bluuebunny/crossref_metadata_2025 huggingface dataset:
Semi-supervised sequence modeling for improved behavioral segmentation
Authors: Whiteway Matthew R , Schaffer Evan S , Wu Anqi , Buchanan E Kelly , Onder Omer F , Mishra Neeli , Paninski Liam
Published: June 2021

A popular approach to quantifying animal behavior from video data is through discrete behavioral segmentation, wherein video frames are labeled as containing one or more behavior classes such as walking or grooming. Sequence models learn to map behavioral features extracted from video frames to discrete behaviors, and both supervised and unsupervised methods are common. However, each approach has its drawbacks: supervised models require a time-consuming annotation step where humans must hand label the desired behaviors; unsupervised models may fail to accurately segment particular behaviors of interest. We introduce a semi-supervised approach that addresses these challenges by constructing a sequence model loss function with (1) a standard supervised loss that classifies a sparse set of hand labels; (2) a weakly supervised loss that classifies a set of easy-to-compute heuristic labels; and (3) a self-supervised loss that predicts the evolution of the behavioral features. With this approach, we show that a large number of unlabeled frames can improve supervised segmentation in the regime of sparse hand labels and also show that a small number of hand labeled frames can increase the precision of unsupervised segmentation.
Crystal structure of the human NKR-P1 bound to its lymphocyte ligand LLT1 reveals receptor clustering in the immune synapse
Authors: Bláha Jan , Skálová Tereza , Kalousková Barbora , Skořepa Ondřej , Cmunt Denis , Pažický Samuel , Poláchová Edita , Abreu Celeste , Stránský Jan , Koval’ Tomáš , Dušková Jarmila , Zhao Yuguang , Harlos Karl , Hašek Jindřich , Dohnálek Jan , Vaněk Ondřej
Published: June 2021

Human NKR-P1 (CD161,KLRB1) and its ligand LLT1 (CLEC2D) are a prototypical inhibitory C-type lectin-like receptor:ligand pair of NK cells with a critical role in homing lymphocytes to immune-privileged sites, particularly in multiple sclerosis, rheumatoid arthritis, and Crohn’s disease. Furthermore, NKR-P1:LLT1 inhibitory signaling is associated with glioblastoma, non-Hodgkin’s lymphoma, breast, and prostate cancer. However, the lack of structural data on the formation of the NKR-P1:LLT1 complex limits our understanding of this signaling. We thus solved the crystal structures of NKR-P1 and the NKR-P1:LLT1 complex. NKR-P1 forms a homodimer with an unexpected arrangement that enables LLT1 binding in two modes, bridging two LLT1 molecules, thereby forming interaction clusters suggestive of an inhibitory immune synapse. Moreover, observing the formation of these clusters by SEC-SAXS analysis in solution and by dSTORM super-resolution microscopy on the cell surface, and following their role in receptor signaling usingin vitrocytotoxicity assay with freshly isolated NK cells, we show how NKR-P1:LLT1 clustering allows these proteins to overcome the weak affinity of C-type lectin-like receptors to their ligands. Furthermore, only the ligation of both primary and secondary LLT1 binding interfaces leads to effective NKR-P1 inhibitory signaling. Therefore, our findings show how inhibitory receptor cross-linking and clustering work together to trigger signal transduction upon cellular contact in the immune synapse.
Rapid cross-sensory adaptation of self-motion perception
Authors: Shalom-Sperber Shir , Chen Aihua , Zaidel Adam
Published: June 2021

Perceptual adaptation is often studied within a single sense. However, our experience of the world is naturally multisensory. Here, we investigated cross-sensory (visual-vestibular) adaptation of self-motion perception. It was previously found that relatively long visual self-motion stimuli (≳ 15s) are required to adapt subsequent vestibular perception, and that shorter duration stimuli do not elicit cross-sensory (visual↔vestibular) adaptation. However, it is not known whether several discrete short-duration stimuli may lead to cross-sensory adaptation (even when their sum, if presented together, would be too short to elicit cross-sensory adaptation). This would suggest that the brain monitors and adapts to supra-modal statistics of events in the environment. Here we investigated whether cross-sensory (visual↔vestibular) adaptation occurs after experiencing several short (1s) self-motion stimuli. Forty-five participants discriminated the headings of a series of self-motion stimuli. To expose adaptation effects, the trials were grouped in 140 batches, each comprising three ‘prior’ trials, with headings biased to the right or left, followed by a single unbiased ‘test’ trial. Right, and left-biased batches were interleaved pseudo-randomly. We found significant adaptation in both cross-sensory conditions (visual prior and vestibular test trials, and vice versa), as well as both unisensory conditions (when prior and test trials were of the same modality – either visual or vestibular). Fitting the data with a logistic regression model revealed that adaptation was elicited by the prior stimuli (not prior choices). These results suggest that the brain monitors supra-modal statistics of events in the environment, even for short-duration stimuli, leading to functional (supra-modal) adaptation of perception.
Bioluminescent Genetically Encoded Glutamate Indicator for Molecular Imaging of Neuronal Activity
Authors: Petersen E. D. , Lapan A.P. , Fillion A.J. , Crespo E. L. , Lambert G. G. , Zanca A. Torreblanca , Orcutt R. , Hochgeschwender U. , Shaner N. C. , Gilad A. A.
Published: June 2021

Genetically encoded optical sensors and advancements in microscopy instrumentation and techniques have revolutionized the scientific toolbox available for probing complex biological processes such as release of specific neurotransmitters. Most genetically encoded optical sensors currently used are based on fluorescence and have been highly successful tools for single-cell imaging in superficial brain regions. However, there remains a need to develop new tools for reporting neuronal activity in vivo within deeper structures without the need for hardware such as lenses or fibers to be implanted within the brain. Our approach to this problem is to replace the fluorescent elements of the existing biosensors with bioluminescent elements. This eliminates the need of external light sources to illuminate the sensor and overcomes several drawbacks of fluorescence imaging such as limited light penetration depth, excitation scattering, and tissue heating that are all associated with the external light needed for fluorescence imaging. Here we report the development of the first genetically encoded neurotransmitter indicators based on bioluminescent light emission. These probes exhibit robust changes in light output in response to extracellular presentation of the excitatory neurotransmitter glutamate. We expect this new approach to neurotransmitter indicator design to enable the engineering of specific bioluminescent probes for multiple additional neurotransmitters in the future, ultimately allowing neuroscientists to monitor activity associated with a specific neurotransmitter as it relates to behavior in a variety of neuronal and psychiatric disorders, among many other applications.
Dataset complexity impacts both MOTU delimitation and biodiversity estimates in eukaryotic 18S rRNA metabarcoding studies
Authors: Santiago Alejandro De , Pereira Tiago José , Mincks Sarah L. , Bik Holly M.
Published: June 2021

How does the evolution of bioinformatics tools impact the biological interpretation of high-throughput sequencing datasets? For eukaryotic metabarcoding studies, in particular, researchers often rely on tools originally developed for the analysis of 16S ribosomal RNA (rRNA) datasets. Such tools do not adequately account for the complexity of eukaryotic genomes, the ubiquity of intragenomic variation in eukaryotic metabarcoding loci, or the differential evolutionary rates observed across eukaryotic genes and taxa. Recently, metabarcoding workflows have shifted away from the use of Operational Taxonomic Units (OTUs) towards delimitation of Amplicon Sequence Variants (ASVs). We assessed how the choice of bioinformatics algorithm impacts the downstream biological conclusions that are drawn from eukaryotic 18S rRNA metabarcoding studies. We focused on four workflows including UCLUST and VSearch algorithms for OTU clustering, and DADA2 and Deblur algorithms for ASV delimitation. We used two 18S rRNA datasets to further evaluate whether dataset complexity had a major impact on the statistical trends and ecological metrics: a “high complexity” (HC) environmental dataset generated from community DNA in Arctic marine sediments, and a “low complexity” (LC) dataset representing individually-barcoded nematodes. Our results indicate that ASV algorithms produce more biologically realistic metabarcoding outputs, with DADA2 being the most consistent and accurate pipeline regardless of dataset complexity. In contrast, OTU clustering algorithms inflate the metabarcoding-derived estimates of biodiversity, consistently returning a high proportion of “rare” Molecular Operational Taxonomic Units (MOTUs) that appear to represent computational artifacts and sequencing errors. However, species-specific MOTUs with high relative abundance are often recovered regardless of the bioinformatics approach. We also found high concordance across pipelines for downstream ecological analysis based on beta-diversity and alpha-diversity comparisons that utilize taxonomic assignment information. Analyses of LC datasets and rare MOTUs are especially sensitive to the choice of algorithms and better software tools may be needed to address these scenarios.
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

Rationale

Hereditary 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.

Objective

We therefore characterised the vascular abnormalities inengmutant zebrafish and investigated whether these are prevented by inhibiting different pathways downstream of VEGF signalling.

Methods and Results

We 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.

Conclusions

These 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

Polo-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.

Significance

The 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

How 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

Studies 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 summary

Studies 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

The 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

The 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.

Importance

Soil 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

Maze 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

The 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

Many 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

(1)

Background

Aberrant 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)

Methods

We 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)

Results

We 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)

Conclusions

Pharmacologic 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

Ecological 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.
Western diet increases COVID-19 disease severity in the Syrian hamster
Authors: Port Julia R. , Adney Danielle R. , Schwarz Benjamin , Schulz Jonathan E. , Sturdevant Daniel E. , Smith Brian J. , Avanzato Victoria A. , Holbrook Myndi G. , Purushotham Jyothi N. , Stromberg Kaitlin A. , Leighton Ian , Bosio Catharine M. , Shaia Carl , Munster Vincent J.
Published: June 2021

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an increased trend of systemic IL-10 and IL-6, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.
The mechanism driving a solid–solid phase transition in a biomacromolecular crystal
Authors: Ramakrishnan Saminathan , Stagno Jason R. , Heinz William F. , Zuo Xiaobing , Yu Ping , Wang Yun-Xing
Published: June 2021

Solid–solid phase transitions (SSPTs) occur between distinguishable crystalline forms. Because of their importance in application and theory in materials science and condensed-matter physics, SSPTs have been studied most extensively in metallic alloys, inorganic salts and small organic molecular crystals, but much less so in biomacromolecular crystals. In general, the mechanisms of SSPTs at the atomic and molecular levels are not well understood. Here, the ordered molecular rearrangements in biomacromolecular crystals of the adenine riboswitch aptamer are described using real-time serial crystallography and solution atomic force microscopy. Large, ligand-induced conformational changes drive the initial phase transition from the apo unit cell (AUC) to the trans unit cell 1 (TUC1). During this transition, coaxial stacking of P1 duplexes becomes the dominant packing interface, whereas P2–P2 interactions are almost completely disrupted, resulting in `floating' layers of molecules. The coupling points in TUC1 and their local conformational flexibility allow the molecules to reorganize to achieve the more densely packed and energetically favorable bound unit cell (BUC). This study thus reveals the interplay between the conformational changes and the crystal phases – the underlying mechanism that drives the phase transition. Using polarized video microscopy to monitor SSPTs in small crystals at high ligand concentration, the time window during which the major conformational changes take place was identified, and the in crystallo kinetics have been simulated. Together, these results provide the spatiotemporal information necessary for informing time-resolved crystallography experiments. Moreover, this study illustrates a practical approach to characterization of SSPTs in transparent crystals.
Please do not disturb: the effect of Zero-Contact Marketing on Korean consumers' decision-making process
Authors: Park Arim , An Hyun Sang , Song Ju Myung , Chung Christina
Published: June 2021

Purpose

This study examines the effectiveness of Zero-Contact Marketing that minimizes contact between employees and consumers in marketplaces by adopting an integrated research framework of motivation theory, servicescape model and the theory of reasoned action (TRA).

Design/methodology/approach

This study randomly collected 314 respondents through an online survey in May 2020 in South Korea. Structural equation modeling (SEM) assessed the overall hypothetical research model.

Findings

Zero-Contact Marketing facilitates the positive impacts of Korean consumers' motivations (intrinsic and extrinsic) and service environment on their word-of-mouth (WOM) intention to spread information about a store offering Zero-Contact Marketing service and the store revisit intention. In addition, consumers' attitude toward Zero-Contact Marketing and shopping pleasure (SPL) has stronger impacts on consumers' WOM intention than they do on the store revisit intention.

Research limitations/implications

The limitation of this study lies in that the survey participants responded only in South Korea, which may lead to biased results. To provide a more generalized insight, this study should be extended by considering consumers in other countries, since many consumers around the world tend to minimize face-to-face interaction and avoid unnecessary interruptions under the current pandemic.

Practical implications

By minimizing the social interaction between employees and consumers, Zero-Contact Marketing may increase consumers' shopping satisfaction with free shopping moments and no disturbance, especially under the COVID-19 pandemic.

Originality/value

The findings provide theoretical contributions by empirically validating the effects of intrinsic and extrinsic motivations and service environment on consumers' internal and external responses in a Zero-Contact retail setting.
Drug places and spaces of problematisation: the melancholy case of a Hungarian needle exchange programme
Authors: Dányi Endre , Csák Róbert
Published: June 2021

Purpose

This paper aims to explore multiple problematisation processes through a former needle exchange programme run by Kék Pont (a non-governmental organisation) in the 8th district of Budapest. By presenting a collage of ethnographic stories, this paper attempts to preserve tacit knowledge associated with the programme and thereby keep its office alive as a “drug place”, the operation of which was made impossible in 2014.

Design/methodology/approach

Drawing on the insights of Foucauldian governmentality studies and actor-network theory, this paper focusses on drug use as a problem in its spatial-material settings. Based on ethnographic fieldwork, the contribution traces multiple problematisation processes and related infrastructures.

Findings

From the needle exchange programme’s perspective, drug use is not a singular problem but the effect of multiple problematisation processes. Although those processes are often in conflict with each other, the question is not which one is right, but how social workers manage to hold them together. It is a fragile achievement that requires years of training and ongoing negotiation with local actors. By eliminating Kék Pont’s 8th district office, the Hungarian Government did not only hinder harm reduction in the area but it had also rendered tacit knowledge associated with the needle exchange programme as a “drug place” inaccessible.

Originality/value

The paper is a melancholy intervention – an attempt to preserve tacit knowledge that had accumulated at the needle exchange programme. The retelling of ethnographic stories about this “drug place” is one way of ensuring that other drug policies remain imaginable.
A quasi-nonlocal coupling method for bond-based peridynamics with classical continuum mechanics
Authors: Jiang Feng , Shen Yongxing
Published: June 2021

Purpose

The purpose of this paper is to propose a novel quasi-nonlocal coupling of the bond-based peridynamic model with the classical continuum mechanics model to fully take advantage of their merits and be free of ghost forces.

Design/methodology/approach

This study reconstructs a total energy functional by introducing a coupling parameter that alters only the nonlocal interactions in the coupling region rather than the whole region and a modified elasticity tensor that affects the local interactions. Then, the consistency of force patch test is enforced in the coupling region to completely eliminate the ghost force in a general energy-based coupling scheme. For a one-dimensional problem, these coupling parameters are further determined through an energy patch test to preserve the energy equivalence or through an l1-regularization. And, for a two- or three-dimensional problem, depending on the existence of a solution to the discretized force patch test, they are determined through an l1-minimization or l1-regularization.

Findings

One- and two-dimensional numerical examples under affine deformation have been conducted to verify the accuracy of the quasi-nonlocal coupling method, which exhibits no ghost force. Moreover, the coupling model can reproduce almost the same deformation behaviors of points near the crack for a cracked plate under tension as that from a pure peridynamic model, the former with a rather low computational cost and an easier application of boundary conditions.

Originality/value

This work is aiming at getting over long-standing ghost force issues in the energy-based coupling scheme. The numerical results from the cracked plate problem are exhibited promising extension to dynamic problems.
Agency costs and credit availability: an international study
Authors: Bahlous-Boldi Mejda
Published: June 2021

Purpose

This paper aims to investigate the link between agency costs mitigation via three levels of rights protection (minority rights protection, enforcing contracts, resolving insolvency issues) provides the propitious climate for financing investment opportunities around the world.

Design/methodology/approach

We use Bartlett’s three-group method to stratify countries based on how well they protect investors as measured by the scores provided in the Doing Business dataset developed by the world bank for 189 countries. We then test a variety of independent hypotheses that the alleviation of agency costs via three levels of protection (minority investors’ rights, contract enforcement, resolving insolvency issues) is associated with better access to credit via the banking system, better valuation of listed firms via the stock market and higher investment and growth.

Findings

Our findings support Agency Theory which explains why the absence of legal protection of external investors leads to stock markets and financial institutions failing to fulfill their role of financing the economy.

Practical implications

The policy implication from this study indicates that countries ought to (1) develop legislation that protects investors’ rights, (2) improve the quality of their judicial system in terms of enforcing the legislation and (3) build the framework for resolving disputes during insolvency as these are important ingredients for a developed financial system.

Originality/value

We use the World bank dataset and a new methodology to quantify the significance of the relationship between minority rights protection, ineffective enforcement, lack of bankruptcy laws and access to firm financing via the banking sector and the stock market. It provides new evidence that the quality of the judicial system in a country matter for firms’ ability to raise financing and enhance value creation.
“I like the first slide. I like how we put it like that [words and pictures on a diagonal]:” composing multimodal texts in a grade four classroom
Authors: Seely Flint Amy , Rohloff Rebecca , Williams Sarah
Published: June 2021

Purpose

Young children often enter formal schooling with a range of digital experiences, including using apps on tablets and engaging with interactive educational toys. The convergence and increased accessibility of digital resources has made it more convenient for young children to navigate multiple modes (e.g. words, images, sound and movement) as they construct meaning across many different texts. The purpose of the study is to examine affordances and choices when students compose multimodal texts.

Design/methodology/approach

Three lines of inquiry support this study: the social construction of writing practices, multiliteracies and multimodality and intertextuality. Data analysis used an iterative two-tiered process of reading, rereading and coding students’ multimodal compositions and supplemental field notes (Creswell, 1998; Strauss and Corbin, 1998).

Findings

Analysis of the 23 multimodal compositions revealed three significant findings related to choice and affordances of multimodal texts: the popularity of Minecraft as a topic choice based on the social interactions of students; semiotic concurrence and semiotic complementarity and sophisticated use of literary techniques (e.g. nonlinear structures, shifting point of view, asides and emojis) across the multimodal stories, particularly those that carried Minecraft themes.

Originality/value

Students’ intentionality with the modes in their compositions suggested they were fully aware of the “complexity, interrelatedness and interdependence between image [animation and sound] and language” (Shanahan, 2013, p. 213).
Promoting awareness of sex trafficking in tourism and hospitality
Authors: Aston Joshua , Wen Jun , Goh Edmund , Maurer Oswin
Published: June 2021

Purpose

This cutting-edge short commentary is intended to raise awareness of sex trafficking in the tourism and hospitality industry. The purpose of this paper is to also advocate for further research to identify and hopefully prevent sex trafficking in related settings.

Design/methodology/approach

This paper provides a descriptive overview of the current knowledge base on sex trafficking in tourism and hospitality. Based on gaps in the literature, future research agendas and directions are suggested.

Findings

Academic research on sex trafficking in tourism and hospitality remains limited. More scholarly attention is needed to this matter. The tourism industry is directly and indirectly associated with sex trafficking (e.g. hotel accommodations and direct consumption of sexual services, such as through sex tourism). Despite legislative efforts by international government agencies to eradicate sex trafficking, the problem remains pervasive. Broader practice- and research-based intervention efforts are needed.

Originality/value

This short commentary advocates for tourism and hospitality researchers to make practical and theoretical industry contributions that may help prevent sex trafficking.