bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic TOR and ERK inhibition mitigates the hereditary haemorrhagic telangiectasia-like phenotype and excesskugelformation in endoglin mutant zebrafish
Authors: Snodgrass Ryan O. , Arthur Helen M. , Chico Timothy J.A. 
Published: June 2021

AbstractRationaleHereditary haemorrhagic telangiectasia (HHT) is an inherited bleeding disorder characterised by arteriovenous malformations (AVMs). Such AVMs affect lungs, liver and brain, whilst telangiectases in mucocutaneous tissues are prone to haemorrhage. HHT type I is caused by loss-of-function endoglin (ENG) mutations. Evidence suggests AVMs result from abnormal responses to VEGF signalling.ObjectiveWe therefore characterised the vascular abnormalities inengmutant zebrafish and investigated whether these are prevented by inhibiting different pathways downstream of VEGF signalling.Methods and ResultsWe used light sheet fluorescence microscopy to visualise the vasculature inengmu130mutant zebrafish. In addition to previously described significantly enlarged dorsal aorta and posterior cardinal vein at 3d post fertilisation,engmu130embryos had an enlarged basilar artery (BA), and increased formation of endothelial“kugeln”on cerebral vessels. Adultengmu130fish developed skin AVMs, retinal vascular abnormalities, and an enlarged heart. Tivozanib (AV951), a VEGF receptor tyrosine kinase inhibitor, prevented development of the abnormally enlarged major vessels and normalised the number ofkugelninengmu130embryos. Inhibiting discrete signalling pathways downstream of VEGFR2 inengmu130embryos gave further insights. Inhibiting TOR or MEK prevented the abnormal trunk and cerebral vasculature phenotype, whilst targeting NOS and MAPK had no effect. Combining subtherapeutic TOR and MEK inhibition prevented the vascular phenotype, suggesting synergy between TOR and MEK/ERK signalling pathways.ConclusionsThese results indicate the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of VEGF signalling, and implicate combination low dose ERK and TOR pathway inhibitors as a therapeutic strategy in HHT.Graphical Abstract
Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics
Authors: Gao Yang , Kabotyanski Elena B. , Villegas Elizabeth , Shepherd Jonathan H. , Acosta Deanna , Hamor Clark , Sun Tingting , Montmeyor-Garcia Celina , He Xiaping , Dobrolecki Lacey E. , Westbrook Thomas F. , Lewis Michael T. , Hilsenbeck Susan G. , Zhang Xiang H.-F. , Perou Charles M. , Rosen Jeffrey M. 
Published: June 2021

AbstractPolo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, PLK2 (chromosome 5q11.2) is frequently deleted in human breast cancers, preferentially in basal-like and triple-negative breast cancer subtypes. Here, we found that PLK2 was tumor suppressive in breast cancer and knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase and that mutations in the kinase domain of PLK2, but not polo-box binding domains, changed their interaction pattern. Furthermore, treatment of syngeneic transplantation mouse tumor models and patient-derived xenografts using the PLK1 inhibitor volasertib alone, or in combination with carboplatin, indicated that PLK2-low breast tumors had a significantly better response to these drugs. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. Taken together, our data suggest PLK2 loss may serve as a biomarker to predict response to PLK1 therapeutics, alone and in combination with chemotherapy.SignificanceThe tumor suppressive role of PLK2, and its relationship with the oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2 low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.
Systemic aneuploidization events drive phenotype switching in Saccharomyces cerevisiae
Authors: Heasley Lydia R. , Argueso Juan Lucas 
Published: June 2021

AbstractHow cells leverage their phenotypic potential to adapt and survive in a changing environment is a complex biological problem, with important implications for pathogenesis and species evolution. One particularly fascinating adaptive approach is the bet hedging strategy known as phenotype switching, which introduces phenotypic variation into a population through stochastic processes. Phenotype switching has long been observed in species across the tree of life, yet the mechanistic causes of switching in these organisms have remained difficult to define. Here we describe the causative basis of colony morphology phenotype switching which occurs among cells of the pathogenic isolate of Saccharomyces cerevisiae, YJM311. From clonal populations of YJM311 cells grown in identical conditions, we identified colonies which displayed altered colony architectures, yet could revert to the wild-type morphology after passaging. Whole genome sequence analysis revealed that these variant clones had all acquired whole chromosome copy number alterations (i.e., aneuploidies). Cumulatively, the variant clones we characterized harbored an exceptional spectrum of karyotypic alterations, with individual variants carrying between 1 and 16 aneuploidies. Most variants harbored unique collections of aneuploidies, indicating that numerous distinct karyotypes could manifest in the same morphological variation. Intriguingly, the genomic stability of these newly aneuploid variant clones modulated how often cells reverted back to the wild-type phenotypic state. We found that such revertant switches were also driven by chromosome missegregation events, and in some cases occurred through a return to euploidy. Together, our results demonstrate that colony morphology switching in this yeast strain is driven by stochastic and systemic aneuploidization events. These findings add an important new perspective to our current understanding of phenotype switching and bet hedging strategies, as well as how environmental pressures perpetuate organismal adaption and genome evolution.
Mouse visual cortex as a limited resource system that self-learns an ecologically-general representation
Authors: Nayebi Aran , Kong Nathan C. L. , Zhuang Chengxu , Gardner Justin L. , Norcia Anthony M. , Yamins Daniel L. K. 
Published: June 2021

AbstractStudies of the mouse visual system have revealed a variety of visual brain areas that are thought to support a multitude of behavioral capacities, ranging from stimulus-reward associations, to goal-directed navigation, and object-centric discriminations. However, an overall understanding of the mouse’s visual cortex, and how it supports a range of behaviors, remains unknown. Here, we take a computational approach to help address these questions, providing a high-fidelity quantitative model of mouse visual cortex and identifying key structural and functional principles underlying that model’s success. Structurally, we find that a comparatively shallow network structure with a low-resolution input is optimal for modeling mouse visual cortex. Our main finding is functional – that models trained with task-agnostic, self-supervised objective functions based on the concept of contrastive embeddings are much better matches to mouse cortex, than models trained on supervised objectives or alternative self-supervised methods. This result is very much unlike in primates where prior work showed that the two were roughly equivalent, naturally leading us to ask the question of why these self-supervised objectives are better matches than supervised ones in mouse. To this end, we show that the self-supervised, contrastive objective builds a general-purpose visual representation that enables the system to achieve better transfer on out-of-distribution visual scene understanding and reward-based navigation tasks. Our results suggest that mouse visual cortex is a low-resolution, shallow network that makes best use of the mouse’s limited resources to create a light-weight, general-purpose visual system – in contrast to the deep, high-resolution, and more categorization-dominated visual system of primates.Author summaryStudies of mouse visual behavior have revealed a multitude of visual abilities, ranging from stimulus-reward associations, to goal-directed navigation, and object-centric discriminations. A principled system-wide model of mouse visual cortex would be useful both in providing an organizing theory for this wide spectrum of behaviors, and enabling practical technology for many model-driven studies of mouse neuroscience more broadly. However, the standard approach to creating quantitatively accurate models of primate visual cortex has been less successful with the mouse system. Here we identify critical computational features needed to capture mouse-specific neural stimulus-response patterns, and illustrate how these features can be interpreted as giving the highly resource-limited mouse brain a comparative advantage in self-learning a task-general visual representation.
Sex-Specific Plasticity Explains Genetic Variation in Sexual Size Dimorphism in Drosophila
Authors: Vea Isabelle M , Wilcox Austin , Frankino W. Anthony , Shingleton Alexander W 
Published: June 2021

AbstractThe difference in body size between females and males, or sexual size dimorphism (SSD), is almost ubiquitous, and yet we have a remarkably poor understanding of the developmental-genetic mechanisms that generate it. Such an understanding is important if we are to distinguish between the many theoretical models of SSD evolution. One such model is the condition dependence hypothesis, which proposes that the body size of the larger sex is also more environmentally sensitive, a phenomenon called sex-specific plasticity (SSP). Because SSP generates differences in female and male body size, selection on plasticity may underlie the evolution of sexual size dimorphism. To test this hypothesis, however, we need to know the genetic architecture of both SSD and SSP, which is challenging because both are characteristics of populations not individuals. Here, we overcome this challenge by using isogenic lineages of Drosophila to measure both SSD and SSP for a genotype. We demonstrate extensive genetic variation for SSD among genotypes that is tightly correlated with variation in SSP, indicating that the same developmental-genetic mechanisms regulate both phenomena. These data support the condition dependence hypothesis and suggest that the observed SSD is a consequence of selection on the developmental-genetic mechanisms that regulate SSP.
Soil protists can actively redistribute beneficial bacteria alongMedicago truncatularoots
Authors: Hawxhurst Christopher J. , Micciulla Jamie L. , Bridges Charles M. , Shor Mikhael , Gage Daniel J. , Shor Leslie M. 
Published: June 2021

AbstractThe rhizosphere is the region of soil directly influenced by plant roots. The microbial community in the rhizosphere includes fungi, protists, and bacteria, all of which play a significant role in plant health. The beneficial bacteriumSinorhizobium melilotiinfects growing root hairs on nitrogen-starved leguminous plants. Infection leads to the formation of a root nodule, whereS. meliloticonverts atmospheric nitrogen to ammonia, a usable form of nitrogen for plants.S. melilotiis often found in biofilms and travels slowly along the roots, leaving developing root hairs at the growing root tips uninfected. Soil protists are an important component of the rhizosphere system who prey on soil bacteria and have been known to egest undigested phagosomes. We show that the soil protist,Colpoda sp., can transportS. melilotidownMedicago truncatularoots. By using pseudo-3D soil microcosms, we directly observed the presence of fluorescently labelledS. melilotialongM. truncatularoots and tracked the displacement of the fluorescence signal over time. Two weeks after co-inoculation, this signal was detected 52 mm, on average, farther down the roots whenColpoda sp. was also present compared with the experimental treatment that contained bacteria but not protists. Direct counts also showed that protists are required for viable bacteria to reach the deeper sections of root systems in our microcosms. Facilitating bacterial transport may be an important mechanism whereby soil protists promote plant health. As a sustainable agriculture biotechnology, protist-facilitated transport has the potential to boost efficacy of bacterial inoculants, thereby helping growers avoid overuse of nitrogen fertilizers and enhance performance of climate-smart, no-till farming practices.ImportanceSoil protists are an important part of the microbial community in the rhizosphere. Plants grown with protists fare better than plants grown without protists. Mechanisms through which protists support plant health include nutrient cycling, alteration of the bacterial community through selective feeding, and consumption of plant pathogens. Here we provide data in support of an additional mechanism: protists act as transport vehicles for bacteria in soil. We show that protist-facilitated transport can deliver plant-beneficial bacteria to the growing tips of roots that may otherwise be sparsely inhabited with bacteria originating from a seed-associated inoculum. By co-inoculatingMedicago truncatularoots with bothS. meliloti, a nitrogen fixing legume symbiont, andColpoda sp., a ciliated protist, we show substantial and statistically significant transport with depth and breadth of bacteria-associated fluorescence as well as transport of viable bacteria. Co-inoculation with shelf-stable encysted soil protists may be employed as a sustainable agriculture biotechnology to better distribute beneficial bacteria and enhance the performance of inoculants.
Engineered Bacteria Computationally Solve Chemically Generated 2X2 Maze Problems
Authors: Sarkar Kathakali , Bonnerjee Deepro , Bagh Sangram 
Published: June 2021

AbstractMaze generating and solving are challenging problems in mathematics and computing. Here we generated simple 2X2 maze problems applying four chemicals and created a set of engineered bacteria, which in a mixed population worked as a computational solver for any such problem. The input-output matrices of a mathematical maze were mapped through a truth table, where the 1 and 0 logic values of four chemical inputs determined the sixteen different 2X2 maze problems on a chemical space. Our engineered bacteria, which consisted of six different genetic logic circuits and distributed among six cell populations processed the chemical information and solved the problems by expressing or not expressing four different fluorescent proteins according to the input-output matrices. The three available ‘solutions’ were visualized by glowing bacteria and for the thirteen cases, where there was no solution no bacteria glowed. This work may have significance in cell based computing and synthetic biology.
Decoding of EEG signals reveals non-uniformities in the neural geometry of colour
Authors: Chauhan Tushar , Jakovljev Ivana , Thompson Lindsay N. , Wuerger Sophie M. , Martinovic Jasna 
Published: June 2021

AbstractThe idea of colour opponency maintains that colour vision arises through the comparison of two chromatic mechanisms, red versus green (RG) and yellow versus blue (YB). The four unique hues, red, green, blue, and yellow, are assumed to appear at the null points of these the two chromatic systems. However, whether unique hues have a distinct signature that can be reliably discerned in neural activity is still an open question. Here we hypothesise that, if unique hues represent a tractable cortical state, they should elicit more robust activity compared to non-unique hues. We use a spatiotemporal decoding approach to reconstruct an activation space for a set of unique and intermediate hues across a range of luminance values. We show that electroencephalographic (EEG) responses carry robust information about isoluminant unique hues within a 100-300 ms window from stimulus onset. Decoding is possible in both passive and active viewing tasks, but is compromised when concurrent high luminance contrast is added to the colour signals. The efficiency of hue decoding is not entirely predicted by their mutual distance in a nominally uniform perceptual colour space. Instead, the encoding space shows pivotal non-uniformities which suggest that anisotropies in neurometric hue-spaces are likely to represent perceptual unique hues. Furthermore, the neural code for hue temporally coincides with the neural code for luminance contrast, thus explaining why potential neural correlates of unique hues have remained so elusive until now.
Can the causal role of brain oscillations be studied through rhythmic brain stimulation?
Authors: Lobo Tanya , Brookes Matthew J , Bauer Markus 
Published: June 2021

AbstractMany studies have investigated the causal relevance of brain-oscillations using rhythmic stimulation, either through direct-brain or sensory stimulation. Yet, how intrinsic rhythms interact with the externally generated rhythm is largely unknown. We either presented a flickered (60 Hz) visual grating or its correspondent unflickered stimulus in a psychophysical change-detection-task during simultaneous MEG-recordings to humans, to test the effect of visual entrainment on induced gamma-oscillations.Notably, we generally observed the co-existence of the broadband induced gamma-rhythm with the entrained flicker-rhythm (reliably measured in each participant), with the peak frequency of the induced response remaining unaltered in approximately half of participants -relatively independently of their native frequency. However, flicker increased broadband induced-gamma-power, and this was stronger in participants with a native frequency closer to the flicker-frequency (‘resonance’), and led to strong phase-entrainment. Presence of flicker did not change behaviour itself, but profoundly altered brain-behaviour correlates across the sample: whilst broadband induced gamma-oscillations correlated with reaction-times for unflickered stimuli (as known previously), for the flicker, the amplitude of the entrained flicker-rhythm (but no more the induced oscillation) correlated with reaction-times. This, however, strongly depended on whether a participant’s peak frequency shifted to the entrained rhythm.Our results suggests that rhythmic brain-stimulation leads to a coexistence of two partially independent oscillations with heterogeneous effects across participants on the ‘downstream relevance’ of these rhythms for behaviour. This may explain the inconsistency of findings related to external entrainment of brain-oscillations and poses further questions towards causal manipulations of brain-oscillations in general.
Casein kinase 1D encodes a novel drug target in Hedgehog-GLI driven cancers and tumor-initiating cells resistant to SMO inhibition
Authors: Peer Elisabeth , Aichberger Sophie Karoline , Vilotic Filip , Gruber Wolfgang , Parigger Thomas , Grund-Gröschke Sandra , Elmer Dominik P. , Rathje Florian , Ramspacher Andrea , Zaja Mirko , Michel Susanne , Hamm Svetlana , Aberger Fritz 
Published: June 2021

Abstract(1)BackgroundAberrant activation of the Hedgehog (HH)/GLI pathway in stem-like tumor initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector Smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH/GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH/GLI driven malignancies.(2)MethodsWe genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity and monitored oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models.(3)ResultsWe show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO-inhibitor sensitive and resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent tumor-initiating cancer cells in vitro and in vivo.(4)ConclusionsPharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor sensitive and resistant tumors.
Hidden paths to endless forms most wonderful: Ecology latently shapes evolution of multicellular development in predatory bacteria
Authors: Fortezza Marco La , Rendueles Olaya , Keller Heike , Velicer Gregory J. 
Published: June 2021

SUMMARYEcological causes of developmental-system evolution, for example from predation, remain under intense investigation. An important open question is the role of latent phenotypes in eco-evo-devo. The predatory bacterium Myxococcus xanthus undergoes aggregative multicellular development upon starvation. Here we use M. xanthus to test whether evolution in several distinct growth environments that do not induce development latently alters developmental phenotypes, including morphology and plasticity, in environments that do induce development. In the MyxoEE-3 evolution experiment, growing M. xanthus populations swarmed across agar surfaces while adapting to distinct conditions varying at factors such as surface stiffness or prey identity. All examined developmental phenotypes underwent extensive and ecologically specific latent evolution, with surface stiffness, prey presence and prey identity all strongly impacting the latent evolution of development. Evolution on hard agar allowed retention of developmental proficiency and extensive stochastic phenotypic radiation, including of reaction norms, with instances of both increased plasticity and canalization. In contrast, evolution on soft agar latently led to systematic loss of development, revealing an ecologically-contingent fitness trade-off between the growth and developmental phases of a multicellular life cycle that is likely determined by details of motility behavior. Similar contingency was observed after evolution during predatory growth in distinct prey environments, with Bacillus subtilis causing greater loss of development and lower stochastic diversification than Escherichia coli. Our results have implications for understanding evolutionary interactions among predation, development and motility in myxobacterial life cycles, and, more broadly, the importance of latent phenotypes for the diversification of developmental systems.