bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-varying Dynamic Network Model For Dynamic Resting State Functional Connectivity in fMRI and MEG imaging
Authors: Jiang Fei , Jin Huaqing , Gao Yijing , Xie Xihe , Cummings Jennifer , Raj Ashish , Nagarajan Srikantan
Published: April 2021

Dynamic resting state functional connectivity (RSFC) characterizes fluctuations that occurs over time in functional brain networks. Existing methods to extract dynamic RSFCs, such as sliding-window and clustering methods, have various limitations due to their inherent non-adaptive nature and high-dimensionality including an inability to reconstruct brain signals, insufficiency of data for reliable estimation, insensitivity to rapid changes in dynamics, and a lack of generalizability across multimodal functional imaging datasets. To overcome these deficiencies, we develop a novel and unifying time-varying dynamic network (TVDN) framework for examining dynamic resting state functional connectivity. TVDN includes a generative model that describes the relation between low-dimensional dynamic RSFC and the brain signals, and an inference algorithm that automatically and adaptively learns to detect dynamic state transitions in data and a low-dimensional manifold of dynamic RSFC. TVDN is generalizable to handle multimodal functional neuroimaging data (fMRI and MEG/EEG). The resulting estimated low-dimensional dynamic RSFCs manifold directly links to the frequency content of brain signals. Hence we can evaluate TVDN performance by examining whether learnt features can reconstruct observed brain signals. We conduct comprehensive simulations to evaluate TVDN under hypothetical settings. We then demonstrate the application of TVDN with real fMRI and MEG data, and compare the results with existing benchmarks. Results demonstrate that TVDN is able to correctly capture the dynamics of brain activity and more robustly detect brain state switching both in resting state fMRI and MEG data.
Disentangling the roles of inter- and intraspecific variation on leaf trait distributions across the eastern United States
Authors: Marconi Sergio , Weinstein Benjamin G. , Lichstein Jeremy W. , Bohlman Stephanie A. , Singh Aditya , White Ethan P.
Published: April 2021

Functional traits are influenced by phylogenetic constraints and environmental conditions, but previous large-scale studies modeled traits either as species weighted averages or directly from the environment, precluding analyses of the relative contributions of inter- and intraspecific variation across regions. We developed a joint model integrating phylogenetic and environmental information to understand and predict the distribution of eight leaf traits across the eastern USA. This model explained 68% of trait variation, outperforming both species-only and environment-only models, with variance attributable to species alone (23%), the environment alone (13%), and their combined effects (25%). The importance of the two drivers varied by trait. Predictions for the eastern USA produced accurate estimates of intraspecific variation and deviated from both species-only and environment-only models. Predictions revealed that intraspecific variation holds information across scales, affects relationships in the leaf economic spectrum and is key for interpreting trait distributions and ecosystem processes within and across ecoregions.
Durotaxis of passive nanoparticles on elastic membranes
Authors: Palaia Ivan , Paraschiv Alexandru , Debets Vincent , Storm Cornelis , Šarić Anđela
Published: April 2021

The transport of macromolecules and nanoscopic particles to a target cellular site is a crucial aspect in many physiological processes. This directional motion is generally controlled via active mechanical and chemical processes. Here we show, by means of molecular dynamics simulations and an analytical theory, that completely passive nanoparticles can exhibit directional motion when embedded in non-uniform mechanical environments. Specifically, we study the motion of a passive nanoparticle adhering to a mechanically non-uniform elastic membrane. We observe a non-monotonic affinity of the particle to the membrane as a function of the membrane’s rigidity, which results in the particle transport. This transport can be both up or down the rigidity gradient, depending on the absolute values of the rigidities that the gradient spans across. We conclude that rigidity gradients can be used to direct average motion of passive macromolecules and nanoparticles on deformable membranes, resulting in the preferential accumulation of the macromolecules in regions of certain mechanical properties.
Teacher Perceptions of Using Robots to Teach Neuroscience in Secondary School
Authors: de Freitas Claudio C. S. , Hanzlick-Burton Camden , Nestorovic Miroslav , DeBoer Jennifer , Gage Gregory J. , Harris Christopher A.
Published: April 2021

The use of robots to help teachers to engage students in STEM subjects has been increasing in recent years, and much progress has been made in K12 schools to incorporate robots in the pedagogy. Recent studies indicate that robots can play a significant role to engage students in neuroscience subjects, but little is known about teachers’ perceptions of using robots to teach neuroscience. In this paper, we present a study based on a survey questionnaire conducted with 84 teachers across multiple high schools in the United States to understand their perceptions about the usefulness of using robots to teach neuroscience. To situate teachers with an example of how robots can be used in neuroscience classrooms, we describe an educational tool called the SpikerBot. Our preliminary results indicate that there is an opportunity for neuroscience-oriented robots in secondary education, provided sufficient on-boarding and training videos.
A repertoire of foraging decision variables in the mouse brain
Authors: Cazettes Fanny , Mazzucato Luca , Murakami Masayoshi , Morais Joao P. , Renart Alfonso , Mainen Zachary F.
Published: April 2021

In any given situation, the environment can be parsed in different ways to define useful decision variables (DVs) for any task, but the way in which this manifold of potential decision strategies is processed to shape behavioral policies is not known. We recorded neural ensembles in the frontal cortex of mice performing a foraging task admitting multiple DVs. Methods developed to uncover the currently employed DV revealed the use of multiple strategies and latent changes in strategy within sessions. Optogenetic manipulations showed that the secondary motor cortex (M2) is needed for mice to use the different DVs in the task. Surprisingly, we found that, regardless of the DV best explaining the behavior of each mouse, M2 activity reflected a full basis set of computations spanning a repertoire of DVs extending beyond those useful for the present task. This form of multiplexing may confer considerable advantages for learning and adaptive behavior.
Acetylated α-tubulin residue K394 regulates microtubule stability to shape the growth of axon terminals
Authors: Saunders Harriet A. J. , Johnson-Schlitz Dena M. , Jenkins Brian V. , Volkert Peter J. , Yang Sihui Z. , Wildonger Jill
Published: April 2021

Microtubules are essential to neuron shape and function. Therefore, the stability of the microtubule cytoskeleton must be carefully regulated. Acetylation of tubulin has the potential to directly tune microtubule stability, and proteomic studies have identified several acetylation sites in α-tubulin. This includes the highly conserved residue lysine 394 (K394), which is located at the αβ-tubulin dimer interface. Using a fly model, we show that α-tubulin K394 is acetylated in the nervous system and is an essential residue. We found that an acetylation-blocking mutation in endogenous α-tubulin, K394R, perturbs the synaptic morphogenesis of motoneurons by reducing microtubule stability. Intriguingly, the K394R mutation has opposite effects on the growth of two functionally and morphologically distinct motoneurons, revealing neuron-type-specific responses when microtubule stability is altered. Eliminating the deacetylase HDAC6 increases K394 acetylation, and the over-expression of HDAC6 reduces microtubule stability similar to the K394 mutant. Thus, our findings implicate α-tubulin K394 and its acetylation in the regulation of microtubule stability and suggest that HDAC6 regulates K394 acetylation during synaptic morphogenesis.
Regulation of neurogenesis and gliogenesis by the matricellular protein CCN2 in the mouse retina
Authors: Mohiuddin Golam , Lopez Genesis , Sinon Jose , Hartnett M. Elizabeth , Bulakhova Anastasiia , Chaqour Brahim
Published: April 2021

Cellular communication network (CCN) 2 is an extracellular matrix protein with cell type- and context-dependent functions. Using a combination of mouse genetics and omic approaches, we show that CCN2 is expressed in early embryonic retinal progenitor cells (RPCs) and becomes restricted to fully differentiated Müller glial cells (MGCs) thereafter. Germline deletion of CCN2 in mice decreases BrdU labeling, reduces RPC pool, and impairs the competency of remaining RPCs to generate early and late born retinal cell types. Retinal hypocellularity and microphthalmia ensue. The transcriptomic changes associated with CCN2 inactivation include reduced marker and transcriptional regulator genes of retinal ganglion cells, photoreceptors and MGCs. Yap (Yes-associated protein), a singular node for transcriptional regulation of growth and differentiation genes, is also a target of CCN2 signals. In an organotypic model ofex vivocultured embryonic retinas, CCN2 and YAP immunoreactivity signals overlap. Lentivirus-mediated YAP expression in CCN2-deficient retinal explants increases the number of differentiating Sox9-positive MGCs. Taken together, our data indicate that CCN2 controls the proliferative and differentiation potentials of RPCs ultimately endowing, a subpopulation thereof, with Müller glial cell fate.

Summary statement

A CCN2-YAP regulatory axis controls retinal progenitor cell growth and lineage commitment to neuronal and glial cell fates.
Mechanisms that ensure speed and fidelity in eukaryotic translation termination
Authors: Lawson Michael R. , Lessen Laura N. , Wang Jinfan , Prabhakar Arjun , Corsepius Nicholas C. , Green Rachel , Puglisi Joseph D.
Published: April 2021

Translation termination, which liberates a nascent polypeptide from the ribosome specifically at stop codons, must occur accurately and rapidly. We established single-molecule fluorescence assays to track the dynamics of ribosomes and two requisite release factors (eRF1 and eRF3) throughout termination using anin vitro-reconstituted yeast translation system. We found that the two eukaryotic release factors bind together to recognize stop codons rapidly and elicit termination via a tightly regulated, multi-step process that resembles tRNA selection during translation elongation. Because the release factors are conserved from yeast to humans, the molecular events that underlie yeast translation termination are likely broadly fundamental to eukaryotic protein synthesis.

One Sentence Summary

Direct visualization of eukaryotic translation reveals the dynamics of termination at stop codons.
Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations inVRK1
Authors: Bos Rémi , Rihan Khalil , El-Bazzal Lara , Bernard-Marissal Nathalie , Quintana Patrice , Jabbour Rosette , Mégarbané André , Bartoli Marc , Brocard Frédéric , Delague Valérie
Published: April 2021

We recently described new pathogenic variants inVRK1, in patients affected with distal Hereditary Motor Neuropathy associated with upper motor neurons signs. Specifically, we provided evidences that hiPSC-derived Motor Neurons (hiPSC-MN) from these patients display Cajal bodies (CBs) disassembly and defects in neurite outgrowth and branching.

We here focused on the Axonal Initial Segment (AIS) and the related firing properties of hiPSC-MNs from these patients. We found that the patient’s Action Potential (AP) was smaller in amplitude, larger in duration, and displayed a more depolarized threshold while the firing patterns were not altered. These alterations were accompanied by a decrease in the AIS length measured in patients’ hiPSC-MNs. These data indicate that mutations in VRK1 impact the AP waveform and the AIS organization in MNs and may ultimately lead to the related motor neuron disease.

Highlights

hiPSC-MNs are functional and sustain firing patterns, typical of spinal MNs

hiPSC-MNs from patients with VRK1 mutations have altered Action Potential

Axonal Initial Segment is shorter in hiPSC-MNs from patients with mutated VRK1

hiPSC-MNs are a useful platform to study Motor Inherited Peripheral Neuropathies

eTOC Blurb

In human spinal Motor Neurons derived from induced Pluripotent Stem Cells from patients with VRK1 -related distal Hereditary Motor Neuropathy, Bos, Rihan et al. show that the mutations inVRK1affect the electrical properties of these neurons: they display defects in the initiation of the Action Potential due to a shortening of the Axonal Initial Segment.
Chemical Editing of Proteoglycan Architecture
Authors: O’Leary Timothy , Critcher Meg , Stephenson Tesia N. , Yang Xueyi , Bartfield Noah H. , Hawkins Richard , Huang Mia L.
Published: April 2021

Proteoglycans are heterogeneous macromolecular glycoconjugates that orchestrate many important cellular processes. While much attention has focused on the poly-sulfated glycosaminoglycan chains that decorate proteoglycans, other important elements of proteoglycan architecture, such as their core proteins and cell surface localization, have garnered less emphasis. Hence, comprehensive structure-function relationships that consider the replete proteoglycan architecture as glycoconjugates are limited. Here, we present a comprehensive approach to study proteoglycan structure and biology by fabricating defined semi-synthetic modular proteoglycans that can be tailored for cell surface display. To do so, we integrate amber codon reassignment in the expression of sequence-fined proteoglycan core proteins, metabolic oligosaccharide engineering to produce functionalizable glycosaminoglycans, and bioorthogonal click chemistry to covalently tether the two components. These materials permit the methodical dissection of the parameters required for optimal binding and function of various proteoglycan-binding proteins, and they can be modularly displayed on the surface of any living cell. We demonstrate that these sophisticated materials can recapitulate the functions of native proteoglycans in mouse embryonic stem cell differentiation and cancer cell spreading, while permitting the identification of the most important contributing elements of proteoglycan architecture toward function. This technology platform will confer structural resolution toward the investigation of proteoglycan structure-function relationships in cell biology.
METLIN Neutral Loss Database Enhances Similarity Analysis
Authors: Aisporna Aries , Benton H. Paul , Galano Jean Marie , Giera Martin , Siuzdak Gary
Published: April 2021

Tandem mass spectrometry (MS2) data is an effective resource for the identification of known molecules and the putative identification of novel, previously uncharacterized molecules (unknowns). Yet, MS2data alone is limited in characterizing structurally closely related molecules with different masses. Neutral loss data is key in retrieving this structural similarity. To facilitate unknown identification and complement METLIN’s MS2fragment ion data for characterizing structurally related molecules, we have created the METLIN neutral loss database (https://metlin-nl.scripps.edu).
Molecular diagnosis of new isolate of tomato yellow leaf curl virus in Iraq
Authors: Alabde Ali , Alisawi Osamah , Fadhal Fadhal Al
Published: April 2021

Tomato yield and quality in Iraq have been threatened by a variable range of infections caused by tomato yellow leaf curl virus. In previous studies, the TYLCV isolates were partially characterized using molecular tests for small fragments not the entire length of the virus. Sample of TYLCV-infected tomato has applied in this study to diagnose complete sequence of TYLCV isolate. Three sets of primers that belong to three well-identified strains in Iraq were used in a PCR technique and interestingly the results were negative. A new Iraqi isolate has been characterized as a first novel Iraqi isolate detected ever using next generation (NGS) and bioinformatics techniques. The NGS platform has produced about 78,232,062 paired reads of the TYLCV-infected tomato var. Oula F1. The complete raw reads of the infected variety have been analyzed using RepeatExplorer pipeline and Map to reference. The full sequence of TYLCV was reconstructed and extracted to consist of 2770 nt and then deposited in Genbank under accession numberMT583814. Copy numbers and genome proportion of this sequence have been calculated that were 3523 and 0,086% respectively. Phylogenetic analyses of full nucleotide sequences confirmed close relationship to Iranian isolate (TYLCV-Kahnooj) than other published viruses. Additionally, a and β DNA satellites have not discovered in the TYLCV-infected sample.
Dissection of the ATPase active site of McdA reveals the sequential steps essential for carboxysome distribution
Authors: Hakim Pusparanee , Vecchiarelli Anthony G.
Published: April 2021

Carboxysomes, the most prevalent and well-studied anabolic bacterial microcompartment, play a central role in efficient carbon fixation by cyanobacteria and proteobacteria. In previous studies, we identified the two-component system called McdAB that spatially distributes carboxysomes across the bacterial nucleoid. McdA, a ParA-like ATPase, forms a dynamic oscillating gradient on the nucleoid in response to carboxysome-localized McdB. As McdB stimulates McdA ATPase activity, McdA is removed from the nucleoid in the vicinity of carboxysomes, propelling these proteinaceous cargos toward regions of highest McdA concentration via a Brownian-ratchet mechanism. However, how the ATPase cycle of McdA governs itsin vivodynamics and carboxysome positioning remains unresolved. Here, by strategically introducing amino acid substitutions in the ATP-binding region of McdA, we sequentially trap McdA at specific steps in its ATP cycle. We map out critical events in the ATPase cycle of McdA that allows the protein to bind ATP, dimerize, change its conformation into a DNA-binding state, interact with McdB-bound carboxysomes, hydrolyze ATP and release from the nucleoid. We also find that McdA is a member of a previously unstudied subset of ParA family ATPases, harboring unique interactions with ATP and the nucleoid for trafficking their cognate intracellular cargos.
Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A
Authors: Lepelley Alice , Mina Erika Della , Van Nieuwenhove Erika , Waumans Lise , Fraitag Sylvie , Rice Gillian I , Dhir Ashish , Frémond Marie-Louise , Rodero Mathieu P , Seabra Luis , Carter Edwin , Bodemer Christine , Buhas Daniela , Callewaert Bert , de Lonlay Pascale , De Somer Lien , Dyment David A , Faes Fran , Grove Lucy , Holden Simon , Hully Marie , Kurian Manju A , McMillan Hugh J , Suetens Kristin , Tyynismaa Henna , Chhun Stephanie , Wai Timothy , Wouters Carine , Bader-Meunier Brigitte , Crow Yanick J
Published: April 2021

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.

Dominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.
A new High-Throughput-Screening-assay for Photoantimicrobials Based on EUCAST Revealed Photoantimicrobials in Cortinariaceae
Authors: Fiala Johannes , Schöbel Harald , Vrabl Pamela , Dietrich Dorothea , Hammerle Fabian , Altmann Desirée Josefine , Stärz Ronald , Peintner Ursula , Siewert Bianka
Published: April 2021

A spark of light might unravel antimicrobial activity of colored compounds, which otherwise would have been classified as inactive. While many mushrooms contain such colorful pigments but lack antimicrobial activity, we wondered if a controlled irradiation is needed to unleash their effect. To explore such photoantimicrobial actions in the Kingdom Fungi, an efficient high-throughput-screening (HTS) assay is needed. Here we report on the establishment of a reliable photoantimicrobial assay based on the EUCAST recommendations, which was validated with known photosensitzers (i.e., curcumin, phenalenone, rose bengal, an hypericum extract, and methylene blue). Furthermore, an improved LED-irradiation setup enabling with only 24 LEDs a homogenous irradiation of a 96-well plate is presented. The established HTS-assay was utilized to screen six colorfulCortinariusextracts unrevealingC. xanthophyllusandC. rufo-olivaceusas promising sources for new photoantimicrobials.
Neural mechanisms of distributed value representations and learning strategies
Authors: Farashahi Shiva , Soltani Alireza
Published: April 2021

Learning appropriate representations of the reward environment is extremely challenging in the real world where there are many options to learn about and these options have many attributes or features. Despite existence of alternative solutions for this challenge, neural mechanisms underlying emergence and adoption of value representations and learning strategies remain unknown. To address this, we measured learning and choice during a novel multi-dimensional probabilistic learning task in humans and trained recurrent neural networks (RNNs) to capture our experimental observations. We found that participants estimate stimulus-outcome associations by learning and combining estimates of reward probabilities associated with the informative feature followed by those of informative conjunctions. Through analyzing representations, connectivity, and lesioning of the RNNs, we demonstrate this mixed learning strategy relies on a distributed neural code and distinct contributions of inhibitory and excitatory neurons. Together, our results reveal neural mechanisms underlying emergence of complex learning strategies in naturalistic settings.
New insights from 33,813 publicly available metagenome-assembled-genomes (MAGs) assembled from the rumen microbiome
Authors: Watson Mick
Published: April 2021

Recent rumen microbiome metagenomics papers1,2have published hundreds of metagenome-assembled genomes (MAGs), comparing them to 4,941 MAGs published by Stewartet al3in order to define novelty. However, there are many more publicly available MAGs from ruminants. In this paper, for the first time, all available resources are combined, catalogued and de-replicated to define putative species-level bins. As well as providing new insights into the constitution of the rumen microbiome, including an updated estimate of the number of microbial species in the rumen, this work demonstrates that a lack of community-adopted standards for the release and annotation of MAGs hinders progress in microbial ecology and metagenomics.
Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation inARID1B-related neurodevelopmental disorders
Authors: Pagliaroli Luca , Porazzi Patrizia , Curtis Alyxandra T. , Scopa Chiara , Mikkers Harald M.M. , Freund Christian , Daxinger Lucia , Deliard Sandra , Welsh Sarah A. , Offley Sarah , Ott Connor A. , Calabretta Bruno , Brugmann Samantha A. , Santen Gijs W.E. , Trizzino Marco
Published: April 2021

The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation.ARID1Band its paralogARID1Aencode for mutually exclusive BAF subunits.De novo ARID1Bhaploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammedARID1B+/-Coffin-Siris patient-derived skin fibroblasts into iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), which includes SMARCA4 and nine additional subunits. ARID1B-BAF acts as a gatekeeper, ensuring exit from pluripotency and lineage commitment, by attenuatingNANOG, SOX2and thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage.

In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+),ARID1B-haploinsufficient CNCCs are also NANOG/OCT4-positive, in stark contrast with theARID1B-wt CNCCs, which are NANOG/OCT4-negative.

These findings suggest a connection betweenARID1Bmutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
Dynamic chromatin regulatory landscape of human CAR T cell exhaustion
Authors: Gennert David G , Lynn Rachel C , Granja Jeff M , Weber Evan W , Mumbach Maxwell R , Zhao Yang , Duren Zhana , Sotillo Elena , Greenleaf William J. , Wong Wing H , Satpathy Ansuman T , Mackall Crystal L , Chang Howard Y
Published: April 2021

Dysfunction in T cells limits the efficacy of cancer immunotherapy1–6. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during theirex vivoexpansion7. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such asPDCD1, CTLA4, andHAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers ofPDCD1suppress the expression of PD-1 in anin vitromodel of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
Sense-and-respond payload delivery using a novel antigen-inducible promoter improves suboptimal CAR-T activation
Authors: Guo Tingxi , Ma Dacheng , Lu Timothy K.
Published: April 2021

Chimeric antigen receptor (CAR)-T cell therapies demonstrate the clinical potential of lymphocytes engineered with synthetic properties. However, CAR-T cells are ineffective in most solid tumors, partly due to inadequate activation of the infused lymphocytes at the site of malignancy. To selectively enhance anti-tumor efficacy without exacerbating off-target toxicities, CAR-T cells can be engineered to preferentially deliver immunostimulatory payloads in tumors. Here, we report a novel antigen-inducible promoter and single-vector sense-and-respond circuit for conditional payload expression in primary human T cells. In therapeutic T cell models, the novel NR4A-based promoter induced higher transgene expression than the conventional NFAT-based promoter under weakly immunogenic conditions, where payload expression is most needed. Minimal activity was detected from the inducible promoters in the absence of antigen and after withdrawal of stimulation. As a functional proof-of-concept, we used the NR4A-based promoter to express cytokines in an anti-mesothelin CAR-T model with suboptimal stimulation, and observed improved proliferation compared to T cells engineered with the conventional NFAT promoter or CAR alone. Our single-vector circuit achieves CAR-directed payload expression under weakly immunogenic conditions and could enable the next generation of cell therapies with enhanced anti-tumor efficacy.
Older adults’ knowledge, beliefs and attitudes about prescription opioids
Authors: Glose Susan , Arms Tamatha , Rowan Noell
Published: April 2021

Purpose

The purpose of this study is to explore the knowledge, beliefs and attitudes surrounding prescription opioid medications of community living older adults in southeast North Carolina.

Design/methodology/approach

A cross-sectional, descriptive, anonymous survey design of participants aged 55 or over was used.

Findings

Study participants (N= 119) reported bias in their attitudes and beliefs about the use and misuse of prescription opioid medications. Multiple regression analyses revealed that gender, age, work, marital status and education level all had significant results in explaining variance in the statistical models. Even though study participants demonstrated high levels of education and understanding of the potential of addiction to opiates, there were a number of misconceptions about prescription pain medications revealed.

Originality/value

There is a dearth of studies looking at older adults’ knowledge, beliefs and attitudes about prescription pain medications. This urges the necessity of increased awareness via further research, presentations and creative discourse to assist in the understanding of precursors of addiction and ways to deal with pain that do not automatically depend on prescription opioid medicines. Implications include outreach to a larger and more diverse sample to address knowledge, beliefs and attitudes surrounding prescription opioid medications of community living older adults in southeast North Carolina and beyond.
Does board structure impact a firm's financial performance? Evidence from the Indian software sector
Authors: Bansal Deepika , Singh Shveta
Published: April 2021

Purpose

The purpose of this study is to examine the impact of board structure on financial performance of Indian software companies. It is an empirical study carried out on 92 software companies from 2011 to 2018.

Design/methodology/approach

The board size, board independence, board meetings, CEO duality, audit, remuneration and nomination committee are used as board structure variables. Two accounting-based measures, return on assets (ROA), return on equity and one market-based measure Tobin's Q are used as a representative of financial performance of software companies. Panel regression is used to test the hypothesis.

Findings

Results demonstrates that board size, board meetings, remuneration and nomination committee have positive impact on more than one performance measures, while audit committee do not have any relation with any of the performance measures. It is also found that CEO duality has negative but significant relation with firm's performance and board independence has negative influence on ROA.

Practical implications

The findings of the study attract the attention of company's policymakers, shareholders to know the importance of board structure in increasing the firm's performance. The outcome of the study has relevance in other developing economies also. The results of the study can be utilised by policymakers and regulatory bodies in the formulation of good corporate government (CG) practices for the enhancement of profitability and market value of companies.

Originality/value

The findings suggest that special attention should be given to quality of CG, specifically board structure while measuring corporate financial performance.
Economic growth and income inequality: a non-linear econometrics analysis of the SADC region, 1990–2015
Authors: Zungu Lindokuhle Talent , Greyling Lorraine , Mbatha Nkanyiso
Published: April 2021

Purpose

The authors investigate the growth–inequality relationship, using panel data from 13 Southern African Development Community (SADC) countries over the period 1990–2015, to test the validity of the Kuznets and Tribble theories. Furthermore, the authors seek to determine the threshold level at which excessive growth hampers inequality.

Design/methodology/approach

The panel smooth transition regression (PSTR) model has several stages. The authors applied the Lagrange multiplier (LM) test to find the appropriate transition variable amongst all candidate variables, to assess the linearity between economic growth and income inequality and to find the sequence for selecting the ordermof the transition function. The authors then estimated the PSTR model, but before facilitating the results, the authors first used the wild cluster bootstrap (WCB)–LM-type test to assess the appropriateness of the selected transition.

Findings

The authors found that at lower growth, income inequality tends to be lower, while if growth increases above US$8,969, inequality tends to increase in the SADC region. The findings combine into aU-shaped relationship, contradicting the Kuznets and Tribble theories.

Originality/value

The contribution of this paper is that it becomes the first to provide the threshold level at which excessive growth increases inequality in the selected countries. This study proposes that policymakers should focus on activities aimed at stimulating growth, in other words, activities such as spending more on infrastructure, drawing up a suitable investment portfolio and spending on technological investment for countries that are below US$8,969. An improvement in these activities will create job opportunities, which in turn will add to economic growth and thus lead to lower income inequality and better social cohesion.
Robust active disturbance attenuation control of an uncertain quadrotor
Authors: Ahmed Nigar , Bhatia Ajeet kumar , Ali Shah Syed Awais
Published: April 2021

Purpose

The aim of this research is to design a robust active disturbance attenuation control (RADAC) technique combined with an extended high gain observer (EHGO) and low pass filter (LPF).

Design/methodology/approach

For designing a RADAC technique, the sliding mode control (SMC) method is used. Since the standard method of SMC exhibits a chattering phenomenon in the controller, a multilayer sliding mode surface is designed for avoiding the chattering. In addition, to attenuate the unwanted uncertainties and disturbances (UUDs), the techniques of EHGO and LPF are deployed. Besides acting as a patch for disturbance attenuation, the EHGO design estimates the state variables. To investigate the stability and effectiveness of the designed control algorithm, the stability analysis followed by the simulation study is presented.

Findings

The major findings include the design of a chattering-free RADAC controller based on the multilayer sliding mode surface. Furthermore, a criterion of integrating the LPF scheme within the EHGO scheme is also developed to attenuate matched and mismatched UUDs.

Practical implications

In practice, the quadrotor flight is opposed by different kinds of the UUDs. And, the model of the quadrotor is a highly nonlinear underactuated model. Thus, the dynamics of the quadrotor model become more complex and uncertain due to the additional UUDs. Hence, it is necessary to design a robust disturbance attenuation technique with the ability to estimate the state variables and attenuate the UUDs and also achieve the desired control objectives.

Originality/value

Designing control methods to attenuate the disturbances while assuming that the state variables are known is a common practice. However, investigating the uncertain plants with unknown states along with the disturbances is rarely taken in consideration for the control design. Hence, this paper presents a control algorithm to address the issues of the UUDs as well as investigate a criterion to reduce the chattering incurred in the controller due to the standard SMC algorithm.
Evidence-based coaching as a supplement to traditional lectures: impact on undergraduates' goal attainment and measures of mental well-being
Authors: Atad Ofer I. , Grant Anthony M.
Published: April 2021

Purpose

This study aimed to examine how the effects of traditional tertiary education (lecture format) on various outcomes – including goal attainment, psychopathology (stress, anxiety and depression), resilience, solution-focused thinking and self-insight – compare to effects of traditional education supplemented by health coaching, delivered through Zoom video-conferencing.

Design/methodology/approach

The study, which involved mature-age Israeli undergraduate students enrolled in a health promotion course (n = 178), used a randomized controlled between-subjects (pre-post) design. Participants were each randomly assigned to a traditional-education condition (n = 90) or to a coaching condition (n = 88). All participants attended 13 weekly course lectures; those in the coaching condition also participated in weekly Zoom-based coaching sessions, with trained health coaches. Each participant completed online questionnaire measures at the beginning and at the end of the semester. Data were analyzed using repeated-measures ANOVA.

Findings

Compared with participants in the traditional-education condition, those in the coaching condition showed, over the course of the semester, significant improvement in goal attainment, solution-focused thinking, self-insight, resilience and psychopathology. Participants in the traditional-education condition showed no change in these measures.

Originality/value

The authors’ findings suggest that health coaching, as a supplement to traditional lectures, can enhance undergraduates' goal attainment and multiple facets of their mental well-being. These findings may have significant practical implications for the vast numbers of students struggling to cope in higher education systems worldwide. The authors further suggest a range of alternative, coaching-inspired interventions that do not require development of a full coaching program.
University lecturers' use of active teaching methods: a segmentation study concerning trust, empowerment, thinking styles and emotional intelligence
Authors: Nghiêm-Phú Bình , Nguyễn Thành Hưng
Published: April 2021

Purpose

The purpose of this study is to examine the adoption of the active learning and teaching methods by university lecturers, taking into account the contribution of certain important factors, including trust, empowerment, thinking styles and emotional intelligence. In addition, this study further reveals the diverse nature of university lecturers with regards to their tendencies to adopt active teaching methods using the segmentation technique of marketing.

Design/methodology/approach

A structured survey was implemented with university lecturers in Hanoi (Vietnam), obtaining a sample of 218 respondents from six universities. Descriptive analysis was carried out to identify the extent of the adoption of these methods. In addition, cluster analysis and analysis of variance were computed to extract and define the segments of university lecturers.

Findings

The findings show that the lecturers, on average, had a tendency to apply active teaching methods. However, the extent of the application of these methods differed among four clusters: “conservatives,” “liberals,” “junior conservatives” and “junior liberals.” In addition, it was found that the degree to which active methods were applied may have been affected by the lecturers' trust in and their empowerment of the students. The application of active methods may also have been influenced by various covert characteristics of the lecturers, including thinking styles (cognition-based) and emotional intelligence (affect-based). The lecturers' overt characteristics, such as age, education and experience, may also have affected their application of active methods, while biological sex seems not to have been a significant factor.

Originality/value

The results of this study expand the literature by explaining the diversity of university lecturers from the perspective of the active teaching and learning methods. They also provide implications for the management of education reform based on the varied implementation of the said methods that has already taken place.
Is tourism pro-poor in India? An empirical investigation using ARDL approach
Authors: Sharma Manu , Mohapatra Geetilaxmi , Giri Arun Kumar
Published: April 2021

Purpose

The purpose of this paper is to examine the relationship between tourism sector development and poverty reduction in India using annual data from 1970 to 2018. The paper attempts to answer the critical question: Is tourism pro-poor in India?

Design/methodology/approach

Stationarity properties of the series are checked by using the ADF unit root test. The paper uses the Auto Regressive Distributed Lag (ARDL) bound testing approach to cointegration to examine the existence of long-run relationships; error-correction mechanism for the short-run dynamics, and Granger non-causality test to test the direction of causality.

Findings

The cointegration test confirms a long-run relationship between tourism development and poverty reduction for India. The ARDL test results suggest that tourism development and economic growth reduces poverty in both the long run and the short run. Furthermore, inflation had a negative and significant short-run impact on the poverty reduction variable. The causality test confirms that there is a positive and unidirectional causality running from tourism development to poverty reduction confirming that tourism development is pro-poor in India.

Research limitations/implications

This study implies that poverty in India can be reduced by tourism sector growth and price stability. For a fast-growing economy with respect to economic growth and tourism sector growth, this may have far-reaching implications toward inclusive growth in India.

Originality/value

This paper is the first of its kind to empirically examine the causal relationship between tourism sector development and poverty reduction in India using modern econometric techniques.
Microfinancial inclusion nexus poverty alleviation: the case of Nigeria
Authors: Ngong Chi Aloysius , Thaddeus Kesuh Jude , Onwumere Josaphat Uchechukwu Joe
Published: April 2021

Purpose

This research examines the long-run relationship between microfinancial inclusion and poverty alleviation in Nigeria from 1990 to 2018.

Design/methodology/approach

the Engle–Granger two-step co-integration and autoregressive distributed lag (ARDL) techniques. Gross domestic product (GDP) per capita proxies poverty reduction. Number of microfinance banks, borrowers of microfinance institutions, commercial bank branches, commercial bank loan to small-scale businesses and broad money supply ratio measure microfinancial inclusion.

Findings

The results indicate a long-run relationship between microfinancial inclusion and poverty reduction. The error correction model reveals that microfinancial inclusion and poverty alleviation converge to long-run equilibrium. The number of microfinance banks, lagged value of borrowed funds and broad money supply negatively influences poverty while the lagged values of number of microfinance banks and broad money supply positively influence poverty.

Research limitations/implications

Effective ways to improve microcredit channels and liquidity flow to the poor through a microfinance bank's intermediation should be promoted by the Central Bank of Nigeria (CBN) using an aggressive policy, which provides access to credit to the poor.

Practical implications

Theoretically, microfinance institutions should increase credit to the poor, especially in rural areas at moderate cost. This study further suggests that many microfinance bank branches should be located in urban and rural areas targeting the poor.

Social implications

Microfinancial inclusion reduces population's poverty in Nigeria and globally.

Originality/value

Contrary to other studies, this paper utilizes number of microfinance institutions and borrowers of microfinance institutions to examine the relationship between microfinancial inclusion and poverty alleviation in Nigeria.
Research of influence mechanism of corporate social responsibility for smart cities on consumers' purchasing intention
Authors: Zhuang Meier , Zhu Wenzhong , Huang Lihui , Pan Wen-Tsao
Published: April 2021

Purpose

The main purpose of this paper is to explore the influence mechanism of corporate social responsibility (CSR) for smart cities on consumers' purchase intention. The authors aim to identify the key components of CSR for smart cities based on the perspective of consumers, namely responsibility toward consumers, environment and community and validate their relationship.

Design/methodology/approach

The authors exploit data collected by questionnaire surveys to estimate the effects of CSR for smart cities on consumers' purchase intentions and to investigate the statistical causality between them. The multilinear regression model is used to figure out the different impact levels of the three dimensions of CSR for smart cities on consumers' purchase intention.

Findings

The results illustrate that CSR for smart cities and its three dimensions all have significant positive impacts on consumers' purchase intentions. Besides, consumer–corporate identity (CCI) exerts a partial mediation effect on this influence mechanism.

Research limitations/implications

This research is based on a rather small sample size. Besides, due to the time limitation and other factors, some other control variables are neglected in the regression model. Therefore, the impact level could be distorted.

Practical implications

The authors put forward management implications according to research conclusions. Corporates should actively fulfill the CSR in the field of consumer responsibility to boost consumers' purchase intention. Corporate should strengthen the interaction with consumers to improve their corporate identity.

Originality/value

The main contribution of this paper is to provide convincing evidence of the impacts of CSR for smart cities on consumer purchase intention (CPI), thus proposing effective measures for corporates to win more consumers by taking on social responsibility for smart cities. This paper takes CCI as mediating variable to deepen the understanding of the impacts of CSR for smart cities on CPI, which is innovative and beneficial to enriching literature in related fields.