bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards improved resistance ofCorynebacterium glutamicumagainst nisin
Authors: Weixler Dominik , Goldbeck Oliver , Seibold Gerd. M. , Eikmanns Bernhard J. , Riedel Christian U.
Published: August 2021

The bacteriocin nisin is one of the best studied antimicrobial peptides. It is widely used as a food preservative due to its antimicrobial activity against various Gram-positive bacteria including human pathogens such asListeriamonocytogenesand others. The receptor of nisin is the universal cell wall precursor lipid II, which is present in all bacteria. Thus, nisin has a broad spectrum of target organisms. Consequently, heterologous production of nisin with biotechnological relevant organisms includingCorynebacterium glutamicumis difficult. Nevertheless, bacteria have evolved several mechanisms of resistance against nisin and other cationic antimicrobial peptides (CAMPs). Here, we transferred resistance mechanisms described in other organisms toC. glutamicumwith the aim to improve nisin resistance. The presented approaches included: expression of (i) nisin immunity genesnisIand/ornisFEGor (ii) nisin ABC-transporter genes ofStaphylococcus aureusand its homologues ofC. glutamicum, (iii) genes coding for enzymes for alanylation or lysinylation of the cell envelope to introduce positive charges, and/or (iv) deletion of genes for porins of the outer membrane. None of the attempts alone increased resistance ofC. glutamicummore than two-fold. To increase resistance ofC. glutamicumto levels that will allow heterologous production of active nisin at relevant titers, further studies are needed.
Integrated annotation and analysis of genomic features reveal new types of functional elements and large-scale epigenetic phenomena in the developing zebrafish
Authors: Baranasic Damir , Hörtenhuber Matthias , Balwierz Piotr , Zehnder Tobias , Mukarram Abdul Kadir , Nepal Chirag , Varnai Csilla , Hadzhiev Yavor , Jimenez-Gonzalez Ada , Li Nan , Wragg Joseph , D’Orazio Fabio , Díaz Noelia , Hernández-Rodríguez Benjamín , Chen Zelin , Stoiber Marcus , Dong Michaël , Stevens Irene , Ross Samuel E. , Eagle Anne , Martin Ryan , Obasaju Pelumi , Rastegar Sepand , McGarvey Alison C. , Kopp Wolfgang , Chambers Emily , Wang Dennis , Kim Hyejeong R. , Acemel Rafael D. , Naranjo Silvia , Lapinski Maciej , Chong Vanessa , Mathavan Sinnakaruppan , Peers Bernard , Sauka-Spengler Tatjana , Vingron Martin , Carninci Piero , Ohler Uwe , Lacadie Scott Allen , Burgess Shawn , Winata Cecilia , van Eeden Freek , Vaquerizas Juan M. , Gómez-Skarmeta José Luis , Onichtchouk Daria , Brown Ben James , Bogdanovic Ozren , Westerfield Monte , Wardle Fiona C. , Daub Carsten O. , Lenhard Boris , Müller Ferenc
Published: August 2021

Zebrafish, a popular model for embryonic development and for modelling human diseases, has so far lacked a systematic functional annotation programme akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created the first central repository to store and process zebrafish developmental functional genomic data. Our Data Coordination Center (https://danio-code.zfin.org) combines a total of 1,802 sets of unpublished and reanalysed published genomics data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements in development, including novel classes with distinct features dependent on their activity in time and space. We delineated the distinction between regulatory elements active during zygotic genome activation and those active during organogenesis, identifying new aspects of how they relate to each other. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predict functional relationships between them beyond sequence similarity, extending the utility of zebrafish developmental genomics to mammals.
Discovery of aryl aminothiazole γ-secretase modulators with novel effects on amyloid β-peptide production
Authors: Bhattarai Sanjay , Liu Lei , Wolfe Michael S.
Published: August 2021

A series of analogs based on a prototype aryl aminothiazole γ-secretase modulator (GSM) were synthesized and tested for their effects on the profile of 37-to-42-residue amyloid β-peptides (Aβ), generated through processive proteolysis of precursor protein substrate by γ-secretase. Certain substitutions on the terminal aryl D ring resulted in an altered profile of Aβ production compared to that seen with the parent molecule. Small structural changes led to concentration-dependent increases in Aβ37 and Aβ38 production without parallel decreases in their precursors Aβ40 and Aβ42, respectively. The new compounds therefore apparently also stimulate carboxypeptidase trimming of Aβ peptides ≥43 residues, providing novel chemical tools for mechanistic studies of processive proteolysis by γ-secretase.

Graphical Abstract
NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and suppresses PDAC initiation
Authors: Cobo Isidoro , Paliwal Sumit , Melià-Alomà Júlia , Torres Ariadna , Martínez-Villarreal Jaime , García Fernando , Millán Irene , del Pozo Natalia , Park Joo-Cheol , MacDonald Ray J. , Muñoz Javier , Real Francisco X.
Published: August 2021

Tissue-specific differentiation is driven by specialized transcriptional networks. Pancreatic acinar cells crucially rely on the PTF1 complex, and on additional transcription factors, to deploy their transcriptional program. Here, we identify NFIC as a novel regulator of acinar differentiation using a variety of methodological strategies. NFIC binding sites are found at very short distances from NR5A2-bound genomic regions and both proteins co-occur in the same complex.Nficknockout mice show reduced expression of acinar genes and, in ChIP-seq experiments, NFIC binds the promoters of acinar genes. In addition, NFIC binds to the promoter of, and regulates, genes involved in RNA and protein metabolism; inNficknockout mice, p-RS6K1 and p-IEF4E are down-regulated indicating reduced activity of the mTOR pathway. In 266-6 acinar cells, NFIC dampens the ER stress program through its binding to ER stress gene promoters and is required for complete resolution of Tunicamycin-mediated ER stress. Normal human pancreata from subjects with low NFIC mRNA levels display reduced epxression of genes down-regulated inNficknockout mice. Consistently, NFIC displays reduced expression upon induced acute pancreatitis and is required for proper recovery after damage. Finally, expression of NFIC is lower in samples of mouse and human pancreatic ductal adenocarcinoma andNficknockout mice develop an increased number of mutantKras-driven pre-neoplastic lesions.
Activity budget and gut microbiota stability and flexibility across reproductive states in wild capuchin monkeys in a seasonal biome
Authors: Webb Shasta E. , Orkin Joseph D. , Williamson Rachel E. , Melin Amanda D.
Published: August 2021

Energy demands associated with pregnancy and lactation are significant forces in mammalian evolution. To mitigate increased energy costs associated with reproduction, female mammals have evolved behavioural and physiological responses. Some species alter activity to conserve energy during pregnancy and lactation, while others experience changes in metabolism and fat deposition. Restructuring of gut microbiota with shifting reproductive states may also help females increase energy harvest from foods, especially during pregnancy. Here, we combine life history data with >13,000 behavioural scans and >300 fecal samples collected longitudinally across multiple years from 33 white-faced capuchin monkey females to examine the relationships among behaviour, gut microbiota composition, and reproductive state. We used 16S-based amplicon sequencing and the DADA2 pipeline to analyze microbial diversity and putative functions. Reproductive state explained some variation in activity, but overall resting and foraging behaviours were relatively stable across the reproductive cycle. We found evidence for increases in biotin synthesis pathways among microbes in lactating females, and that relatoe abundance of major phyla among the states was small but significant. Otherwise, gut microbiota structure and estimated functions were not substantially different among reproductive states. These data contribute to a broader understanding of plasticity in response to physiological shifts associated with mammalian reproduction.
Combined single cell proteomics and transcriptomics reveals discrete human tendon cells populations persist in vitro and on fibrous scaffolds
Authors: Kendal Adrian , Lach Antonina , Mouthuy Pierre-Alexis , Brown Rick , Loizou Constantinos , Rogers Mark , Sharp Robert , Carr Andrew
Published: August 2021

Chronic tendinopathy represents a growing burden to healthcare services in an active and ageing global population. The ability to identify, isolate and interrogate, in vitro, key pathogenic and reparative tendon cell populations is essential to developing precision therapies and implantable materials.

Human hamstring tendon cells were cultured for 8 days on either tissue culture plastic or aligned electrospun fibres made of polydioxanone (absorbable polymer). Combined single cell surface proteomics and unbiased single cell transcriptomics (CITE-Seq) revealed six discrete cell clusters, four of which shared key gene expression determinants with ex vivo human cell clusters. These were PTX3_PAPPA, POST_SCX, DCN_LUM and ITGA7_NES cell clusters. Surface proteomics found that PTX3_PAPPA cells were CD10+CD26+CD54+. ITGA7_NES cells were CD146+, and POSTN_SCX cells were CD90+CD95+CD10+.

Three clusters preferentially survived and proliferated on the aligned electrospun fibres; DCN_LUM, POSTN_SCX, and PTX3_PAPPA. They maintained high expression of tendon matrix associated genes, includingCOL1A1, COL1A2, COL3A1, ELN, FBLN1, and up-regulated genesets enriched for TNF-Ɣsignalling via NFκB, IFN-Ɣ signalling and IL-6/ STAT3 signalling. When cells were pre-selected based on surface protein markers, a similar up-regulation of pro-inflammatory signalling pathways was observed, particularly inPTX3gene expressing CD10+CD26+CD54+ cells, with increased expression of genes associated with TNF-αsignalling and IFN-γ signalling.

Discrete human tendon cell sub populations persist in vitro culture and can be recognised by specific gene and surface protein signatures. Aligned PDO fibres promote the survival of three clusters, including pro-inflammatoryPTX3expressing CD10+CD26+CD54+ cells found in chronic tendon disease.
Benchmarking artificial intelligence methods for end-to-end computational pathology
Authors: Laleh Narmin Ghaffari , Muti Hannah Sophie , Lavinia Loeffler Chiara Maria , Echle Amelie , Saldanha Oliver Lester , Mahmood Faisal , Lu Ming Y. , Trautwein Christian , Langer Rupert , Dislich Bastian , Buelow Roman D. , Grabsch Heike Irmgard , Brenner Hermann , Chang-Claude Jenny , Alwers Elizabeth , Brinker Titus J. , Khader Firas , Truhn Daniel , Gaisa Nadine T. , Boor Peter , Hoffmeister Michael , Schulz Volkmar , Kather Jakob Nikolas
Published: August 2021

Artificial intelligence (AI) can extract subtle visual information from digitized histopathology slides and yield scientific insight on genotype-phenotype interactions as well as clinically actionable recommendations. Classical weakly supervised pipelines use an end-to-end approach with residual neural networks (ResNets), modern convolutional neural networks such as EfficientNet, or non-convolutional architectures such as vision transformers (ViT). In addition, multiple-instance learning (MIL) and clustering-constrained attention MIL (CLAM) are being used for pathology image analysis. However, it is unclear how these different approaches perform relative to each other. Here, we implement and systematically compare all five methods in six clinically relevant end-to-end prediction tasks using data from N=4848 patients with rigorous external validation. We show that histological tumor subtyping of renal cell carcinoma is an easy task which approaches successfully solved with an area under the receiver operating curve (AUROC) of above 0.9 without any significant differences between approaches. In contrast, we report significant performance differences for mutation prediction in colorectal, gastric and bladder cancer. Weakly supervised ResNet-and ViT-based workflows significantly outperformed other methods, in particular MIL and CLAM for mutation prediction. As a reason for this higher performance we identify the ability of ResNet and ViT to assign high prediction scores to highly informative image regions with plausible histopathological image features. We make all source codes publicly available athttps://github.com/KatherLab/HIA, allowing easy application of all methods on any end-to-end problem in computational pathology.
Construction of competing endogenous RNA interaction networks as prognostic markers in metastatic melanoma
Authors: He Zan , Xin Zijuan , Peng Yongfei , Zhao Hua , Fang Xiangdong
Published: August 2021

Malignant melanoma (MM) is a highly aggressive, metastatic cancer originating from melanocytes. These tumors have an extremely poor prognosis. MM accounts for 4% of skin cancers with an 80% mortality rate. The median survival of patients with metastatic melanoma is approximately six months, with a five-year survival rate of less than 10%. In recent years, the incidence of melanoma has gradually increased and has become one of the deadliest cancers. Competitive endogenous RNA (ceRNA) models the mechanism by which long chain non-coding RNAs (lncRNAs) play a regulatory role in the disease. LncRNAs can act as a sponge, competitively attracting small RNAs (micoRNAs; miRNAs) and interfering with miRNA function. This can affect the expression of target gene messenger RNAs (mRNAs), ultimately promoting tumorigenesis and tumor progression. Bioinformatics analysis may identify potentially prognostic and therapeutically-relevant differentially expressed genes in MM, as well as lncRNAs, miRNAs and mRNAs that are interconnected through the ceRNA network. This may provide further insight into gene regulation and the prognosis of metastatic melanoma. Weighted co-expression networks were used to identify lncRNA and mRNA modules associated with the metastatic phenotype, as well as the co-expression genes contained in the modules. We used 17 lncRNAs, six miRNAs, and 11 mRNAs to construct a ceRNA interaction network with a regulatory role in patients with metastatic melanoma. The prognostic risk model was used as a sorter to classify the survival prognosis of melanoma patients. Four groups of ceRNA interaction triplets were obtained, and miR-3662 may be used in the treatment of metastatic melanoma patients. Experiments confirmed the regulating relationship and phenotype of this assumption. This study provides new targets to regulate the metastatic process, predict metastatic potential and determine that miR-3662 may be used in the treatment of melanoma.
DSResSol: A sequence-based solubility predictor created with dilated squeeze excitation residual networks
Authors: Madani Mohammad , Lin Kaixiang , Tarakanova Anna
Published: August 2021

Protein solubility is an important thermodynamic parameter critical for the characterization of a protein’s function, and a key determinant for the production yield of a protein in both the research setting and within industrial (e.g. pharmaceutical) applications. Thus, a highly accurate in silico bioinformatics tool for predicting protein solubility from protein sequence is sought. In this study, we developed a deep learning sequence-based solubility predictor, DSResSol, that takes advantage of the integration of squeeze excitation residual networks with dilated convolutional neural networks. The model captures the frequently occurring amino acid k-mers and their local and global interactions, and highlights the importance of identifying long-range interaction information between amino acid k-mers to achieve higher performance in comparison to existing deep learning-based models. DSResSol uses protein sequence as input, outperforming all available sequence-based solubility predictors by at least 5% in accuracy when the performance is evaluated by two different independent test sets. Compared to existing predictors, DSResSol not only reduces prediction bias for insoluble proteins, but also predicts soluble proteins within the test sets with an accuracy that is at least 13% higher. We derive the key amino acids, dipeptides, and tripeptides contributing to protein solubility, identifying glutamic acid and serine as critical amino acids for protein solubility prediction. Overall, DSResSol can be used for fast, reliable, and inexpensive prediction of a protein’s solubility to guide experimental design.

Availability

The source code, datasets, and web server for this model are available at https://github.com/mahan-fcb/DSResSol
Relevance of Auditory Errors Decreases When Errors Are Introduced Suddenly
Authors: Chao Sara-Ching , Daliri Ayoub
Published: August 2021

Purpose

When the speech motor system encounters errors, it generates adaptive responses to compensate for the errors. We previously showed that adaptive responses to task-irrelevant errors are significantly smaller than responses to task-relevant errors when errors are introduced gradually. The current study aimed to examine responses to task-irrelevant and task-relevant errors when errors are introduced suddenly.

Method

We used an adaptation paradigm in which participants experienced task-relevant errors (induced by formant-shift perturbations) and task-irrelevant errors (induced by formant-clamp perturbations). For one group of participants (N = 30), we applied the perturbations gradually. The second group of participants (N = 30) received the perturbations suddenly. We designed the perturbations based on participant-specific vowel configurations such that a participant’s first and second formants of /ε/ were perturbed toward their /æ/. To estimate adaptive responses, we measured formant changes (within 0–100 ms of the vowel onset) in response to the formant perturbations.

Results

We found that (1) the difference between adaptive responses to formant-shift and formant-clamp perturbations was the smallest for the suddenly introduced perturbations, and (2) responses to formant-shift perturbations positively correlated with responses to formant-clamp perturbations for the suddenly (but not gradually) introduced perturbations.

Conclusions

These results showed that the speech motor system responds to task-relevant errors and task-irrelevant errors more differently when errors are introduced gradually than suddenly. Overall, the speech motor system evaluates the relevance of errors and uses its evaluation to modulate its adaptive responses to errors.
Synergistic Phase Separation of Two Pathways Promotes Integrin Clustering and Integrin Adhesion Complex Formation
Authors: Case L.B. , Henry L. , Rosen M.K.
Published: August 2021

Integrin adhesion complexes (IACs) are integrin-based plasma membrane-associated compartments where cells sense environmental cues. The physical mechanisms and molecular interactions that mediate nascent IAC formation are unclear. We found that both p130Cas (“Cas”) and Focal adhesion kinase (“FAK”) undergo liquid-liquid phase separation in vitro under physiologic conditions. Cas- and FAK- driven phase separation is sufficient to reconstitute kindlin-dependent integrin clustering in vitro. In vitro condensates and cellular IACs exhibit similar sensitivities to environmental perturbations including changes in temperature and pH. Furthermore, mutations that inhibit or enhance phase separation in vitro reduce or increase the number of IACs in cells, respectively. Finally, we find that the Cas and FAK pathways act synergistically to promote phase separation, integrin clustering and IAC formation in vitro and in cells. We propose that Cas- and FAK- driven phase separation provides an intracellular trigger for integrin clustering and nascent IAC formation.
Intrinsically disordered pathogen effector alters the STAT1 dimer to prevent recruitment of co-transcriptional activators CBP/p300
Authors: Huang Zhou , Liu Hejun , Nix Jay , Knoverek Catherine R. , Bowman Gregory R. , Amarasinghe Gaya K. , Sibley L. David
Published: August 2021

Signal transducer and activator of transcription (STATs) proteins signal from cell-surface receptors to drive transcription of immune response genes. The parasiteToxoplasma gondiiblocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectantly remain silenced. Here we define a core repeat region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural studies demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface altered its conformation and prevented recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription.
Surveying the global landscape of post-transcriptional regulators
Authors: Reynaud Kendra , McGeachy Anna , Noble David , Meacham Zuriah , Ingolia Nicholas
Published: August 2021

Numerous proteins regulate gene expression by modulating mRNA translation and decay. In order to uncover the full scope of these post-transcriptional regulators, we conducted an unbiased survey that quantifies regulatory activity across the budding yeast proteome and delineates the protein domains responsible for these effects. Our approach couples a tethered function assay with quantitative single-cell fluorescence measurements to analyze ∼50,000 protein fragments and determine their effects on a tethered mRNA. We characterize hundreds of strong regulators, which are enriched for canonical and unconventional mRNA-binding proteins. Regulatory activity typically maps outside the RNA-binding domains themselves, highlighting a modular architecture that separates mRNA targeting from post-transcriptional regulation. Activity often aligns with intrinsically disordered regions that can interact with other proteins, even in core mRNA translation and degradation factors. Our results thus reveal networks of interacting proteins that control mRNA fate and illuminate the molecular basis for post-transcriptional gene regulation.
Molecular studies into Copine-4 function in Retinal Ganglion Cells
Authors: Goel Manvi , Aponte Angel M. , Wistow Graeme , Badea Tudor C.
Published: August 2021

The molecular mechanisms underlying morphological diversity in retinal cell types are poorly understood. We have previously reported that several members of the Copine family of Ca-dependent membrane adaptors are expressed in Retinal Ganglion Cells (RGCs) and transcriptionally regulated by Brn3 transcription factors. Several Copines are enriched in the retina and their over-expression leads to morphological changes reminiscent of neurite formation in HEK293 cells. However, the role of Copines in the retina is largely unknown. Here we focus on Cpne4, a Copine whose expression is restricted to RGCs. Over-expression of Cpne4 in RGCs in vivo led to formation of large varicosities on the dendrites but did not otherwise visibly affect dendrite or axon formation. Protein interactions studies using yeast two hybrid analysis from whole retina cDNA revealed two Cpne4 interacting proteins - HCFC1 and Morn2. Mass Spectrometry analysis of retina lysate pulled down using Cpne4 or its vonWillebrand A (vWA) domain identified a further 207 interacting proteins. Gene Ontology (GO) analysis of Cpne4 interactors suggests its involvement in several metabolic and signaling pathways, including processes related to vesicle trafficking, intracellular membrane bound organelles, and plasma membrane associated structures, including neurites. We conclude that, consistent with its domain structure, Cpne4 may be involved in assembly and trafficking of several membrane associated cell compartments.
Visualizing conformational space of functional biomolecular complexes by deep manifold learning
Authors: Wu Zhaolong , Chen Enbo , Zhang Shuwen , Ma Yinping , Liu Congcong , Yin Chang-Cheng , Mao Youdong
Published: August 2021

The cellular functions are executed by biological macromolecular complexes in nonequilibrium dynamic processes, which exhibit a vast diversity of conformational states. Solving conformational continuum of important biomolecular complexes at atomic level is essential to understand their functional mechanisms and to guide structure-based drug discovery. Here we introduce a deep learning framework, named AlphaCryo4D, which enables atomic-level cryogenic electron microscopy reconstructions of conformational continuum. AlphaCryo4D integrates 3D deep residual learning with manifold embedding of energy landscapes, which simultaneously improves 3D classification accuracy and reconstruction resolution via an energy-based particle-voting algorithm. By applications of this approach to analyze five experimental datasets, we demonstrate its generality in breaking resolution barrier of visualizing dynamic components of functional complexes, in choreographing continuous inter-subunit motions and in exploring their ‘hidden’ conformational space. Our approach expands the realm of structural ensemble determination to the nonequilibrium regime at atomic level, thus potentially transforming biomedical research and therapeutic development.
Multiple macroecological laws do characterize various aspects of microbiota dynamics
Authors: Tchourine Konstantine , Carballo-Pacheco Martin , Vitkup Dennis
Published: August 2021

In this letter we address the potential confusion related to our recent demonstration that multiple macroecological laws describe short- and long-term dynamics of microbial communities. Specifically, we clarify that these laws, similarly to many other relationships observed in nature, are characterized not just by the existence of scaling, but also by certain characteristic values of the scaling exponents. By performing proper statistical analysis, we demonstrate that the relationships sensitive to temporal bacterial dynamics are not reproduced in the shuffled data. We also discuss that there is no clear evidence in the data that macroecological relationships in microbiota are primarily driven by external or environmental factors. Proper statistical analyses of the data suggest that the dynamics of gut microbiota, even on a constant diet, contains rich temporal structure. Therefore, it is likely that complex and non-linear internal dynamics may be primarily responsible for the observed macroecological laws in microbiota and other ecological communities.
Arap1 Loss Causes RPE Phagocytic Dysfunction and Subsequent Photoreceptor Death
Authors: Shao Andy , Lopez Antonio Jacobo , Chen JiaJia , Tham Addy , Javier Seanne , Quiroz Alejandra , Frick Sonia , Levine Edward M. , Kent Lloyd K.C. , Leonard Brian C. , Murphy Christopher J. , Glaser Thomas M. , Moshiri Ala
Published: August 2021

Purpose

Arap1 is an Arf-directed GTPase-activating protein (GAP) shown to modulate actin cytoskeletal dynamics by regulating Arf and Rho family members. We have previously shown that Arap1-/- mice develop photoreceptor degeneration similar to the human condition retinitis pigmentosa (RP), corroborated by fundus examination, histopathology, and ERG analysis. However, Arap1 expression was not detected in photoreceptors, but in Müller Glia and retinal pigment epithelium (RPE), suggesting a non-cell-autonomous mechanism for degeneration. The aim of this study was to elucidate the role of retinal Arap1 in photoreceptor maintenance.

Methods

Albino Arap1-/- mice were generated via breeding pigmented Arap1-/- mice onto a Tyr-/- C57BL/6J background. Conditional knockout (cKO) mice were generated for Müller Glia/RPE, Müller Glia, and RPE via targeting Cralbp, Glast, and Vmd2 promoters, respectively, to drive Cre recombinase expression to knock out Arap1. Mice were analyzed by fundus photography, optical coherence tomography (OCT), histology, and immunohistochemistry. Arap1 binding partners were assayed by affinity purification mass spectrometry.

Results

Vmd2-Cre Arap1tm1c/tm1c and Cralbp-Cre Arap1tm1c/tm1c mice, but not Glast-Cre Arap1tm1c/tm1c mice, recapitulated the photoreceptor degeneration phenotype originally observed in germline Arap1−/− mice. These findings were corroborated by fundus exam, OCT, and histological analysis. Mass spectrometry analysis of ARAP1 co-immunoprecipitation identified putative binding partners of ARAP1, revealing numerous interactants involved in phagocytosis, cytoskeletal composition, intracellular trafficking, and endocytosis. Quantification of rod outer segment (OS) phagocytosis in vivo demonstrated a clear phagocytic defect in Arap1−/− mice compared to Arap1+/+ littermate controls while cone phagocytosis was preserved.

Conclusions

Arap1 expression, specifically in RPE, is necessary for photoreceptor survival due to its indispensable function in RPE phagocytosis. We propose a model in which Arap1 regulates G-protein function for nonmuscle myosin II targeting during phagocytosis. This novel role of Arap1 is important for further understanding of both the diversity of its functions and the complex molecular regulation of RPE phagocytosis.
Engineering site-selective incorporation of fluorine into natural product analogs
Authors: Sirirungruang S. , Ad O. , Privalsky T. M. , Ramesh S. , Sax J. L. , Dong H. , Baidoo E. E. K. , Amer B. , Khosla C. , Chang M. C. Y.
Published: August 2021

While bioactive compounds are commonly derived both by human design as well as from living organisms, man-made and natural products typically display very different structural characteristics. As such, a longstanding goal in the discovery of new molecular function is to develop approaches to incorporate the advantageous elements of both groups of molecules, thereby expanding the molecular space accessible for this purpose. In this work, we report the engineering a fluorine-selective enzyme that can complement mutated acyltransferase (AT) domains of a modular polyketide synthase, which are the main determinants of the identity and location of substituents on polyketides, to produce different fluorinated regioisomers of the erythromycin precursor in vitro. We further show that by engineering cell uptake of fluorinated building blocks, we can control fluorine selectivity in vivo to produce selectively fluorinated polyketides using engineered E. coli. These results demonstrate that it is possible to introduce fluorine, a key synthetic design element for drug development, selectively into the scaffold of a complex natural product and produce these analogs by microbial fermentation.
SteadyCellPhenotype: A web-based tool for the modeling of biological networks with ternary logic
Authors: Knapp Adam C. , Vieira Luis Sordo , Laubenbacher Reinhard , Chifman Julia
Published: August 2021

We introduce SteadyCellPhenotype, a browser based interface for the analysis of ternary biological networks. It includes tools for deterministically finding all steady states of a network, as well as the simulation and visualization of trajectories with publication quality graphics. Stochastic simulations allow us to approximate the size of the basin for attractors and deterministic simulations of trajectories nearby specified points allow us to explore the behavior of the system in that neighborhood.

Availability

https://github.com/knappa/steadycellphenotypeMITLicense

Contact

chifman@american.edu
Antibodies control metabolism by regulating insulin homeostasis
Authors: Amendt Timm , Allies Gabriele , Nicolò Antonella , El Ayoubi Omar , Young Marc , Röszer Tamás , Setz Corinna S. , Warnatz Klaus , Jumaa Hassan
Published: August 2021

Homeostasis of metabolism by hormone production is crucial to maintain physiological integrity and disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibodies recognizing insulin are key regulators of blood glucose and metabolism controlling insulin concentrations. In fact, antibody-deficient mice and immunodeficiency patients show sub-physiological blood glucose, which becomes normal after total IgG injection. We show that insulin-specific IgG antibodies found in the serum of wildtype mice or healthy individuals are responsible for this regulation. Interestingly, we identify two fractions of anti-insulin IgM which differ in their affinity to insulin. The low affinity IgM fraction (anti-insulin IgMlow) neutralizes insulin and leads to increased blood glucose while the high affinity IgM fraction (anti-insulin IgMhigh) protects insulin from neutralization by anti-insulin IgG thereby preventing blood glucose dysregulation. In contrast to anti-insulin IgMhigh, anti-insulin IgMlowbinds to dsDNA suggesting that it is multi-specific. This multi-specificity mediates the formation of larger immune complexes containing insulin which results in increased uptake and degradation of insulin by macrophages in the presence of anti-insulin IgMlowas compared to anti-insulin IgMhigh. To demonstrate that high affinity anti-insulin IgM acts as protector of insulin and counteracts insulin neutralization by anti-insulin IgG, we expressed the variable regions of the same anti-insulin antibody as IgG or IgM. Strikingly, only the anti-insulin IgM regulated insulin function and prevented IgG-mediated neutralization of insulin and subsequent blood glucose dysregulation. Since anti-insulin IgMhighis generated in the course of an immune response and affinity maturation, its protective role suggests that preventing autoimmune damage and maintaining physiological homeostasis requires adaptive tolerance mechanisms that generate protective IgM antibodies during memory responses.
X-ray Laue diffraction by sectioned multilayers. I. Pendellösung effect and rocking curves
Authors: Punegov Vasily I.
Published: August 2021

Using the Takagi–Taupin equations, X-ray Laue dynamical diffraction in flat and wedge multilayers is theoretically considered. Recurrence relations are obtained that describe Laue diffraction in structures that are inhomogeneous in depth. The influence of sectioned depth, imperfections and non-uniform distribution of the multilayer period on the Pendellösung effect and rocking curves is studied. Numerical simulation of Laue diffraction in multilayer structures W/Si and Mo/Si is carried out. It is shown that the determination of sectioned depths based on the period of the interference fringes of the experimental rocking curves of synchrotron radiation is not always correct.
Research on workpiece location algorithm based on improved SSD
Authors: Li Lin , Fu Mingheng , Zhang Tie , Ying Wu He
Published: August 2021

Purpose

To improve production efficiency, industrial robots are expected to replace humans to complete the traditional manual operation on grasping, sorting and assembling workpieces. These implementations are closely related to the accuracy of workpiece location. However, workpiece location methods based on conventional machine vision are sensitive to the factors such as light intensity and surface roughness. To enhance the robustness of the workpiece location method and improve the location accuracy, a workpiece location algorithm based on improved Single Shot MultiBox Detector (SSD) is proposed.

Design/methodology/approach

The proposed algorithm integrates a weighted bi-directional feature pyramid network into SSD. A feature fusion architecture is structured by the combination of low-resolution, strong semantic features and high-resolution, weak semantic features. The architecture is built through a top-down pathway, bottom-up pathway, lateral connections and skip connections. To avoid treating all features equally, learnable weights are introduced into each feature layer to characterize its importance. More detailed information from the low-level layers is injected into the high-level layers, which could improve the accuracy of workpiece location.

Findings

It is found that the maximum location error at the center point calculated from the proposed algorithm is decreased by more than 22% compared with that of the SSD algorithm. Besides, the average location error evolves a decrease by at least 5%. In the trajectory prediction experiment of the workpiece center point, the results of the proposed algorithm demonstrate that the average location error is below 0.13 mm and the maximum error is no more than 0.23 mm.

Originality/value

In this work, a workpiece location algorithm based on improved SSD is developed to extract the center point of the workpiece. The results demonstrate that the proposed algorithm is beneficial for workpiece location. The proposed algorithm can be readily used in a variety of workpieces or adapted to other similar tasks.
Forecasting stock price movement: new evidence from a novel hybrid deep learning model
Authors: Zhao Yang , Chen Zhonglu
Published: August 2021

Purpose

This study explores whether a new machine learning method can more accurately predict the movement of stock prices.

Design/methodology/approach

This study presents a novel hybrid deep learning model, Residual-CNN-Seq2Seq (RCSNet), to predict the trend of stock price movement. RCSNet integrates the autoregressive integrated moving average (ARIMA) model, convolutional neural network (CNN) and the sequence-to-sequence (Seq2Seq) long–short-term memory (LSTM) model.

Findings

The hybrid model is able to forecast both linear and non-linear time-series component of stock dataset. CNN and Seq2Seq LSTMs can be effectively combined for dynamic modeling of short- and long-term-dependent patterns in non-linear time series forecast. Experimental results show that the proposed model outperforms baseline models on S&P 500 index stock dataset from January 2000 to August 2016.

Originality/value

This study develops the RCSNet hybrid model to tackle the challenge by combining both linear and non-linear models. New evidence has been obtained in predicting the movement of stock market prices.
Cultural differences in gift recipients’ attitude and behavior toward disliked gifts
Authors: Pusaksrikit Theeranuch , Chinchanachokchai Sydney
Published: August 2021

Purpose

The purpose of this paper is to examine the effects of cultural differences and the types of relationship closeness involved in recipients’ emotional and behavioral reactions after receiving disliked gifts.

Design/methodology/approach

Collecting data from Thailand and the USA, two experiments were conducted in a 2 (self-construal: independent/interdependent) × 2 (relationship closeness: close/distant) between-subjects design. Study 1 explores the recipients’ feelings and reactions upon receipt of a disliked gift. Study 2 explores the disposition process for a disliked gift.

Findings

The results show that a recipient’s emotions, reaction and disposition process can be affected by cultural differences and relationship closeness: specifically that close and distant relationships moderate the relationship between self-construal and gift-receiving attitudes and behaviors.

Research limitations/implications

Future research can investigate representative groups from other countries to broaden the generalizability of the findings.

Practical implications

This understanding can guide gift-givers when selecting gifts for close or distant recipients across cultures. Additionally, it can help retailers develop and introduce new marketing strategies by applying self-construal as a marketing segmentation tool for gift purchase and disposition.

Originality/value

This research is among the first studies to offer insights into how individuals in different cultures manage disliked gifts they receive from people in either close or distant relationships.
Accuracy assessment and performance analysis of raster to vector conversions on LULC data – India
Authors: Auradkar Prafullata Kiran , Raykar Atharva , Agarwal Ishitha , Sitaram Dinkar , R. Manavalan
Published: August 2021

Purpose

The purpose of this paper is to convert real-world raster data into vector format and evaluate loss of accuracy in the conversion process. Open-source Geographic Information System (GIS) is used in this process and system resource utilizations were measured for conversion and accuracy analysis methods. Shape complexity attributes were analyzed in co-relation to the observed conversion errors.

Design/methodology/approach

The paper empirically evaluated the challenges and overheads involved in the format conversion algorithms available in open-source GIS with real-world land use and land cover (LULC) map data of India. Across the different LULC categories, geometric errors of varying density were observed in Quantum GIS (QGIS) algorithm. Area extents of original raster data were compared to the vector forms and the shape attributes such as average number of vertices and shape irregularity were evaluated to explore the possible correlation.

Findings

The results indicate that Geographic Resources Analysis Support System provides near error-free conversion algorithm. At the same time, the overall time taken for the conversion and the system resource utilizations were optimum as compared to the QGIS algorithm. Higher vector file sizes were generalized and accuracy loss was tested.

Research limitations/implications

Complete shape complexity analysis could not be achieved, as the weight factor for the irregularity of the shapes is to be varied based on the demography as well as on the LULC category.

Practical implications

Because of the higher system resource requirements of topological checker tool, positional accuracy checks for the converted objects could not be completed.

Originality/value

This paper addresses the need of accuracy analysis of real-world spatial data conversions from raster to vector format along with experimental setups challenges and impact of shape complexity.
Post-purchase behaviour from customer perceived value of mobile payment services
Authors: Hsiao Ming-Hsiung
Published: August 2021

Purpose

Mobile payment (MP), near field communication-based particularly, has become one of the future payment tools. This study aims to indicate the difference between consumer users and non-users by examining the effect of MP users’ perceived value on their satisfaction and on MP non-users behavioural intention. Once those MP users’ have achieved satisfaction, the study then investig ates how consumers bring about the need recognition and are more desirable to buy more products.

Design/methodology/approach

This study develops a research model, which examines the effect of consumer perceived value, including utilitarian value, technicality and perceived risk, on MP users’ satisfaction and MP non-users behavioural intention. In methodology, it adopts structural equation modelling to verify the proposed research model for empirical studies. The data set consists of 161 MP users and 277 non-users of consumers.

Findings

The findings show that consumers, both MP users and non-users included, are encouraged to improve utilitarian value if they are favourable to adopt MP services. Relatively, female users emphasize more on perceived risk, whilst male users emphasize more on technicality. Moreover, MP non-users and female users still have much concern about perceived risk such that they are inclined to avoid adopting MP services.

Originality/value

Past research has examined the adoption of MP services from the perspective of consumers with a focus on the perceived value, satisfaction and behavioural intention. However, only limited research examined the post-purchase evaluation of MP users. The study fills this gap by clarifying the difference between consumer users and non-users in the effect of MP users’ perceived value on their satisfaction and on their non-users behavioural intention.
Who is a “Senior”? Looking for a definition in the healthcare system
Authors: Consolandi Monica
Published: August 2021

Purpose

Seniors are nowadays at the core of important reflections to understand both how to ensure them a proper quality of life and better recognize their social role, providing them services and proper health care to value them as persons and resources. This paper aims to find a through definition about who is a senior, in the author’s opinion the starting point to help them flourishing.

Design/methodology/approach

As an example of definitions, an online dictionary and two geriatric text-books are quoted, highlighting qualities and rights referred to seniors especially in the delicate context of the health-care system.

Findings

The lack of a commonly shared perspective on this delicate kind of patient entails the difficulty to reach a coherent and satisfying definition about who a senior is.

Originality/value

The lack of a commonly shared definition leads to inevitable misunderstandings and could explain the arduousness of considering seniors in all their aspects. Further investigations are suggested.
Defence strategies in an online community of caregivers
Authors: Zummo Marianna Lya
Published: August 2021

Purpose

The purpose of this paper is to understand caregivers’ discursive constructions and responses to their unwanted (family and social) role as resulting in exchanges on social media. Online group platforms are understood as particularly suitable for the expression of intimate feelings among adults, for meeting and exhibiting stigma issues, and for the circulation of information and support (Suler, 2004; McCormack, 2010; Pounds et al., 2018).

Design/methodology/approach

This paper draws from digital Conversation Analysis (Giles et al., 2015), and considers data after combining quantitative (corpus analysis) and qualitative methods, from a critical discourse analysis perspective. The Stereotype Content Model (SCM; Fiske et al., 2002) is used together with collocation analysis to understand categorisations, which ultimately result in a defence strategy (Assimakopoulos et al., 2017) to negotiate the Self and the Others (Tannen, 1992).

Findings

Considering that the digital environment allows a discursive negotiation of identities, data suggest that these interactions are expressions of membership construction, group solidarity and empowerment, that normalise and legitimise emotions with the ultimate goal of (self-)acceptance.

Originality/value

This study provides a basis for further research on caregivers’ self-positioning in power-relations with others.