bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-time decoding of 5 finger movements from 2 EMG channels for mixed reality human-computer interaction
Authors: McDermott Eric J. , Zwiener Thimm , Ziemann Ulf , Zrenner Christoph
Published: October 2021

The search for optimized forms of human-computer interaction (HCI) has intensified alongside the growing potential for the combination of biosignals with virtual reality (VR) and augmented reality (AR) to enable the next generation of personal computing. At the core, this requires decoding the user’s biosignals into digital commands. Electromyography (EMG) is a biosensor of particular interest due to the ease of data collection, the relatively high signal-to-noise-ratio, its non-invasiveness, and the ability to interpret the signal as being generated by (intentional) muscle activity. Here, we investigate the potential of using data taken from a simple 2-channel EMG setup to differentiate 5 distinct movements. In particular, EMG was recorded from two bipolar sensors over small hand muscles (extensor digitorum,flexor digitorum profundus) while a subject performed 50 trials of dorsal extension and return for each of the five digits. The maximum and the mean values across the trial were determined for each channel and used as features. A k-nearest neighbors (kNN) classification was performed and overall 5-class classification accuracy reached 94% when using the full trial’s time window, while simulated real-time classification reached 90.4% accuracy when using the constructed kNN model (k=3) with a 280ms sliding window. Additionally, unsupervised learning was performed and a homogeneity of 85% was achieved. This study demonstrates that reliable decoding of different natural movements is possible with fewer than one channel per class, even without taking into account temporal features of the signal. The technical feasibility of this approach in a real-time setting was validated by sending real-time EMG data to a custom Unity3D VR application through a Lab Streaming Layer to control a user interface. Further use-cases of gamification and rehabilitation were also examined alongside the integration of eye-tracking and gesture recognition for a sensor fusion approach to HCI and user intent.
Axial motion estimation and correction for simultaneous multi-plane two-photon calcium imaging
Authors: Valle Andres Flores , Seelig Johannes D.
Published: October 2021

Two-photon imaging in behaving animals is typically accompanied by brain motion. For functional imaging experiments, for example with genetically encoded calcium indicators, such brain motion induces changes in fluorescence intensity. These motion related intensity changes or motion artifacts cannot easily be separated from neural activity induced signals. While lateral motion within the focal plane can be corrected by computationally aligning images, axial motion, out of the focal plane, cannot easily be corrected.

Here, we develop an algorithm for axial motion correction for non-ratiometric calcium indicators taking advantage of simultaneous multi-plane imaging. Using at least two simultaneously recorded focal planes, the algorithm separates motion related and neural activity induced changes in fluorescence intensity. The developed motion correction approach allows axial motion estimation and correction at high frame rates for isolated structures in the imaging volume in vivo, such as sparse expression patterns in the fruit fly brain.
In Situ Surface-Directed Assembly of 2D Metal Nanoplatelets for Drug-Free Treatment of Antibiotic-Resistant Bacteria
Authors: Fathi Parinaz , Roslend Ayman , Alafeef Maha , Esch Mandy B. , Pan Dipanjan
Published: October 2021

The development of antibiotic resistance among bacterial strains is a major global public health concern. To address this, drug-free antibacterial approaches are needed. High-touch surfaces in particular can serve as a means for the spread of bacteria and other pathogens from one infected person to another. Copper surfaces have long been known for their antibacterial properties. To further enhance the surface’s antibacterial properties, we used a one-step surface modification technique to assemble 2D copper chloride nanoplatelets directly onto copper surfaces such as copper tape, transmission electron microscopy (TEM) grids, electrodes, and granules. The nanoplatelets were formed using copper ions from the copper surfaces, enabling their direct assembly onto these surfaces in a one-step process that does not require separate nanoparticle synthesis. The synthesis of the nanoplatelets was confirmed with TEM, scanning electron microscopy, energy dispersive spectroscopy (EDS), x-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR). Antibacterial properties of the surfaces with copper chloride nanoplatelets were demonstrated in multi-drug-resistant (MDR) E. coli. The presence of copper chloride nanoplatelets on the surface led to a marked improvement in antibacterial properties compared to the untreated copper surfaces. Surfaces with copper chloride nanoplatelets affected bacterial cell morphology, prevented bacterial cell division, reduced their viability, damaged bacterial deoxyribonucleic acid (DNA), and altered protein expression. In particular, proteins corresponding to cell division, DNA division, and mediation of copper toxicity were down-regulated. This work presents a robust method to directly assemble copper chloride nanoplatelets onto any copper surface to imbue it with improved antibacterial properties. To demonstrate that our method of particle generation can be used with other metal surfaces, we also demonstrate the synthesis of other metal-derived nanoarchitectures on a variety of metal surfaces.
Evolutionary Strategies Applied to Artificial Gene Regulatory Networks
Authors: Moreira André L. L. , Rennó-Costa César
Published: October 2021

Evolution optimizes cellular behavior throughout sequential generations by selecting the successful individual cells in a given context. As gene regulatory networks (GRNs) determine the behavior of single cells by ruling the activation of different processes - such as cell differentiation and death - how GRNs change from one generation to the other might have a relevant impact on the course of evolution. It is not clear, however, which mechanisms that affect GRNs effectively favor evolution and how. Here, we use a population of computational robotic models controlled by artificial gene regulatory networks (AGRNs) to evaluate the impact of different genetic modification strategies in the course of evolution. The virtual agent senses the ambient and acts on it as a bacteria in different phototaxis-like tasks - orientation to light, phototaxis, and phototaxis with obstacles. We studied how the strategies of gradual and abrupt changes on the AGRNs impact evolution considering multiple levels of task complexity. The results indicated that a gradual increase in the complexity of the performed tasks is beneficial for the evolution of the model. Furthermore, we have seen that larger gene regulatory networks are needed for more complex tasks, with single-gene duplication being an excellent evolutionary strategy for growing these networks, as opposed to full-genome duplication. Studying how GRNs evolved in a biological environment allows us to improve the computational models produced and provide insights into aspects and events that influenced the development of life on earth.
Joint Alignment and Tree Inference
Authors: Pečerska Jūlija , Gil Manuel , Anisimova Maria
Published: October 2021

Multiple sequence alignment and phylogenetic tree inference are connected problems that are often solved as independent steps in the inference process. Several attempts at doing simultaneous inference have been made, however currently the available methods are greatly limited by their computational complexity and can only handle small datasets. In this manuscript we introduce a combinatorial optimisation approach that will allow us to resolve the circularity of the problem and efficiently infer both alignments and trees under maximum likelihood.
Direct quantification of ligand-induced lipid and protein microdomains with distinctive signaling properties
Authors: Wirth Daniel , Paul Michael D. , Pasquale Elena B. , Hristova Kalina
Published: October 2021

Lipid rafts are known as highly ordered lipid domains that are enriched in saturated lipids such as the ganglioside GM1. While lipid rafts are believed to exist in cells and to serve as signaling platforms through their enrichment in signaling components, they have never been directly observed in the plasma membrane without treatments that artificially cluster GM1 into large lattices. Here we report that microscopic GM1-enriched domains can form, without lipid cross-linking, in the plasma membrane of live mammalian cells expressing the EphA2 receptor tyrosine kinase in response to its ligand ephrinA1-Fc. The GM1-enriched microdomains form concomitantly with EphA2-enriched microdomains, but only partially co-localize with them. To gain insight into how plasma membrane heterogeneity controls signaling, we quantify the degree of EphA2 segregation and study initial EphA2 signaling steps in both EphA2-enriched and EphA2-depleted domains. By measuring dissociation constants, we demonstrate that EphA2 oligomerization is the same in EphA2-enriched and -depleted domains. However, EphA2 interacts preferentially with its downstream effector SRC in EphA2-depleted domains. The ability to induce microscopic GM1-enriched domains in live cells using a ligand for a transmembrane receptor will give us unprecedented opportunities to study the biology of lipid rafts.
Niosome encapsulated doxycycline-hyclate for potentiation of acne therapy: formulation and characterization
Authors: Kashani-Asadi-Jafari Fatemeh , Hadjizadeh Afra
Published: October 2021

Acne is the pilosebaceous units’ disorder. The most important cause of acne is the colonization of bacteria in the follicles. Among antibiotics, doxycycline-hyclate kills a wide range of bacteria. To prevent oral administration’s side effects, overcome the barriers of conventional topical treatment, and improve the therapeutic effectiveness, doxycycline-hyclate was loaded into four niosomal formulations with different percentages of constituents (span 60 and cholesterol) prepared by the thin-film hydration method. Then, one of the four formulations with the most appropriate particle size of 362.88 ± 13.05 nm to target the follicles, percentage of drug entrapment efficiency of 56.3 ± 2.1%, in vitro drug release of 54.93 ± 1.99% after 32 hours, and the lowest permeation of the drug through the Wistar rat skin, was selected. Then, its toxicity on human dermal fibroblasts (HDF) by MTT method after 72 hours, its antibacterial activity against the main acne-causing bacteria via antibiogram test, and its effect on Wistar rat skin drug deposition were measured. Improved cell viability, increased antibacterial activity, and an approximately three-fold increase in drug deposition were the optimal niosomal formulation features relative to the free drug. Overall, this study demonstrated the ability of nano-niosomes containing doxycycline-hyclate to treat skin acne.
Sex Differences in Brain Tumor Glutamine Metabolism Reveal Sex-Specific Vulnerabilities to Treatment
Authors: Sponagel Jasmin , Jones Jill K. , Frankfater Cheryl , Zhang Shanshan , Tung Olivia , Cho Kevin , Tinkum Kelsey L. , Gass Hannah , Nunez Elena , Spitz Douglas R. , Chinnaiyan Prakash , Schaefer Jacob , Patti Gary J. , Graham Maya S. , Mauguen Audrey , Grkovski Milan , Dunphy Mark P. , Krebs Simone , Luo Jingqin , Rubin Joshua B. , Ippolito Joseph E.
Published: October 2021

Sex differences in normal metabolism are well described, but whether they persist in cancerous tissue is unknown. We assessed metabolite abundance in glioblastoma surgical specimens and found that male glioblastomas are enriched for amino acids, including glutamine. Using PET imaging, we found that gliomas in male patients exhibit significantly higher glutamine uptake. These sex differences were well-modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and TCA cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase-mediated TCA cycle replenishment. Thus, clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism is an opportunity to improve treatments for all patients through further laboratory and clinical research.
All2: A tool for selecting mosaic mutations from comprehensive multi-cell comparisons
Authors: Sarangi Vivekananda , Jang Yeongjun , Suvakov Milovan , Bae Taejeong , Fasching Liana , Sekar Shobana , Tomasini Livia , Mariani Jessica , Vaccarino Flora M. , Abyzov Alexej
Published: October 2021

Accurate discovery of somatic mutations in a cell is a challenge that partially lays in immaturity of dedicated analytical approaches. Approaches comparing cell’s genome to a control bulk sample miss common mutations, while approaches to find such mutations from bulk suffer from low sensitivity. We developed a tool, All2, which enables accurate filtering of mutations in a cell from exhaustive comparison of cells’ genomes to each other without data for bulk(s). Based on all pair-wise comparisons, every variant call (point mutation, indel, and structural variant) is classified as either a germline variant, mosaic mutation, or false positive. As All2 allows for considering dropped-out regions, it is applicable to whole genome and exome analysis of cloned and amplified cells. By applying the approach to a variety of available data, we showed that its application reduces false positives, enables sensitive discovery of high frequency mutations, and is indispensable for conducting high resolution cell lineage tracing. All2 is freely available at https://github.com/abyzovlab/All2.
SPF: A Spatial and Functional Data Analytic Approach to cell Imaging data
Authors: Vu Thao , Wrobel Julia , Bitler Benjamin G. , Schenk Erin L. , Jordan Kimberly R. , Ghosh Debashis
Published: October 2021

The tumor microenvironment (TME), which characterizes the tumor and its surroundings, plays a critical role in understanding cancer development and progression. Recent advances in imaging techniques enable researchers to study spatial structure of the TME at a single-cell level. Investigating spatial patterns and interactions of cell subtypes within the TME provides useful insights into how cells with different biological purposes behave, which may consequentially impact a subject’s clinical outcomes. We utilize a class of well-known spatial summary statistics, the K-function and its variants, to explore inter-cell dependence as a function of distances between cells. Using techniques from functional data analysis, we introduce an approach to model the association between these summary spatial functions and subject-level outcomes, while controlling for other clinical scalar predictors such as age and disease stage. In particular, we leverage the additive functional Cox regression model (AFCM) to study the nonlinear impact of spatial interaction between tumor and stromal cells on overall survival in patients with non-small cell lung cancer, using multiplex immunohistochemistry (mIHC) data. The applicability of our approach is further validated using a publicly available Multiplexed Ion beam Imaging (MIBI) triple-negative breast cancer dataset.
easyfm: An easy software suite for file manipulation of Next Generation Sequencing data on desktops
Authors: Jung Hyungtaek , Jeon Brendan , Ortiz-Barrientos Daniel
Published: October 2021

Storing and manipulating Next Generation Sequencing (NGS) file formats is an essential but difficult task in biological data analysis. The easyfm (easy file manipulation) toolkit (https://github.com/TaekAndBrendan/easyfm) makes manipulating commonly used NGS files more accessible to biologists. It enables them to perform end-to-end reproducible data analyses using a free standalone desktop application (available on Windows, Mac and Linux). Unlike existing tools (e.g. Galaxy), the Graphical User Interface (GUI)-based easyfm is not dependent on any high-performance computing (HPC) system and can be operated without an internet connection. This specific benefit allow easyfm to seamlessly integrate visual and interactive representations of NGS files, supporting a wider scope of bioinformatics applications in the life sciences.

Author summary

The analysis and manipulation of NGS data for understanding biological phenomena is an increasingly important aspect in the life sciences. Yet, most methods for analysing, storing and manipulating NGS data require complex command-line tools in HPC or web-based servers and have not yet been implemented in comprehensive, easy-to-use software. This is a major hurdle preventing more general application in the field of NGS data analysis and file manipulation. Here we present easyfm, a free standalone Graphical User Interface (GUI) software with Python support that can be used to facilitate the rapid discovery of target sequences (or user’s interest) in NGS datasets for novice users. For user-friendliness and convenience, easyfm was developed with four work modules and a secondary GUI window (herein secondary window), covering different aspects of NGS data analysis (mainly focusing on FASTA files), including post-processing, filtering, format conversion, generating results, real-time log, and help. In combination with the executable tools (BLAST+ and BLAT) and Python, easyfm allows the user to set analysis parameters, select/extract regions of interest, examine the input and output results, and convert to a wide range of file formats. To help augment the functionality of existing web-based and command-line tools, easyfm, a self-contained program, comes with extensive documentation (hosted at https://github.com/TaekAndBrendan/easyfm) including a comprehensive step-by-step guide.
The distribution of fitness effects of spontaneous mutations in Chlamydomonas reinhardtii inferred using frequency changes under experimental evolution
Authors: Böndel Katharina B. , Samuels Toby , Craig Rory J. , Ness Rob W. , Colegrave Nick , Keightley Peter D.
Published: October 2021

The distribution of fitness effects (DFE) for new mutations is fundamental for many aspects of population and quantitative genetics. In this study, we have inferred the DFE in the single-celled alga Chlamydomonas reinhardtii by estimating changes in the frequencies of 254 spontaneous mutations under experimental evolution and equating the frequency changes of linked mutations with their selection coefficients. We generated seven populations of recombinant haplotypes by crossing seven independently derived mutation accumulation lines carrying an average of 36 mutations in the homozygous state to a mutation-free strain of the same genotype. We then allowed the populations to evolve under natural selection in the laboratory by serial transfer in liquid culture. We observed substantial and repeatable changes in the frequencies of many groups of linked mutations, and, surprisingly, as many mutations were observed to increase as decrease in frequency. We developed a Bayesian Monte Carlo Markov Chain method to infer the DFE. This computes the likelihood of the observed distribution of changes of frequency, and obtains the posterior distribution of the selective effects of individual mutations, while assuming a two-sided gamma distribution of effects. We infer that the DFE is a highly leptokurtic distribution, and that approximately equal proportions of mutations have positive and negative effects on fitness. This result is consistent with what we have observed in previous work on a different C. reinhardtii strain, and suggests that a high fraction of new spontaneously arisen mutations are advantageous in a simple laboratory environment.
Host diversity and behavior determine patterns of interspecies transmission and geographic diffusion of avian Influenza A subtypes among North American wild reservoir species
Authors: Hicks Joseph T. , Friedman Kimberly , Qiu Xueting , Kim Do-Kyun , Hixson James E. , Krauss Scott , Webby Richard J. , Webster Robert G. , Bahl Justin
Published: October 2021

Wild birds can carry avian influenza viruses (AIV), including those with pandemic or panzootic potential, long distances. Even though AIV has a broad host range, few studies account for host diversity when estimating AIV spread. We analyzed AIV genomic sequences from North American wild birds, including 303 newly sequenced isolates, to estimate interspecies transmission and geographic diffusion patterns among multiple co-circulating subtypes. Our results show high transition rates within Anseriformes and Charadriiformes, but limited transitions between these orders. Patterns of interspecies transmission were positively associated with breeding habitat range overlap, and negatively associated with host genetic distance. Distance between regions (negative correlation) and summer temperature at origin (positive correlation) were strong predictors of diffusion. Taken together, this study demonstrates that host diversity and ecology can determine evolutionary processes that underlie AIV natural history and spread. Understanding these processes can provide important insights for effective control of AIV.
Managed culls mean extinction for a marine mammal population when combined with extreme climate impacts
Authors: Davis Katrina J
Published: October 2021

Human actions led to the worldwide decline of marine mammal populations in the 18th–19th centuries. However, the global uptake in protective legislation during the 20th century has recently allowed many marine mammal populations to recover. This positive trend is particularly true of pinnipeds (e.g., seals and sea lions), whose recovering populations are increasingly in conflict with fisheries. Many fisheries organisations call for managed culls of sea lion populations to reduce competition for target fish species as well as damage to catch and fishing gear through operational interactions. However, despite widespread perceptions that sea lion populations are generally increasing, to-date culls have been considered or implemented without quantitative evidence of their impacts on seal lion population viability. This knowledge gap is particularly concerning given the expected increase in extreme climate conditions, such as extreme El Niño events, which together with culls could push sea lion populations in some parts of the world into the extinction vortex. In this analysis, I develop and parameterise stochastic matrix population models of the South American sea lion (Otaria flavescens) to project the impact of (1) three cull scenarios with different intensity and temporal frequency targeting adult females, (2) extreme El Niño events whose frequency is modelled using a Markovian transition matrix, (3) and the interaction of culls and extreme climate events on population dynamics. I focus on the Chilean population of O. flavescens, where recent increases in sea lion numbers have triggered widespread conflict with small-scale fisheries, and where sea lion populations will increasingly be affected by extreme El Niño conditions. I find that sea lion populations decline below minimum viable population sizes under all scenarios involving culls and extreme climate events. By explicitly considering parameter uncertainty, this approach is a call to action for future research to focus on collecting stage-specific, annual population data to reduce uncertainty regarding marine mammal vital rates.
Phenotypic plasticity, life cycles, and the evolutionary transition to multicellularity
Authors: Tang Si , Pichugin Yuriy , Hammerschmidt Katrin
Published: October 2021

Understanding the evolutionary transition to multicellularity is a key problem in evolutionary biology (1–4). While around 25 independent instances of the evolution of multicellular existence are known across the tree of life (5), the ecological conditions that drive such transformations are not well understood. The first known transition to multicellularity occurred approximately 2.5 billion years ago in cyanobacteria (5–7), and today’s cyanobacteria are characterized by an enormous morphological diversity, based upon which they have been classified into five sections. They range from single-celled species (section I), unicellular cyanobacteria with packet-like phenotypes, e.g., tetrads (section II) and simple filamentous species (section III) to highly differentiated filamentous ones (sections IV and V) (8–10). The unicellular cyanobacterium Cyanothece sp. ATCC 51142, an isolate from the intertidal zone of the U.S. Gulf Coast (11), has been classified as a section I species, and it phylogenetically clusters with the other N2-fixing unicellular cyanobacteria (12).

Here we report a facultative multicellular life cycle for a unicellular cyanobacterium, where multicellular filaments and unicellular stages alternate. In a series of experiments we identify the environmental factors underlying the phenotypic switch between the two morphologies. Then we experimentally confirm that the dissolution of filaments into solitary cells is triggered by changes in the external environment, which in turn is modified by the Cyanothece cells. Finally, using numerical models, we test a number of hypotheses regarding the nature of the environmental cues and the physical mechanisms underlying filament dissolution. While results predict that the observed response can be caused by an excreted compound in the medium, we cannot fully exclude changes in nutrient availability (as in (13,14)). The best-fit modeling results demonstrate a nonlinear effect of the compound, which is characteristic for density-dependent sensing systems (15,16). Further, filament fragmentation is predicted to occur by means of connection cleavage rather than by cell death of every alternate cell, which is corroborated by results from fluorescent and scanning electron microscopy. The phenotypic switch between the single-celled and multicellular morphology constitutes an environmentally dependent life cycle, which likely represents an important step en route to permanent multicellularity.
Extracellular matrix stiffness and TGFβ2 regulate YAP/TAZ activity in human trabecular meshwork cells
Authors: Li Haiyan , Raghunathan VijayKrishna , Stamer W. Daniel , Ganapathy Preethi S. , Herberg Samuel
Published: October 2021

Primary open-angle glaucoma progression is associated with increased human trabecular meshwork (HTM) stiffness and elevated transforming growth factor beta 2 (TGFβ2) levels in aqueous humor. Increased transcriptional activity of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), central players in mechanotransduction, are implicated in glaucomatous HTM (GTM) cell dysfunction. Yet, the detailed mechanisms underlying YAP/TAZ modulation in HTM cells in response to alterations in extracellular matrix (ECM) stiffness and TGFβ2 levels are not well understood. Using biomimetic ECM hydrogels with tunable stiffness, here we show that increased ECM stiffness elevates YAP/TAZ transcriptional activity potentially through modulating focal adhesions and cytoskeletal rearrangement. Furthermore, TGFβ2 increased YAP/TAZ nuclear localization in both normal and glaucomatous HTM cells, which was prevented by inhibiting extracellular-signal-regulated kinase and Rho-associated kinase signaling pathways. Filamentous (F)-actin depolymerization reversed TGFβ2-induced YAP/TAZ nuclear localization. YAP/TAZ depletion using siRNA or verteporfin decreased focal adhesions, ECM remodeling and cell contractile properties. Similarly, YAP/TAZ inactivation with verteporfin partially blocked TGFβ2-induced HTM/GTM hydrogel contraction and stiffening. Collectively, our data provide evidence for a pathologic role of aberrant YAP/TAZ signaling in glaucomatous HTM cell dysfunction, and may help inform strategies for the development of novel multifactorial approaches to prevent progressive ocular hypertension in glaucoma.
Strong spatial population structure shapes the temporal coevolutionary dynamics of costly female preference and male display
Authors: Tschol Maximilian , Reid Jane M. , Bocedi Greta
Published: October 2021

Female mating preferences for exaggerated male display traits are commonplace. Yet, comprehensive understanding of the evolution and persistence of costly female preference through indirect (Fisherian) selection in finite populations requires some explanation for the persistence of additive genetic variance (Va) underlying sexual traits, given that directional preference is expected to deplete Va in display and hence halt preference evolution. However, the degree to which Va, and hence preference-display coevolution, may be prolonged by spatially variable sexual selection arising solely from limited gene flow and genetic drift within spatially structured populations has not been examined. Our genetically and spatially explicit model shows that spatial population structure arising in an ecologically homogeneous environment can facilitate evolution and long-term persistence of costly preference given small subpopulations and low dispersal probabilities. Here, genetic drift initially creates spatial variation in female preference, leading to persistence of Va in display through “migration-bias” of genotypes maladapted to emerging local sexual selection, thus fuelling coevolution of costly preference and display. However, costs of sexual selection increased the probability of subpopulation extinction, limiting persistence of high preference-display genotypes. Understanding long-term dynamics of sexual selection systems therefore requires joint consideration of coevolution of sexual traits and metapopulation dynamics.
A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant-negative impact on CSF1R signaling
Authors: Stables Jennifer , Green Emma K. , Sehgal Anuj , Patkar Omkar , Keshvari Sahar , Taylor Isis , Ashcroft Maisie E. , Grabert Kathleen , Wollscheid-Lengeling Evi , Szymkowiak Stefan , McColl Barry W. , Adamson Antony , Humphreys Neil E. , Mueller Werner , Starobova Hana , Vetter Irina , Shabestari Sepideh Kiani , Blurton-Jones Matthew M. , Summers Kim M. , Irvine Katharine M. , Pridans Clare , Hume David A.
Published: October 2021

Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout; with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+ mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein which expands tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborization were reduced in the Csf1rE631K/+ mice as in ALSP patients. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that disease-associated CSF1R mutations encode dominant negative repressors of CSF1R signaling. We speculate that leukoencephalopathy associated with human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.

Summary Statement

This study describes the effect of a human disease-associated mutation in the mouse CSF1R gene on postnatal development and growth factor responsiveness of cells of the macrophage lineage.
Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis
Authors: Boland Sebastian , Swarup Sharan , Ambaw Yohannes A. , Richards Ruth C. , Fischer Alexander W. , Singh Shubham , Aggarwal Geetika , Spina Salvatore , Nana Alissa L. , Grinberg Lea T. , Seeley William W. , Surma Michal A. , Klose Christian , Paulo Joao A. , Nguyen Andrew D. , Harper J. Wade , Walther Tobias C. , Farese Robert V.
Published: October 2021

Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis1, a severe neurodevelopmental disease, in humans and neuroinflammation in mice2. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD)3,4. The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides5,6. Despite intensive investigation, the function of granulins and the reason why their absence causes neurodegeneration remain unclear. Here, we investigated PGRN function in lipid degradation, a major function of lysosomes. We show that PGRN-knockout human cells, PGRN-deficient murine brain, and frontal lobes of human brains from patients with GRN mutation-related FTD have increased levels of gangliosides, highly abundant sialic acid–containing glycosphingolipids (GSL) that are degraded in lysosomes. Probing how PGRN deficiency causes these changes, we found normal levels and activities of enzymes that catabolize gangliosides. However, levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism7, were markedly reduced in PGRN-deficient cells and patient brain tissues. These data indicate that granulins are required to maintain BMP levels, which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. This aberrant accumulation of gangliosides may contribute to neuroinflammation and neurodegeneration susceptibility.
Serum glycoprotein markers in non-alcoholic steato-hepatitis and hepatocellular carcinoma
Authors: Ramachandran Prasanna , Xu Gege , Huang Hector H. , Rice Rachel , Zhou Bo , Lind-paintner Klaus , Serie Daniel
Published: October 2021

Fatty liver disease progresses through stages of fat accumulation and inflammation to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis and eventually hepatocellular carcinoma (HCC). Currently available diagnostic tools for HCC lack sensitivity and specificity and deliver little value to patients. In this study, we investigated the use of circulating serum glycoproteins to identify a panel of potential prognostic markers that may be indicative of progression from the healthy state to NASH and further to HCC. Serum samples were processed using a standard pre-analytical sample preparation protocol and were analyzed using a novel high throughput glycoproteomics platform. We analyzed 413 glycopeptides, representing 57 abundant serum proteins and compared among the three phenotypes. Our initial dataset contained healthy, NASH, and HCC serum samples. We analyzed normalized abundance of common glycoforms and found 40 glycopeptides with statistically significant differences in abundances in NASH and HCC compared to controls. Summary level relative abundance of core-fucosylated, sialylated and branched glycans containing glycopeptides were higher in NASH and HCC as compared to controls. We replicated some of our findings in an independent set of samples of individuals with benign liver conditions and HCC, respectively. Our results may be of value in the management of liver diseases.

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TES-1/Tes protects junctional actin networks under tension from self-injury during epidermal morphogenesis in the C. elegans embryo
Authors: Lynch Allison M. , Lucas Bethany G. , Winkelman Jonathan D. , Martin Sterling C.T. , Block Samuel D. , Audhya Anjon , Gardel Margaret L. , Hardin Jeff
Published: October 2021

During embryonic morphogenesis, the integrity of epithelial tissues depends on the ability of cells in tissue sheets to undergo rapid changes in cell shape while preventing self-injury to junctional actin networks. LIM domain-containing repeat (LCR) proteins are recruited to sites of strained actin filaments in cultured cells [1–3], and are therefore promising candidates for mediating self-healing of actin networks, but whether they play similar roles in living organisms has not been determined. Here, we establish roles for Caenorhabditis elegans TES-1/Tes, an actin-binding LCR protein present at apical junctions, during epithelial morphogenesis. TES-1::GFP is recruited to apical junctions during embryonic elongation, when junctions are under tension; in embryos in which stochastic failure of cell elongation occurs, TES-1 is only strongly recruited to junctions in cells that successfully elongate, and recruitment is severely compromised in genetic backgrounds in which cell shape changes do not successfully occur. tes-1 mutant embryos display junctional F-actin defects, and loss of TES-1 strongly enhances tension-dependent injury of junctional actin networks in hypomorphic mutant backgrounds for CCC components, suggesting that TES-1 helps to prevent self-injury of junctional actin networks during rapid cell shape change. Consistent with such role, a fragment of TES-1 containing its LIM domains localizes to stress fiber strain sites (SFSS) in cultured vertebrate cells. Together, these data establish TES-1 as a tension-sensitive stabilizer of the junctional actin cytoskeleton during embryonic morphogenesis.
Crystal Structures of Ferritin Grown by the Microbatch Method in the Presence of Agarose and Electric Field Shows Enhanced Metal Binding
Authors: Seetharaman Aditya , Babu Priyadharshine Ramesh , Ismail Maham , Miller Darcie J , Stojanoff Vivian
Published: October 2021

Ferritin is an ubiquitous iron storage protein found in all kingdoms of life. Ferritin is essential for iron homeostasis and is involved in a wide range of physiological and pathological processes. Several structures of ferritin in complex with small molecules and metal ions have been reported. Here we report the crystal structures of Horse Spleen Ferritin, in which the crystals were grown by employing a novel approach adopting the microbatch experiments performed in the presence and absence of electric field using a 2% agarose pellet of CdSO4. We observed that 1) these structures contain increased number of Cd ions as compared to the crystallization of same protein by others using different methods. 2) The externally applied electric field reduced the number of nucleation and with fewer nucleation the size of the crystals increased. 3) There is no significant conformational change observed among these structures. 4) Irrespective of the externally applied electric field, this agarose microbatch crystallization method facilitates the retaining of increased number of bound metal ions with ferritin to mimic the possible in vivo environment.
Labeling of Synthetic Oligonucleotides Using the Klenow Fragment of E. coli DNA Polymerase I
Authors: Green Michael R. , Sambrook Joseph
Published: October 2021

In this method, a short primer is hybridized to an oligonucleotide template whose sequence is the complement of the desired radiolabeled probe. The primer is then extended using the Klenow fragment to incorporate [α-32P]dNTPs in a template-directed manner. After the reaction, the template and product are separated by denaturation followed by electrophoresis through a polyacrylamide gel under denaturing conditions. With this method, it is possible to generate oligonucleotide probes that contain several radioactive atoms per molecule of oligonucleotide and to achieve specific activities as high as 2 × 1010 cpm/µg of probe. Because the end product of the reaction is dsDNA, whose strands must be separated and the labeled product isolated, this method is generally not used to prepare nonradiolabeled oligonucleotides.
Examining internet banking user’s continuance intention through the lens of technology continuance theory and task technology fit model
Authors: Rahi Samar , Abd Ghani Mazuri
Published: October 2021

Purpose

The long-term success of internet banking (IB) services is connected with continuous use. Therefore, examining factors which influence IB user continuance intention is important. Grounded in technology continuance theory, bank transparency and task technology fit (TTF) model, the purpose of this study is to develop a unified technology continuance model to investigate IB user continuance intention.

Design/methodology/approach

The research model was empirically tested with 348 responses. Respondents included in this study had prior experience with IB services. For hypotheses testing, the structural equation modelling approach was used.

Findings

Findings indicate that the research model has substantial power in explaining IB user continuance intention. Importance performance matrix analysis revealed that bank transparency had the highest importance in determining IB user continuance intention. Therefore, factors like user satisfaction and perceived usefulness have shown a medium level of importance in determining IB user continuance intention. Satisfaction is influenced by perceived usefulness and confirmation and established a significant impact on IB user continuance intention.

Practical implications

The findings of this research are useful for bank managers and policymakers to develop and design IB services according to user’s expectations. Results demonstrate that expectation confirmation and perceived usefulness are antecedents of IB user satisfaction and IB user continuance intention. In addition to that bank, transparency has shown a significant effect on user expectation and IB user continuance intention. These findings established that accuracy in sharing bank information and clarity in transaction charges encourage the user to continue the use of IB services.

Originality/value

The current study develops a unified technology continuance model based on the TTF model and technology continuance theory and investigates IB user continuance intention. Moreover, bank transparency is added in the technology continuance model and established a significant impact towards user expectation confirmation and continuance intention. These findings contribute to the limited body of research in the context of IB user continuance intention and enrich information system literature.
The open innovation journey along heterogeneous modes of knowledge-intensive marketing collaborations: a cross-sectional study of innovative firms in Europe
Authors: Papa Armando , Mazzucchelli Alice , Ballestra Luca Vincenzo , Usai Antonio
Published: October 2021

Purpose

Previous research focused on open innovation (OI) suggests that enterprises benefit from adopting the journey; however, the relationship among OI, marketing journey and knowledge-intensive innovation marketing activities (KIIMA) remains unclear. The present study proposes a conceptual model of the marketing journey linking heterogeneous modes of marketing collaboration to knowledge-intensive activities.

Design/methodology/approach

The conceptual model was tested via ordinary least squares (OLS) linear regression based on a sample of data drawn from the Eurostat database.

Findings

The results indicate that strategies are a robust proxy for evaluating KIIMA, and partnerships, heterogeneous sources of knowledge and different marketing modes for collaboration among European knowledge-intensive firms are core antecedents of KIIMA, such as new-product development and marketing innovation, as well as firms' sustainable competitive advantage.

Originality/value

This study fills the gap by tracking the role of the journey within marketing collaborations on KIIMA, and it intervenes in the debate about interactive marketing innovation mechanisms. The study contributes to OI, knowledge management and the marketing literature by identifying the heterogeneous modes for marketing collaborations under which the marketing journey enhances knowledge-intensive activities such as those for marketing innovation.
Placebo outsourcing: when does provider’s bluffing enhance customer satisfaction?
Authors: Florea Dorian Laurentiu , Barbu Cătălin Mihail , Rotea Claudia Cristina
Published: October 2021

Purpose

Drawing on signaling theory, this paper aims to argue in favor of a “placebo outsourcing effect” (POE) consisting of a positive relationship between provider’s bluffing and customer satisfaction.

Design/methodology/approach

The authors applied prediction-oriented segmentation SEM on a dyadic sample of 171 outsourcing relationships.

Findings

The authors highlighted two segments that display a form of POE, representing about three-quarters of the customer-provider dyads. The first segment exhibits a positive relationship between the provider’s bluffing and customer satisfaction that is further strengthened by the provider’s reputation and customer’s operational capabilities, while for the other segment, the provider’s bluffing has positive interactions with both operational capabilities and outsourcing experience. These findings show that service providers have reached the bluffing proficiency that enables them to bluff customer firms with varying levels of operational capabilities and outsourcing experience by using the most appealing signals for every type of customer.

Practical implications

Based on the findings, the authors provided to customer firms extensive guidelines to avoid the POE by frustrating service provider’s bluffing proficiency.

Originality/value

This study’s originality resides in the amendment of the disconfirmation paradigm of satisfaction in the outsourcing context by introducing and testing the POE.