bluuebunny/crossref_metadata_2025 huggingface dataset:
Umbilical cord blood-derived cell therapy for perinatal brain injury: A systematic review & meta-analysis of preclinical studies - Part A
Authors: Nguyen Timothy , Purcell Elisha , Smith Madeleine , Penny Tayla , Paton Madison CB , Zhou Lindsay , Jenkin Graham , Miller Suzanne L , McDonald Courtney A , Malhotra Atul
Published: October 2022

Introduction

Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment.

Objectives

To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury.

Methods

MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence.

Results

Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95%CI (0.32, 0.74), P<0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), P<0.0001), astrogliosis (GM, SMD 0.56; 95%CI (0.12, 1.01), P=0.01), microglial activation (WM, SMD 1.03; 95%CI (0.40, 1.66), P=0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), P<0.0001); as well as improved neuron number (SMD 0.86; 95%CI (0.39, 1.33), P=0.0003), oligodendrocyte number (GM, SMD 3.35; 95%CI (1.00, 5.69), P=0.005) and motor function (cylinder test, SMD 0.49; 95%CI (0.23, 0.76), P=0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low.

Conclusions

UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.

SIGNIFICANCE STATEMENT

Perinatal brain injury can lead to significant long-term neurodevelopmental deficits. There are limited treatment options available, and new interventions are urgently required. Through assessment of preclinical studies, this systematic review and meta-analysis shows that umbilical cord blood-derived cell therapy is an efficacious treatment for perinatal brain injury across a wide range of neuropathological and functional domains, albeit with low certainty of evidence. It also identified knowledge gaps, including that future studies should focus on non-hypoxic ischemic models, preterm models, large animal models and should explore the heterogeneity that exists in treatment protocols.
Genetic exchange shapes ultra-small Patescibacteria metabolic capacities in the terrestrial subsurface
Authors: Gios Emilie , Mosley Olivia E. , Takeuchi Nobuto , Handley Kim M.
Published: October 2022

Bacterial genomes are highly dynamic entities, mostly due to the extent of horizontal gene transfer (HGT) occurring in these organisms. HGT is thought to be the main driver of genetic variation and adaptation to local environment in bacteria. However, little is known about the modalities of HGT within natural microbial communities, especially the implications of genetic exchange for streamlined microorganisms such as Patescibacteria (Candidate Phyla Radiation). We searched for evidence of genetic exchange in 125 Patescibacteria genomes recovered from aquifer environments and detected the presence of hundreds of genomic islands, individually transferred genes and prophage combined, with up to 29% of genome length attributed to HGT. Results show that most individual gene transfer events occurred between Patescibacteria, but donors were also phylogenetically diverse groundwater microorganisms. Using gene donor-recipient information, we identified one potential host (Omnitrophota) of the ultra-small bacteria, and confirmed this by matching relative abundance patterns across 16 groundwater samples. A wide variety of metabolic functions were introduced in Patescibacteria genomes by HGT including transcription, translation and DNA replication, recombination and repair. This study illustrates the evolutionarily dynamic nature of Patescibacteria genomes despite the constraints of streamlining, and that HGT in these organisms is also mediated via viral infection.
Distinct modes of heat shock transcription factor interactions with mitotic chromosomes
Authors: Price Rachel M. , Budzyński Marek A. , Shen Junzhou , Mitchell Jennifer E. , Kwan James Z.J. , Teves Sheila S.
Published: October 2022

A large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, TFs from the same DBD family can display distinct binding behaviors during mitosis. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is globally decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF2 DBD alone can coat mitotic chromosomes, but is insufficient to promote HSF1 coating. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.
GBP2 aggregates LPS and activates the caspase-4 inflammasome independent of the bacterial encapsulation factor GBP1
Authors: Dickinson Mary S. , Kutsch Miriam , Sistemich Linda , Hernandez Dulcemaria , Piro Anthony S. , Needham David , Lesser Cammie F. , Herrmann Christian , Coers Jörn
Published: October 2022

Sensing and killing of intracellular bacterial pathogens are important features of cell-autonomous immunity. The cytokine gamma-interferon (IFNγ) enhances cell-autonomous immunity through upregulation of interferon stimulated genes such as guanylate binding proteins (GBPs). GBPs promote defense against Gram-negative cytosolic bacteria in part through the induction of an inflammatory cell death pathway called pyroptosis. To activate pyroptosis, GBPs facilitate caspase-4 sensing of the Gram-negative bacterial outer membrane component lipopolysaccharide (LPS). There are seven human GBP paralogs and it is unclear how each GBP contributes to LPS sensing and pyroptosis induction. GBP1 forms a multimeric microcapsule on the surface of cytosolic bacteria through direct interactions with LPS and recruits caspase-4 to bacteria, a process deemed essential for caspase-4 activation. In contrast to GBP1, closely related paralog GBP2 is unable to bind bacteria on its own but requires GBP1 for direct bacterial binding. Unexpectedly, we find that GBP2 overexpression can restore Gram-negative-induced pyroptosis in GBP1KOcells, without GBP2 binding to the bacterial surface. A mutant of GBP1 that lacks the triple arginine motif required for microcapsule formation also rescues pyroptosis in GBP1KOcells, showing that binding to bacteria is dispensable for GBPs to promote pyroptosis. Instead, we find that GBP2, like GBP1, directly binds and aggregates ‘free’ LPS through protein polymerization. This provides a novel mechanistic framework for non-canonical inflammasome activation where GBP1 or GBP2 assemble cytosol-contaminating LPS into a protein-LPS interface for caspase-4 activation as part of a coordinated host response to Gram-negative bacterial infections.

Significance Statement

Sensing Gram-negative bacterial lipopolysaccharide by human caspase-4 is critical for host defense to intracellular Gram-negative bacterial pathogens. Human guanylate binding proteins (GBPs) facilitate caspase-4 activation in response to Gram-negative infections by a poorly understood mechanism. The prevailing model suggests GBP1 binding to bacteria and consequential recruitment of caspase-4 to the bacterial surface are essential for triggering this host response. Here, we show GBP1 binding to bacteria is dispensable for caspase-4 activation and identify GBP2 as an additional lipopolysaccharide-binding protein that can functionally replace GBP1. We demonstrate that GBP1 and GBP2 share the ability to form lipopolysaccharide-protein complexes, which, we propose, allow caspase-4 activation. Our study provides a new mechanistic framework for cytosolic LPS sensing.
The evolution of age-specific resistance to infectious disease
Authors: Buckingham Lydia J. , Bruns Emily L. , Ashby Ben
Published: October 2022

Abstract

Innate, infection-preventing resistance often varies between host life-stages. Juveniles are more resistant than adults in some species, whereas the opposite pattern is true in others. This variation cannot always be explained by prior exposure or physiological constraints and so it has been hypothesised that trade-offs with other life-history traits may be involved. However, little is known about how trade-offs between various life-history traits and resistance at different life-stages affect the evolution of age-specific resistance. Here, we use a mathematical model to explore how trade-offs with natural mortality, reproduction and maturation combine to affect the evolution of resistance at different life-stages. Our results show that certain combinations of trade-offs have substantial effects on whether adults or juveniles are more resistant, with trade-offs between juvenile resistance and adult reproduction inherently more costly than trade-offs involving maturation or mortality (all else being equal), resulting in consistent evolution of lower resistance at the juvenile stage even when infection causes a lifelong fecundity reduction. Our model demonstrates how the differences between patterns of age-structured resistance seen in nature may be explained by variation in the trade-offs involved and our results suggest conditions under which trade-offs tend to select for lower resistance in juveniles than adults.
Risk factors for household transmission of SARS-Cov-2: a modelling study in the French national population-based EpiCov cohort
Authors: Novelli Sophie , Opatowski Lulla , Manto Carmelite , Rahib Delphine , de Lamballerie Xavier , Warszawski Josiane , Meyer Laurence
Published: October 2022

Background

Households are specific transmission settings, as they involve close and repeated contacts between individuals of different generations. Household surveys provide a unique opportunity to better understand SARS-CoV-2 transmission and the role of individual characteristics.

Here, we assessed the risk of SARS-CoV-2 acquisition from household and community exposure according to age, family ties, and socioeconomic and living conditions using data from the nationwide population-based EpiCov cohort/ORCHESTRA collaboration in November-December 2020.

Methods

A history of SARS-CoV-2 infection was defined by a positive Euroimmun Anti-SARS-CoV-2 ELISA IgG result in November-December 2020. We applied stochastic chain binomial models fitted to the final distribution of infections in households to data from 17,983 individuals ≥5 years enrolled from 8,165 households. Models estimated the competing risks of being infected from community and household exposure.

Results

Young adults aged 18-24 years had the highest risk of extra-household infection (8.9%, [95% credible interval, Crl]: 7.5 – 10.4), whereas the oldest (>75) and the youngest (6-10) had the lowest risk, 2.6% (1.8 – 3.5) and 3.4% (1.9 – 5.2), respectively. Extra-household infection was also independently associated with socioeconomic conditions. Within households, the probability of person-to-person transmission increased with age: 10.6% (5.0 – 17.9) among 6-10-year-olds to 43.1% (32.6 – 53.2) among 65-74-year-olds. It was higher between partners 29.9% (25.6 - 34.3) and from mother to child 29.1% (21.4 – 37.3) than between individuals related by other family ties.

Conclusion

In 2020 in France, the main factors identified for extra-household infection were age and socioeconomic conditions. Intra-household infection mainly depended on age and family ties.

Key Messages

Young adults aged 18-24 years had the highest probability of extra-household SARS-Cov-2 acquisition over the year 2020: 8.9%, 95% credible interval (95%Crl) 7.5 – 10.4.

The probability of extra-household infection increased with family income and population density in the municipality of residence and was higher in the French regions most affected by the waves of SARS-CoV-2.

When estimating the probability of person-to-person transmission of SARS-CoV-2, the 65-74 year-olds had the highest susceptibility, i.e. the highest probability of SARS-CoV-2 acquisition when exposed to an infected household member (22.1%, 16.4 – 28.2)

The probability of transmission was the highest between partners (29.9%, 25.6 – 34.3). The probability of transmission was higher from mother to child than from father to child: 29.1%, (21.4 – 37.3) and 14.0% (5.9 – 22.8), respectively. The probability of transmission from child to parent was higher from children <12 years than for older children: 11.8% (2.5 – 25.1) and 4.1% (0.9 – 9.0), respectively.
Functional neural architecture of cognitive control mediates the relationship between individual differences in bilingual experience and behaviour
Authors: Carter Felix , DeLuca Vincent , Segaert Katrien , Mazaheri Ali , Krott Andrea
Published: October 2022

Bilinguals have often, but not always, been found to outperform monolinguals on domain-general attentional control. Inconsistent findings have been argued to stem, at least partly, from treating bilingualism as a uniform category and from not considering how neural adaptations to bilingual experiences modulate behavioural outcomes. The present study investigated how patterns of language experience, including language switching behaviour, duration and intensity/diversity of bilingual language use, influence the brain processes underlying cognitive control, and how these in turn translate to cognitive control performance. We examined reaction times and spectral dynamics of the electroencephalograms (EEG) of two-hundred-and-thirty-nine participants (about 70% bilinguals) with diverse language experiences during two cognitive control paradigms testing interference suppression (flanker and Simon task). Using structural equation modelling, we found that different bilingual experience factors were related with neurocognitive measures, which in turn were related with behavioural interference effects, for the flanker but not the Simon task. More specifically, increased frequency of language switching and intensity / diversity of bilingual language usage was negatively related to induced top-down control measures (especially midline-frontal theta), which in turn was beneficial for interference control. In contrast, duration of bilingual engagement correlated negatively with evoked bottom-up control measures (especially P3) and was therefore detrimental to interference control. We demonstrate here for the first time how the different factors of bilingual experience lead to different neural adaptations which impact behavioural outcomes.

Significance statement

Like other intensive experiences, bilingualism leads to brain adaptations. It results in structural changes in language areas, and, due to demands on language control, in brain areas associated with domain-general cognitive control. Related to this, bilinguals often outperform monolinguals on cognitive control tasks. But what is often ignored is that bilingualism is a multi-dimensional phenomenon, with variations such as diversity of language usage and duration of language use. The present large-scale study of neural functioning in bilingualism revealed for the first time how individual differences in bilingual experience lead to adaptations to brain functioning which in turn affect cognitive control behaviour. It exemplifies how the complexity of individual experiences plays a fundamental role in brain function.
Natural variation in Arabidopsis responses toPlasmodiophora brassicaereveals an essential role for RPB1
Authors: Ochoa Juan Camilo , Mukhopadhyay Soham , Bieluszewski Tomasz , Jedryczka Malgorzata , Malinowski Robert , Truman William
Published: October 2022

Despite the identification of clubroot resistance genes in various Brassica crops our understanding of the genetic basis of immunity toPlasmodiophora brassicaeinfection in the model plantArabidopsis thalianaremains limited. To address this issue we performed a screen of 142 natural accessions and identified 11 clubroot resistant Arabidopsis lines. Genome wide association analysis identified several genetic loci significantly linked with resistance. Three genes from two of these loci were targeted for deletion by CRISPR/Cas9 mutation in resistant accessions Est-1 and Uod-1. Deletion ofResistance to Plasmodiophora brassicae 1(RPB1) rendered both lines susceptible to theP. brassicaepathotype P1+. Further analysis ofrpb1knock-out Est-1 and Uod-1 lines showed that the RPB1 protein is required for activation of downstream defence responses, such as the expression of phytoalexin biosynthesis geneCYP71A13. RPB1 has no known functional domains or homology to previously characterised proteins. The clubroot susceptible Arabidopsis accession Col-0 lacks a functionalRPB1gene; when Col-0 is transformed withRPB1expression driven by its native promoter it is capable of activatingRPB1expression in response to infection but this is not sufficient to confer resistance. Constitutive over-expression ofRPB1in Col-0 leads to drastically reduced growth and activation of stress-responsive genes. Furthermore, we found that transient expression ofRPB1inNicotiana tabacuminduced programmed cell death in leaves. We conclude that RPB1 is a critical component of the defence response toP. brassicaeinfection in Arabidopsis, acting downstream of pathogen recognition but required for the elaboration of effective resistance.
Atomic force microscopy evidences the underlying fibrillar formation mechanism of S100A9 neurodegenerative protein family
Authors: Marcuello Carlos
Published: October 2022

Withdrawn reason

The author has withdrawn the manuscript because additional results with complementary techniques are expected to complement the already gathered data and thus, having a more complete overview of the impact of several conditions of interest on the S100A9 fibrillation processes. Therefore, the author do not wish this work to be cited as reference for the project. If you have any questions, please contact with the author.
ASD gene Bcl11a regulates subcellular RNA localization, associative circuitry, and social behavior
Authors: Durak Omer , Kim Ji-Yoon , Tillman Dustin E. , Itoh Yasuhiro , Wettstein Marit R. , Greig Luciano C. , Addison Thomas A. , Macklis Jeffrey D.
Published: October 2022

Precise, area-specific connectivity of interhemispheric callosal projection neurons (CPN) in the cerebral cortex is critical for sensory, associative, and behavioral functions. CPN circuitry, which connects and integrates the cerebral hemispheres via the corpus callosum, is centrally implicated in autism spectrum disorder (ASD) and intellectual disability (ID). Though transcriptional controls regulating CPN subtype and areal development are partially understood, downstream subcellular molecular machinery that implements CPN circuitry is essentially unknown. Here, we identify that the highly penetrant ASD/ID risk gene Bcl11a/Ctip1 is critical developmentally for appropriate and precise areal targeting of superficial layer CPN (CPNSL) projections, and that its deletion strikingly re-routes some CPNSL projections subcortically, causes dramatic disruption to subcellular CPNSL growth cone (GC) molecular machinery, and disrupts social behavior and cognition in mice. CPNSL-specific embryonic deletion of Bcl11a causes loss of correct homotopic targeting in the contralateral cortex, re-routes a substantial proportion of axonal projections through the anterior commissure, and induces strikingly aberrant, but specific and precise, projections to the basolateral amygdala. Importantly, bilateral deletion of Bcl11a from CPNSL results in abnormal social behavior and working memory. Mechanistically, we identify dysregulation of the CPNSL axonal GC-localized transcriptome in Bcl11a nulls, due to either aberrant transcription or trafficking of individual transcripts. These molecular mis-localizations disrupt axon guidance and CPNSL circuitry formation. Together, this work identifies critical functions for Bcl11a in CPNSL axonal connectivity, development of functional associative-social circuitry, and regulation of subtype-specific subcellular molecular machinery in vivo, revealing novel GC-localized transcripts that regulate precise axonal targeting and circuit formation. These results elucidate development and ASD/ID disease-related circuit disruption of CPNSL, and the importance of understanding circuit-specific subcellular molecular machinery by neurons.
Mechanisms underlying divergent relationships between Ca2+and YAP/TAZ signaling
Authors: Khalilimeybodi A. , Fraley S.I. , Rangamani P.
Published: October 2022

Yes-associated protein (YAP) and its homolog TAZ are transducers of several biochemical and biomechanical signals, serving to integrate multiplexed inputs from the microenvironment into higher-level cellular functions such as proliferation, differentiation, apoptosis, migration, and hemostasis. Emerging evidence suggests that Ca2+is a key second messenger that closely connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+have reported contradictory YAP/TAZ responses: In some studies, a reduction in Ca2+influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+influx activates YAP/TAZ. Importantly, Ca2+and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+-mediated YAP/TAZ signaling to investigate how temporal dynamics and crosstalk of signaling pathways interacting with Ca2+can alter YAP/TAZ response, as observed in experiments. By including six signaling modules (e.g., GPCR, IP3-Ca2+, Kinases, RhoA, F-actin, and Hippo-YAP/TAZ) that interact with Ca2+, we investigated both transient and steady-state cell response to Angiotensin II and thapsigargin stimuli. The model predicts stimuli, Ca2+transient, and frequency-dependent relationships between Ca2+and YAP/TAZ primarily mediated by signaling species like cPKC, DAG, CaMKII, and F-actin. Model results illustrate the role of Ca2+dynamics and CaMKII bistable response in switching the direction of changes in Ca2+-induced YAP/TAZ activity for different stimuli. Frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. This study provides new insights into the underlying mechanisms responsible for the controversial Ca2+-YAP/TAZ relationship observed in experiments.
Manganese-dependent microRNA trimming by 3’→5’ exonucleases generates 14-nucleotide or shorter tiny RNAs
Authors: Sim GeunYoung , Kehling Audrey C. , Park Mi Seul , Secor Jackson , Divoky Cameron , Zhang Huaqun , Malhotra Nipun , Bhagdikar Divyaa , El-Wahaband Ekram Abd , Nakanishi Kotaro
Published: October 2022

MicroRNAs (miRNAs) are about 22-nucleotide (nt) non-coding RNAs forming the effector complexes with Argonaute (AGO) proteins to repress gene expression. Although tiny RNAs (tyRNAs) shorter than 19 nt have been found to bind to plant and vertebrate AGOs, their biogenesis remains a long-standing question. Here, our in vivo and in vitro studies show several 3’→5’ exonucleases, such as interferon-stimulated gene 20 kDa (ISG20), three prime repair exonuclease 1 (TREX1), and ERI1 (enhanced RNAi, also known as 3’hExo), capable of trimming AGO-associated full-length miRNAs to 14 nt or shorter tyRNAs. Their guide trimming occurs in a manganese-dependent manner but independently of the guide sequence and the loaded four human AGO paralogs. We also show that ISG20-mediated guide trimming makes Argonaute3 (AGO3) a slicer. Given the high Mn2+ concentrations in stressed cells, virus-infected cells, and neurodegeneration, our study sheds light on the roles of the Mn2+-dependent exonucleases in remodeling gene silencing.
A 3D bioprintable hydrogel with tuneable stiffness for exploring cells encapsulated in matrices of differing stiffnesses
Authors: Du Eric Y. , Jung MoonSun , Skhinas Joanna , Tolentino Maria K. , Jamshidi Niloufar , Houng Jacinta , Tjandra Kristel C. , Engel Martin , Utama Rob , Tilley Richard , Kavallaris Maria , Gooding J. Justin
Published: October 2022

In vitro cell models have undergone a shift from 2D models on glass slides to 3D models that better reflect the native 3D microenvironment. 3D bioprinting promises to progress the field by allowing the high throughput production of reproducible cell-laden structures with high fidelity. As this technology is relatively new, the current stiffness range of printable matrices surrounding the cells that mimics the extracellular matrix environment remains limited. The work presented here aims to expand the range of stiffnesses by utilising a 4-armed polyethylene glycol with maleimide functionalised arms. The complementary crosslinkers comprised a matrix metalloprotease (MMP)-degradable peptide and a 4-armed thiolated polymer which were adjusted in ratio to tune the stiffness. The modularity of this system allows for a simple method of controlling stiffness and the addition of biological motifs. The application of this system in drop-on-demand printing is validated in this work using MCF-7 cells which were monitored for viability and proliferation. This study shows the potential of this system for the high-throughput investigation of the effects of stiffness and biological motif compositions in relation to cell behaviours.
Machine Learning Optimization of Candidate Antibodies Yields Highly Diverse Sub-nanomolar Affinity Antibody Libraries
Authors: Li Lin , Gupta Esther , Spaeth John , Shing Leslie , Jaimes Rafael , Caceres Rajmonda Sulo , Bepler Tristan , Walsh Matthew E.
Published: October 2022

Therapeutic antibodies are an important and rapidly growing drug modality. However, the design and discovery of early-stage antibody therapeutics remain a time and cost-intensive endeavor. In this work, we present an end-to-end Bayesian, language model-based method for designing large and diverse libraries of high-affinity single-chain variable fragments (scFvs). We integrate target-specific binding affinities with information from millions of natural protein sequences in a probabilistic machine learning framework to design thousands of scFvs that are then empirically measured. In a head-to-head comparison with a directed evolution approach, we show that the best scFv generated from our method represents a 28.8-fold improvement in binding over the best scFv from the directed evolution. Additionally, 99% of the designed scFvs in our most successful library are improvements over the initial candidate scFv. By comparing a library’s predicted success to actual measurements, we demonstrate our method’s ability to explore tradeoffs between library success and diversity during the design phase and prior to experimental testing. The results of our work highlight the significant impact machine learning models can have on scFv development. We expect our end-to-end method to be broadly applicable and able to provide value to other protein engineering tasks.
UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer
Authors: Harrington Brittney S. , Kamdar Rahul , Ning Franklin , Korrapati Soumya , Caminear Michael W. , Hernandez Lidia F. , Butcher Donna , Edmondson Elijah , Traficante Nadia ,   Australian Ovarian Cancer Study Group, Gough Madeline , Rogers Rebecca , Lourie Rohan , Shetty Jyoti , Tran Bao , Elloumi Fathi , Abdelmaksoud Abdalla , Lal Nag Madhu , Mazan-Mamczarz Krystyna , House Carrie D. , Hooper John D. , Bowtell David D. L. , Annunziata Christina M.
Published: October 2022

Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix (ECM) and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to delineate UGDH expression in histological and molecular subtypes of EOC. High UGDH expression was observed in the majority of high-grade serous ovarian cancers with variable expression in clear cell, mucinous and endometrioid histotypes. A distinctive prognostic difference was revealed when serous cancers were stratified by molecular subtype, where high UGDH was associated with poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Ovarian cancer cell lines were subtyped according to the molecular subtypes, and we examined the effect of modulating UGDH expression in cell lines representing the C1/Mesenchymal subtype and C4/Differentiated subtypes. Knockdown of UGDH in the C1/Mesenchymal subtype reduced spheroid viability, sphere-formation and the CD133+/ALDH high TIC population. Conversely, overexpression of UGDH in the differentiated subtype enhanced spheroid formation but reduced the TIC population. Inflammatory cytokine expression was altered by UGDH expression. In co-culture models, altering UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins. The effect of UGDH knockdown or overexpression in the C1/Mesenchymal and C4/Differentiated subtypes, respectively, was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH reduced tumor burden in C1/Mesenchymal xenografts compared to controls. These data show that modulation of UGDH expression in tumors influences cells in the microenvironment and reveals distinct roles for UGDH in the mesenchymal and differentiated molecular subtypes of EOC. UGDH is a potential therapeutic target in TICs, for the treatment of metastatic and recurrent EOC, particularly in patients with the mesenchymal molecular subtype.
Surface glia predominantly contribute to the development of ALS/FTD in Drosophila model
Authors: Snow Brittany Anne , Stevenson Ciara Crowley , Kaur Jasdeep , Lee Seung Gee , Wei Yanan , Miao Hongyu , Kim Woo Jae
Published: October 2022

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration in the primary motor neurons. C9orf72 repeat expansion mutation is the most prevalent genetic causes of ALS/FTD. Due to the complexity of ALS, there has been no successful therapy for the condition. The traditional neurocentric concept of ALS derives in part from the assumption that the degradation of motor neuron (MN) cells in ALS is driven by cell-autonomous mechanisms, however, recent research has focused on the non-cell-autonomous pathogenic mechanisms such as glial, immune cells and blood-brain barriers participate in the degeneration of MNs in ALS. Drosophila melanogaster is widely used as a genetic model for ALS, giving essential mechanistic data on disease onset and development. Using newly developed genetic tools to individually mark each subtype of the adult glial system in the fruit fly, we demonstrate that surface glia are the major glial subtypes for the pathogenesis of C9orf72-mediated ALS/FTD.
Comparison of interferometric light microscopy with nanoparticle tracking analysis for the study of extracellular vesicles and bacteriophages
Authors: Sausset Romain , Krupova Zuzana , Guédon Eric , Peron Sandrine , Grangier Alice , Petit Marie-Agnès , De Sordi Luisa , De Paepe Marianne
Published: October 2022

Research on extracellular vesicles (EVs) and bacteriophages (phages) has been steadily expanding over the past decades as many of their roles in medicine, biology, and ecosystems have been unveiled. Such interest has brought about the need for new tools to quantify and determine the sizes of these biological nanoparticles. A new device based on interferometric light microscopy (ILM), the Videodrop, was recently developed for this purpose. Here, we compared this new device to two nanoparticle tracking analysis (NTA) devices, the NanoSight and the ZetaView, for the analysis of EVs and phages. We used EVs isolated from bacteria, fecal samples, bovine milk and human cells, and phages of various sizes and shape, ranging from 30 to 120 nm of diameter. While NTA instruments correctly enumerated most phages, the Videodrop detected only the largest one, indicating a lower sensitivity threshold compared to the NTA devices. Nevertheless, the performance of the Videodrop compared favorably to that of the NTA devices for the determination of the concentration of eukaryotic EV samples. The NanoSight instrument provided the most precise size distributions but the Videodrop was by far the most time-saving device, making it worthy of consideration for studies conducted on a large number of samples.
The plastidial protein MRC promotes starch granule initiation in wheat leaves but delays B-type granule initiation in the endosperm
Authors: Chen Jiawen , Chen Yi , Watson-Lazowski Alexander , Hawkins Erica , Barclay J. Elaine , Fahy Brendan , Denley Bowers Robin , Corbin Kendall , Warren Frederick J. , Blennow Andreas , Uauy Cristobal , Seung David
Published: October 2022

The spatial and temporal patterns by which starch granules initiate vary greatly between species and organs, but molecular factors that contribute to these diverse patterns are poorly understood. We reveal distinct organ-specific roles of the MYOSIN-RESEMBLING CHLOROPLAST PROTEIN (MRC) in regulating granule initiation in the endosperm and leaves of wheat. We isolated three independent TILLING mutants of tetraploid wheat (Triticum turgidumcv. Kronos) with premature stop or missense mutations in the A-genome homeolog, which we showed to be the only active homeolog in tetraploid wheat due to a disruption of the B-genome homeolog. Wheat endosperm contains both large A-type granules initiated during early grain development, and small B-type granules that initiate about 10 – 15 days later. Themrcmutants had significantly smaller A-type granules and a higher relative volume of B-type granules in the endosperm than the wild type. Whereas B-type granules initiated 15 - 20 days post anthesis (dpa) in the wild-type, they appeared as early as 10 dpa in themrc-1mutant, suggesting a role for MRC in suppressing B-type granule initiation during early grain development. By contrast, MRC promotes granule initiation in leaves: mutants carrying premature stop mutations inMRChad fewer granules per chloroplast than the wild type. These contrasting roles of MRC among wheat organs provide new insight into functional diversification of granule initiation proteins, and suggest that they may facilitate the diverse patterns of granule initiation observed across species and organs.
Modeling YAP fusions: a paradigm for investigating rare cancers?
Authors: Sahebjam Solmaz , Gilbert Mark R.
Published: October 2022

Loss of the NF2 tumor suppressor gene is a common finding in meningiomas, and more recently YAP1 fusions have been found in a subset of pediatric NF2 wild-type meningiomas. In the previous issue of Genes & Development, Szulzewsky and colleagues (pp. 857–870) showed that TEAD-dependent YAP1 activity by either the loss of the NF2 gene or YAP1-MAML2 fusion is an oncogenic process promoting meningioma tumorigenesis. Furthermore, pharmacological inhibition of YAP1-TEAD resulted in antitumor activity in both YAP1 fusion-positive and NF2 mutant meningiomas. Together, these data indicate that disruption of the YAP1-TEAD interaction raises a potential therapeutic option for these tumors that requires future investigation.
The gold price – Inflation relation in the case of Vietnam: empirical investigation in the presence of structural breaks
Authors: Duong Thuy Hang
Published: October 2022

Purpose

This paper investigates the relationship between domestic gold prices and inflation in Vietnam based on the monthly series of the gold price index and consumer price index over the period of December 2001–July 2020.

Design/methodology/approach

The co-integration between the domestic gold price and inflation is examined within the autoregressive distributed lag-error correction (ARDL bounds testing) framework. This paper also applies the vector error correction model (VECM) and impulse response function analysis to explore the causal relationship between these two variables. Moreover, since both gold and inflation series are likely to have structural changes over time, a unit root test controlling for significant breaks is employed in this paper.

Findings

Findings from the ARDL bounds testing model suggest the presence of a co-integration between the underlying variables. The VECM indicates that shocks in inflation lead to a negative response to gold prices in the long run. In the short term, only fluctuations in gold prices impact inflation, and this causality is unidirectional.

Research limitations/implications

Gold is regarded as a critical financial asset to preserve wealth from inflation pressure in the case of Vietnam. These findings propose implications for both investors and policymakers.

Originality/value

Empirical results suggest that inflation has a long-term impact on gold prices in the Vietnamese market. In the existence of a permanent inflationary shock, domestic prices of gold respond negatively to this shock; hence, gold can act as a good hedge against inflation in Vietnam.
Use of work-space at home under COVID-19 conditions in the UAE
Authors: Hiyasat Rund , Sosa Marco , Ahmad Lina
Published: October 2022

Purpose

The study assesses user satisfaction of workspaces modified at home in response to the COVID-19 pandemic, thereby analyzing the flexibility of modern homes in the twenty-first century in the United Arab Emirates.

Design/methodology/approach

Data was collected using a structured online survey from 113 participants about their home office created to accommodate working/studying from home. Analysis of survey revealed the importance of type of residence in affecting satisfaction of functionality and well-being.

Findings

The collected demographic variables played a crucial role in affecting satisfaction with various elements, from indoor air quality of the working space to the amount of natural light received by the space. Finally, participants who felt the need to add color and change furniture layout, experienced feelings of productivity, commitment and motivation by working from home. The same participants decided to keep the amended changes to their living spaces, even after they return to working from their offices. The study concludes by presenting implications of this experience on future home designs; thereby offering suggestions of authorities, and designers to produce more flexible and resilient houses.

Research limitations/implications

A relatively small sample with limited professions was considered. Further research recommendations include increasing the sample size to target more categories of the residents of the UAE. Future research can expand the criteria used to evaluate satisfaction and include noise levels as well as accessibility.

Practical implications

The study offers suggestions to authorities and designers to produce more flexible and resilient homes, taking demographics into consideration. Roof gardens, shading devices and privacy needs are crucial elements for the future home.

Originality/value

The research provides enough information to inform designers about the future of space interiors, how well they are configured, serviced and how adaptable they are, in order to enhance user satisfaction.

Highlights

Satisfaction was affected by individual differences.

Those who changed furniture layout showed least average satisfaction.

Females reported higher satisfaction with indoor air quality and lighting than males.
PetroSahand International Group: investigating the reasons for strategy implementation failure – focusing on organization capitals such as alignment, leadership, and organizational culture
Authors: Dehghan Salmasi Soroush , Nasr Arash Khalili , Dadashzadeh Yashar
Published: October 2022

Learning outcomes

After completing the case, students will be able to understand the reasons for the lack of successful strategy implementation in companies, especially engineering, procurement and construction (EPC) and general contractors in Iran’s oil, gas and petrochemical industry; understand the importance of alignment as an organization capital in successful strategy implementation and familiarize themselves with assessing the alignment readiness of companies; understand the importance of leadership as an organization capital in successful strategy implementation, comprehend one of the most essential theories of leadership in the world of management and familiarize themselves with assessing leadership readiness using this theory; and understand the importance of leadership as an organization capital in successful strategy implementation, comprehend one of the most essential models of organizational culture in the world of management and understand how to assess the readiness of organizational culture in companies.

Case overview / synopsis

This case discusses the reasons for strategy implementation failure at PetroSahand International Group, one of the most prominent EPC and general contractors in the oil, gas and petrochemical industry in Iran. This case also examines organization capitals such as alignment, leadership and organizational culture, the three most important factors for the successful implementation of strategies, at this company. PetroSahand is an international, project-oriented company that has been able to successfully complete more than 100 large domestic and international projects during its four decades of activity. However, the company is currently facing many difficulties such as overdue debts and projects.

Complexity academic level

The target audience of this case are graduates and undergraduates in the courses of Strategic Planning, Strategic Management, Strategy Implementation, Strategy in Action and Change Management. Additionally, this case study can be useful for senior managers of companies and can help in the successful implementation of strategies as well as improving their company’s alignment, leadership and organizational culture.

Supplementary materials

Teaching Notes are available for educators only.

Subject code

CSS 11: Strategy.
The effects of fear of missing out on social media posting preferences
Authors: Xi Yue , Huo Jiale , Zhao Xinran , Jiang Yushi , Yang Qiang
Published: October 2022

Purpose

Fear of missing out (FOMO) has become a common phenomenon on social media. This study aims to examine how FOMO influences consumer preferences for posting about identity-relevant products on social media.

Design/methodology/approach

In this research, three studies were conducted to explore the effects of FOMO in different real-life situations. Study 1 was conducted in a laboratory setting in China. Study 2 includes two experiments, one that was conducted in China and one in the USA. Study 3 was conducted in a workplace setting in China.

Findings

The results of Study 1 indicate that when consumers experience FOMO, they prefer to post about identity-relevant (vs functional) products to a greater extent than usual. Study 2 examines the role of self-esteem and identifies self-presentation and the avoidance of social attention as underlying mechanisms. Thus, consumers with high (or low) self-esteem tend to be more motivated to present themselves positively (or to avoid social attention) when experiencing FOMO. Furthermore, Study 3 reveals the moderating role of supportive interactions; that is, the interaction between FOMO and consumer self-esteem is most likely to exert an effect when consumers receive many supportive interactions.

Research limitations/implications

This research demonstrates that posting identity-relevant content on social media is a coping strategy that individuals may adopt when experiencing FOMO. Moreover, self-esteem can predict how individuals cope with FOMO by identifying self-presentation and avoidance of social attention as the mechanisms underlying effects. Although this research attempts to avoid interference from other factors between in the relationship FOMO and the control conditions, it seems possible that more socially relevant information may be presented in the FOMO condition.

Practical implications

Because FOMO can be manipulated and posting types can be predicted, this research provides important implications for brands on how to create or post content to better engage consumers.

Originality/value

This research supports the role of FOMO as a driver of on consumer posting preferences on social media.
Actores sociales construyendo visiones comunitarias en el sur global
Authors: Vargas Lama Fredy
Published: October 2022

Propósito

Identificar los aspectos que los Actores Sociales consideran en la construcción de futuros compartidos en las comunidades. En su aplicación en los países emergentes, especialmente en el Sur Global, a menudo se pasan por alto las particularidades socioculturales de las comunidades y los actores, generando fricciones o conflictos sociales. Este artículo presenta dos elementos críticos que contribuyen al debate: a) la importancia de entender a los Actores Sociales dentro de un modelo de generación de futuros comunitarios en los países emergentes; b) los factores relevantes que influyen en los actores en un ejercicio de construcción de futuros en las comunidades.

Diseño/metodología/enfoque

A partir de la investigación cualitativa, se utilizó un estudio de caso de prospectiva comunitaria del futuro: El futuro de Puerto Gaitán 2037 (Meta, Colombia). Se aplicó un método de recolección de información a partir de la observación de los participantes y el análisis de la documentación. El método de análisis fue el DQA (Análisis Cualitativo Deductivo).

Hallazgos

La participación de Los Actores Sociales presenta un modelo de cinco elementos relevantes que influyen en los actores para la construcción exitosa de futuros en las comunidades. Los primeros cuatro factores, revelados por la teoría, existen en la realidad. Asimismo, se demuestra un quinto factor: el Pensamiento a Largo Plazo, que se evidencia en un Modelo de aplicación de Estudios de Futuros para el contexto específico, aplicable al caso de comunidades en países del Sur Global.

Originalidad/valor

Si bien existen ejemplos aislados de recomendaciones respecto a estudios para generar el futuro de las comunidades, este es el primer estudio que presenta factores concretos que contribuyen a orientar la construcción de futuros comunitarios desde Actores Sociales, especialmente en países del Sur Global como Colombia. También es uno de los primeros estudios en utilizar el DQA como método de análisis en un tema de Estudios de Futuros.