bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diverse innate immune factors protect yeast from lethal viral pathogenesis
Authors: Chau Sabrina , Gao Jie , Diao Annette J. , Cao Shi Bo , Azhieh Amirahmad , Davidson Alan R. , Meneghini Marc D. 
Published: February 2022

AbstractIn recent years, newly characterized anti-viral systems have proven to be remarkably conserved from bacteria to mammals, demonstrating that unique insights into these systems can be gained by studying microbial organisms. Despite the enthusiasm generated by these findings, the key microbial model organism Saccharomyces cerevisiae (budding yeast) has been minimally exploited for studies of viral defense, primarily because it is not infected with exogenously transmitted viruses. However, most yeast strains are infected with an endogenous double stranded RNA (dsRNA) virus called L-A, and previous studies identified conserved antiviral systems that attenuate L-A replication. Although these systems do not completely eradicate L-A, we show here that they do prevent proteostatic stress and lethality caused by L-A over-proliferation. Exploiting this new finding, we demonstrate that the genetic screening methods available in yeast can be used to identify additional conserved antiviral systems. Using these approaches, we discovered antiviral functions for the yeast homologs of polyA-binding protein (PABPC1) and the La-domain containing protein Larp1, which are both involved in viral innate immunity in humans. We also identified new antiviral functions for the RNA exonucleases REX2 and MYG1, both of which have distinct but poorly characterized human and bacterial homologs. These findings highlight the potential of yeast as a powerful model system for the discovery and characterization of conserved antiviral systems.Significance StatementThe budding yeast Saccharomyces cerevisiae has been minimally exploited for investigation of host-virus interactions despite its chronic infection with a double-stranded RNA virus called L-A. Controverting its presumed harmless nature, we show here that L-A causes pathogenesis in cells lacking parallel-acting viral attenuation pathways. Taking advantage of the genetic tools available in budding yeast, we identify several highly conserved proteins to play a role in antiviral defense. Some of these have been recently identified in humans to be involved in viral innate immunity, thus highlighting the potential of budding yeast as a model organism to identify and investigate new antiviral systems.
Expression of fatty acid synthase genes and their role in development and arboviral infection of Aedes aegypti
Authors: Chotiwan Nunya , Brito-Sierra Carlos A. , Ramirez Gabriella , Lian Elena , Hill Catherine A. , Perera Rushika 
Published: February 2022

AbstractBackgroundFatty acids are the building blocks of complex lipids essential for living organisms. In mosquitoes, fatty acids are involved in cell membrane production, energy conservation and expenditure, innate immunity, development, and reproduction. Fatty acids are synthesized by a multifunctional enzyme complex called fatty acid synthase (FAS). Several paralogues of FAS were found in the Aedes aegypti (Ae. aegypti) mosquito. However, the molecular characteristics and the expression of some of these paralogues have not been investigated.MethodsGenome assemblies of Ae. aegypti were analyzed and orthologues of human FAS were identified. Phylogenetic analysis and in silico molecular characterization were performed to identify the functional domains of the Ae. aegypti FAS (AaFAS). Quantitative analysis and loss-of-function experiments were performed to determine the significance of different AaFAS transcripts in various stages of development, expression following different diets and the impact of AaFAS on dengue virus, serotype 2 (DENV2) infection and transmission.ResultsWe identified seven putative FAS genes in the Ae. aegypti genome assembly, based on nucleotide similarity to the FAS proteins (tBLASTn) of humans, other mosquitoes and invertebrates. Bioinformatics and molecular analyses suggested that only five of the FAS genes produce mRNA and therefore represent complete gene models. Expression levels of AaFAS varied among developmental stages and between male and female Ae. aegypti. Quantitative analyses revealed that expression of AaFAS1, the putative orthologue of the human FAS, was highest in adult females. Transient knockdown (KD) of AaFAS1 did not induce a complete compensation by other AaFAS genes but limited DENV2 infection of Aag2 cells in culture and the midgut of the mosquito.ConclusionAaFAS1 is the predominant AaFAS in the adult mosquitoes. It has the highest amino acid similarity to human FAS and contains all enzymatic domains typical of human FAS. AaFAS1 also facilitated DENV2 replication in both cell culture and in mosquito midguts. Our data suggest that AaFAS1 may play a role in transmission of dengue viruses, and could represent a target for intervention strategies.
Efficacy and Safety of Tregopil, a Novel, Ultra-Rapid Acting Oral Prandial Insulin Analog, as Part of a Basal-Bolus Regimen in Type 2 Diabetes: A Randomized, Active Controlled Phase 3 Study
Authors: Lebovitz Harold E , Fleming Alexander , Cherrington Alan D , Joshi Shashank , Athalye Sandeep N. , Loganathan Subramanian , Vishweswaramurthy Ashwini , Panda Jayanti , Marwah Ashwani 
Published: February 2022

ABSTRACTOBJECTIVEEfficacy and safety of ultra-rapid acting oral prandial insulin Tregopil (Tregopil) was compared with insulin aspart (IAsp) in patients with type-2 diabetes on stable doses of insulin glargine and metformin.RESEARCH DESIGN AND METHODSIn this open-label, active-controlled trial, patients with type-2 diabetes, with HbA1c ≥7% and ≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized (1:1:1) to Tregopil (30 mg [n=30], 45 mg [n=31]) and IAsp (n=30; dose titrated based on self-monitored blood glucose [SMBG]). Postprandial plasma glucose excursion (PPGE) and PPG were assessed from the standardized test meal (STM) and 9- point SMBG. The primary outcome measure was change from baseline (CFB) in HbA1c at week 24.RESULTSThe Tregopil (30 mg) arm showed significantly lesser 1-h PPGE (CFB) excursion after the STM versus IAsp (Estimated Treatment Difference [ETD], 95% CI, -45.33 mg/dL [-71.91, -8.75], P=0.001) and 1-h PPG trended towards a better control. The combined Tregopil group (30+45 mg) showed lower PPGE at 15 mins as compared to IAsp. Meal-wise analysis showed lower 1-h PPGE and PPG in the Tregopil groups post-breakfast. Clinically significant hypoglycemia was lower with Tregopil groups versus IAsp (rate ratio: 0.69).CONCLUSIONSTregopil demonstrated an ultra-fast onset and short-duration prandial insulin profile with good safety. Tregopil improved the 1-h PPG and overall PPG control compared to IAsp. A further reduction in HbA1c compared to baseline was not observed, likely as a result of variability in the control of fasting glucose level over the duration of the study.
Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models
Authors: Mohajeri Kiana , Yadav Rachita , D’haene Eva , Boone Philip M. , Erdin Serkan , Gao Dadi , Moyses-Oliveira Mariana , Bhavsar Riya , Currall Benjamin , O’Keefe Kathryn , Lowther Chelsea , Lucente Diane , Burt Nicholas D. , Salani Monica , Larson Matthew , Menten Björn , Tai Derek J.C. , Gusella James F. , Vergult Sarah , Talkowski Michael E. 
Published: February 2022

ABSTRACTPoint mutations and structural variants directly disrupting the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs), while recent studies have also implicated altered noncoding regulation of MEF2C expression in NDDs. However, the impact of haploinsufficiency of MEF2C on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern regulation of MEF2C. To explore the transcriptional and functional changes associated with coding and noncoding structural variants, we generated an allelic series of 204 isogenic iPSC-derived neuronal cell lines harboring CRISPR-engineered mutations that directly delete predominant isoforms of MEF2C, as well as deletions to the boundaries of topologically associating domains (TADs) and chromatin loops encompassing MEF2C. We then performed systematic profiling of mutation-specific alterations to transcriptional signatures, regulatory interactions, chromatin contacts, and electrophysiological effects. Our analyses reveal that direct deletion of MEF2C causes differential expression of genes enriched for neurodevelopmental and synaptic-associated pathways, accompanied by a significant reduction in synaptic firing and synchrony in neurons. By contrast, we observe robust buffering against MEF2C regulatory disruption upon deletion of a distal 5q14.3 TAD and loop boundary; however, homozygous loss of proximal loop boundary resulted in significant down-regulation of MEF2C expression and significantly reduced electrophysiological activity that was comparable to direct MEF2C disruption. Collectively, our findings demonstrate the functional impact of MEF2C haploinsufficiency in human-derived neural models and highlight the complex interactions of gene regulation and chromatin topology that challenge a priori regulatory predictions of structural variant disruption to three-dimensional genome organization.
Revisiting the origin of interleukin 1 (IL-1) based on biological activities of IL-1 in anamniotes and their sub-functionalization in amniotes
Authors: Hasel de Carvalho Eva , Bartok Eva , Stölting Helen , Bajoghli Baubak , Leptin Maria 
Published: February 2022

AbstractThe cytokine Interleukin 1 (IL-1) is an evolutionary innovation of vertebrates. Fish and amphibia have oneIL1gene, while mammals have two copies ofIL1,IL1AandIL1B, with distinct expression patterns and differences in their proteolytic activation. Our current understanding of the evolutionary history of IL-1 is mainly based on phylogenetic analyses, but this approach provides no information on potentially different functions of IL-1 homologs, and it remains unclear which biological activities identified for IL-1α and IL-1β in mammals are present in lower vertebrates. Here, we usein vitroandin vivoexperimental models to examine the expression patterns and cleavage of IL-1 proteins from various species. We found that IL-1 in the teleost medaka shares the transcriptional patterns of mammalian IL-1α, and its processing also resembles that of mammalian IL-1α, which is sensitive to cysteine protease inhibitors specific for the calpain and cathepsin families. By contrast, IL-1 proteins in reptiles also include biological properties of IL-1β. Therefore, we propose that duplication of the ancestral IL1 gene led to segregation of expression patterns and protein processing that characterizes the two extant forms of IL-1 in mammals.
The connectional anatomy of visual mental imagery: evidence from a patient with left occipito-temporal damage
Authors: Hajhajate Dounia , Kaufmann Brigitte , Liu Jianghao , Siuda-Krzywicka Katarzyna , Bartolomeo Paolo 
Published: February 2022

AbstractMost of us can use our “mind’s eye” to mentally visualize things that are not in our direct line of sight, an ability known as visual mental imagery. Extensive left temporal damage can impair patients’ visual mental imagery experience, but the critical locus of lesion is unknown. Our recent meta-analysis of 27 fMRI studies of visual mental imagery highlighted a well-delimited region in the left lateral midfusiform gyrus, which was consistently activated during visual mental imagery, and which we called the Fusiform Imagery Node (FIN). Here we describe the connectional anatomy of FIN in neurotypical participants and in RDS, a right-handed patient with an extensive occipitotemporal stroke in the left hemisphere. The stroke provoked right homonymous hemianopia, alexia without agraphia, and color anomia. Despite these deficits, RDS had normal subjective experience of visual mental imagery and reasonably preserved behavioral performance on tests of visual mental imagery of object shape, object color, letters, faces, and spatial relationships. We found that the FIN was spared by the lesion. We then assessed the connectional anatomy of the FIN in the MNI space and in the patient’s native space, by visualizing the fibers of the inferior longitudinal fasciculus (ILF) and of the arcuate fasciculus (AF) passing through the FIN. In both spaces, the ILF connected the FIN with the anterior temporal lobe, and the AF linked it with frontal regions. Our evidence is consistent with the hypothesis that the FIN is a node of a brain network dedicated to voluntary visual mental imagery. The FIN could act as a bridge between visual information and semantic knowledge processed in the anterior temporal lobe and in the language circuits.
Engineering Agrobacterium tumefaciens adhesion to target cells
Authors: Pierrat Xavier , Pham Alix , Wong Jeremy P. H. , Al-Mayyah Zainebe , Persat Alexandre 
Published: February 2022

AbstractAgrobacterium tumefaciens is a plant pathogen commonly repurposed for genetic modification of crops. Despite its versatility, it remains inefficient at transferring DNA to many hosts, including to animal cells. Like many pathogens, physical contact between A. tumefaciens and host cells promotes infection efficacy. Thus, improving the strength and specificity of A. tumefaciens to target cells has the potential for enhancing DNA transfer for biotechnological and therapeutic purposes. Here we demonstrate a methodology for engineering genetically-encoded exogeneous adhesins at the surface of A. tumefaciens. We identified an autotransporter gene we named Aat, that is predicted to show canonical β-barrel and passenger domains. We engineered the β-barrel scaffold and linker (Aatβ) to display synthetic adhesins susceptible to rewire A. tumefaciens to alternative host targets. As a proof of concept, we leveraged the versatility of a VHH domain to rewire A. tumefaciens adhesion to yeast and mammalian hosts displaying a GFP target receptor. Finally, to demonstrate how synthetic A. tumefaciens adhesion can improve transfer to host cells, we showed improved protein translocation into HeLa cells using a sensitive split luciferase reporter system. Engineering A. tumefaciens adhesion has therefore a strong potential in generating complex heterogeneous cellular assemblies and in improving DNA transfer efficiency against non-natural hosts.
Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells
Authors: Inguito Kameron L. , Schofield Mandy M. , Faghri Arya D. , Bloom Ellen T. , Heino Marissa , Elliott Dawn M. , Parreno Justin 
Published: February 2022

AbstractThe actin cytoskeleton is a central mediator between mechanical force and cellular phenotype. In tendon, it is speculated that mechanical stress deprivation regulates gene expression by filamentous (F−) actin destabilization. However, the molecular mechanisms that stabilize tenocyte F-actin networks remain unclear. Tropomyosins (Tpms) are master regulators of F-actin networks. There are over 40 mammalian Tpm isoforms, with each isoform having the unique capability to stabilize F-actin sub-populations. Thus, the specific Tpm(s) expressed by a cell defines overall F-actin organization. Here, we investigated F-actin destabilization by stress deprivation of tendon and tested the hypothesis that stress fiber-associated Tpm(s) stabilize tenocyte F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon fascicles downregulated tenocyte genes (collagen-I, tenascin-C, scleraxis, α-smooth muscle actin) and upregulated matrix metalloproteinase-3. Concomitant with mRNA modulation were increases in DNAse-I/Phallodin (G/F-actin) staining, confirming F-actin destabilization by tendon stress deprivation. To investigate the molecular regulation of F-actin stabilization, we first identified the Tpms expressed by mouse tendons. Tendon cells from different origins (tail, Achilles, plantaris) express three isoforms in common: Tpm1.6, 3.1, and 4.2. We examined the function of Tpm3.1 since we previously determined that it stabilizes F-actin stress fibers in lens epithelial cells. Tpm3.1 associated with F-actin stress fibers in native and primary tendon cells. Inhibition of Tpm3.1 depolymerized F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin stability in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.
Transcriptomic mapping of the metzincin landscape in human trophoblasts
Authors: Wächter Jasmin , Shannon Matthew J , Castellana Barbara , Baltayeva Jennet , Beristain Alexander G. 
Published: February 2022

ABSTRACTThe metzincin family of metalloproteases coordinates cell and tissue developmental processes through regulation of growth factor availability, receptor signaling, and cell-cell/cell-matrix adhesion. During placental development, while distinct roles for metzincin proteases in controlling specific trophoblast functions have been described, a comprehensive assessment of metzincins during discrete stages of trophoblast differentiation has yet to be performed. Here we provide a comprehensive single cell transcriptomic resource of metzincin protease expression in diverse states of human trophoblasts from first trimester placental and decidual tissues. In the 8 distinct trophoblasts states categorized [four progenitor cytotrophoblast (CTB), one syncytiotrophoblast precursor (SCTp), two column CTB (cCTB), and one extravillous trophoblast (EVT) state], we identified 24 metzincin genes. These included 12 adamalysins, 2 pappalysins, 3 astacins and 7 matrixins. Cell trajectory modeling shows that expression of most (19/24) metzincins increases across CTB to EVT differentiation, though select proteases also increase as CTB fuse into syncytiotrophoblast. Within the CTB niche, single-cell velocity ordering identified 11 metzincins (ADAM10, -17, MMP14, -15, -19, -23B, ADAMTS1, -6, -19, TLL-1, -2) expressed in progenitors proximal to the predicted origin. Analysis of metzincin-substrate interactions within the CTB niche revealed ∼150 substrates and binding partners, includingFBN2as anADAMTS6-specific substrate preferentially expressed in trophoblast progenitors. Together, this work characterizes the metzincin transcriptomic landscape in human first trimester trophoblasts and establishes insight into the roles specific proteases perform within distinct trophoblast niches and across differentiation. This resource serves as a guide for future investigations into the roles of metzincin proteases in human placental development.Summary StatementSingle cell RNA sequencing characterizes the expression of multiple metzincin proteases within first trimester placental trophoblasts. Examination of protease-substrate interactions within cytotrophoblasts identifies potential interactions between ADAMTS6 and FBN2.HighlightsSingle cell RNA sequencing identifies 24 distinct metzincin proteases expressed in human first trimester trophoblastsLineage trajectory modelling shows that metzincin genes are dynamic and likely control processes in progenitor, mid-point, and end-point states of trophoblast differentiation.ADAMTS6, and its putative substrate FBN2, localize specifically to progenitor trophoblasts
Unreal influence: leveraging AI in influencer marketing
Authors: Sands Sean , Campbell Colin L. , Plangger Kirk , Ferraro Carla 
Published: February 2022

Purpose
This paper aims to examine how consumers respond to social media influencers that are created through artificial intelligence (AI) and compares effects to traditional (human) influencers.

Design/methodology/approach
Across two empirical studies, the authors examine the efficacy of AI social media influencers. With Study 1, the authors establish baseline effects for AI influencers and investigate how social-psychological distance impacts consumer perceptions. The authors also investigate the role of an influencer’s agency – being autonomous or externally managed – to test the boundaries of the results and determine the interactive effects between influencer type and influencer agency. Study 2 acts as an extension and validation of Study 1, whereby the authors provide generalisability and overlay the role of need for uniqueness as a moderated mediator.

Findings
The authors show that there are similarities and differences in the ways in which consumers view AI and human influencers. Importantly, the authors find no difference in terms of intention to follow or personalisation. This suggests that consumers are equally open to follow an AI or human influencer, and they perceive the level of personalisation provided by either influencer type as similar. Furthermore, while an AI influencer is generally perceived as having lower source trust, they are more likely to evoke word-of-mouth intentions. In understanding these effects, the authors show that social distance mediates the relationship between influencer type and the outcomes the authors investigate. Results also show that AI influencers can have a greater effect on consumers who have a high need for uniqueness. Finally, the authors find that a lack of influencer agency has a detrimental effect.

Research limitations/implications
The studies investigate consumers’ general response to AI influencers within the context of Instagram, however, future research might examine consumers’ response to posts promoting specific products across a variety of category contexts and within different social media platforms.

Practical implications
The authors find that in some ways, an AI influencer can be as effective as a human influencer. Indeed, the authors suggest that there may be a spill-over effect from consumer experiences with other AI recommendation systems, meaning that consumers are open to AI influencer recommendations. However, the authors find consistent evidence that AI influencers are trusted less than traditional influencers, hence the authors caution brands from rushing to replace human influencers with their AI counterparts.

Originality/value
This paper offers novel insight into the increasingly prominent phenomenon of the AI influencer. Specifically, it takes initial steps towards developing understanding as to how consumers respond to AI influencers and contrast these effects with human influencers.