing many features.

Item-level lexical integration is unaffected by feature overlap.
Do El Niño events beget generations of reproductively deficient adults?
Authors: Ortega Santiago , Rodríguez Cristina , Drummond Hugh
Published: March 2019

Warm ocean waters during El Niño events deplete primary productivity, with cascading effects through the food chain that profoundly affect many marine and terrestrial species, commonly increasing adult mortality and offspring starvation. With global warming, events will double and increasingly threaten the depletion or extinction of some animal populations.

Because adverse environments experienced during infancy generally induce reproductive deficits in adulthood, El Niño events are also expected to affect animals born during them, engendering generations of adults with reduced reproductive potential and exacerbating demographic impacts.

We made the first test of this idea, using the blue-footed booby, a piscivorous apex predator of the eastern tropical Pacific Ocean. Surprisingly, detailed monitoring of 18 generations over a 27-year period detected no deficits in the annual breeding success, offspring viability, lifespan or lifetime reproductive success of generations of adults born during El Niño years.

These results testify to remarkable developmental resilience extending across the lifespan. However, there was evidence that this resilience was supported by two mechanisms of quality control of adult generations from El Niño years.

First, viability selection on nestlings and fledglings was more severe for El Niño birth cohorts than ordinary cohorts.

Second, in El Niño years, adult boobies self-selected for breeding. There was no increase in the proportional representation of either high quality breeders or breeders in their peak years (middle-age), but there was an increase in old-young adult pairings, which in this population produce the most viable fledglings.

The blue-footed booby appears to be immune to the expected developmental impact of El Niño on the reproductive value of adult generations. The susceptibilities and resilience of other species need to be explored, to better predict the demographic impacts of this accelerating climatic oscillation.
Ligands, receptors and transcription factors that mediate inter-cellular and intra-cellular communication during ovarian follicle development
Authors: Bernabé Beatriz Peñalver , Woodruff Teresa , Broadbelt Linda J , Shea Lonnie D
Published: March 2019

Reliably producing a competent oocyte entails a deeper comprehension of ovarian follicle maturation, a very complex process that includes meiotic maturation of the female gamete, the oocyte, together with the mitotic divisions of the hormone-producing somatic cells. In this report, we investigate mice ovarian folliculogenesis in vivo using publically available time-series microarrays from primordial to antral stage follicles. Manually curated protein interaction networks were employed to identify autocrine and paracrine signaling between the oocyte and the somatic cells (granulosa and theca cells) and the oocyte and cumulus and mural cells at multiple stages of follicle development. We established protein binding interactions between expressed genes that encoded secreted factors and expressed genes that encoded cellular receptors. Some of computationally identified signaling interactions are well established, such as the paracrine signaling from the oocyte to the somatic cells through the secreted oocyte growth factor Gdf9; while others are novel connections in term of ovarian folliculogenesis, such as the possible paracrine connection from somatic secreted factor Ntn3 to the oocyte receptor Neo1. Additionally, we identify several of the likely transcription factors that might control the dynamic transcriptome during ovarian follicle development, noting that the YAP/TAP signaling is very active in vivo. This novel dynamic model of signaling and regulation can be employed to generate testable hypotheses regarding follicle development, guide the improvement of culture media to enhance in vitro ovarian follicle maturation and possibly as novel therapeutic targets for reproductive diseases.
SCOPE: a normalization and copy number estimation method for single-cell DNA sequencing
Authors: Wang Rujin , Lin Dan-Yu , Jiang Yuchao
Published: March 2019

Whole genome single-cell DNA sequencing (scDNA-seq) enables characterization of copy number profiles at the cellular level. This technology circumvents the averaging effects associated with bulk-tissue sequencing and increases resolution while decreasing ambiguity in tracking the evolutionary history of cancer. ScDNA-seq data is, however, highly sparse and noisy due to the biases and artifacts that are introduced during the library preparation and sequencing procedure. Here, we propose SCOPE, a normalization and copy number estimation method for scDNA-seq data of cancer cells. The main features of SCOPE include: (i) a Poisson latent factor model for normalization, which borrows information across cells and regions to estimate bias, using negative control cells identified by cell-specific Gini coefficients; (ii) modeling of GC content bias using an expectation-maximization algorithm embedded in the normalization step, which accounts for the aberrant copy number changes that deviate from the null distributions; and (iii) a cross-sample segmentation procedure to identify breakpoints that are shared across cells from the same subclone. We evaluate SCOPE on a diverse set of scDNA-seq data in cancer genomics, using array-based calls of purified bulk samples as gold standards and whole-exome sequencing and single-cell RNA sequencing as orthogonal validations; we find that, compared to existing methods, SCOPE offers more accurate copy number estimates. Further, we demonstrate SCOPE on three recently released scDNA-seq datasets by 10X Genomics: we show that it can reliably recover 1% cancer cell spike-ins from a background of normal cells and that it successfully reconstructs cancer subclonal structure from ∼10,000 breast cancer cells.
A Bile Duct-on-a-Chip with Organ-Level Functions
Authors: Du Yu , Khandekar Gauri , Llewellyn Jessica , Polacheck William , Chen Christopher S. , Wells Rebecca G.
Published: March 2019

Chronic cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are frequently associated with damage to the barrier function of the biliary epithelium, but barrier function is difficult to study in vivo and has not been recapitulated in vitro. Here we report the development of a bile duct-on-a-chip that phenocopies not only the tubular architecture of the bile duct in three dimensions, but also its barrier functions. We demonstrated that mouse cholangiocytes in the channel of the device became polarized and formed mature tight junctions, and that the permeability of the cholangiocyte monolayer was comparable to that measured ex vivo for the rat bile duct. Permeability decreased significantly when cells formed a compacted monolayer with cell densities comparable to that seen in vivo. This device enabled independent access to the apical and basolateral surfaces of the cholangiocyte channel, allowing proof-of-concept toxicity studies with the biliary toxin biliatresone and the bile acid glycochenodeoxycholic acid. The cholangiocyte basolateral side was more vulnerable than the apical side to treatment with either agent, suggesting a protective adaptation of the apical surface that is normally exposed to bile. Further studies revealed a protective role of the cholangiocyte apical glycocalyx, wherein disruption of the glycocalyx with neuraminidase increased the permeability of the cholangiocyte monolayer after treatment with glycochenodeoxycholic acid. Conclusion: This bile duct-on-a-chip captured essential features of a simplified bile duct in structure and organ-level functions and represents a novel in vitro platform to study the pathophysiology of the bile duct using cholangiocytes from a variety of sources.
The application of oyster reefs in shoreline protection: Are we over‐engineering for an ecosystem engineer?
Authors: Morris Rebecca L. , Bilkovic Donna M. , Boswell Maura K. , Bushek David , Cebrian Just , Goff Joshua , Kibler Kelly M. , La Peyre Megan K. , McClenachan Giovanna , Moody Josh , Sacks Paul , Shinn Jenny P. , Sparks Eric L. , Temple Nigel A. , Walters Linda J. , Webb Bret M. , Swearer Stephen E.
Published: March 2019

Oyster reef living shorelines have been proposed as an effective alternative to traditional coastal defence structures (e.g. bulkheads, breakwaters), with the benefit that they may keep pace with sea‐level rise and provide co‐benefits, such as habitat provision. However, there remains uncertainty about the effectiveness of shoreline protection provided by oyster reefs, which limits their broader application.

We draw evidence from studies along the east and gulf coasts of the United States, where much research and implementation of oyster reef restoration has occurred, to better define the existing gaps in our understanding of the use of restored oyster reefs for shoreline protection.

We find potential disconnects between ecological and engineering functions of reefs. In response, we outline how engineering and ecological principles are used in the design of oyster reef living shorelines and highlight knowledge gaps where an integration of these disciplines will lead to their more effective application.

Synthesis and applications. This work highlights the necessary steps to advance the application of oyster reef living shorelines. Importantly, future research should focus on appropriate designs and conditions needed for these structures to effectively protect our coasts from erosion, while supporting a sustainable oyster population, thereby providing actionable nature‐based alternatives for coastal defence to diverse end‐users.
A nation‐wide survey of neonicotinoid insecticides in agricultural land with implications for agri‐environment schemes
Authors: Humann‐Guilleminot Ségolène , Binkowski Łukasz J. , Jenni Lukas , Hilke Gabriele , Glauser Gaétan , Helfenstein Fabrice
Published: March 2019

Neonicotinoids are the most widely used class of insecticides globally. However, the link between farming practices and the extent of contamination of soils and crops by neonicotinoid insecticides, as well as the extent of such contamination in organic fields and ecological focus areas (EFAs) are currently unclear.

We measured the concentrations of five neonicotinoid insecticides (imidacloprid, clothianidin, thiamethoxam, thiacloprid, acetamiprid) in 702 soil and plant samples in 169 cultivated fields and EFAs from 62 conventional, integrated production and organic farms distributed over the entire lowland of Switzerland.

We detected neonicotinoids in 93% of organic soils and crops, and more than 80% of EFA soils and plants—two types of arable land supposedly free of insecticides. We also tested 16 samples of organic seeds, of which 14 were positive for neonicotinoids.

Finally, we calculated hazard quotients (HQs) and potentially affected fractions for 72 beneficial and 12 pest species. Under a field‐realistic scenario, we found that between 5.3%–8.6% of above‐ground invertebrate species may be exposed to lethal concentrations of clothianidin, and 31.6%–41.2% to sublethal concentrations, in “integrated production” and conventional fields. We also found that 1.3%–6.8% (up to 12.5% based on HQs) of the beneficial invertebrate species may be exposed to sublethal concentrations of neonicotinoids in EFAs and organic fields. In contrast, no pest species would be exposed to lethal concentrations, even under a worst‐case scenario.

Synthesis and applications. Our study suggests that diffuse contamination by neonicotinoids may harm a significant fraction of non‐target beneficial species. The use of neonicotinoids on crops may threaten biodiversity in refuge areas, while also potentially jeopardizing the practice of organic farming by impeding the biological control of pests. On the basis of our results, we call for a reduction in the dispersion and overuse of neonicotinoid insecticides in order to prevent any detrimental effects on biodiversity and ecosystem services associated with agroecosystems.
The evolution of cleavage voting in four Western countries: Structural, behavioural or political dealignment?
Authors: GOLDBERG ANDREAS C.
Published: March 2019

Since the heyday of cleavage voting in the 1960s and 1970s, the majority of studies presents evidence of a decline in cleavage voting – caused by either structural or behavioural dealignment. Structural dealignment denotes changes in group size responsible for a decrease in cleavage voting, whereas behavioural dealignment concerns weakening party–voter links over time. A third phenomenon posited in this article is the collective voting abstention of certain (social) groups, here referred to as ‘political dealignment’, which results in a new type of division of voting versus abstention. The purpose of this article is to examine the three underlying mechanisms for the decline in social class and religious cleavage voting across four Western countries (Great Britain, the Netherlands, Switzerland and the United States) over the last 40–60 years using longitudinal post‐election data. The results prove a strong presence of political dealignment and increasing turnout gaps regarding both the class and religious cleavage. Furthermore, whenever a decline in cleavage voting is present, it is mainly caused by changes in the social groups’ behaviour and less by changing social structures in a country.
Delay discounting and reward sensitivity in a 2 × 2 study of bipolar disorder and alcohol dependence
Authors: Mellick William , Tolliver Bryan K. , Brenner Helena , Prisciandaro James J.
Published: March 2019

Background and Aims

Separate studies have shown increased delay discounting in people with bipolar disorder (BD) and people with alcohol dependence (AD) relative to people without mental health problems. Delay discounting was compared in people with no mental health problems, AD, BD and AD plus BD. Associations of delay discounting with self‐reported impulsivity and reward sensitivity were also assessed.

Design

The study was a two‐by‐two factorial comparative observational design.

Setting

Data were collected at baseline diagnostic visits as part of a neuroimaging study at a medical university in South Carolina, USA.

Participants

Twenty‐two BD + AD, 33 BD, 28 AD and 27 people without mental health problems participated.

Measurements

Diagnostic and clinician‐rated symptom measures, self‐report questionnaires and a computerized delay discounting task were administered. Two‐by‐two general linear univariate models were tested to examine between‐group differences on discounting rates, and bivariate correlations and hierarchical regression analyses were performed to examine associations between discounting rates and self‐reported reward sensitivity and impulsivity.

Findings

There was a significant main effect of AD (P = 0.006, η2 = 0.068). The main effect of BD and the BD × AD interaction terms were non‐significant (P ≥ 0.293, η2 ≤ 0.010). Reward sensitivity and impulsivity were not significantly associated with discounting rates after adjustment for the other (P ≥ 0.089).

Conclusions

People with alcohol dependence appear to have higher delay discounting, while previously found associations between bipolar disorder and delay discounting may be secondary to alcohol use disorder.
Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia
Authors: Choi Rihwa , Sohn Insuk , Kim Min‐Ji , Woo Hye In , Lee Ji Won , Ma Youngeun , Yi Eun Sang , Koo Hong Hoe , Lee Soo‐Youn
Published: March 2019

Aims

We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea.

Methods

From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6‐mercaptopurine were included in the study. One hundred and twenty‐three variants in 43 genes, includingTMPTandNUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction‐restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses.

Results

The genetic polymorphisms in theABCC4,AHCY,ATIC,FAM8A6P,GART,GNG2,GSTA1,MTHFD1,MTHFR,NUDT15,PACSIN2,TYMSandXDHgenes, and an intronic polymorphism betweenHIVEP2andAIG1, andTPMTgenotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in theABCC4,ADK,ATIC,GART,GMPS,GSTP1,IMPDH1,ITPA,KCNMA1,MOCOS,MTRR,NUDT15,SLC19A1,SLC28A3,SLC29A1,SLCO1B1,TYMPandXDHgenes were associated with thiopurine‐related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05).

Conclusions

Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.
Children's Inferences About Friendship and Shared Preferences Based on Reported Information
Authors: Afshordi Narges
Published: March 2019

Two experiments (total N = 195) examined third‐party inferences about friendship and shared preferences from reported dyadic information. Four‐year‐olds (N = 48) inferred friendship between individuals based on reports of prosocial behavior, and similarity, but not based on arbitrary links. Children privileged prosocial behavior over similarity when asked to adjudicate between the two. Adults (N = 120) were tested online and showed the same overall pattern of inferences. Furthermore, 4‐year‐olds (N = 27) expected individuals who had engaged in prosocial behavior to be playmates as well as friends, and to share preferences for novel games, but not novel foods. These findings shed crucial light on preschoolers' third‐party friendship inferences, and add to our knowledge of their concept of friendship.
The Influence of Direct and Overheard Messages on Children's Attitudes Toward Novel Social Groups
Authors: Lane Jonathan D. , Conder Emily B. , Rottman Joshua
Published: March 2019

Individuals often develop negative biases toward unfamiliar or denigrated groups. Two experimental studies were conducted to investigate the extent to which brief negative messages about novel social groups influence children's (4‐ to 9‐year‐olds'; N = 153) intergroup attitudes. The studies examined the relative influence of messages that are provided directly to children versus messages that are overheard and examined whether the force of these messages varies with children's age. According to implicit and explicit measures of children's intergroup attitudes, children rapidly internalized messages demeaning novel groups, thus forming negative attitudes toward outgroups merely on the basis of hearsay. These effects were generally stronger among older children, and were particularly pronounced when the message was provided directly to children.
Leisure Reading (But Not Any Kind) and Reading Comprehension Support Each Other—A Longitudinal Study Across Grades 1 and 9
Authors: Torppa Minna , Niemi Pekka , Vasalampi Kati , Lerkkanen Marja‐Kristiina , Tolvanen Asko , Poikkeus Anna‐Maija
Published: March 2019

This study examines associations between leisure reading and reading skills in data of 2,525 students followed from age 7 to 16. As a step further from traditional cross‐lagged analysis, a random intercept cross‐lagged panel model was used to identify within‐person associations of leisure reading (books, magazines, newspapers, and digital reading), reading fluency, and reading comprehension. In Grades 1–3 poorer comprehension and fluency predicted less leisure reading. In later grades more frequent leisure reading, particularly of books, predicted better reading comprehension. Negative associations were found between digital reading and reading skills. The findings specify earlier findings of correlations between individuals by showing that reading comprehension improvement, in particular, is predicted by within‐individual increases in book reading.
Not all abdominal masses after colorectal cancer surgery are malignant: intra‐abdominal fibromatosis masquerading as recurrence
Authors: Panagiotopoulou I. G. , Shah N. , Rowaiye B. , Chandrakumaran K. , Carr N. J. , Moran B.
Published: March 2019

Aim

Intra‐abdominal fibromatosis is an unusual mesenchymal tumour that can be locally aggressive without any metastatic potential. Fibromatosis may simulate cancer recurrence on imaging surveillance for colorectal cancer follow‐up. The optimal treatment of recurrent peritoneal malignancy is cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Confirmatory biopsy of lesions suspicious for colorectal cancer recurrence may not be feasible, thereby rendering surgery the safest option. Our aim was to determine the incidence of fibromatosis in a cohort of patients undergoing CRS and HIPEC for suspected colorectal cancer recurrence.

Methods

One hundred and seventy‐one CRS and HIPEC cases were performed at our Peritoneal Malignancy Institute between February 2007 and October 2018 for colorectal peritoneal metastases and were included in a prospectively maintained database.

Results

A total of 49 (29%) of 171 cases were performed for primary colorectal cancer with peritoneal metastases, whereas 122 (71%) of 171 cases were performed for suspected colorectal cancer recurrence detected on surveillance imaging after primary colorectal cancer resection. On histological analysis of the resected specimen, five (4.1%) of 122 cases undergoing CRS and HIPEC for colorectal recurrence had fibromatosis.

Conclusion

Fibromatosis can masquerade as colorectal cancer recurrence. In this series it occurred with an incidence of 4.1% among a cohort of patients undergoing CRS and HIPEC for probable recurrence. Surgical resection may be the only option to confirm the diagnosis and rule out malignancy.
Eight autopsy cases of melanoma brain metastases showing angiotropism and pericytic mimicry. Implications for extravascular migratory metastasis
Authors: Rodewald Ann‐Katrin , Rushing Elisabeth J. , Kirschenbaum Daniel , Mangana Joanna , Mittmann Christiane , Moch Holger , Lugassy Claire , Barnhill Raymond L. , Mihic‐Probst Daniela
Published: March 2019

Background

Metastatic tumor spread is a complex multistep process. Due to the blood‐brain barrier, metastasis to the central nervous system is restrictive with a distinct predilection for certain tumor types. In melanoma patients, brain metastasis is a common endpoint with the majority showing evidence of widespread disease at autopsy. In a previous murine melanoma model, we have shown that melanoma cells migrate along preexisting vessels into the brain, showing angiotropism/vascular co‐option and pericytic mimicry.

Methods

Using conventional morphology and immunohistochemistry, we analyze brain metastases from eight autopsy cases. In addition, tissue clearing, which enables three‐dimensional visualization over a distance of 100 μm is used.

Results

We show the angiotropic localization of melanoma deposits in the brains in all eight autopsy cases. Tissue clearing techniques have allowed visualization of melanoma cells in one case exclusively along the abluminal surface of brain blood vessels over a distance of 100 μm, thus showing pericytic mimicry.

Conclusions

Our analyses show clear‐cut evidence of angiotropism and pericytic mimicry of melanoma cells within the brain over some distance. In addition, these results support the hypothesis of metastasis along pathways other than hematogenous spread, or extravascular migratory metastasis (EVMM). During EVMM, melanoma cells may metastasize to the brain through pericytic mimicry, circumventing the blood‐brain barrier.
Adaptive working memory training can reduce anxiety and depression vulnerability in adolescents
Authors: Beloe Patricia , Derakshan Nazanin
Published: March 2019

Adolescents can be at heightened risk for anxiety and depression, with accumulating research reporting on associations between anxiety and depression and cognitive impairments, implicating working memory and attentional control deficits. Several studies now point to the promise of adaptive working memory training to increase attentional control in depressed and anxious participants and reduce anxiety and depression symptoms, but this has not been explored in a non‐clinical adolescent population. The current study explored the effects of adaptive dual n‐back working memory training on sub‐clinical anxiety and depression symptomology in adolescents. Participants trained on either an online adaptive working memory task or non‐adaptive control task for up to 20 days. Primary outcome measures were self‐reported anxiety and depression symptomology, before and after intervention, and at 1‐month follow‐up. Self‐reported depression (p = 0.003) and anxiety (p = 0.04) decreased after training in the adaptive n‐back group relative to the non‐adaptive control group in the intention‐to‐treat sample (n = 120). These effects were sustained at follow‐up. Our findings constitute proof of principle evidence that working memory training may help reduce anxiety and depression vulnerability in a non‐clinical adolescent population. We discuss the findings’ implications for reducing risk of internalizing disorders in youth and the need for replication.
Does Autonomy Matter in State Owned Enterprises? Evidence from Performance Contracts in India
Authors: Gunasekar Sangeetha , Sarkar Jayati
Published: March 2019

Empirical evidence on the effect of managerial autonomy on the performance of state‐owned enterprises (SOE) is surprisingly scant despite autonomy being a preferred reform instrument over partial privatization in many countries. Using longitudinal data on performance contracts of state‐owned enterprises in India, this paper finds that managerial autonomy is associated with significant increases in enterprise profitability and efficiency. Further, using India's unique reform experience where both managerial autonomy and partial privatization were pursued side by side, the paper finds that while the positive effects of autonomy continue post‐partial privatization, the effects of partial privatization on performance are ambiguous. Specifically, once autonomy is controlled for, partial privatization has a positive effect on SOE profitability only after it crosses a critical level of government disinvestment. The findings suggest that organizational reforms such as granting managerial autonomy can be an important policy instrument in improving SOE performance particularly in cases where governments are unable to make substantial disinvestments.
Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement
Authors: Xu Mengting , Hua Yuyun , Qi Yan , Meng Guoliang , Yang Shengju
Published: March 2019

Hydrogen sulphide (H2S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 μmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T‐AOC), expression of vascular endothelial growth factor (VEGF), dynamin‐related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 μmol/L) pre‐administration for 4 hours, cell migration rate, DRP1, OPA1 and α–smooth muscle actin (α‐SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T‐AOC in the wound. NaHS also promoted skin fibroblasts migration and α‐SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.
Hypothesis: Wound‐induced TLR3 activation stimulates endogenous retinoic acid synthesis and signalling during regeneration
Authors: Kim Dongwon , Garza Luis A.
Published: March 2019

Although the mechanism is unclear, it has been shown that genetically normal adult mice with a large wound form de novo morphogenesis of hair follicles in wound‐induced hair neogenesis (WIHN)(1). We focused on how tissues recognize damage signals and identified that double‐stranded RNA (dsRNA)‐mediated toll‐like receptor 3 (TLR3) activation stimulates WIHN. Here, we propose a hypothesis that TLR3 stimulates retinoic acid synthesis and signalling to allow for regeneration, suggesting that common clinical methods of facial rejuvenation in human subjects through damage (such as lasers or dermabrasion), and the use of topical retinoids reflect the same biologic pathway.
Long non‐coding RNAs in ocular diseases: new and potential therapeutic targets
Authors: Zhang Lixia , Dong Yanhan , Wang Yujie , Gao Jinning , Lv Jiayi , Sun Jingguo , Li Mengjie , Wang Meng , Zhao Zhihong , Wang Jianxun , Xu Wenhua
Published: March 2019

Long non‐coding RNAs (lncRNAs) are non‐protein coding transcripts containing more than 200 nucleotides. In the past, lncRNAs were considered as ‘transcript noise’ or ‘pseudogenes’ and were thus ignored. However, in recent years, lncRNAs have been proven to regulate gene expression at the epigenetic, transcriptional and translational level, and thereby influence cell proliferation, apoptosis, viability, immune response and oxidative stress. Furthermore, increasing evidence points to their involvement in different diseases, including cancer and heart diseases. Recently, lncRNAs were shown to be differentially expressed in ocular tissues and play a significant role in the pathogenesis of ophthalmological disorders such as glaucoma, corneal diseases, cataract, diabetic retinopathy, proliferative vitreoretinopathy and ocular tumors. In this review, we summarize the classification and mechanisms of known lncRNAs, while detailing their biological functions and roles in ocular diseases. Moreover, we provide a concise review of the clinical relevance of lncRNAs as novel, potential therapeutic targets in the treatment of eye diseases.
A high‐throughput screening for inhibitors of riboflavin synthase identifies novel antimicrobial compounds to treat brucellosis
Authors: Serer María Inés , Carrica Mariela del Carmen , Trappe Jörg , López Romero Sandra , Bonomi Hernán Ruy , Klinke Sebastián , Cerutti María Laura , Goldbaum Fernando Alberto
Published: March 2019

Brucella spp. are pathogenic intracellular Gram‐negative bacteria adapted to life within cells of several mammals, including humans. These bacteria are the causative agent of brucellosis, one of the zoonotic infections with the highest incidence in the world and for which a human vaccine is still unavailable. Current therapeutic treatments against brucellosis are based on the combination of two or more antibiotics for prolonged periods, which may lead to antibiotic resistance in the population. Riboflavin (vitamin B2) is biosynthesized by microorganisms and plants but mammals, including humans, must obtain it from dietary sources. Owing to the absence of the riboflavin biosynthetic enzymes in animals, this pathway is nowadays regarded as a rich resource of targets for the development of new antimicrobial agents. In this work, we describe a high‐throughput screening approach to identify inhibitors of the enzymatic activity of riboflavin synthase, the last enzyme in this pathway. We also provide evidence for their subsequent validation as potential drug candidates in an in vitro brucellosis infection model. From an initial set of 44 000 highly diverse low molecular weight compounds with drug‐like properties, we were able to identify ten molecules with 50% inhibitory concentrations in the low micromolar range. Further Brucella culture and intramacrophagic replication experiments showed that the most effective bactericidal compounds share a 2‐Phenylamidazo[2,1‐b][1,3]benzothiazole chemical scaffold. Altogether, these findings set up the basis for the subsequent lead optimization process and represent a promising advancement in the pursuit of novel and effective antimicrobial compounds against brucellosis.
Daylength helps temperate deciduous trees to leaf‐out at the optimal time
Authors: Fu Yongshuo H. , Zhang Xuan , Piao Shilong , Hao Fanghua , Geng Xiaojun , Vitasse Yann , Zohner Constantin , Peñuelas Josep , Janssens Ivan A.
Published: March 2019

Global warming has led to substantially earlier spring leaf‐out in temperate‐zone deciduous trees. The interactive effects of temperature and daylength underlying this warming response remain unclear. However, they need to be accurately represented by earth system models to improve projections of the carbon and energy balances of temperate forests and the associated feedbacks to the Earth's climate system. We studied the control of leaf‐out by daylength and temperature using data from six tree species across 2,377 European phenological network (www.pep725.eu), each with at least 30 years of observations. We found that, in addition to and independent of the known effect of chilling, daylength correlates negatively with the heat requirement for leaf‐out in all studied species. In warm springs when leaf‐out is early, days are short and the heat requirement is higher than in an average spring, which mitigates the warming‐induced advancement of leaf‐out and protects the tree against precocious leaf‐out and the associated risks of late frosts. In contrast, longer‐than‐average daylength (in cold springs when leaf‐out is late) reduces the heat requirement for leaf‐out, ensuring that trees do not leaf‐out too late and miss out on large amounts of solar energy. These results provide the first large‐scale empirical evidence of a widespread daylength effect on the temperature sensitivity of leaf‐out phenology in temperate deciduous trees.
Effects of ultrasound‐assisted frying on the physiochemical properties and microstructure of fried meatballs
Authors: Wang Yan , Zhang Wangang , Zhou Guanghong
Published: March 2019

The aim of this study was to investigate the effects of power ultrasound (0, 200, 400, 600 and 800 W, 20 kHz) on the quality of fried meatballs. The frying time and frying temperature were also considered as fixed factors. The meatballs were fried for 8, 12 and 16 min at 120, 140 and 160 °C. Results showed that the ultrasonic groups saved about 1 to 3 min than the control group to 80 °C. Hardness, springiness, cohesiveness and chewiness of fried meatballs were significantly different among different ultrasonic treatments (P < 0.05). As for colour, the ultrasonic treatments could significantly increase the L*values. Cooking yield was from 82.58% to 85.50% in ultrasonic treatments at 120 °C for 8 min. High moisture retention and cooking yield were shown in fried‐assisted ultrasound treatments and were consistent with the microstructure of scanning electron microscopy (SEM). Our data show that ultrasound‐assisted frying could improve the quality of meatballs.
Validation of the International Tumor Budding Consensus Conference (2016) recommendations in oral tongue squamous cell carcinoma
Authors: Xie Nan , Yu Pei , Liu Haichao , Liu Xiqiang , Hou Jinsong , Chen Xiaohua , Huang Hongzhang , Wang Cheng
Published: March 2019

Background

Tumor budding is a valuable prognostic marker in oral tongue squamous cell carcinoma (OTSCC) but lacks a standardized scoring system. The aim of this study was to evaluate the prognostic value of tumor budding for OTSCC patients based on the scoring system recommended by the International Tumor Budding Consensus Conference (ITBCC) 2016.

Methods

Tumor budding was scored as ITBCC recommended in 255 patients with OTSCC. Then, associations between tumor budding and clinicopathologic parameters were examined. Among them, 136 patients with follow‐up data available were used to evaluate overall survival (OS) by the Kaplan‐Meier method. Prognostic value of tumor budding was assessed by Cox regression analysis. The inter‐observer and intra‐observer agreement was calculated by the kappa statistic.

Results

Tumor budding score was associated with lymph node metastasis, differentiation, invasive pattern, lymphoid infiltrate, tumor relapse, invasive depth, and reduced OS in OTSCC patients. The Cox analysis showed high budding score was an independent prognostic factor in patients with all clinical stage and patients with clinical early‐stage OTSCC. The high kappa values were achieved in intra‐observer and inter‐observer.

Conclusions

International Tumor Budding Consensus Conference scoring system is a simple, reliable, and reproducible method to measure tumor budding in OTSCC, which should be included in the routine pathological report.
A revealed preference index of urban amenities: Using travel demand as a proxy
Authors: Broxterman Daniel A. , Kuang Chun
Published: March 2019

We introduce an index of urban amenities based on hotel night stays that can rank most US metros for the years 1990 through 2015. This naive index can be used on its own to study changes in amenity level or with other measures to reduce omitted variable bias. Researchers can also use the index to create panel datasets from more sophisticated cross‐sectional indexes. Empirical testing shows the bundle of amenities associated with hotel stays has substantial effects on variation in housing prices across cities and time, validating our proxy variable approach. Testing for an association with wages is inconclusive.