bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric Plasma and Platelet Transfusions on Extracorporeal Membrane Oxygenation: A Subgroup Analysis of Two Large International Point-Prevalence Studies and the Role of Local Guidelines*
Authors: Nellis Marianne E. , Saini Arun , Spinella Philip C. , Davis Peter J. , Steiner Marie E. , Tucci Marisa , Cushing Melissa , Demaret Pierre , Stanworth Simon J. , Leteurtre Stephane , Karam Oliver
Published: October 2019

Objectives:

To describe the indications and thresholds for plasma and platelet transfusions for pediatric extracorporeal membrane oxygenation, to compare responses to these transfusions and to describe institutional protocols directing their administration.

Design:

Subgroup analysis of two prospective, observational studies paired with survey of sites who enrolled subjects into this cohort.

Setting:

Fifty-one PICUs in 13 countries.

Patients:

Children (3 d to 16 yr old) were enrolled if they received a plasma or platelet transfusion while on extracorporeal membrane oxygenation during one of the predefined screening weeks.

Interventions:

None.

Measurements and Main Results:

Forty-eight children on extracorporeal membrane oxygenation received plasma transfusions and 90 received platelet transfusions. Sixty percent of plasma transfusions (29/48) and 79% of the platelet transfusions (71/90) were given for prophylaxis of bleeding. The median (interquartile range) international normalized ratio prior to transfusion, known in 75% of the patients (36/48), was 1.45 (1.20–1.85). The median (interquartile range) total platelet count prior to transfusion, known in all of the patients, was 70 × 109/L (52–90 × 109/L). The international normalized ratio and total platelet count values prior to transfusion did not vary based on bleeding versus nonbleeding indications. The median (interquartile range) reduction in international normalized ratio for mild coagulopathies (international normalized ratio ≤ 2.0) was 0.1 (0.4–0), median (interquartile range) increase in fibrinogen was 0.2 g/L (0.1–0.4 g/L) and median increase in total platelet count was 34 × 109/L (10–74 × 109/L). Through the course of their admission, children supported by extracorporeal membrane oxygenation received a total median (interquartile range) dose of 75 mL/kg (36–159 mL/kg) of plasma transfusions and 92 mL/kg (42–239 mL/kg) of platelet transfusions. Institutional protocols varied but provided guidance for platelet transfusions more commonly.

Conclusions:

Children supported by extracorporeal membrane oxygenation receive large volumes of plasma and platelet transfusions with some institutional guidance in the form of protocols, but significant variation in practice. Interventional studies are necessary to provide evidence to direct the transfusion of hemostatic products in children supported by extracorporeal membrane oxygenation.
The Association Between Marital Status, Coronary Computed Tomography Imaging Biomarkers, and Mortality in a Lung Cancer Screening Population
Authors: Celeng Csilla , Takx Richard A.P. , Lessmann Nikolas , Maurovich-Horvat Pál , Leiner Tim , Išgum Ivana , de Jong Pim A.
Published: October 2019

Purpose:

The purpose of this study was to elucidate the impact of being unmarried on coronary computed tomography (CT) imaging biomarkers and mortality in a lung cancer screening population.

Materials and Methods:

In this retrospective case-control study, 5707 subjects (3777 married; mean age: 61.9±5.1 y and 1930 unmarried; mean age: 61.9±5.3 y) underwent low-dose CT as part of the National Lung Screening Trial (NLST). The median follow-up time was 6.5 (Q1-Q3: 5.6 to 6.9) years. Being unmarried was defined as never married, widowed, separated, or divorced. Being married was defined as married or living as married. Our primary endpoint was cardiovascular disease (CVD)-related death; our secondary endpoint was all-cause mortality. Coronary CT imaging biomarkers (calcium score, density, and volume) on low-dose chest CT scan were calculated using dedicated automatic software. Weighted Cox proportional-hazards regression was performed to examine the association between marital status and death. Kaplan-Meier curves were generated to visualize subject survival.

Results:

Being unmarried was significantly associated with an increased risk for CVD-related death (hazard ratio [HR]: 1.58; 95% confidence interval [CI]: 1.31-1.91) and all-cause mortality (HR: 1.39; 95% CI: 1.26-1.53), which remained significant even after adjusting for traditional cardiovascular risk factors (HR CVD death: 1.75; 1.44-2.12 and HR all-cause mortality: 1.58; 95% CI: 1.43-1.74) and coronary calcium score (HR CVD death: 1.58; 95% CI: 1.31-1.91 and HR all-cause mortality: 1.40; 95% CI: 1.27-1.54).

Conclusions:

Being unmarried is associated with an increased CVD-related death and all-cause mortality mainly due to cardiovascular etiology. On the basis of this, marital status might be taken into consideration when assessing individuals’ health status.
Patients With Persistently Low MELD-Na Scores Continue to Be at Risk of Liver-related Death
Authors: Mazumder Nikhilesh R. , Atiemo Kofi , Daud Amna , Kho Abel , Abecassis Michael , Levitsky Josh , Ladner Daniela P.
Published: October 2019

Background.

The vast majority of patients with cirrhosis have low Model for End-Stage Liver Disease–Sodium (MELD-Na) scores; however, the ability for the MELD-Na score to predict patient outcomes at low scores is unclear.

Methods.

Adult patients in a multicenter, Chicago-wide database of medical records with International Classification of Disease, Ninth Edition codes of cirrhosis and without a history of hepatocellular carcinoma were included. Records were linked with the state death registry, and death certificates were manually reviewed. Deaths were classified as “liver-related,” “non-liver-related,” and “non-descript” as adjudicated by a panel comprised of a transplant surgeon, a hepatologist, and an internist. A sensitivity analysis was performed where patients with hepatocellular carcinoma were included.

Results.

Among 7922 identified patients, 3999 patients had MELD-Na scores that were never higher than 15. In total, 2137 (27%) patients died during the study period with higher mortality rates for the patients in the high MELD-Na group (19.4 (41.6%) versus 4.1 (12.6%) per 100 person-y, P < 0.001). The high MELD-Na group died of a liver-related cause in 1142 out of 1632 (70%) as compared to 240 out of 505 (47.5%) deaths in the low MELD-Na group. There was no difference in the distribution of subcategory of liver-related death between low and high MELD-Na groups. Among subclassification of liver-related deaths, the most common cause of death was “Infectious” in both groups.

Conclusions.

Despite persistently low MELD-Na scores, patients with cirrhosis still experience high rates of liver-related mortality.
Antibodies Against ARHGDIB and ARHGDIB Gene Expression Associate With Kidney Allograft Outcome
Authors: Senev Aleksandar , Otten Henny G. , Kamburova Elena G. , Callemeyn Jasper , Lerut Evelyne , Van Sandt Vicky , Kuypers Dirk , Emonds Marie-Paule , Naesens Maarten
Published: October 2019

Background.

The impact of donor-specific anti-HLA antibodies (DSA) on antibody-mediated rejection (AMR) and kidney allograft failure is well established. However, the relevance of non-HLA antibodies remains unclear.

Methods.

We investigated 13 pretransplant non-HLA antibodies and their association with histology of AMR (AMRh) and kidney allograft failure. We included single kidney recipients (n = 203) with AMRh, according to the Banff 2017 classification and matched AMRh-free controls (n = 219). Non-HLA antibodies were assessed using multiplex Luminex assay.

Results.

Of the selected non-HLA antibodies (against agrin, adipocyte plasma membrane-associated protein, Rho GDP-dissociation inhibitor 2 [ARHGDIB], Rho guanine nucleotide exchange factor 6, angiotensin-II type 1 receptor, endothelin type A receptor, lamin B1, BPI fold-containing family B member 1, peroxisomal trans-2-enoyl-coenzyme A reductase, phospholipase A2 receptor, protein kinase C zeta type, tubulin beta-4B class IVb, vimentin), only antibodies against ARHGDIB (adjusted median fluorescence intensity [aMFI] ≥ 1000), a minor histocompatibility antigen, associated with graft failure, in univariate and multivariate models (hazard ratio = 2.7; 95% confidence interval [CI],1.3-5.4; P = 0.007). There was a 19.5-fold (95% CI, 6.0-63.9; P < 0.0001) increased risk of graft failure in patients positive for both DSA and anti-ARHGDIB antibodies (aMFI ≥ 1000) versus patients negative for both DSA and anti-ARHGDIB antibodies, compared with a 4.4-fold (95% CI, 2.4-8.2; P < 0.0001) increased risk in patients with only DSA, and a 4.1-fold (95% CI, 1.4-11.7; P = 0.009) increased risk in patients with only anti-ARHGDIB antibodies above 2000 aMFI. AMRh associated with increased intrarenal expression of the ARHGDIB gene. In the absence of AMRh and DSA, anti-ARHGDIB antibodies were not clearly associated with graft failure.

Conclusions.

The presence of pretransplant anti-ARHGDIB antibodies has an additive effect in patients with DSA on the risk of graft failure via AMRh. Other investigated non-HLA antibodies, including antibodies against angiotensin-II type 1 receptor, did not contribute to risk stratification and could not explain the histology of AMR in the absence of DSA.
Imlifidase Inhibits HLA Antibody-mediated NK Cell Activation and Antibody-dependent Cell-mediated Cytotoxicity (ADCC) In Vitro
Authors: Ge Shili , Chu Maggie , Choi Jua , Louie Sabrina , Vo Ashley , Jordan Stanley C. , Toyoda Mieko
Published: October 2019

Background.

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important pathway responsible for antibody-mediated rejection (AMR). Imlifidase (IdeS) cleaves human IgG into F(ab’)2 and Fc fragments, potentially inhibiting ADCC. Here we examined the effect of IdeS on allo-antibody-mediated NK cell activation (Allo-CFC) and ADCC in vitro.

Methods.

For Allo-CFC, normal whole blood was incubated with third-party peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody positive (HS) or negative (NC) sera to measure IFNγ+ NK cell%. For ADCC, normal PBMCs were incubated with Farage B (FB) cells with HS or NC sera to measure 7-AAD+ lysed FB cell%. To assess the effect of IdeS on these assays, serum-treated PBMCs (Allo-CFC-1) and serum used for PBMC pretreatment (Allo-CFC-2) in Allo-CFC, and serum used for ADCC were preincubated with IdeS. Sera from IdeS-treated patients were also tested for Allo-CFC (Allo-CFC-3).

Results.

IFNγ+ NK cell% were significantly elevated in HS versus NC sera in Allo-CFC-1 (10 ± 3% versus 2 ± 1%, P = 0.001), Allo-CFC-2 (20 ± 10% versus 4 ± 2%, P = 0.01) and 7AAD+ FB cell% (11 ± 3% versus 4 ± 2%, P = 0.02) in ADCC. These were significantly reduced by IdeS treatment. Patient sera with significantly reduced anti-HLA antibody levels at 1 day postimlifidase lost the capacity to activate NK cells in Allo-CFC-3, but those at 1–3 months postimlifidase regained the capacity.

Conclusions.

IdeS inhibited NK cell activation and ADCC in vitro and in treated patients. These results and reported inhibition of complement activating anti-HLA antibodies by IdeS suggest its possible role in treatment of AMR.
Turbulence induces clustering and segregation of non-motile, buoyancy-regulating phytoplankton
Authors: Borgnino Matteo , Arrieta Jorge , Boffetta Guido , De Lillo Filippo , Tuval Idan
Published: October 2019

Turbulence plays a major role in shaping marine community structure as it affects organism dispersal and guides fundamental ecological interactions. Below oceanographic mesoscale dynamics, turbulence also impinges on subtle physical–biological coupling at the single cell level, setting a sea of chemical gradients and determining microbial interactions with profound effects on scales much larger than the organisms themselves. It has been only recently that we have started to disentangle details of this coupling for swimming microorganisms. However, for non-motile species, which comprise some of the most abundant phytoplankton groups on Earth, a similar level of mechanistic understanding is still missing. Here, we explore by means of extensive numerical simulations the interplay between buoyancy regulation in non-motile phytoplankton and cellular responses to turbulent mechanical cues. Using a minimal mechano-response model, we show how such a mechanism would contribute to spatial heterogeneity and affect vertical fluxes and trigger community segregation.
Core–shell nanospheres behind the blue eyes of the bay scallopArgopecten irradians
Authors: Harris Olivia K. , Kingston Alexandra C. N. , Wolfe Caitlin S. , Ghoshroy Soumitra , Johnsen Sönke , Speiser Daniel I.
Published: October 2019

The bay scallopArgopecten irradians(Mollusca: Bivalvia) has dozens of iridescent blue eyes that focus light using mirror-based optics. Here, we test the hypothesis that these eyes appear blue because of photonic nanostructures that preferentially scatter short-wavelength light. Using transmission electron microscopy, we found that the epithelial cells covering the eyes ofA. irradianshave three distinct layers: an outer layer of microvilli, a middle layer of random close-packed nanospheres and an inner layer of pigment granules. The nanospheres are approximately 180 nm in diameter and consist of electron-dense cores approximately 140 nm in diameter surrounded by less electron-dense shells 20 nm thick. They are packed at a volume density of approximately 60% and energy-dispersive X-ray spectroscopy indicates that they are not mineralized. Optical modelling revealed that the nanospheres are an ideal size for producing angle-weighted scattering that is bright and blue. A comparative perspective supports our hypothesis: epithelial cells from the black eyes of the sea scallopPlacopecten magellanicushave an outer layer of microvilli and an inner layer of pigment granules but lack a layer of nanospheres between them. We speculate that light-scattering nanospheres help to prevent UV wavelengths from damaging the internal structures of the eyes ofA. irradiansand other blue-eyed scallops.
Self-assembly, buckling and density-invariant growth of three-dimensional vascular networks
Authors: Kirkegaard Julius B. , Nielsen Bjarke F. , Trusina Ala , Sneppen Kim
Published: October 2019

The experimental actualization of organoids modelling organs from brains to pancreases has revealed that much of the diverse morphologies of organs are emergent properties of simple intercellular ‘rules’ and not the result of top-down orchestration. In contrast to other organs, the initial plexus of the vascular system is formed by aggregation of cells in the process known as vasculogenesis. Here we study this self-assembling process of blood vessels in three dimensions through a set of simple rules that align intercellular apical–basal and planar cell polarity. We demonstrate that a fully connected network of tubes emerges above a critical initial density of cells. Through planar cell polarity, our model demonstrates convergent extension, and this polarity furthermore allows for both morphology-maintaining growth and growth-induced buckling. We compare this buckling with the special vasculature of the islets of Langerhans in the pancreas and suggest that the mechanism behind the vascular density-maintaining growth of these islets could be the result of growth-induced buckling.
James Petiver's ‘
Kind Friends
’ and ‘
Curious Persons
’ in the Atlantic World: commerce, colonialism and collecting
Authors: Murphy Kathleen Susan
Published: October 2019

In 1695, James Petiver concluded the first ‘century’ of his
Musei Petiveriani
by observing that he had received the specimens described within it from his ‘
Kind Friends
from divers parts of the World’ and ‘
Curious Persons
… Abroad’. This essay examines Petiver's network of such ‘Kind Friends’ and ‘Curious Persons’ in the Atlantic World. The composition of Petiver's network reflected many of the broader patterns of English commerce in the Atlantic at the turn of the eighteenth century. Moreover, England's growing overseas empire and its expanding commercial activity required a parallel expansion in maritime labour. Mariners were correspondingly central to Petiver's work as a naturalist and collector in the region. The importance of slavery and the slave trade to Atlantic economic and social structures meant that the naturalist relied on the institutions, infrastructures and individuals of the slave trade and plantation slavery. A social history of Petiver's Atlantic network reveals how the naturalist utilized the routes of commerce and colonialism to collect specimens, as well as to collect the correspondents who might provide them from West Africa, Spanish America, the Caribbean and mainland North America. It demonstrates the entangled histories of commerce, colonialism, collecting and the production of natural knowledge.
Functional consequences of the long-term decline of reef-building corals in the Caribbean: evidence of across-reef functional convergence
Authors: Estrada-Saldívar Nuria , Jordán-Dalhgren Eric , Rodríguez-Martínez Rosa E. , Perry Chris , Alvarez-Filip Lorenzo
Published: October 2019

Functional integrity on coral reefs is strongly dependent upon coral cover and coral carbonate production rate being sufficient to maintain three-dimensional reef structures. Increasing environmental and anthropogenic pressures in recent decades have reduced the cover of key reef-building species, producing a shift towards the relative dominance of more stress-tolerant taxa and leading to a reduction in the physical functional integrity. Understanding how changes in coral community composition influence the potential of reefs to maintain their physical reef functioning is a priority for their conservation and management. Here, we evaluate how coral communities have changed in the northern sector of the Mexican Caribbean between 1985 and 2016, and the implications for the maintenance of physical reef functions in the back- and fore-reef zones. We used the cover of coral species to explore changes in four morpho-functional groups, coral community composition, coral community calcification, the reef functional index and the reef carbonate budget. Over a period of 31 years, ecological homogenization occurred between the two reef zones mostly due to a reduction in the cover of framework-building branching (Acroporaspp.) and foliose-digitiform (Porites poritesandAgaricia tenuifolia) coral species in the back-reef, and a relative increase in non-framework species in the fore-reef (Agaricia agaricitesandPorites astreoides). This resulted in a significant decrease in the physical functionality of the back-reef zone. At present, both reef zones have negative carbonate budgets, and thus limited capacity to sustain reef accretion, compromising the existing reef structure and its future capacity to provide habitat and environmental services.
Strong evidence of an information-theoretical conservation principle linking all discrete systems
Authors: Hatton Les , Warr Gregory
Published: October 2019

Diverse discrete systems share common global properties that lack a unifying theoretical explanation. However, constraining the simplest measure of total information (Hartley–Shannon) in a statistical mechanics framework reveals a principle, the conservation of Hartley–Shannon information (CoHSI) that directly predicts both known and unsuspected common properties of discrete systems, as borne out in the diverse systems of computer software, proteins and music. Discrete systems fall into two categories distinguished by their structure:
heterogeneous
systems in which there is a distinguishable order of assembly of the system’s components from an alphabet of unique tokens (e.g. proteins assembled from an alphabet of amino acids), and
homogeneous
systems in which unique tokens are simply binned, counted and rank ordered. Heterogeneous systems are characterized by an implicit distribution of component lengths, with sharp unimodal peak (containing the majority of components) and a power-law tail, whereas homogeneous systems reduce naturally to Zipf’s Law but with a drooping tail in the distribution. We also confirm predictions that very long components are inevitable for heterogeneous systems; that discrete systems can exhibit simultaneously both heterogeneous and homogeneous behaviour; and that in systems with more than one consistent token alphabet (e.g. digital music), the alphabets themselves show a power-law relationship.
Interspecific hybridization can generate functional novelty in cichlid fish
Authors: Selz O. M. , Seehausen O.
Published: October 2019

The role of interspecific hybridization in evolution is still being debated. Interspecific hybridization has been suggested to facilitate the evolution of ecological novelty, and hence the invasion of new niches and adaptive radiation when ecological opportunity is present beyond the parental species niches. On the other hand, hybrids between two ecologically divergent species may perform less well than parental species in their respective niches because hybrids would be intermediate in performance in both niches. The evolutionary consequences of hybridization may hence be context-dependent, depending on whether ecological opportunities, beyond those of the parental species, do or do not exist. Surprisingly, these complementary predictions may never have been tested in the same experiment in animals. To do so, we investigate if hybrids between ecologically distinct cichlid species perform less well than the parental species when feeding on food either parent is adapted to, and if the same hybrids perform better than their parents when feeding on food none of the species are adapted to. We generated two first-generation hybrid crosses between species of African cichlids. In feeding efficiency experiments we measured the performance of hybrids and parental species on food types representing both parental species niches and additional ‘novel’ niches, not used by either of the parental species but by other species in the African cichlid radiations. We found that hybrids can have higher feeding efficiencies on the ‘novel’ food types but typically have lower efficiencies on parental food types when compared to parental species. This suggests that hybridization can generate functional variation that can be of ecological relevance allowing the access to resources outside of either parental species niche. Hence, we provide support for the hypothesis of ecological context-dependency of the evolutionary impact of interspecific hybridization.
Ecological opportunity shapes a large Arctic charr species radiation
Authors: Doenz Carmela J. , Krähenbühl Andrin K. , Walker Jonas , Seehausen Ole , Brodersen Jakob
Published: October 2019

Ecological opportunity is considered a crucial factor for adaptive radiation. Here, we combine genetic, morphological and ecological data to assess species and ecomorphological diversity of Artic charr in six lakes of a catchment in southernmost Greenland, where only charr and stickleback occur. Because the diversity of habitats and resources increases with lake size, we predict a positive association between lake size and the extent of ecomorphological diversity. The largest lake of the catchment harbours the largest Arctic charr assemblage known today. It consists of six genetically differentiated species belonging to five ecomorphs (anadromous, littoral benthic, profundal dwarf, planktivorous, piscivorous), of which the latter comprises two ecomorphologically extremely similar species. Lakes of intermediate size contain two ecomorphologically and genetically distinct species. Small lakes harbour one genetically homogeneous, yet sometimes ecomorphologically variable population. Supporting our prediction, lake size is positively correlated with the extent of ecomorphological specialization towards profundal, pelagic and piscivorous lifestyle. Furthermore, assemblage-wide morphospace increases sharply when more than one genetic cluster is present. Our data suggest that ecological opportunity and speciation jointly determine phenotypic expansion in this charr radiation.
Towards ecologically valid biomarkers: real-life gait assessment in cerebellar ataxia
Authors: Ilg Winfried , Seemann Jens , Giese Martin , Traschütz Andreas , Schöls Ludger , Timmann Dagmar , Synofzik Matthis
Published: October 2019

BACKGROUND

With disease-modifying drugs on the horizon for degenerative ataxias, motor biomarkers are highly warranted. While ataxic gait and its treatment-induced improvements can be captured in laboratory-based assessments, quantitative markers of ataxic gait in real life will help to determine ecologically meaningful improvements.

OBJECTIVES

To unravel and validate markers of ataxic gait in real life by using wearable sensors.

METHODS

We assessed gait characteristics of 43 patients with degenerative cerebellar disease (SARA:9.4±3.9) compared to 35 controls by 3 body-worn inertial sensors in three conditions: (1) laboratory-based walking; (2) supervised free walking; (3) real-life walking during everyday living (subgroup n=21). Movement analysis focussed on measures of movement smoothness and spatio-temporal step variability.

RESULTS

A set of gait variability measures was identified which allowed to consistently identify ataxic gait changes in all three conditions. Lateral step deviation and a compound measure of step length categorized patients against controls in real life with a discrimination accuracy of 0.86. Both were highly correlated with clinical ataxia severity (effect size ρ=0.76). These measures allowed detecting group differences even for patients who differed only 1 point in the SARAp&g subscore, with highest effect sizes for real-life walking (d=0.67).

CONCLUSIONS

We identified measures of ataxic gait that allowed not only to capture the gait variability inherent in ataxic gait in real life, but also demonstrate high sensitivity to small differences in disease severity - with highest effect sizes in real-life walking. They thus represent promising candidates for quantitative motor markers for natural history and treatment trials in ecologically valid contexts.
Evidence of massive leukemic progenitor expansion in blood during molecular recurrence after TKI discontinuation in chronic myeloid leukemia (CML)
Authors: Turhan Ali G , Hugues Patricia , Sorel Nathalie , Desterke Christophe , Bourhis Jean-Henri , Bennaceur-Griscelli Annelise , Chomel Jean-Claude
Published: October 2019

Chronic myeloid leukemia (CML) represents one of the major success stories of targeted therapies of the 21st century with the use of tyrosine kinase inhibitors (TKIs). Following discontinuation of TKIs in deep molecular remission context, at least half of the patients experience molecular relapse. Cellular events occurring during this phase are not yet established. In this work, we show a massive amplification of clonogenic progenitors or CFCs (colony-forming cells) in the peripheral blood of patients in molecular recurrence after a TKI discontinuation. We demonstrate, by qRT-PCR analysis on individual and pooled CFCs, that leukemic clonogenic progenitor expansion in the peripheral blood represents the first cellular event before any evidence of cytological change. These findings also suggest that the amplification of the leukemic clone during the first stages of CML takes place not only in the bone marrow but also in the peripheral blood.
Characterising strategy use during the performance of hippocampal-dependent tasks
Authors: Clark Ian A. , Monk Anna M. , Maguire Eleanor A.
Published: October 2019

Recalling the past, thinking about the future and navigating in the world are linked with a brain structure called the hippocampus. Precisely how the hippocampus enables these critical cognitive functions is still debated. The strategies people use to perform tasks associated with these functions have been under-studied, and yet such information could augment our understanding of the associated cognitive processes and neural substrates. Here, we devised and deployed an in-depth protocol to examine the explicit strategies used by 217 participants to perform four naturalistic tasks widely acknowledged to be hippocampal-dependent, namely, those assessing scene imagination, autobiographical memory recall, future thinking and spatial navigation. In addition, we also investigated strategy use for three laboratory-based memory tasks, one of which is held to be hippocampal-dependent – concrete verbal paired associates – and two tasks which are likely hippocampal-independent – abstract verbal paired associates and the dead or alive semantic memory test. We found that scene visual imagery was the dominant strategy not only when mentally imagining scenes, but also during autobiographical memory recall, when thinking about the future and during navigation. Moreover, scene visual imagery strategies were used most frequently during the concrete verbal paired associates task, whereas verbal strategies were most prevalent for the abstract verbal paired associates task and the dead or alive semantic memory task. The ubiquity of specifically scene visual imagery use across a range of tasks may attest to its, perhaps underappreciated, importance in facilitating cognition, whilst also aligning with perspectives that emphasise a key role for the hippocampus in constructing scene imagery.
Highly expressed miR-375 is not an intracellular oncogene in Merkel cell polyomavirus-associated Merkel cell carcinoma
Authors: Fan Kaiji , Zebisch Armin , Horny Kai , Schrama David , Becker Jürgen C.
Published: October 2019

miR-375 is a highly abundant miRNA in Merkel cell carcinoma (MCC), in other cancers it acts either as a tumor suppressor or oncogene. While free-circulating miR-375 serves as surrogate marker for tumor burden in patients with advanced MCC, its function within MCC cells has not been established. Nearly complete miR-375 knockdown in MCC cell lines was achieved using antagomiRs via nucleofection. Neither cell viability, growth characteristics nor morphology were altered by this knockdown. miR-375 target genes and related signaling pathways were determined using ENCORI revealing Hippo signaling and EMT-related genes likely to be regulated. Thus, their expression was analyzed by multiplexed qRT-PCR after miR-375 knockdown demonstrating only a limited change in expression. In summary, highly effective miR-375 knockdown in classical MCC cell lines did neither significantly change cell viability, morphology, nor oncogenic signaling pathways. These observations render miR-375 an unlikely intracellular oncogene in MCC cells, thus suggesting to address likely functions of miR-375 for intercellular communication of MCC.
Chlamydomonas sp. UWO241 exhibits constitutively high cyclic electron flow and rewired metabolism under high salinity
Authors: Kalra Isha , Wang Xin , Cvetkovska Marina , Jeong Jooyeon , McHargue William , Zhang Ru , Hüner Norman , Yuan Joshua S. , Morgan-Kiss Rachael
Published: October 2019

The Antarctic green alga Chlamydomonas sp. UWO241 (UWO241) was isolated from the deep photic zone of a permanently Antarctic ice-covered lake. Adaptation to permanent low temperatures, hypersalinity, and extreme shade has resulted in survival strategies in this halotolerant psychrophile. One of the most striking phenotypes of UWO241 is an altered photosystem I (PSI) organization and constitutive PSI cyclic electron flow (CEF). To date, little attention has been paid to CEF during long-term stress acclimation and the consequences of sustained CEF in UWO241 are not known. In this study, we combined photobiology, proteomics, and metabolomics to understand the underlying role of sustained CEF in high salinity stress acclimation. High salt-grown UWO241 exhibited increased thylakoid proton motive flux and an increased capacity for NPQ. A Bestrophin-like Cl- channel was identified in the whole cell proteomes and transcriptome of UWO241 which likely supports ion homeostasis during high transthylakoid pH. Under high salt, a significant proportion of the upregulated enzymes were associated with the Calvin Benson Bassham Cycle (CBB), secondary metabolite biosynthesis, and protein translation. Two key enzymes of the Shikimate pathway, DAHP synthase and chorismate synthase, were also upregulated, as well as indole-3-glycerol phosphate synthase, an enzyme involved in biosynthesis of L-tryptophan and indole acetic acid. In addition, several compatible solutes (glycerol, proline and sucrose) accumulated to high levels in high salt-grown UWO241 cultures. We suggest that UWO241 maintains constitutively high CEF with associated PSI-cytb6f supercomplex to support robust growth and strong photosynthetic capacity under a constant growth regime of low temperatures and high salinity.
Hybridization disrupts growth-defense strategies and reveals trade-offs masked in unadmixed populations of a perennial plant
Authors: Fetter Karl C. , Nelson David M. , Keller Stephen R.
Published: October 2019

Organisms are constantly challenged by pathogens and pests which can drive the evolution of growth-defense strategies. Plant stomata are essential for gas-exchange during photosynthesis and conceptually lie at the intersection of the physiological demands of growth and exposure to foliar fungal. Generations of natural selection for locally adapted growth-defense strategies can eliminate variation between traits, potentially masking trade-offs and selection conflicts that may have existed in the past. Hybrid populations offer a unique opportunity to reset the clock on selection and to study potentially maladaptive trait variation before selection removes it. We study the interactions of growth, stomatal, ecopysiological, and disease resistance traits in Poplars(Populus)after infection by the leaf rustMelampsora medusae.Phenotypes were measured in a common garden and genotyped at 227K SNPs. We isolate the effects of hybridization on trait variance, discover correlations between stomatal, ecophysiology and disease resistance, examine trade-offs and selection conflicts, and explore the evolution of growth-defense strategies potentially mediated by selection for stomatal traits on the upper leaf surface. These results suggest an important role for stomata in determining growth-defense strategies in organisms susceptible to foliar pathogens, and reinforces the contribution of hybridization studies towards our understanding of trait evolution.
Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment
Authors: Rhodes Adam , Hillen Thomas
Published: October 2019

Metastatic seeding of distant organs can occur in the very early stages of primary tumor development. Once seeded, these micrometastases may enter a dormant phase that can last decades. Curiously, the surgical removal of the primary tumor can stimulate the accelerated growth of distant metastases, a phenomenon known asmetastatic blow-up. Although several theories have been proposed to explain metastaticdormancyandblow-up, most mathematical investigations have ignored the important pro-tumor effects of the immune system. In this work, we address that shortcoming by developing an ordinary differential equation model of the immune-mediated theory of metastasis. We include both anti- and pro-tumor immune effects, in addition to the experimentally observed phenomenon of tumor-induced immune cell phenotypic plasticity. Using geometric singular perturbation analysis, we derive a rather simple model that captures the main processes and, at the same time, can be fully analyzed. Literature-derived parameter estimates are obtained, and model robustness is demonstrated through a sensitivity analysis. We determine conditions under which the parameterized model can successfully explain both metastatic dormancy and blow-up. Numerical simulations suggest a novel measure to predict the occurrence of future metastatic blow-up, in addition to new potential avenues for treatment of clinically undetectable micrometastases.
Short-term circulating tumor cell dynamics in mouse xenograft models and implications for liquid biopsy
Authors: Williams Amber L. , Fitzgerald Jessica E. , Ivich Fernando , Sontag Eduardo D. , Niedre Mark
Published: October 2019

Motivation

Circulating tumor cells (CTCs) are widely studied using liquid biopsy methods that analyze single, fractionally-small peripheral blood (PB) samples. However, little is known about fluctuations in CTC numbers that occur over short timescales in vivo, and how these may affect accurate enumeration from blood samples.

Methods

We recently developed an instrument called ‘diffuse in vivo flow cytometry’ (DiFC) that allows continuous, non-invasive counting of rare, green fluorescent protein expressing CTCs in large deeply-seated blood vessels in mice. Here, we used DiFC to study short-term changes in CTC numbers in multiple myeloma and Lewis lung carcinoma xenograft models. We analyzed 35- to 50-minute data sets, with intervals corresponding to approximately 1, 5, 10 and 20% of the PB volume, as well as changes over 24-hour periods.

Results

For rare CTCs, the use of short DiFC intervals (corresponding to small PB samples) frequently resulted in no detections. For more abundant CTCs, CTC numbers frequently varied by an order of magnitude or more over the time-scales considered. This variability far exceeded that expected by Poisson statistics, and instead was consistent with rapidly changing mean numbers of CTCs in the PB.

Conclusions

Because of these natural temporal changes, accurately enumerating CTCs from fractionally small blood samples is inherently problematic. The problem is likely to be compounded for multicellular CTC clusters or specific CTC subtypes. However, we also show that enumeration can be improved by averaging multiple samples, analysis of larger volumes, or development of new methods for enumeration of CTCs directly in vivo.
Replaying the evolutionary tape to investigate subgenome dominance in allopolyploid Brassica napus
Authors: Bird Kevin A. , Niederhuth Chad , Ou Shujun , Gehan Malia , Pires J. Chris , Xiong Zhiyong , VanBuren Robert , Edger Patrick P.
Published: October 2019

Interspecific hybridization and allopolyploidization merges evolutionarily distinct parental genomes (subgenomes) into a single nucleus. A frequent observation is that one subgenome is “dominant” over the other subgenome, having a greater number of reatined duplicate genes and being more highly expressed. Which subgenome becomes dominantly expressed in allopolyploids remains poorly understood. Here we “replayed the evolutionary tape” with six isogenic resynthesized Brassica napus (rapeseed) allopolyploid lines and investigated subgenome dominance patterns over the first ten generations. We found that the same subgenome was consistently more dominantly expressed in all lines and generations. Furthermore, DNA methylation differences between subgenomes mirrored the observed gene expression bias towards the Brassica oleracea derived ‘C’ subgenome in all lines and generations. These differences in gene expression and methylation were also found when comparing the progenitor genomes, suggesting subgenome dominance is related to inherited parental genome differences rather than a byproduct of allopolyploidization. Gene network analyses indicated an enrichment for network interactions and several biological functions for ‘C’ subgenome biased pairs, but no enrichment was observed for ‘A’ subgenome biased pairs. These findings demonstrate that “replaying the evolutionary tape” in allopolyploids results in repeatable and predictable subgenome expression dominance patterns based on preexisting genetic differences among the parental species. These findings have major implications regarding the genotypic and phenotypic diversity observed following plant hybridization in both ecological and agricultural contexts.
Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP signaling pathway in the remodeling of blood vessels
Authors: Yamashiro Yoshito , Thang Bui Quoc , Ramirez Karina , Shin Seung Jae , Kohata Tomohiro , Ohata Shigeaki , Nguyen Tram Anh Vu , Ohtsuki Sumio , Nagayama Kazuaki , Yanagisawa Hiromi
Published: October 2019

Rationale

The extracellular matrix (ECM) initiates mechanical cues and transduces intracellular signaling through matrix-cell interactions. In the blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from ECM and how they coordinate with a mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood.

Objective

The aim of this study was to elucidate the crucial mediator(s) and molecular signaling pathway(s) involved in matrix mechanotransduction during remodeling of the vessel wall.

Methods and Results

We performed secretome analysis using rat vascular smooth muscle cells (SMCs) under cyclic stretch and examined matrix-cell interactions and cell behavior. We found that the matricellular protein thrombospondin-1 (Thbs1) was secreted upon cyclic stretch and bound to integrin αvβ1, thereby recruiting vinculin and establishing focal adhesions. RNA-sequence (RNA-seq) analysis revealed that deletion of Thbs1 in vitro markedly affected the target gene expression of Yes-associated protein (YAP). Consistently, we found that Thbs1 promotes nuclear shuttling of YAP in response to cyclic stretch, which depends on the small GTPase Rap2 and Hippo pathway, and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload by transverse aortic constriction (TAC), whereas it suppressed neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall.

Conclusions

Thbs1 serves as a mechanical stress-triggered extracellular mediator of mechanotransduction that acts via integrin αvβ1 to establish focal adhesions and promotes nuclear shuttling of YAP. We thus propose a novel mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

Subject codes

Vascular Disease

Genetically Altered and Transgenic Models

Vascular Biology

Cell Signaling/Signal Transduction
Structural conservation and diversity of PilZ-related domains
Authors: Galperin Michael Y. , Chou Shan-Ho
Published: October 2019

The widespread bacterial second messenger cyclic diguanylate (c-di-GMP) regulates a variety of processes, including protein secretion, motility, cell development, and biofilm formation. C-di-GMP-dependent responses are often mediated by its binding to the cytoplasmic receptors that contain the PilZ domain. We present here comparative structural and sequence analysis of various PilZ-related domains and describe three principal types of them: (i) the canonical PilZ domain, whose structure includes a six-stranded beta-barrel and a C-terminal alpha-helix; (ii) an atypical PilZ domain that contains two extra alpha-helices and forms stable tetramers, and (iii) divergent PilZ-related domains, which include the eponymous PilZ protein and PilZN (YcgR_N) and PilZNR (YcgR_2) domains. We refine the second c-di-GMP binding motif of PilZ as [D/N]hSxxG and show that the hydrophobic residue h of this motif interacts with a cluster of conserved hydrophobic residues, helping maintain the PilZ domain fold. We describe several novel PilZN-type domains that are fused to the canonical PilZ domains in specific taxa, such as spirochetes, actinobacteria, cellulosolytic clostridia, deltaproteobacteria, and aquificae. We propose that the evolution of three major groups of PilZ domains included (i) fusion of pilZ with other genes, which produced Alg44, cellulose synthase, and other multidomain proteins; (ii) insertion of a ∼200-bp fragment, which resulted in the formation of tetramer-forming PilZ proteins, and (iii) tandem duplication of pilZ genes, which led to the formation of PilZ dimers and YcgR-like proteins.

IMPORTANCE

Cyclic di-GMP is a ubiquitous bacterial second messenger that regulates motility, biofilm formation and virulence of many bacterial pathogens. The PilZ domain is a widespread c-di-GMP receptor that binds c-di-GMP through its RxxxR and [D/N]xSxxG motifs; some PilZ domains lack these motifs and are unable to bind c-di-GMP. We used structural and sequence analysis to assess the diversity of PilZ-related domains and define their common features. We show that the hydrophobic residue h in the second motif is highly conserved; it may serve as a readout for c-di-GMP binding. We describe three principal classes of PilZ-related domains: canonical, tetramer-forming, and divergent PilZ domains, and propose the evolutionary pathways that led to the emergence of these PilZ types.
Difficulties with speech-in-noise perception related to fundamental grouping processes in auditory cortex
Authors: Holmes Emma , Zeidman Peter , Friston Karl J. , Griffiths Timothy D.
Published: October 2019

In our everyday lives, we are often required to follow a conversation when background noise is present (“speech-in-noise” perception). Speech-in-noise perception varies widely—and people who are worse at speech-in-noise perception are also worse at fundamental auditory grouping, as assessed by figure-ground tasks. Here, we examined the cortical processes that link difficulties with speech-in-noise perception to difficulties with figure-ground perception using functional magnetic resonance imaging (fMRI). We found strong evidence that the earliest stages of the auditory cortical hierarchy (left core and belt areas) are similarly disinhibited when speech-in-noise and figure-ground tasks are more difficult (i.e., at target-to-masker ratios corresponding to 60% than 90% thresholds)—consistent with increased cortical gain at lower levels of the auditory hierarchy. Overall, our results reveal a common neural substrate for these basic (figure-ground) and naturally relevant (speech-in-noise) tasks—which provides a common computational basis for the link between speech-in-noise perception and fundamental auditory grouping.
Digitally Deconstructing Leaves in 3D Using X-ray Microcomputed Tomography and Machine Learning
Authors: Théroux-Rancourt Guillaume , Jenkins Matthew R. , Brodersen Craig R. , McElrone Andrew , Forrestel Elisabeth J. , Earles J. Mason
Published: October 2019

Premise of the study

X-ray microcomputed tomography (microCT) can be used to measure 3D leaf internal anatomy, providing a holistic view of tissue organisation. Previously, the substantial time needed for segmenting multiple tissues limited this technique to small datasets, restricting its utility for phenotyping experiments and limiting our confidence in the conclusion of these studies due to low replication numbers.

Methods and Results

We present a Python codebase for random-forest machine learning segmentation and 3D leaf anatomical trait quantification which dramatically reduces the time required to process single leaf microCT scans into detailed segmentations. By training the model on each scan using 6 hand segmented image slices out of >1500 in the full leaf scan, it achieves >90% accuracy in background and tissue segmentation.

Conclusion

Overall, this 3D segmentation and quantification pipeline can reduce one of the major barriers to using microCT imaging in high-throughput plant phenotyping.