bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Performance of Laboratory-Developed Liquid Chromatography–Tandem Mass Spectrometry Tests and a Food and Drug Administration–Approved Immunoassay for the Therapeutic Drug Monitoring of Everolimus
Authors: Schniedewind Björn , Meyer Eric J. , Christians Uwe
Published: October 2019

Background:

Laboratory-developed tests (LDTs) are analytical tests developed and validated “in-house” for clinical diagnosis. Regulatory agencies, such as the United States Food and Drug Administration (FDA), encourage using regulatory-approved assays rather than LDTs. In the ongoing Zortracker everolimus study, samples were provided monthly to participating clinical laboratories that conduct therapeutic drug monitoring of everolimus. This allowed for the long-term (6-year) comparison of the performance of liquid chromatography–tandem mass spectrometry (LC-MS/MS) assays, which are LDTs, to the FDA-approved everolimus Quantitative Microsphere System (QMS).

Methods:

Each laboratory received the same 3 blinded samples. LC-MS/MS and QMS assays were compared using Passing Bablok regression analysis. Data were analyzed in 12-month periods to detect trends over time.

Results:

The slopes of the Passing Bablok regression curves remained unchanged in 2013 and 2014 (reference LC-MS/MS; test QMS: slope = 0.934 and 1.008). However, by 2016, the slope increased significantly to between 1.111 and 1.320, then dropped to 0.980 in 2017 and 0.912 in 2018, suggestive of changes in QMS bias compared with LC-MS/MS over longer periods. Outliers did not affect these results. The interlaboratory variability of LC-MS/MS and QMS remained unchanged from 2013 to 2015, with coefficients of variation of 15.3%, 18.4%, and 17.2% for LC-MS/MS, and 13.0%, 13.1%, and 15.3% for QMS, respectively, per year. At the end of the observation period, the average coefficients of variation in LC-MS/MS laboratories dropped to 14.3%, 12.6%, and 14.2%, whereas the variability in QMS laboratories was 19.5%, 13.3%, and 19.6% in 2016, 2017, and 2018, respectively.

Conclusions:

Initially, QMS everolimus concentrations in patient samples were comparable with those detected in LC-MS/MS laboratories. However, concentration bias of the QMS assay significantly changed within 6 years, emphasizing the need for long-term, independent performance tracking of therapeutic drug monitoring assays, including FDA-approved assays.
Emerging Role of Myeloid-derived Suppressor Cells in the Biology of Transplantation Tolerance
Authors: Shao Liang , Pan Shan , Zhang Qiu-ping , Jamal Muhammad , Rushworth Gerard-Martin , Xiong Jie , Xiao Rui-jing , Sun Jia-xing , Yin Qian , Wu Ying-jie , Lie Albert K.W.
Published: October 2019

Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells, are characterized by their immunosuppressive abilities through the secretion of various cytokines such as inducible nitric oxide synthase, nitric oxide, reactive oxygen species, transforming growth factor-β, and arginase-1. Accumulating evidence highlights its potential role in maintaining immune tolerance in solid organ and hematopoietic stem cell transplantation. Mechanistically, MDSCs-induced transplant tolerance is mainly dependent on direct suppression of allogeneic reaction or strengthened cross-talk between MDSCs and Treg or NKT cells. Adopted transfer of in vitro– or in vivo–induced MDSCs by special drugs therefore becomes a potential strategy for maintaining transplantation tolerance. In this review, we will summarize the previously published data about the role of MDSCs in the biology of transplantation tolerance and gain insights into the possible molecular mechanism governing this process.
Quantitative genetics of body size evolution on islands: an individual-based simulation approach
Authors: Diniz-Filho José Alexandre F. , Jardim Lucas , Rangel Thiago F. , Holden Phillip B. , Edwards Neil R. , Hortal Joaquín , Santos Ana M. C. , Raia Pasquale
Published: October 2019

According to the island rule, small-bodied vertebrates will tend to evolve larger body size on islands, whereas the opposite happens to large-bodied species. This controversial pattern has been studied at the macroecological and biogeographical scales, but new developments in quantitative evolutionary genetics now allow studying the island rule from a mechanistic perspective. Here, we develop a simulation approach based on an individual-based model to model body size change on islands as a progressive adaptation to a moving optimum, determined by density-dependent population dynamics. We applied the model to evaluate body size differentiation in the pigmy extinct homininHomo floresiensis,showing that dwarfing may have occurred in only about 360 generations (95% CI ranging from 150 to 675 generations). This result agrees with reports suggesting rapid dwarfing of large mammals on islands, as well as with the recent discovery that small-sized hominins lived in Flores as early as 700 kyr ago. Our simulations illustrate the power of analysing ecological and evolutionary patterns from an explicit quantitative genetics perspective.
How eyelashes can protect the eye through inhibiting ocular water evaporation: a chemical engineering perspective
Authors: Zou Siyu , Zha Jinping , Xiao Jie , Chen Xiao Dong
Published: October 2019

Bionics is a fascinating subject that has inspired many inventions through learning from biological structures and functions. In this work, a coupled multi-physics model has been developed to characterize ocular water evaporation with realistic eyelash structures taken into account. From a chemical engineering perspective, the protective function of human eyelashes in terms of evaporation inhibition has been rationally revealed. Systematic investigations were carried out to elucidate the effects of different eyelash lengths, orientations and inlet air directions on water evaporation on the ocular surface. The results clearly demonstrate that regardless of inlet air directions and eyelash orientations, increasing eyelash length from zero to an optimal length can effectively reduce water evaporation. However, further increase in the eyelash length can lead to enhanced evaporation. For the normal and parallel inlet air directions, the optimal eyelash length is around 15–30% of the eye width and can offer approximately 10–30% evaporation reduction when compared with the cases without eyelashes. These values are independent of the eyelash orientation. This investigation provides valuable data for in-depth understanding of the protective function of the eyelashes, which can be used in the future to improve and optimize bionic designs inspired by human eyelashes.
Smooth muscle contractility causes the gut to grow anisotropically
Authors: Khalipina Diana , Kaga Yusuke , Dacher Nicolas , Chevalier Nicolas R.
Published: October 2019

The intestine is the most anisotropically shaped organ, but, when grown in culture, embryonic intestinal stem cells form star- or sphere-shaped organoids. Here, we present evidence that spontaneous tonic and phasic contractions of the circular smooth muscle of the embryonic gut cause short-timescale elongation of the organ by a purely mechanical, self-squeezing effect. We present an innovative culture set-up to achieve embryonic gut growth in culture and demonstrate by three different methods (embryological, pharmacological and microsurgical) that gut elongational growth is compromised when smooth muscle contractions are inhibited. We conclude that the cumulated short-term mechanical deformations induced by circular smooth muscle lead to long-term anisotropic growth of the gut, thus demonstrating a self-consistent way by which the function of this organ (peristalsis) directs its shape (morphogenesis). Our model correctly predicts that longitudinal smooth muscle differentiation later in embryogenesis slows down elongation, and that several mice models with defective gut smooth muscle contractility also exhibit gut growth defects. We lay out a comprehensive scheme of forces acting on the gut during embryogenesis and of their role in the morphogenesis of this organ. This knowledge will help design efficient
in vitro
organ growth protocols and handle gut growth pathologies such as short bowel syndrome.
An efficient numerical approach for simulating contact in origami assemblages
Authors: Zhu Yi , Filipov Evgueni T.
Published: October 2019

Origami-inspired structures provide novel solutions to many engineering applications. The presence of self-contact within origami patterns has been difficult to simulate, yet it has significant implications for the foldability, kinematics and resulting mechanical properties of the final origami system. To open up the full potential of origami engineering, this paper presents an efficient numerical approach that simulates the panel contact in a generalized origami framework. The proposed panel contact model is based on the principle of stationary potential energy and assumes that the contact forces are conserved. The contact potential is formulated such that both the internal force vector and the stiffness matrix approach infinity as the distance between the contacting panel and node approaches zero. We use benchmark simulations to show that the model can correctly capture the kinematics and mechanics induced by contact. By tuning the model parameters accordingly, this methodology can simulate the thickness in origami. Practical examples are used to demonstrate the validity, efficiency and the broad applicability of the proposed model.
Capture from the wild has long-term costs on reproductive success in Asian elephants
Authors: Lahdenperä Mirkka , Jackson John , Htut Win , Lummaa Virpi
Published: October 2019

Capturing wild animals is common for conservation, economic or research purposes. Understanding how capture itself affects lifetime fitness measures is often difficult because wild and captive populations live in very different environments and there is a need for long-term life-history data. Here, we show how wild capture influences reproduction in 2685 female Asian elephants (Elephas maximus) used in the timber industry in Myanmar. Wild-caught females demonstrated a consistent reduction in breeding success relative to captive-born females, with significantly lower lifetime reproduction probabilities, lower breeding probabilities at peak reproductive ages and a later age of first reproduction. Furthermore, these negative effects lasted for over a decade, and there was a significant influence on the next generation: wild-caught females had calves with reduced survival to age 5. Our results suggest that wild capture has long-term consequences for reproduction, which is important not only for elephants, but also for other species in captivity.
Bark coverage shifts assembly processes of microbial decomposer communities in dead wood
Authors: Hagge Jonas , Bässler Claus , Gruppe Axel , Hoppe Björn , Kellner Harald , Krah Franz-Sebastian , Müller Jörg , Seibold Sebastian , Stengel Elisa , Thorn Simon
Published: October 2019

Bark protects living trees against environmental influences but may promote wood decomposition by fungi and bacteria after tree death. However, the mechanisms by which bark determines the assembly process and biodiversity of decomposers remain unknown. Therefore, we partially or completely removed bark from experimentally felled trees and tested with null modelling whether assembly processes were determined by bark coverage and if biodiversity of molecularly sampled fungi and bacteria generally benefited from increasing bark cover. The community composition of fungi, wood-decaying fungi (subset of all fungi) and bacteria clearly separated between completely debarked, partly debarked and control trees. Bacterial species richness was higher on control trees than on either partly or completely debarked trees, whereas the species richness of all fungi did not differ. However, the species richness of wood-decaying fungi was higher on partially and completely debarked trees than on control trees. Deterministic assembly processes were most important in completely debarked trees, a pattern consistent for fungi and bacteria. Our findings suggest that human disturbances in forests shift the dominant assembly mechanism from stochastic to deterministic processes and thus alter the diversity of wood-inhabiting microorganisms.
Recalibration of the insect evolutionary time scale using Monte San Giorgio fossils suggests survival of key lineages through the End-Permian Extinction
Authors: Montagna Matteo , Tong K. Jun , Magoga Giulia , Strada Laura , Tintori Andrea , Ho Simon Y. W. , Lo Nathan
Published: October 2019

Insects are a highly diverse group of organisms and constitute more than half of all known animal species. They have evolved an extraordinary range of traits, from flight and complete metamorphosis to complex polyphenisms and advanced eusociality. Although the rich insect fossil record has helped to chart the appearance of many phenotypic innovations, data are scarce for a number of key periods. One such period is that following the End-Permian Extinction, recognized as the most catastrophic of all extinction events. We recently discovered several 240-million-year-old insect fossils in the Mount San Giorgio Lagerstätte (Switzerland–Italy) that are remarkable for their state of preservation (including internal organs and soft tissues), and because they extend the records of their respective taxa by up to 200 million years. By using these fossils as calibrations in a phylogenomic dating analysis, we present a revised time scale for insect evolution. Our date estimates for several major lineages, including the hyperdiverse crown groups of Lepidoptera, Hemiptera: Heteroptera and Diptera, are substantially older than their currently accepted post-Permian origins. We found that major evolutionary innovations, including flight and metamorphosis, appeared considerably earlier than previously thought. These results have numerous implications for understanding the evolution of insects and their resilience in the face of extreme events such as the End-Permian Extinction.
Long-term research needed to avoid spurious and misleading trends in sustainability attributes of no-till
Authors: Cusser Sarah , Bahlai Christie , Swinton Scott M. , Robertson G. Philip , Haddad Nick M.
Published: October 2019

Agricultural management recommendations based on short-term studies can produce findings inconsistent with long-term reality. Here, we test the long-term relative profitability and environmental sustainability of continuous no-till agriculture practices on crop yield, soil moisture, and N2O fluxes. Using a moving window approach, we investigate the development and stability of several attributes of continuous no-till as compared to conventional till agriculture over a 29-year period at a site in the upper Midwest, U.S. We find that over a decade is needed to detect the consistent benefits of no-till on important attributes at this site. Both crop yield and soil moisture required periods 15 years or longer to generate patterns consistent with 29-year trends. Only marginally significant trends for N2O fluxes appeared in this period. Importantly, significant but misleading short-term trends appeared in more than 20% of the periods examined. Relative profitability analysis suggests that 10 years after initial implementation, 86% of periods recuperated the initial expense of no-till implementation, with the probability of higher relative profit increasing with longevity. Results underscore the essential importance of decade and longer studies for revealing the long-term dynamics and emergent outcomes of agricultural practices for different sustainability attributes and are consistent with recommendations to support the long-term adoption of no-till management.

GRAPHICAL ABSTRACT

HIGHLIGHTS

We test long-term effects of no-till on yield, soil moisture, and N2O fluxes

We examine 29 years of data with a moving window and relative profitability method

It takes at least a decade to detect consistent benefits of no-till

Shorter studies can produce significant but misleading findings

Long studies are essential to reveal the dynamics of agricultural management
Enhancing fMRI language lateralization indices by homotopic mapping
Authors: Pesci Matteo , van Steensel Mariska , Ramsey Nick , Raemaekers Mathijs
Published: October 2019

The non-invasive nature of fMRI would make it an excellent tool for determining language lateralization, potentially replacing the WADA test that is now considered the gold standard. However, while the result of the WADA test has 3 straightforward categories, i.e. left, right, or bilateral language lateralization, fMRI lateralization indices (LIs) are on a continuous scale between −1 (completely right lateralized) and 1 (completely left lateralized), requiring arbitrary thresholding to come to a useful clinical measure. We hypothesize that the absence of clear categories in fMRI LIs is in part linked to imperfect fMRI task control and/or homotopically mapped language activity in the non-dominant hemisphere. In this study we attempt to account for these sources of brain activity by making a detailed homotopic comparison between voxels in the language areas and their homologues, which is now possible using the Cgrid toolbox. 36 epilepsy were included who underwent presurgical fMRI including a picture naming and verb generation task, in addition to the WADA test, functional Transcranial Doppler sonography (fTCD), or Electrocortical stimulation (ECS). LIs were calculated using a traditional approach, and a novel approach based on the paired comparison between language voxels and their homologues. We observed that lateralization indices came in closer alignment with those established by the WADA test, ECS, of fTCD. Activity maps indicated that the accounting for imperfect fMRI task control was at least part of the reason for the improvement when using the new approach. This Cgrid based approach could help fMRI replacing the more invasive WADA test in the future.
PANDAA-monium: Intentional violations of conventional qPCR design enables rapid, HIV-1 subtype-independent drug resistance SNP detection
Authors: MacLeod Iain J. , Rowley Christopher F. , Essex M.
Published: October 2019

Global efforts to ensure that 90% of all HIV-infected people receiving antiretroviral therapy (ART) will be virally suppressed by 2020 could be crippled by increases in acquired and transmitted HIV drug resistance (HIVDR), which challenge ART efficacy. The long-term sustainability of ART treatment programs is contingent on effective HIVDR monitoring yet current Sanger sequencing genotypic resistance tests are inadequate for large-scale implementation in low- and middle-income countries (LMICs). A simple, rapid, affordable HIVDR diagnostic would radically improve the treatment paradigm in LMICs by facilitating informed clinical decision-making upon ART failure. Although point mutation assays can be broadly deployed in this context, the primary challenge arises from extensive sequence variation surrounding targeted drug resistance mutations (DRMs). Here, we systematically and intentionally violate the canonical principles of qPCR design to develop a novel assay, Pan-Degenerate Amplification and Adaptation (PANDAA), that mitigates the impact of DRM-proximal secondary polymorphisms on probe-based qPCR performance to enable subtype-independent, focused resistance genotyping. Using extremely degenerate primers with 3’ termini overlapping the probe-binding site, the HIV-1 genome is adapted through site-directed mutagenesis to replace secondary polymorphisms flanking the target DRM during the initial qPCR cycles. We show that PANDAA can quantify key HIV DRMs present at ≥5% and has diagnostic sensitivity and specificity of 96.9% and 97.5%, respectively, to detect DRMs associated with ART failure. PANDAA is an innovative solution for HIVDR genotyping and is an advancement in qPCR technology that could be applicable to any scenario where target-proximal genetic variability has been a roadblock in diagnostic development.
Metabolomic profiling of mouse mammary tumor derived cell lines reveals targeted therapy options for cancer subtypes
Authors: Ogrodzinski Martin P. , Lunt Sophia Y.
Published: October 2019

Breast cancer is a heterogeneous disease with several subtypes that currently do not have targeted therapy options. Metabolomics has the potential to uncover novel targeted treatment strategies by identifying metabolic pathways required for cancer cells to survive and proliferate. Here, we used tumor-derived cell lines derived from the MMTV-Myc mouse model to investigate metabolic pathways that are differentially utilized between two subtypes of breast cancer. Using mass spectrometry-based metabolomics techniques, we identified differences in glycolysis, the tricarboxylic acid cycle, glutathione metabolism, and nucleotide metabolism between subtypes. We further show the feasibility of targeting these pathways in a subtype-specific manner using metabolism-targeting compounds.
Chromatin accessibility and histone acetylation in the regulation of competence in early development
Authors: Esmaeili Melody , Blythe Shelby A. , Tobias John W. , Zhang Kai , Yang Jing , Klein Peter S.
Published: October 2019

As development proceeds, inductive cues are interpreted by competent tissues in a spatially and temporally restricted manner. While key inductive signaling pathways within competent cells are well-described at a molecular level, the mechanisms by which tissues lose responsiveness to inductive signals are not well understood. Localized activation of Wnt signaling before zygotic gene activation inXenopus laevisleads to dorsal development, but competence to induce dorsal genes in response to Wnts is lost by the late blastula stage. We hypothesize that loss of competence is mediated by changes in histone modifications leading to a loss of chromatin accessibility at the promoters of Wnt target genes. We use ATAC-seq to evaluate genome-wide changes in chromatin accessibility across several developmental stages. Based on overlap with p300 binding, we identify thousands of putative cis-regulatory elements at the gastrula stage, including sites that lose accessibility by the end of gastrulation and are enriched for pluripotency factor binding motifs. Dorsal Wnt target gene promoters are not accessible after the loss of competence in the early gastrula while genes involved in mesoderm and neural crest development maintain accessibility at their promoters. Inhibition of histone deacetylases increases acetylation at the promoters of dorsal Wnt target genes and extends competence for dorsal gene induction by Wnt signaling. Histone deacetylase inhibition, however, is not sufficient to extend competence for mesoderm or neural crest induction. These data suggest that chromatin state regulates the loss of competence to inductive signals in a context-dependent manner.
Comparative genomics identifies putative signatures of sociality in spiders
Authors: Tong Chao , Najm Gabriella M. , Pinter-Wollman Noa , Pruitt Jonathan N. , Linksvayer Timothy A.
Published: October 2019

Comparative genomics has begun to elucidate the genomic basis of social life in insects but insight into the genomic basis of spider sociality has lagged behind. To begin to characterize genomic signatures associated with the evolution of social life in spiders, we performed one of the first spider comparative genomics studies including five solitary species and two social species, representing two independent origins of sociality in the genus Stegodyphus. We found that the two social spider species had a large expansion of gene families associated with transport and metabolic processes and an elevated genome-wide rate of molecular evolution compared with the five solitary spider species. Genes that were rapidly evolving in the two social species relative to the five solitary species were enriched for transport, behavior, and immune functions, while genes that were rapidly evolving in the solitary species were enriched for energy metabolism processes. Most rapidly evolving genes in the social species S. dumicola were broadly expressed across four tissues and enriched for transport functions, but 12 rapidly evolving genes showed brain-specific expression and were enriched for social behavioral processes. Altogether, our study identifies putative genomic signatures and potential candidate genes associated with spider sociality. These results indicate that future spider comparative genomic studies, including broader sampling and additional independent origins of sociality, can further clarify the genomic causes and consequences of social life.
A space-saving visual screening method, Glycine max FAST, for generating transgenic soybean
Authors: Iwabuchi Kosei , Shimada Takashi L. , Yamada Tetsuya , Hara-Nishimura Ikuko
Published: October 2019

Soybean is an important crop plant for food and biofuel production, and there have been considerable efforts to develop transgenic soybean lines with higher seed oil contents and/or seed yields. However, the process of screening transgenic lines is laborious and requires a large amount of space. Here, we describe a powerful screening method, Glycine max Fluorescence-Accumulating Seed Technology (GmFAST), which is based on a seed-specific fluorescent marker. The marker is composed of a soybean seed-specific promoter coupled to the OLE1-GFP gene, which encodes GFP fused to the oil-body membrane protein OLEOSIN1 of Arabidopsis thaliana. We introduced the marker gene into cotyledonary nodes of G. max Kariyutaka via Agrobacterium-mediated transformation and regenerated heterozygous transgenic plants. OLE1-GFP-expressing soybean seeds can be selected nondestructively using a fluorescence stereomicroscope. Among T2 seeds, the most strongly fluorescent seeds were homozygous. GmFAST uses one-tenth of the growing space required for the conventional method. This space-saving method will contribute to facilitating transformation of soybean. OLE1-GFP was localized specifically to oil bodies in the cotyledon cells of seeds, but it did not affect oil content per seed, the size and density of the oil bodies, or oil composition. One of the homozygous lines (line #8) showed a 44% increase in the seed pod number, which resulted in 41% and 30% increases in seed yield and total oil production, respectively, compared with the wild type. In line #8, OLE1-GFP was inserted into the intron of Glyma13g30950, causing its overexpression. An increase in seed pod number was confirmed in Arabidopsis thaliana plants that overexpressed the Arabidopsis ortholog of Glyma13g30950, E6L1. These results suggest that line #8 is a valuable resource for agricultural and industrial applications. Taken together, GmFAST provides a space-saving visual and non-destructive screening method for soybean transformation, thereby increasing the chance of developing useful soybean lines.
Detection of antibodies against a conserved capsid epitope as the basis of a novel universal serological test for foot-and-mouth disease
Authors: Asfor A , Howe N , Grazioli S , Berryman S , Parekh K , Wilsden G , Ludi A , King DP , Parida S , Brocchi E , Tuthill TJ
Published: October 2019

Diagnostic tests for foot-and-mouth disease (FMD) include the detection of antibodies against either the viral non-structural proteins or the capsid. The detection of antibodies against the structural proteins (SP) of the capsid can be used to monitor seroconversion in both infected and vaccinated animals. However, SP tests need to be tailored to the individual FMD virus serotype and their sensitivity performances may be affected by antigenic variability within each serotype and mismatching between tests reagents. As a consequence, FMD Reference Laboratories need to maintain contingency to employ multiple type-specific assays for large-scale serological surveillance and post-vaccination monitoring in the event of FMD outbreaks. In this study, a highly conserved region in the N terminus of FMDV capsid protein VP2 (VP2N) was characterised using a panel of intertypic-reactive monoclonal antibodies. This revealed a universal epitope in VP2N which could be used as a peptide antigen to detect FMDV-specific antibodies against all types of the virus. A VP2-peptide ELISA (VP2-ELISA) was optimised using experimental and reference antisera from immunized, convalescent and negative animals (n=172). The VP2-ELISA is universal, simple and provided sensitive (98.6 %) and specific (93%) detection of antibodies to all FMDV strains used in this study. We anticipate that this SP test could have utility for sero-surveillance during virus incursions in FMD-free countries and as an additional screening tool to assess FMD virus circulation in endemic countries.
Light-mediated decreases in cyclic di-GMP levels are potentiated by pyocyanin and inhibit structure formation inPseudomonas aeruginosabiofilms
Authors: Kahl Lisa Juliane , Price-Whelan Alexa , Dietrich Lars E. P.
Published: October 2019

Light is known to trigger regulatory responses in diverse organisms including slime molds, animals, plants, and phototrophic bacteria. However, light-dependent processes in non-phototrophic bacteria, and those of pathogens in particular, have received comparatively little research attention. In this study, we examined the impact of light on multicellular development inPseudomonas aeruginosa, a leading cause of biofilm-based bacterial infections, using a colony morphology assay. In this assay,P. aeruginosastrain PA14 grown in the dark forms vertical structures (i.e., “wrinkles”) on the third day of incubation. We found that growth in blue light inhibited wrinkle formation until the fifth day and that this required the phenazine pyocyanin, a redox-active metabolite produced by PA14. Light-dependent inhibition of wrinkling was also correlated with low levels of cyclic di-GMP (c-di-GMP), consistent with the role of this signal in stimulating biofilm matrix production. Though phenazine-null biofilms also showed lower levels of c-di-GMP and subtle effects on wrinkling when grown in the light, their overall levels of c-di-GMP were higher than those of the wild type. This indicates that phenazines and light simultaneously promote c-di-GMP degradation such that c-di-GMP is pushed to a minimum level, yielding a pronounced macroscopic phenotype. A screen of enzymes with the potential to catalyze c-di-GMP synthesis or degradation identified four proteins that contribute to light-dependent inhibition of biofilm wrinkling. Together, these results provide a foundation for understanding the significance of light-dependent regulation inP. aeruginosa.

Importance

The response to light in non-phototrophic bacteria (i.e., chemotrophs) is relatively understudied in comparison to light-mediated behavior in eukaryotes and phototrophic bacteria. Though they do not depend on light for growth, chemotrophic bacteria could benefit from sensing this cue when it correlates with other parameters that are important for metabolism. In this paper, we describe light-dependent effects on a cellular signal that controls the development of multicellular assemblages, called biofilms, inPseudomonas aeruginosa. We found that light at intensities that are not harmful to human cells inhibited biofilm maturation.P. aeruginosais a leading cause of chronic lung infections in people with cystic fibrosis and of hospital-acquired infections. AsP. aeruginosa’s recalcitrance to treatment is attributed in part to its facile formation of biofilms, this study provides insight into a mechanism that could be inhibited via new therapeutic tools, such as photodynamic therapy.
Sugars dominate the seagrass rhizosphere
Authors: Maggie Sogin E. , Michellod Dolma , Gruber-Vodicka Harald , Bourceau Patric , Geier Benedikt , Meier Dimitri V. , Seidel Michael , Ahmerkamp Soeren , Schorn Sina , D’Angelo Grace , Procaccini Gabriele , Dubilier Nicole , Liebeke Manuel
Published: October 2019

Seagrasses are one of the most efficient sinks of carbon dioxide on Earth1: They bury carbon 35 times faster than tropical rainforests on a per unit area basis2. While we know that carbon sequestration in terrestrial plants is intimately linked to the microorganisms living in their soils3–6, the interactions of seagrasses with their rhizospheres are poorly understood. We show that three seagrass species from two oceans excrete simple sugars, mainly sucrose, into their rhizosphere that accumulate to over 200 µM. Such high concentrations are at least 80 times higher than previously observed in the ocean, and surprising, as sugars are quickly consumed by microorganisms. In situ analyses and incubation experiments indicated that phenolic compounds from the seagrass inhibited microbial consumption of sucrose. Metagenomic and metatranscriptomic analyses of the microbial communities in the seagrass rhizosphere revealed that many members had the genes for degrading sucrose, but these were only expressed by a few specialists that also expressed genes for degrading phenolics. Our results explain why sucrose accumulates under seagrass meadows, where it comprises as much as 40% of the dissolved organic carbon. Destruction of extant seagrass canopies would allow sediment microorganisms to consume the tremendous deposits of sucrose buried underneath their meadows, thereby releasing large amounts of CO2 into the oceans and atmosphere.
Potent and lasting seizure suppression by systemic delivery of antagomirs targeting miR-134 timed with blood-brain barrier disruption
Authors: Reschke C. R. , Silva L. F. A. , Vangoor V. R. , Rosso M. , David B. , Cavanagh B. L. , Connolly N. M. C. , Brennan G. P. , Sanz-Rodriguez A. , Mooney C. , Batool A. , Greene C. , Brennan M. , Conroy R. M. , Rüber T. , Prehn J. H. M. , Campbell M. , Pasterkamp R. J. , Henshall D. C.
Published: October 2019

RNA therapies such as oligonucleotides (OGNs) offer precision treatments for a variety of neurological diseases, including epilepsy but their deployment is hampered by the blood brain barrier (BBB). Here we used brain imaging and assays of serum proteins and tracer extravasation, to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically-injected antisense OGNs targeting microRNA-134 (Ant-134) into the brain parenchyma. A single intraperitoneal injection of Ant-134 two hours after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at three months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces disease-modifying effects after systemic injection in mice when timed with BBB disruption and may be a clinically-viable approach for this and other disease-modifying microRNA therapies.
Coordination during group departures and group progressions in the tolerant multilevel society of wild Guinea baboons (Papio papio)
Authors: Montanari Davide , Hambuckers Julien , Fischer Julia , Zinner Dietmar
Published: October 2019

Objectives

Most primate species live in groups, and temporal and spatial coordination of activities of individuals is essential for maintaining group cohesion, and there is still considerable debate to which degree social organization, the extent of despotism, and resource distribution shape group coordination processes. As different baboon species exhibit considerable variation in all of these factors, they constitute an excellent test case to resolve this debate.

Materials and Methods

We analyzed group departures and progressions of Guinea baboons,Papio papio, in the Niokolo Koba National Park in Senegal. Guinea baboons live in a multi-level society with strong male bonds and a lack of a clear dominance hierarchy between males.

Results

Two-thirds of departures were initiated by adult males, and one third by adult females. Although initiators were more likely to signal than followers, signaling did not affect the initiation success. During group progression, males that were not affiliated with females were predominantly found in the front, while affiliated males, females and young were observed more frequently closer to the center of the group, and no preferences for rear positions. Overall, affiliated subjects were more likely to depart and travel together.

Discussion

The group departures in Guinea baboons differed strikingly from the elaborate ‘negotiation’ behaviors among male hamadryas baboons,Papio hamadryas. We did not observe that specific individuals dominated the group coordination. Neither social organization, variation in despotism, nor resource distribution alone explain variation between species. Future studies should test whether specific combinations of factors promote the occurrence of negotiation processes.

Research Highlights

In wild Guinea baboons, both adult males and females initiated group departures

Initiators signaled during departures, but this did not affect initiation success

Solitary males were predominantly found at the front during group progression
Acute and repeated intranasal oxytocin differentially modulate brain-wide functional connectivity
Authors: Pagani Marco , De Felice Alessia , Montani Caterina , Galbusera Alberto , Papaleo Francesco , Gozzi Alessandro
Published: October 2019

Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. Moreover, little is known of the neuroadaptive cascade triggered by long-term administration of this peptide at the network level. To address these questions, we applied fMRI-based circuit mapping in adult mice upon acute and repeated (seven-day) intranasal dosing of OXT. We report that acute and chronic OXT administration elicit comparable fMRI activity as assessed with cerebral blood volume mapping, but entail largely different patterns of brain-wide functional connectivity. Specifically, acute OXT administration focally boosted connectivity within key limbic components of the rodent social brain, whereas repeated dosing led to a prominent and widespread increase in functional connectivity, involving a strong coupling between the amygdala and extended cortical territories. Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.
Abscission couples cell division to embryonic stem cell fate
Authors: Chaigne Agathe , Labouesse Celine , Agnew Meghan , Hannezo Edouard , Chalut Kevin J , Paluch Ewa K
Published: October 2019

Cell fate transitions are key to development and homeostasis. It is thus essential to understand the cellular mechanisms controlling fate transitions. Cell division has been implicated in fate decisions in many stem cells, including neuronal and epithelial progenitors. In other stem cells, such as embryonic stem (ES) cells, the role of division remains unclear. Here we show that exit from naïve pluripotency in mouse ES cells generally occurs after a division. We further show that exit timing is strongly correlated between sister cells, which remain connected by cytoplasmic bridges long after division, and that bridge abscission progressively accelerates as cells exit naïve pluripotency. Finally, interfering with abscission impairs exit from naïve pluripotency. Altogether, our data indicate that a switch in the division machinery leading to faster abscission is crucial for pluripotency exit. Our study identifies abscission as a key step coupling cell division to fate transitions.
Mammary epithelial cells have lineage-restricted metabolic identities
Authors: Mahendralingam Mathepan , Aliar Kazeera , Elisabeth Casey Alison , Pellacani Davide , Kim Hyeyeon , Ignatchenko Vladimir , Valero Mar Garcia , Palomero Luis , Sinha Ankit , Stambolic Vid , Alam Mina , Schimmer Aaron , Berman Hal , Angel Pujana Miquel , Eaves Connie , Kislinger Thomas , Khokha Rama
Published: October 2019

Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show that mammary populations have cell type-specific metabolic programs. Primary human breast cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of electron transport chain subunits and capacity for oxidative phosphorylation, whereas basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages. Computational analysis indicated that breast cancer subtypes retain metabolic features of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary cells partly explain breast cancer metabolic heterogeneity and rationalize targeting subtype-specific metabolic vulnerabilities to advance breast cancer therapy.
A Single-Cell Atlas and Lineage Analysis of the Adult Drosophila Ovary
Authors: Rust Katja , Byrnes Lauren , Yu Kevin Shengyang , Park Jason S. , Sneddon Julie B. , Tward Aaron D. , Nystul Todd G.
Published: October 2019

The Drosophila ovary is a widely used model for germ cell and somatic tissue biology. We have used single-cell RNA-sequencing to build a comprehensive cell atlas of the adult Drosophila ovary containing unique transcriptional profiles for every major cell type in the ovary, including the germline and follicle stem cells. Using this atlas we identify novel tools for identification and manipulation of known and novel cell types and perform lineage tracing to test cellular relationships of previously unknown cell types. By this we discovered a new form of cellular plasticity in which inner germarial sheath cells convert to follicle stem cells in response to starvation.

Graphical Abstract
Influence of selective treatment onHaematobia irritansinfestation of untreated cattle
Authors: Miraballes Cecilia , Stryhn Henrik , Barros Antonio Thadeu M. , Lucas Martin , Domingues Luísa Nogueira , Ribeiro Rodrigo , Monge Macarena , Fraga Alvaro , Riet-Correa Franklin
Published: October 2019

To reduce the use of insecticide treatments againstHaematobia irritanswe evaluated the impact of treating 15% of the bovines, with the greatest number of flies including bulls, with 40% diazinon ear tags, on the infestation of untreated cows. Horn fly susceptibility to diazinon was measured before and after treatment, and peaks of infestation were recorded. Three groups of Bradford bovines were evaluated: Group 1 (control untreated), Group 2 (15% treated) and Group 3 (control 100% treated). Weekly counts of horn flies were performed on the same animals for 78 days. Two peaks of infestation were recorded, and a higher number of horn flies occurred in the untreated control group than in the untreated cows of the selectively treated group throughout the entire period of the study, except for a single week. The horn fly field population was significantly more susceptible to diazinon than the reference susceptible strain both before and after insecticide treatment. In conclusion, treatment of 15% of the most infested animals from a herd, with 40% diazinon ear tags, quickly reduced horn fly infestations of the entire herd and may be a practical approach for horn fly control, reducing costs and chemical use.
rsCaMPARI: an erasable marker of neuronal activity
Authors: Sha Fern , Abdelfattah Ahmed S. , Patel Ronak , Schreiter Eric R.
Published: October 2019

Identifying and comparing active neuron ensembles underlying complex behaviors is a key challenge in neuroscience. Recent tools such as CaMPARI have enabled the optical marking and selection of active neuron populations. However, CaMPARI photoconversion is permanent and irreversible, limiting its utility when multiple activity snapshots must be compared within the same sample. We sought to overcome these limitations by developing an erasable neuronal activity marker based on a reversibly switchable fluorescent protein. Here we introduce rsCaMPARI, a reversibly switchable calcium marker that enables spatiotemporally precise marking, erasing, and remarking of active neuron populations under brief, user-defined time windows of light exposure. rsCaMPARI photoswitching kinetics are modulated by calcium concentration when illuminating with blue light, and the fluorescence can be reset with violet light. We demonstrate the utility of rsCaMPARI for marking and remarking active neuron populations in freely-swimming zebrafish.
Multivoxel Pattern of Blood Oxygen Level Dependent Activity can be sensitive to stimulus specific fine scale responses
Authors: Vizioli Luca , De Martino Federico , Petro Lucy S , Kersten Daniel , Ugurbil Kamil , Yacoub Essa , Muckli Lars
Published: October 2019

1.

At ultra-high field, fMRI voxels can span the sub-millimeter range, allowing the recording of blood oxygenation level dependent (BOLD) responses at the level of fundamental units of neural computation, such as cortical columns and layers. This sub-millimeter resolution, however, is only nominal in nature as a number of factors limit the spatial acuity of functional voxels. Multivoxel Pattern Analysis (MVPA) may provide a means to detect information at finer spatial scales that may otherwise not be visible at the single voxel level due to limitations in sensitivity and specificity. Here, we evaluate the spatial scale of stimuli specific BOLD responses in multivoxel patterns exploited by linear Support Vector Machine, Linear Discriminant Analysis and Naïve Bayesian classifiers across cortical depths in V1. To this end, we artificially misaligned the testing relative to the training portion of the data in increasing spatial steps, then investigated the breakdown of the classifiers’ performances. A one voxel shift led to a significant decrease in decoding accuracy (p<.05) across all cortical depths, indicating that stimulus specific responses in a multivoxel pattern of BOLD activity exploited by multivariate decoders can be as precise as the nominal resolution of single voxels (here .8 mm isotropic). Our results further indicate that large draining vessels, prominently residing in proximity of the pial surface, do not, in this case, hinder the ability of MVPA to exploit fine scale patterns of BOLD signals. We argue that tailored analytical approaches can help overcoming limitations in high-resolution fMRI and permit studying the mesoscale organization of the human brain with higher sensitivities.