bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPRa screen identifies a role for c-KIT signaling in tamoxifen resistance, potentially through upregulation of ABC transporters
Authors: Marks Brooke A. , Choate Lauren A. , Sams Kelly , Zhu Lina , Waidyaratne Gavisha , Danko Charles G. , Coonrod Scott A. 
Published: August 2022

AbstractResistance to endocrine therapy is a common problem in patients with estrogen receptor alpha (ERα) positive breast cancer. In this study, we took a non-biased genome-wide approach to identify novel mechanisms of endocrine resistance using a clustered regularly interspaced short palindromic repeats (CRISPR) activating (CRISPRa) screen. Results from the screen identified 109 candidate resistance-associated genes, with several of these genes, such as EGFR and SRC, having been previously associated with endocrine resistance. One candidate gene that has not been previously associated with endocrine resistance is the tyrosine kinase receptor, c-KIT. We further tested for associations between c-KIT and endocrine resistance and found that c-KIT overexpressing cells proliferate more rapidly in the presence of tamoxifen compared to control cell lines. To gain deeper insight into the potential role of c-KIT signaling in tamoxifen resistance, we next performed precision nuclear run-on and sequencing (PRO-seq) analysis of c-KIT overexpressing cells to identify downstream factors that may mediate the c-KIT response. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the overexpressed genes found that the only class of factors that was significantly induced by c-KIT was the ATP-binding cassette (ABC) transporters; specifically, ABCA1, ABCA4, and ABCG1. Interestingly, overexpression of two of these ABC transporters, ABCA1 and ABCG1, significantly correlated with worse prognosis in ERα+ breast cancer patients following endocrine therapy. We then tested for potential therapeutic effects of c-KIT inhibition on endocrine resistance and found that the c-KIT inhibitor Gleevec appears to synergize with tamoxifen to suppress MCF-7-S cell growth. Together, our findings support the hypothesis that c-KIT signaling promotes endocrine resistance via the induction of ABC transporter activity. Additionally, our studies suggest that inhibition of c-KIT signaling may represent a novel strategy for preventing or overcoming endocrine resistance in ERα+ patients.
Accurate prediction of transition metal ion location via deep learning
Authors: Dürr Simon L. , Levy Andrea , Rothlisberger Ursula 
Published: August 2022

AbstractMetal ions are essential cofactors for many proteins. In fact, currently, about half of the structurally characterized proteins contain a metal ion. Metal ions play a crucial role for many applications such as enzyme design or design of protein-protein interactions because they are biologically abundant, tether to the protein using strong interactions, and have favorable catalytic properties e.g. as Lewis acid. Computational design of metalloproteins is however hampered by the complex electronic structure of many biologically relevant metals such as zinc that can often not be accurately described using a classical force field. In this work, we develop two tools - Metal3D (based on 3D convolutional neural networks) and Metal1D (solely based on geometric criteria) to improve the identification and localization of zinc and other metal ions in experimental and computationally predicted protein structures. Comparison with other currently available tools shows that Metal3D is the most accurate metal ion location predictor to date outperforming geometric predictors including Metal1D by a wide margin using a single structure as input. Metal3D outputs a confidence metric for each predicted site and works on proteins with few homologes in the protein data bank. The predicted metal ion locations for Metal3D are within 0.70 ± 0.64 Å of the experimental locations with half of the sites below 0.5 Å. Metal3D predicts a global metal density that can be used for annotation of structures predicted using e.g. AlphaFold2 and a per residue metal density that can be used in protein design workflows for the location of suitable metal binding sites and rotamer sampling to create novel metalloproteins. Metal3D is available as easy to use webapp, notebook or commandline interface.
Evidence for a travel direction signal in humans that is independent of head direction
Authors: Cheng You , Ling Sam , Stern Chantal E. , Huang Andrew , Chrastil Elizabeth R. 
Published: August 2022

AbstractWe often assume that travel direction is redundant with head direction, but from first principles these two factors provide differing spatial information. Although head direction has been found to be a fundamental component of human navigation, it is unclear how self-motion signals for travel direction contribute to forming a travel trajectory. Employing a novel motion adaptation paradigm from visual neuroscience designed to preclude a contribution of head direction, we found high-level aftereffects of perceived travel direction, indicating that travel direction is a fundamental component of human navigation. Interestingly, we discovered a higher frequency of reporting perceived travel toward the adapted direction compared to a no-adapt control – an aftereffect that runs contrary to low-level motion aftereffects. This travel aftereffect was maintained after controlling for possible response biases and approaching effects, and it scaled with adaptation duration. These findings demonstrate the first evidence of how a pure travel direction signal might be represented in humans, independent of head direction.
An expanded phylogeny of Setaria (Poaceae, Panicoideae, Paniceae) and its relationships within the subtribe Cenchrinae
Authors: Delfini Carolina , Acosta Juan M. , Pensiero José F. , Aliscioni Sandra S. 
Published: August 2022

AbstractSetaria P. Beauv. is the largest genus of the “bristle clade”, including between 115 and 160 species. Previous molecular phylogenetic studies showed Setaria likely to be para- or polyphyletic, retrieving several clades apparently consistent in all analyses and correlated with the geographic origin of species. In this study, we evaluate the phylogeny of the subtribe Cenchrinae using parsimony, likelihood, and Bayesian inference based on the plastid marker ndhF and increasing the number of sampled species. Our main objective was analyze American taxa with inflorescences of the “Paspalidium type” (i.e., subgenera Paurochaetium and Reverchoniae) to test whether they, as traditionally circumscribed, form a natural group. Our findings recovered both subgenera as polyphyletic, with their species distributed in different morphologically distinctive clades and not necessarily correlated with the geographic origin. Additionally, we were able to include a second voucher of species that were imprecisely located in previous studies and define their placements in the tree, as well as confirm that Setaria is polyphyletic as currently delineated. A comparison with the results from other studies, comments on Stenotaphrum Trin. and a brief discussion on conflicting placements in the “Cenchrus clade”, and of Acritochaete Pilg. are also included here.
Golgi-dependent Reactivation and Regeneration of Quiescent Neural Stem Cells
Authors: Gujar Mahekta R. , Gao Yang , Teng Xiang , Deng Qiannan , Tan Ye Sing , Toyama Yusuke , Wang Hongyan 
Published: August 2022

SummaryThe ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis and regeneration. InDrosophila, quiescent neural stem cells (qNSCs) extend a primary protrusion, which is removed prior to NSC reactivation. Here, we have unravelled that qNSC protrusions can be regenerated upon injury. This regeneration process relies on the Golgi apparatus which acts as the major acentrosomal microtubule-organizing centre in qNSCs. A Golgi-resident GTPase Arf1 and its guanine-nucleotide exchange factor Sec71 promote NSC reactivation and regeneration via the regulation of microtubule growth. Arf1 physically associates with its new effector Mini Spindles (Msps)/XMAP215, a microtubule polymerase. Finally, Arf1 functions upstream of Msps to target the cell-adhesion molecule E-cadherin to NSC-neuropil contact sites during NSC reactivation. Our findings have establishedDrosophilaqNSCs as a new regeneration model and identified a novel Arf1/Sec71-Msps pathway in the regulation of microtubule growth and NSC reactivation.
Phenotype switching in a global method for agent-based models of biological tissue
Authors: Bergman Daniel , Jackson Trachette L. 
Published: August 2022

AbstractAgent-based models (ABMs) are an increasingly important tool for understanding the complexities presented by phenotypic and spatial heterogeneity in biological tissue. The resolution a modeler can achieve in these regards is unrivaled by other approaches. However, this comes at a steep computational cost limiting either the scale of such models or the ability to explore, parameterize, analyze, and apply them. When the models involve molecular-level dynamics, especially cell-specific dynamics, the limitations are compounded. We have developed a global method for solving these computationally expensive dynamics significantly decreases the computational time without altering the behavior of the system. Here, we extend this method to the case where cells can switch phenotypes in response to signals in the microenvironment. We find that the global method in this context preserves the temporal population dynamics and the spatial arrangements of the cells while requiring markedly less simulation time. We thus add a tool for efficiently simulating ABMs that captures key facets of the molecular and cellular dynamics in heterogeneous tissue.Author summaryAgent-based models (ABMs) are an important tool for understanding how cells and molecular compounds interact to produce complex, emergent behavior. The principal feature of ABMs that set them apart from other types of models is their ability to capture the diversity of cells in a tissue. However, this feature comes at the cost of long simulation times, reducing the ability to apply the findings of these models to improve our understanding of living organisms. We present here a means of simulating ABMs using a more efficient method, called the global method, when the cells are undergoing discrete, phenotypic changes in response to molecular cues. We demonstrate that the global method preserves the key features of the ABM while performing simulations much faster. This allows for more efficient testing of biological hypotheses in a mathematical framework that captures key facets of the diversity in biological tissue.
Structure and Neutralization Mechanism of a Human Antibody Targeting a Complex Epitope on Zika Virus
Authors: Adams Cameron , Carbaugh Derek L. , Shu Bo , Ng Thiam-Seng , Castillo Izabella N. , Bowmik Ryan , Segovia-Chumbez Bruno , Puhl Ana C. , Graham Stephen , Diehl Sean A. , Lazear Helen M. , Lok Shee-mei , de Silva Aravinda M. , Premkumar Lakshmanane 
Published: August 2022

AbstractWe currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency.
Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis
Authors: Klistorner Samuel , Van der Walt Anneke , Barnett Michael H , Butzkueven Helmut , Kolbe Scott , Parratt John , Yiannikas Con , Klistorner Alexander 
Published: August 2022

AbstractObjectivesPeople with Multiple Sclerosis (MS) have a larger choroid plexus (CP) volume than healthy controls. We investigated CP volume in early MS by quantitatively assessing brain MRI scans in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established Relapsing Remitting Multiple Sclerosis (RRMS) and healthy controls.MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion-weighted images were acquired from 44 CIS ON patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 healthy controls were also included for comparison.ResultsANOVA revealed significantly larger CP volumes in both ON CIS and RRMS groups compared to healthy controls (p<0.001 for both), but no difference between ON CIS and RRMS patients (p=0.9)Twenty-three ON CIS patients who converted to CDMS during 10 years of follow-up demonstrated CP volume similar to RRMS patients, but significantly larger compared to healthy controls (p<0.001). Increased CP volume was identified even in a sub-group of patients without MS-like lesions at baseline (p<0.001).A significant (∼6%) transient increase of CP volume was observed following a new bout of inflammation, which, however, returned to pre-inflammatory state few months later. CP volume was not associated with the severity of acute inflammation of the optic nerve or long-term optic nerve axonal loss, not with brain lesion load or severity of tissue damage within lesions.InterpretationOur data demonstrate that enlarged CP can be observe very early in a disease, transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.
Improved cell-free transcription-translation reactions in microfluidic chemostats augmented with hydrogel membranes for continuous small molecule dialysis
Authors: Lavickova Barbora , Grasemann Laura , Maerkl Sebastian J 
Published: August 2022

AbstractIncreasing protein production capacity of the PURE cell-free transcription-translation (TX-TL) system will be key to implementing complex synthetic biological circuits, and to establish a fully self-regenerating system as a basis for the development of a synthetic cell. Under steady-state conditions, the protein synthesis capacity of the PURE system is likely at least one order of magnitude too low to express sufficient quantities of all PURE protein components. This is in part due to the fact that protein synthesis can’t be sustained during the entire dilution cycle, especially at low dilution rates. We developed a microfluidic chemostat augmented with semi-permeable membranes that combines steady-state reactions and continuous dialysis as a possible solution to enhance protein synthesis at steady-state. In batch operation, the continuous dialysis of low molecular weight components via the membranes extended protein synthesis by over an order of magnitude from 2 hours to over 30 hours, leading to a seven-fold increase in protein yield. In chemostat operation, continuous dialysis enabled sustained protein synthesis during the entire dilution cycle even for low dilution rates, leading to six-fold higher protein levels at steady state. The possibility to combine and independently manipulate continuous dialysis and chemostat operation renders our dialysis chemostat a promising technological basis for complex cell-free synthetic biology applications that require enhanced protein synthesis capacity.
Accuracy of non-parametric species richness estimators across taxa and regions
Authors: Soukainen Arttu , Cardoso Pedro 
Published: August 2022

AbstractNon-parametric species richness estimators are efficient and widely used when sampling is incomplete. There is little consensus on which of the available estimators works best across taxa and regions. Until now no work compared existing algorithms with multiple datasets encompassing contrasting scenarios.We used data from 62 inventories worldwide at different spatial scales, including 20 vertebrate, 22 invertebrate and 20 plant datasets, and compared the accuracy of the most used non-parametric estimators (Chao and Jackknife) and improvements to their original formulations.Our results highlight the good performance of the Jackknife estimators for incidence data, especially the P-corrected first order jackknife estimator (Jack1inP). This algorithm ranked most often the best or among the best performing estimators using two measures of accuracy that measure deviation from expectation along the accumulation curve.We argue that Jack1inP can be considered a universal estimator for species richness, regardless of taxon, temporal and spatial scales, or completeness of the sampling. More research should however be directed towards finding the precise contexts when each estimator might perform best.
The aperiodic exponent of subthalamic field potentials reflects excitation/inhibition balance in Parkinsonism: a cross-species study in vivo
Authors: Wiest Christoph , Torrecillos Flavie , Pogosyan Alek , Bange Manuel , Muthuraman Muthuraman , Groppa Sergiu , Hulse Natasha , Hasegawa Harutomo , Ashkan Keyoumars , Baig Fahd , Morgante Francesca , Pereira Erlick A. , Mallet Nicolas , Magill Peter J. , Brown Peter , Sharott Andrew , Tan Huiling 
Published: August 2022

AbstractPeriodic features of neural time series data, such as local field potentials (LFP), are often quantified using power spectra. While the aperiodic exponent of spectra is typically disregarded, it is nevertheless modulated in a physiologically-relevant manner and was recently hypothesised to reflect excitation/inhibition (E/I) balance in neuronal populations. Here, we used a cross-species in vivo electrophysiological approach to test the E/I hypothesis in the context of experimental and idiopathic Parkinsonism. We demonstrate in dopamine-depleted rats that aperiodic exponents and power at 30-100 Hz in subthalamic nucleus (STN) LFPs reflect defined changes in basal ganglia network activity; higher aperiodic exponents tally with lower levels of STN neuron firing and a balance tipped towards inhibition. Using STN-LFPs recorded from awake Parkinson’s patients, we show that higher exponents accompany dopaminergic medication and deep brain stimulation (DBS) of STN, consistent with untreated Parkinson’s manifesting as reduced inhibition and hyperactivity of STN. These results suggest that the aperiodic exponent of STN-LFPs in Parkinsonism reflects E/I balance, and might be a candidate biomarker for adaptive DBS.
Mutations in the SmAPRR2 transcription factor suppressing chlorophyll pigmentation in the eggplant fruit peel are key drivers of a diversified colour palette
Authors: Arrones Andrea , Mangino Giulio , Alonso David , Plazas Mariola , Prohens Jaime , Portis Ezio , Barchi Lorenzo , Giuliano Giovanni , Vilanova Santiago , Gramazio Pietro 
Published: August 2022

SummaryUnderstanding the mechanisms by which chlorophylls are synthesized in the eggplant (Solanum melongena) fruit peel is of great relevance for eggplant breeding. A multi-parent advanced generation inter-cross (MAGIC) population and a germplasm collection have been screened for green pigmentation in the fruit peel and used to identify candidate genes for this trait. A genome-wide association study (GWAS) performed with 420 MAGIC individuals revealed a major association on chromosome 8 close to a gene similar to APRR2. Two variants in SmAPRR2, predicted as having a high impact effect, were associated with the absence of fruit chlorophyll pigmentation in the MAGIC population, and a large deletion of 5.27 kb was found in two reference genomes of accessions without chlorophyll in the fruit peel. The validation of the candidate gene SmAPRR2 was performed by its sequencing in a set of MAGIC individuals and through its de novo assembly in 277 accessions from the G2P-SOL eggplant core collection. Two additional mutations in SmAPRR2 associated with the lack of chlorophyll were identified in the core collection set. The phylogenetic analysis of APRR2 reveals orthology within Solanaceae and suggests that specialization of APRR2-like genes occurred independently in Cucurbitaceae and Solanaceae. A strong geographical differentiation was observed in the frequency of predominant mutations in SmAPRR2, resulting in a lack of fruit chlorophyll pigmentation and suggesting that this phenotype may have arisen and been selected independently several times. This study represents the first identification of a major gene for fruit chlorophyll pigmentation in the eggplant fruit.
Layered business continuity and disaster recovery model
Authors: Stamenkov Gjoko 
Published: August 2022

PurposeThe purpose of this study is to address the problem of a plethora of potential plans related to business continuity and disaster recovery.Design/methodology/approachA review of the relevant academic articles, standards and guidelines related to business continuity and disaster recovery was conducted, and the discussed plans include critical information infrastructure plans, disaster recovery plans, information system contingency plans, business continuity plans and continuity of operations plans.FindingsThe content of each plan is explained. A layered business continuity and disaster recovery model is proposed, which consolidates all plans in a coherent manner.Originality/valueRelationships, similarities and differences among each pair of plans are discussed, and the longitudinal validity and applicability of plans are presented.
Synecdochising student identities: EAL teachers' positioning of adult EAL students in Australia
Authors: Sumithran Suma , Chowdhury Raqib , Barnes Melissa 
Published: August 2022

PurposeAdult student identities within EAL (English as an Additional Language) classrooms have often been positioned as static, homogenised and exoticised within scholarly literature. Within such positioning, teachers have embraced pedagogical practices which classify students by country of origin and represent student identities within binaries of Self and the Other, limiting these students' identity positionings for adoption within the EAL classroom. As a result, students are often rendered voiceless by essentialist discourses on culture and identity in the classroom that serve to replicate and reinforce dominant societal discourses and strengthen existing institutional power structures.Design/methodology/approachBy drawing on a postcolonial theoretical framework comprising theories of race, identity, power, representation, synecdoche and Third Space, this paper interrogates current literature to understand the complex multidimensional and dynamic cultural identities of adult EAL students.FindingsThis paper reveals that adult EAL students are still being oversimplified within the classroom, not just disadvantaging students and institutions, but also hindering multicultural pedagogies.Originality/valueThis paper suggests that teachers require opportunities for critical reflection incorporated within a critical pedagogy in decolonised classrooms that can not only build respectful and equitable awareness of their students' cultural identities and educational and historical backgrounds but provide important implications for effective pedagogical practices.