bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Learning-Based Unlearning of Dataset Bias for MRI Harmonisation and Confound Removal
Authors: Dinsdale Nicola K. , Jenkinson Mark , Namburete Ana I. L.
Published: October 2020

Increasingly large MRI neuroimaging datasets are becoming available, including many highly multi-site multi-scanner datasets. Combining the data from the different scanners is vital for increased statistical power; however, this leads to an increase in variance due to nonbiological factors such as the differences in acquisition protocols and hardware, which can mask signals of interest.

We propose a deep learning based training scheme, inspired by domain adaptation techniques, which uses an iterative update approach to aim to create scanner-invariant features while simultaneously maintaining performance on the main task of interest, thus reducing the influence of scanner on network predictions. We demonstrate the framework for regression, classification and segmentation tasks with two different network architectures.

We show that not only can the framework harmonise many-site datasets but it can also adapt to many data scenarios, including biased datasets and limited training labels. Finally, we show that the framework can be extended for the removal of other known confounds in addition to scanner. The overall framework is therefore flexible and should be applicable to a wide range of neuroimaging studies.

1.

Highlights

We demonstrate a flexible deep-learning-based harmonisation framework

Applied to age prediction and segmentation tasks in a range of datasets

Scanner information is removed, maintaining performance and improving generalisability

The framework can be used with any feedforward network architecture

It successfully removes additional confounds and works with varied distributions
C/EBPβ-LIP dually activates glycolysis and the malate aspartate shuttle to maintain NADH/NAD+ homeostasis
Authors: Ackermann Tobias , Zuidhof Hidde R. , Kortman Gertrud , Rutten Martijn G. S. , Broekhuis Mathilde , Zaini Mohamad Amr , Hartleben Götz , Calkhoven Cornelis F.
Published: October 2020

Oncogene-induced metabolic reprograming supports cell growth and proliferation. Yet, it also links cancer cell survival to certain metabolic pathways and nutrients. In order to synthesise amino acids and nucleotidesde novofor growth and proliferation, cancer cells depend on glycolysis, the cytoplasmic oxidation of glucose, which generates necessary metabolic intermediates and ATP. During glycolysis, NAD+ is used as the oxidizing agent and is thereby reduced into NADH. To ensure high glycolysis rates and maintain NADH/NAD+ homeostasis, cytoplasmic NAD+ has to be regenerated. The mitochondria are the major sites of NADH reoxidation into NAD+ where NADH-derived electrons enter the electron transport chain for ATP production. Since NADH/NAD+ cannot cross membranes, the malate-aspartate shuttle (MAS) or the glycerol-3-phosphate shuttle (GPS) are used as intermediate electron carriers. In addition, cytoplasmic NAD+ is generated by NADH-electron transfer to pyruvate, reducing it to lactate (the Warburg effect). NADH/NAD+ homeostasis plays a pivotal role in cancer cell survival, but our knowledge about the involved regulatory mechanisms is still limited. Here, we show that the proto-oncogenic transcription factor C/EBPβ-LIP stimulates both glycolysis and the MAS. Inhibition of glycolysis with ongoing C/EBPβ-LIP-induced MAS activity results in NADH depletion and apoptosis that can be rescued by inhibiting either the MAS or other NADH-consuming processes. Therefore, beyond the discovery of C/EBPβ-LIP as a dual activator of glycolysis and the MAS, this study indicates that simultaneous inhibition of glycolysis and lowering of the NADH/NAD+ ratio may be considered to treat cancer.
Unrestrained Gαi2Signaling Disrupts Normal Neutrophil Trafficking, Aging, and Clearance
Authors: Yan Serena Li-Sue , Hwang Il-Young , Kamenyeva Olena , Kabat Juraj , Kim Ji Sung , Park Chung , Kehrl John H.
Published: October 2020

Neutrophil trafficking, homeostatic and pathogen elicited, depends upon chemoattractant receptor triggered heterotrimeric G-protein Gαiβγ signaling, whose magnitude and kinetics are governed by RGS protein/Gαiinteractions. Yet how in totality RGS proteins shape neutrophil chemoattractant receptor activated responses remains unclear. Here, we show that C57Bl/6 neutrophils with genomic knock-in of a mutation that disables all RGS protein-Gαi2interactions (G184S) cannot properly balance chemoattractant receptor signaling, nor appropriately respond to inflammatory insults. Mutant neutrophils accumulate in bone marrow, spleen, lung, and liver; despite neutropenia and an intrinsic inability to properly mobilize from bone marrow.In vitrothey rapidly adhere to ICAM-1 coated plates, but poorly adhere to blood vessel endotheliumsin vivo. Those few neutrophils that cross endotheliums migrate haphazardly. Following Concanavalin-A administration fragmented G184S neutrophils accumulate in liver sinusoids leading to thrombo-inflammation and perivasculitis. Thus, neutrophil Gαi2/RGS protein interactions limit and facilitate Gαi2signaling allowing normal neutrophil trafficking, aging, and clearance.
Efficient mixed model approach for large-scale genome-wide association studies of ordinal categorical phenotypes
Authors: Bi Wenjian , Zhou Wei , Dey Rounak , Mukherjee Bhramar , Sampson Joshua N , Lee Seunggeun
Published: October 2020

In genome-wide association studies (GWAS), ordinal categorical phenotypes are widely used to measure human behaviors, satisfaction, and preferences. However, due to the lack of analysis tools, methods designed for binary and quantitative traits have often been used inappropriately to analyze categorical phenotypes, which produces inflated type I error rates or is less powerful. To accurately model the dependence of an ordinal categorical phenotype on covariates, we propose an efficient mixed model association test, Proportional Odds Logistic Mixed Model (POLMM). POLMM is demonstrated to be computationally efficient to analyze large datasets with hundreds of thousands of genetic related samples, can control type I error rates at a stringent significance level regardless of the phenotypic distribution, and is more powerful than other alternative methods. We applied POLMM to 258 ordinal categorical phenotypes on array-genotypes and imputed samples from 408,961 individuals in UK Biobank. In total, we identified 5,885 genome-wide significant variants, of which 424 variants (7.2%) are rare variants with MAF < 0.01.
Coming together – symbiont acquisition and early development ofBathymodiolusmussels
Authors: Franke Maximilian , Geier Benedikt , Hammel Jörg U. , Dubilier Nicole , Leisch Nikolaus
Published: October 2020

Symbiotic associations between animals and microorganisms are widespread and have a profound impact on the ecology, behaviour, physiology, and evolution of the host. Research on deep-sea mussels of the genusBathymodiolushas revealed how chemosynthetic symbionts sustain their host with energy, allowing them to survive in the nutrient-poor environment of the deep ocean. However, to date, we know little about the initial symbiont colonization and how this is integrated into the early development of these mussels. Here we analysed the early developmental life stages ofB. azoricus, “B”. childressiandB. puteoserpentisand the changes that occur once the mussels are colonized by symbionts. We combined synchrotron-radiation based µCT, correlative light and electron microscopy and fluorescence in situ hybridization to show that the symbiont colonization started when the animal settled on the sea floor and began its metamorphosis into an adult animal. Furthermore, we observed aposymbiotic life stages with a fully developed digestive system which was streamlined after symbiont acquisition. This suggests that bathymodiolin mussels change their nutritional strategy from initial filter-feeding to relying on the energy provided by their symbionts. After ∼35 years of research on bathymodiolin mussels, we are beginning to answer fundamental ecological questions concerning their life cycle and the establishment of symbiosis.
Major role of IgM in the neutralizing activity of convalescent plasma against SARS-CoV-2
Authors: Gasser Romain , Cloutier Marc , Prévost Jérémie , Fink Corby , Ducas Éric , Ding Shilei , Dussault Nathalie , Landry Patricia , Tremblay Tony , Laforce-Lavoie Audrey , Lewin Antoine , Beaudoin-Bussières Guillaume , Laumaea Annemarie , Medjahed Halima , Larochelle Catherine , Richard Jonathan , Dekaban Gregory A. , Dikeakos Jimmy D. , Bazin Renée , Finzi Andrés
Published: October 2020

Characterization of the humoral response to SARS-CoV-2, the etiological agent of Covid-19, is essential to help control the infection. In this regard, we and others recently reported that the neutralization activity of plasma from COVID-19 patients decreases rapidly during the first weeks after recovery. However, the specific role of each immunoglobulin isotype in the overall neutralizing capacity is still not well understood. In this study, we selected plasma from a cohort of Covid-19 convalescent patients and selectively depleted immunoglobulin A, M or G before testing the remaining neutralizing capacity of the depleted plasma. We found that depletion of immunoglobulin M was associated with the most substantial loss of virus neutralization, followed by immunoglobulin G. This observation may help design efficient antibody-based COVID-19 therapies and may also explain the increased susceptibility to SARS-CoV-2 of autoimmune patients receiving therapies that impair the production of IgM.
Smaller Hippocampal Volume among Black and Latinx Youth Living in High-Stigma Contexts
Authors: Hatzenbuehler Mark L , Weissman David G , McKetta Sarah , Lattanner Micah R , Ford Jessie V , Barch Deanna M , McLaughlin Katie A
Published: October 2020

Background

To determine whether being raised in a stigmatizing context influences neurodevelopment in children.

Methods

We drew data from one of the first national, multi-site neuroimaging studies with substantial variability in sociopolitical contexts: the Adolescent Brain and Cognitive Development study (N=11,534;M=9.9 years). We measured structural stigma surrounding gender, race, and Latinx ethnicity using objective state-level indicators of social policies and prejudicial attitudes and individual-level experiences of perceived discrimination, and examined associations with two neural markers: hippocampal volume and amygdala reactivity to threat.

Results

In a pre-registered analysis, we find that Black (B=−57.27,p=0.025) and Latinx (B=−41.02,p=0.037) youths raised in higher-stigma environments have smaller hippocampal volume than youths raised in low-stigma contexts, controlling for demographics and family socioeconomic status. This association was marginal among girls (p=0.082). The magnitude of the observed difference in hippocampal volume between high and low structural stigma contexts was equivalent to a $20,000 difference in annual family income. Stigmatizing environments were unrelated to hippocampal volume in non-stigmatized youth, providing evidence of specificity. Perceived discrimination was unrelated to hippocampal volume among any of the stigmatized groups. No associations between individual or structural forms of stigma and amygdala reactivity to threat were observed in the stigmatized groups.

Conclusions

We provide novel evidence that an objective measure of stigma at the contextual level (structural stigma) may have a stronger influence on neurodevelopment than subjective perceptions of stigma measured at the individual level, suggesting that contextual approaches may yield new insights into neurodevelopment.
Identification of signaling pathways, matrix-digestion enzymes, and motility components controllingVibrio choleraebiofilm dispersal
Authors: Bridges Andrew A. , Fei Chenyi , Bassler Bonnie L.
Published: October 2020

Bacteria alternate between being free-swimming and existing as members of sessile multicellular communities called biofilms. The biofilm lifecycle occurs in three stages: cell attachment, biofilm maturation, and biofilm dispersal.Vibrio choleraebiofilms are hyper-infectious and biofilm formation and dispersal are considered central to disease transmission. While biofilm formation is well-studied, almost nothing is known about biofilm dispersal. Here, we conduct an imaging screen forV. choleraemutants that fail to disperse, revealing three classes of dispersal components: signal transduction proteins, matrix-degradation enzymes, and motility factors. Signaling proteins dominated the screen and among them, we focused on an uncharacterized two-component sensory system that we name DbfS/DbfR for Dispersal of Biofilm Sensor/Regulator. Phospho-DbfR represses biofilm dispersal. DbfS dephosphorylates and thereby inactivates DbfR, which permits dispersal. Matrix degradation requires two enzymes: LapG, which cleaves adhesins, and RbmB, which digests matrix polysaccharide. Reorientations in swimming direction, mediated by CheY3, are necessary for cells to escape from the porous biofilm matrix. We suggest that these components act sequentially: signaling launches dispersal by terminating matrix production and triggering matrix digestion and, subsequently, cell motility permits escape from biofilms. This study lays the groundwork for interventions that modulateV. choleraebiofilm dispersal to ameliorate disease.

Significance statement

The pathogenVibrio choleraealternates between the free-swimming state and existing in sessile multicellular communities known as biofilms. Transitioning between these lifestyles is key for disease transmission.V. choleraebiofilm formation is well studied, however, almost nothing is known about howV. choleraecells disperse from biofilms, precluding understanding of a central pathogenicity step. Here, we conducted a high-content imaging screen forV. choleraemutants that failed to disperse. Our screen revealed three classes of components required for dispersal: signal transduction, matrix degradation, and motility factors. We characterized these components to reveal the sequence of molecular events that choreographV. choleraebiofilm dispersal. Our report provides a framework for developing strategies to modulate biofilm dispersal to prevent or treat disease.
Autophagy is required for midbrain dopaminergic axon development and their responsiveness to guidance cues
Authors: Profes M.S. , Saghatelyan A. , Lévesque M.
Published: October 2020

Mesodiencephalic dopamine (mDA) neurons play a wide range of brain functions. Distinct subtypes of mDA neurons regulate these functions but the molecular mechanisms that drive the mDA circuit formation are largely unknown. Here we show that autophagy, the main recycling cellular pathway, is present in the growth cones of developing mDA neurons and its level changes dynamically in response to guidance cues. To characterize the role of autophagy in mDA axon growth/guidance, we knocked-out (KO) essential autophagy genes (Atg12, Atg5)in mice mDA neurons. Autophagy deficient mDA axons exhibit axonal swellings and decreased branching bothin vitroandin vivo, likely due to aberrant microtubule looping. Strikingly, deletion of autophagy-related genes, blunted completely the response of mDA neurons to chemo-repulsive and chemo-attractive guidance cues. Our data demonstrate that autophagy plays a central role in regulating mDA neurons development, orchestrating axonal growth and guidance.
mTORC2 combats cellular stress and potentiates immunity during viral infection
Authors: Suryawanshi Rahul K , Patil Chandrashekhar D. , Agelidis Alex , Koganti Raghuram , Ames Joshua M. , Koujah Lulia , Yadavalli Tejabhiram , Madavarju Krishnaraju , Shantz Lisa M. , Shukla Deepak
Published: October 2020

Herpes simplex virus type 1 (HSV-1) causes ocular and orofacial infections, which are generally well controlled by the host and nonlethal. In rare cases, HSV-1 causes encephalitis, which leads to permanent brain injuries, memory loss or even death. Host factors protect the organism from viral infections by activating the immune response. However, the factors that confer neuroprotection during viral encephalitis are unknown. Here we show that mammalian target of rapamycin complex 2 (mTORC2) is essential for the host survival of ocular HSV-1 infectionsin vivo. We found that the loss of mTORC2 causes systemic HSV-1 infection not only because of weak innate and adaptive immune responses but also due to increased ocular and neuronal cell death, which becomes lethal over time. Furthermore, we found that mTORC2 mediates cell survival channels through the inactivation of the proapoptotic factor FoxO3a. Our results demonstrate how mTORC2 potentiates host defenses against viral infections as well as implicating mTORC2 as a necessary host factor for survival. We anticipate our findings may help develop new therapeutic window for severe HSV-1 infections, such as herpes simplex encephalitis.
Technical Note: Quantifying music-dance synchrony with the application of a deep learning-based 2D pose estimator
Authors: Potempski Filip , Sabo Andrea , Patterson Kara K
Published: October 2020

Dance interventions are more effective at improving gait and balance outcomes than other rehabilitation interventions. Repeated training may culminate in superior motor performance compared to other interventions without synchronization. This technical note will describe a novel method using a deep learning-based 2D pose estimator: OpenPose, alongside beat analysis of music to quantify movement-music synchrony during salsa dancing. This method has four components: i) camera setup and recording, ii) tempo/downbeat analysis and waveform cleanup, iii) OpenPose estimation and data extraction, and iv) synchronization analysis. Two trials were recorded: one in which the dancer danced synchronously to the music and one where they did not. The salsa dancer performed a solo basic salsa step continuously for 90 seconds to a salsa track while their movements and the music were recorded with a webcam. This data was then extracted from OpenPose and analyzed. The mean synchronization value for both feet was significantly lower in the synchronous condition than the asynchronous condition, indicating that this is an effective means to track and quantify a dancer’s movement and synchrony while performing a basic salsa step.
Efficient Similarity-Preserving Unsupervised Learning using Modular Sparse Distributed Codes and Novelty-Contingent Noise
Authors: Rinkus Rod
Published: October 2020

There is increasing realization in neuroscience that information is represented in the brain, e.g., neocortex, hippocampus, in the form sparse distributed codes (SDCs), a kind of cell assembly. Two essential questions are: a) how are such codes formed on the basis of single trials, and how is similarity preserved during learning, i.e., how do more similar inputs get mapped to more similar SDCs. I describe a novel Modular Sparse Distributed Code (MSDC) that provides simple, neurally plausible answers to both questions. An MSDC coding field (CF) consists ofQWTA competitive modules (CMs), each comprised ofKbinary units (analogs of principal cells). The modular nature of the CF makes possible a single-trial, unsupervised learning algorithm that approximately preserves similarity and crucially, runs in fixed time, i.e., the number of steps needed to store an item remains constant as the number of stored items grows. Further, once items are stored as MSDCs in superposition and such that their intersection structure reflects input similarity, both fixed time best-match retrieval and fixed time belief update (updating the probabilities of all stored items) also become possible. The algorithm’s core principle is simply to add noise into the process of choosing a code, i.e., choosing a winner in each CM, which is proportional to the novelty of the input. This causes the expected intersection of the code for an input, X, with the code of each previously stored input, Y, to be proportional to the similarity of X and Y. Results demonstrating these capabilities for spatial patterns are given in the appendix.
Integration of prophages into CRISPR loci remodels viral immunity inStreptococcus pyogenes
Authors: Varble Andrew , Campisi Edmondo , Euler Chad W. , Fyodorova Jessica , Rostøl Jakob T , Fischetti Vincent A. , Marraffini Luciano A.
Published: October 2020

CRISPR loci are composed of short DNA repeats separated by sequences that match the genomes of phages and plasmids, known as spacers. Spacers are transcribed and processed to generate RNA guides used by CRISPR-associated nucleases to recognize and destroy the complementary nucleic acids of invaders. To counteract this defense, phages can produce small proteins that inhibit these nucleases. Here we demonstrate that the ΦAP1.1 temperate phage utilizes an alternate approach to antagonize the type II-A CRISPR response inStreptococcus pyogenes. Immediately after infection this phage expresses a canonical anti-CRISPR, AcrIIA23 that prevents Cas9 function, allowing ΦAP1.1 to integrate into the direct repeats of the CRISPR locus and neutralizing immunity. However,acrIIA23is not transcribed during lysogeny and phage integration/excision cycles can result in the deletion and/or transfer of spacers, enabling a complex modulation of the type II-A CRISPR immune response.
Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation
Authors: Nichols Eva K. , Chuang Hsiu-Chun , Davis Matthew T. , Geiger Kristina M. , Li Rick Z. , Arnold Madeline L. , Lin Patrick M. , Misra Rhea , Coscoy Laurent , Saijo Kaoru
Published: October 2020

Maternal immune activation (MIA) increases likelihood of altered neurodevelopmental outcomes. Maternal cytokines are proposed to affect fetal brain development in mice; however, the contribution of fetal immunity to neurodevelopmental disorders is largely unexplored. Here, we show that MIA mediated by Toll-like receptor 3 (TLR3), but not other TLRs, induces a specific set of behavioral phenotypes including decreased sociability and increased restricted repetitive behavior in offspring. Accordingly, these behavioral phenotypes were absent when offspring were deficient forTrif, the downstream adapter molecule of TLR3. Using single-cell RNA sequencing, we identified clusters of border-associated macrophages that were significantly enriched in the fetal brain following TLR3-MIA, and these clusters were diminished inTrif−/−fetal brains.Moreover, we found that triggering TLR3-TRIF in offspring can occur through transplacental viral infection, resulting in altered behavioral phenotypes. Collectively, our data indicate that fetal innate immunity contributes to MIA-induced atypical behaviors in mice.
The transcription factor CLAMP is required for neurogenesis inDrosophila melanogaster
Authors: Tsiarli Maria A. , Conard Ashley M. , Xu Lucy , Nguyen Erica , Larschan Erica N.
Published: October 2020

Neural stem cell (NSC) differentiation is controlled by cell-intrinsic and external signals from the stem cell niche including niche surface glia (SG). However, the mechanisms by which transcription factors drive NSC differentiation within the niche remain largely unknown. Here, we show that the transcription factor, Chromatin-linked adaptor for MSL proteins (CLAMP) is required for NSC differentiation. CLAMP promotes transcription of genes involved in stemness, proliferation, and glial development and represses transcription of genes involved in neurogenesis and niche survival. Consistent with transcriptional changes, CLAMP promotes NSC proliferation and SG production. Furthermore, glial-specific knock-down ofclampcauses similar phenotypes toclampnull mutants. CLAMP motifs are present at many target genes including the glial-determining gene,glial cells missing, andNotch, a key regulator of neurogenesis. Collectively, our results suggest that CLAMP regulates a transcriptional program which drives NSC proliferation and differentiationviacell-intrinsic and niche-dependent mechanisms that involve niche glia.
Canonical babbling during vocal turn taking and independent vocal play
Authors: Long Helen L. , Ramsay Gordon , Bowman Dale D. , Burkhardt-Reed Megan M. , Oller D. Kimbrough
Published: October 2020

There is a growing body of research emphasizing the role of social and endogenous motivations in human development. The present study evaluated canonical babbling across the second-half year of life using all-day recordings of 98 infants participating in a longitudinal study. Canonical babbling ratios were calculated from human coding along with Likert-scale ratings on vocal turn taking and vocal play in each segment. Ratios across all infants were significantly elevated during high turn taking and also during high vocal play. We conclude that both social and endogenous motivations may drive infants’ tendencies to produce their most advanced vocal forms.
HextractoR: an R package for automatic extraction of hairpins from genome-wide data
Authors: Yones Cristian , Macchiaroli Natalia , Kamenetzky Laura , Stegmayer Georgina , Milone Diego
Published: October 2020

Extracting stem-loop sequences (hairpins) from genome-wide data is very important nowadays for some data mining tasks in bioinformatics. The genome preprocessing is very important because it has a strong influence on the later steps and the final results. For example, for novel miRNA prediction, all well-known hairpins must be properly located. Although there are some scripts that can be adapted and put together to achieve this task, they are outdated, none of them guarantees finding correspondence to well-known structures in the genome under analysis, and they do not take advantage of the latest advances in secondary structure prediction. We present here an R package for automatic extraction of hairpins from genome-wide data (HextractorR). HextractoR makes an exhaustive and smart analysis of the genome in order to obtain a very good set of short sequences for further processing. Moreover, genomes can be processed in parallel and with low memory requirements. Results obtained showed that HextractoR has effectively outperformed other methods.

HextractoR it is freely available atCRANandSourceforge.
Inferring Thalamocortical Monosynaptic Connectivity In-Vivo
Authors: Liew Yi Juin , Pala Aurélie , Whitmire Clarissa J , Stoy William A , Forest Craig R , Stanley Garrett B
Published: October 2020

Abstract/Summary

As the tools to simultaneously record electrophysiological signals from large numbers of neurons within and across brain regions become increasingly available, this opens up for the first time the possibility of establishing the details of causal relationships between monosynaptically connected neurons and the patterns of neural activation that underlie perception and behavior. Although recorded activity across synaptically connected neurons has served as the cornerstone for much of what we know about synaptic transmission and plasticity, this has largely been relegated toex-vivopreparations that enable precise targeting under relatively well-controlled conditions. Analogous studiesin-vivo, where image-guided targeting is often not yet possible, rely on indirect, data-driven measures, and as a result such studies have been sparse and the dependence upon important experimental parameters has not been well studied. Here, using in-vivo extracellular single unit recordings in the topographically aligned rodent thalamocortical pathway, we sought to establish a general experimental and computational framework for inferring synaptic connectivity. Specifically, attacking this problem within a statistical signal-detection framework utilizing experimentally recorded data in the ventral-posterior medial (VPm) region of the thalamus and the homologous region in layer 4 of primary somatosensory cortex (S1) revealed a trade-off between network activity levels needed for the data-driven inference and synchronization of nearby neurons within the population that result in masking of synaptic relationships. Taken together, we provide a framework for establishing connectivity in multi-site, multi-electrode recordings based on statistical inference, setting the stage for large-scale assessment of synaptic connectivity within and across brain structures.

New & Noteworthy

Despite the fact that all brain function relies on the long-range transfer of information across different regions, the tools enabling us to measure connectivity across brain structures are lacking. Here, we provide a statistical framework for identifying and assessing potential monosynaptic connectivity across neuronal circuits from population spiking activity that generalizes to large-scale recording technologies that will help us to better understand the signaling within networks that underlies perception and behavior.
Precision Cas9 Genome Editingin vivowith All-in-one, Self-targeting AAV Vectors
Authors: Ibraheim Raed , Tai Phillip W. L. , Mir Aamir , Javeed Nida , Wang Jiaming , Rodríguez Tomás , Nelson Samantha , Khokhar Eraj , Mintzer Esther , Maitland Stacy , Cao Yueying , Tsagkaraki Emmanouela , Wolfe Scot A. , Wang Dan , Pai Athma A. , Xue Wen , Gao Guangping , Sontheimer Erik J.
Published: October 2020

Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutationsin vivorequire homology-directed repair (HDR) templates. Here, we describe single-vector, ∼4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an HDR template. We also examine the utility of Nme2Cas9 target sites in the vector for self-inactivation. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice. These results will enable single-vector AAVs to achieve diverse therapeutic genome editing outcomes.
O-GlcNAc modification of nuclear pore complexes accelerates bi-directional transport
Authors: Yoo Tae Yeon , Mitchison Timothy J
Published: October 2020

Macromolecular transport across the nuclear envelope depends on facilitated diffusion through nuclear pore complexes (NPCs). The interior of NPCs contains a permeability barrier made of phenylalanine-glycine (FG) repeat domains that selectively facilitates the permeation of cargoes bound to nuclear transport receptors (NTRs). FG repeats in NPC are a major site of O-linked N-acetylglucosamine (O-GlcNAc) modification, but the functional role of this modification in nucleocytoplasmic transport is unclear. We developed high-throughput assays based on optogenetic probes to quantify the kinetics of nuclear import and export in living human cells. We found that increasing O-GlcNAc modification of the NPC accelerated NTR-facilitated nucleocytoplasmic transport of proteins in both directions, and decreasing modification slowed transport. Super-resolution imaging revealed strong enrichment of O-GlcNAc at the FG-repeat barrier. O-GlcNAc modification also accelerated passive permeation of a small, inert protein through NPCs. We conclude that O-GlcNAc modification accelerates nucleocytoplasmic transport by enhancing the non-specific permeability the FG-repeat barrier, perhaps by steric inhibition of interactions between FG repeats.

Nuclear pore complexes mediate nuclear transport and are highly modified with O-linked N-acetylglucosamine (O-GlcNAc) on FG repeat domains. Using a new quantitative live-cell imaging assay, Yoo and Mitchison demonstrate acceleration of nuclear import and export by O-GlcNAc modification.
Bio-Orthogonal Chemistry Enables Solid Phase Synthesis of Long RNA Oligonucleotides
Authors: He Muhan , Wu Xunshen , Haruehanroengra Phensinee , Khan Irfan , Sheng Jia , Royzen Maksim
Published: October 2020

Solid phase synthesis of RNA oligonucleotides which are over 100-nt in length remains to be challenging due to the complexity of purification of the target strands from the failure sequences. This work describes a non-chromatographic strategy that will enable routine solid phase synthesis of long RNA strands. The optimized five-step process is based on bio-orthogonal inverse electron demand Diels-Alder chemistry betweentrans-cyclooctene (TCO) and tetrazine (Tz) and entails solid phase synthesis of RNA on a photo-labile support. The target oligonucleotide strands are selectively tagged with Tz. After photocleavage from the solid support, the target oligonucleotide strands can be captured and purified from the failure sequences using immobilized TCO. The approach was optimized using a model 20-mer DNA strand and was successfully applied towards synthesis of 76-nt long tRNA and 101-nt long sgRNA. Purity of the isolated oligonucleotides was evaluated using gel electrophoresis and mass spectrometry, while functional fidelity of the sgRNA was confirmed using CRISPR-Cas9 experiments and flow cytometry.
CoRa –A general approach for quantifying biological feedback control
Authors: Gómez-Schiavon Mariana , El-Samad Hana
Published: October 2020

Feedback control is a fundamental underpinning of life, underlying homeostasis of biological processes at every scale of organization, from cells to ecosystems. The ability to evaluate the contribution and limitations of feedback control mechanisms operating in cells is a critical step for understanding and ultimately designing feedback control systems with biological molecules. Here, we introduceCoRa–orControlRatio–, a general framework that quantifies the contribution of a biological feedback control mechanism to adaptation using a mathematically controlled comparison to an identical system that does not contain the feedback.CoRaprovides a simple and intuitive metric with broad applicability to biological feedback systems.
TMEM41B is a pan-flavivirus host factor
Authors: Hoffmann H.-Heinrich , Schneider William M , Rozen-Gagnon Kathryn , Miles Linde A , Schuster Felix , Razooky Brandon , Jacobson Eliana , Wu Xianfang , Yi Soon , Rudin Charles M , MacDonald Margaret R , McMullan Laura K , Poirier John T , Rice Charles M
Published: October 2020

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of theFlaviviridaefamily that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of theCoronaviridaealso required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.

HIGHLIGHTS

TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.

TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.

TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.

TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.
225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models
Authors: Garg Ravendra , Allen Kevin J.H. , Dawicki Wojciech , Geoghegan Eileen M. , Ludwig Dale L. , Dadachova Ekaterina
Published: October 2020

Purpose

Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy.225Actinium-lintuzumab (225Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer.

Experimental design

Here we investigated the potential for225Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML.

Results

We demonstrated that225Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models.

Conclusions

There results suggest that the combination of225Ac-lintuzumab with venetoclax may be a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML.
How transformational leadership facilitates radical and incremental innovation: the mediating role of individual psychological capital
Authors: Le Phong Ba
Published: October 2020

Purpose

Given the important role of innovation capability in helping firms to innovate and adapt to a fast-paced and unpredictable environment, the purpose of this study is to investigate and deepen knowledge of how transformational leadership affects radical and incremental innovation via the mediating role of positive psychological capital.

Design/methodology/approach

The paper used structural equation modeling and cross-sectional design to test proposal hypotheses based on the empirical data collected from 379 participants in 89 manufacturing and service firms.

Findings

The results of this study revealed the positive and significant influence of transformational leadership on radical and incremental innovation. The findings highlighted the mediating role of individual psychological capital in the relationship between transformational leadership and aspects of innovation capability.

Practical implications

Organizations should invest and stress on practicing transformational leadership style for their managers/directors to foster and enhance individual psychological capital and innovation capabilities.

Originality/value

The paper has extended theory of innovation management by discussing and highlighting the important role of transformational leadership and psychological capital in fostering specific aspects of innovation namely radical and incremental innovation.
Trust, knowledge sharing, and innovative work behavior: empirical evidence from Poland
Authors: Kmieciak Roman
Published: October 2020

Purpose

The purpose of this paper is to assess the effects of two types of trust (vertical and horizontal trust) on knowledge sharing (knowledge donating and knowledge collecting) and the impact of knowledge sharing on innovative work behavior (idea generation and idea realization). The study also explores the mediating role of knowledge sharing.

Design/methodology/approach

Partial least squares path modeling and data collected from 252 participants at one large Polish capital group were used to test the research hypotheses.

Findings

The results showed that both vertical trust and horizontal trust are positively related to knowledge donating and knowledge collecting. Contrary to knowledge collecting, knowledge donating is significantly related to idea generation, which is highly correlated with idea realization. There is no direct relation between knowledge sharing behavior and idea realization. Knowledge donating mediates the relationship between vertical trust and idea generation.

Research limitations/implications

Self-reports and the cross-sectional nature of the data collection are the main limitations of this study.

Practical implications

The results allow managers to better understand what factors and processes contribute to greater employee innovativeness.

Originality/value

To the best of the author's knowledge, the study is the first to examine the relationships among vertical trust, horizontal trust, knowledge donating, knowledge collecting, idea generation and idea realization in an integrated way. This paper answered the questions (1) which type of trust is more important for knowledge sharing, and (2) which type of knowledge sharing behavior is more important for innovative work behavior. This paper investigated whether differences in the strength of relationships between constructs are significant.
Numerical investigation of three-dimensional nanofluid flow with heat and mass transfer on a nonlinearly stretching sheet using the barycentric functions
Authors: Torkaman Soraya , Barid Loghmani Ghasem , Heydari Mohammad , Wazwaz Abdul-Majid
Published: October 2020

Purpose

The purpose of this paper is to investigate a three-dimensional boundary layer flow with considering heat and mass transfer on a nonlinearly stretching sheet by using a novel operational-matrix-based method.

Design/methodology/approach

The partial differential equations that governing the problem are converted into the system of nonlinear ordinary differential equations (ODEs) with considering suitable similarity transformations. A direct numerical method based on the operational matrices of integration and product for the linear barycentric rational basic functions is used to solve the nonlinear system of ODEs.

Findings

Graphical and tabular results are provided to illustrate the effect of various parameters involved in the problem on the velocity profiles, temperature distribution, nanoparticle volume fraction, Nusselt and Sherwood number and skin friction coefficient. Comparison between the obtained results, numerical results based on the Maple's dsolve (type = numeric) command and previous existing results affirms the efficiency and accuracy of the proposed method.

Originality/value

The motivation of the present study is to provide an effective computational method based on the operational matrices of the barycentric cardinal functions for solving the problem of three-dimensional nanofluid flow with heat and mass transfer. The convergence analysis of the presented scheme is discussed. The benefit of the proposed method (PM) is that, without using any collocation points, the governing equations are converted to the system of algebraic equations.
Impact of human capital strategies on employee attitudes and behavior: a view of internal and external labor markets
Authors: Liu Min-Shi , Liu Nien-Chi
Published: October 2020

Purpose

According to human capital theory, companies derive economic value from the knowledge, skills and abilities (KSAs) of their employees. Research conducted by strategic human resource management has focused on how investment in human capital can create a competitive advantage for an organization. The purpose of the paper is, therefore, to investigate how the choice of different human capital acquisition strategies – “make or buy” – can influence employee attitudes and behavior.

Design/methodology/approach

This study explores the relationship between internal and external human capital strategies and employee’s attitudes and behavior in Taiwan's IC (integrated circuit) design industry. The cross-sectional dataset derives from a sample of 49 human resource departments and 497 employees from 25 different IC design companies.

Findings

The findings indicate that the decisions made on human capital strategies have an important influence on employee’s attitude and behavior. The results also show that a climate of trust and perceived organizational support is a cross-level mechanism for both human capital strategy and employees' attitudes and behavior.

Originality/value

There has been little research on the cross-level analysis of human capital acquisition strategies that can influence employee’s attitudes and behavior. This study verified that internal and external human capital strategies do affect employees' individual perceptions of organizational support via the organizational-level climate of trust, which in turn influences employees' attitudes and behavior. This cross-level mechanism indeed will facilitate new insights into the nature of strategic human resource management.
Clarifying strategic alignment in the public procurement process
Authors: Plantinga Henrico , Voordijk Hans , Dorée André
Published: October 2020

Purpose

While the need for strategic alignment in public management has been recognized, there is a lack of conceptual clarity to support its application in practice. Focusing on the specific field of public procurement, this paper clarifies and illustrates how the concept of strategic alignment can be applied when strategizing the public procurement process.

Design/methodology/approach

The current literature on strategic alignment in public procurement is critically reviewed to identify ambiguities that hamper its application in practice. Based on this review, an analytical framework is developed that conceptualizes strategic alignment as that between the procurement instruments used in a sourcing project and the corresponding higher-level strategies. The framework is empirically illustrated by applying it in a case study that reconstructs the procurement strategy for an innovation project

Findings

Strategic alignment in the public procurement process can be demonstrated by identifying, explicating and logically linking reasoning and trade-off decisions on competing priorities across multiple levels and dimensions of strategy

Originality/value

Although creating alignment between policy and public procurement practice is generally held to be important in the public management literature, it is only discussed on high levels of abstraction. This paper provides clarity by investigating alignment in greater detail.
Impact of occupational migration of unskilled labourer from domestic agriculture on farm business income in source households of Assam, India
Authors: Islam Bodrul , Guha Pradyut
Published: October 2020

Purpose

The present study aims at examining the determinants of occupational migration of unskilled labourer from domestic agriculture and their impact on farm business income (FBI) in Assam, India.

Design/methodology/approach

Primary data for this study were collected during June–November, 2019 from 224 farm (cultivator) households in two contiguous districts in central Brahmaputra valley of Assam. The study used three-stage least square (3SLS) estimation technique for jointly determining the factors influencing migration and remittances and their impact on FBI.

Findings

The result of this study confirms that occupational migration of unskilled labourer from domestic agriculture significantly reduced household FBI. In contrast to the inflow of remittances from migrants helped in increasing the FBI. The migration in the study area considerably influenced by household size, total value of assets holding, networking influence, distance to commercial bank and flood proneness of the village; while the number of migrants, number of dependents and age of migrants seen to be strong predictor of inflow of remittances. Findings of present study offer evidence in support of the new economics of labour migration (NELM) theory.

Research limitations/implications

The study is restricted to a single crop (paddy) and constrained by the collection of longitudinal data with a revisit to the farm household pre and post-migration of the unskilled labourer from household agriculture.

Originality/value

This paper is based on a novel data set that has especially been collected to examine the determinants of occupational migration from agriculture and their impact on the FBI in Assam that has not been studied before.