bluuebunny/crossref_metadata_2025 huggingface dataset:
PAXfusion proteins deregulate gene networks controlling mitochondrial translation in pediatric rhabdomyosarcoma
Authors: Kalita Bhargab , Martinez-Cebrian Gerard , McEvoy Justina , Allensworth Melody , Knight Michelle , Magli Alessandro , Perlingeiro Rita C R , Dyer Michael A. , Stewart Elizabeth , Dynlacht Brian David
Published: August 2024

Alveolar rhabdomyosarcoma (ARMS) patients harboring PAX3-FOXO1 and PAX7-FOXO1 fusion proteins exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood cancer. To uncover mechanisms that contribute to tumor initiation, we developed a novel muscle progenitor model and used epigenomic approaches to unravel genome re-wiring events mediated by PAX3/7 fusion proteins. Importantly, these regulatory mechanisms are conserved across established ARMS cell lines, primary tumors, and orthotopic-patient derived xenografts. Among the key targets of PAX3- and PAX7-fusion proteins, we identified a cohort of oncogenes, FGF receptors, and genes essential for mitochondrial metabolism and protein translation, which we successfully targeted in preclinical trials. Our data suggest an explanation for the relative paucity of recurring mutations in this tumor, provide a compelling list of actionable targets, and suggest promising new strategies to treat this tumor.
Activated Interferon Signaling Suppresses Age-Dependent Liver Cancer
Authors: Havas Aaron P. , Lande Kathryn , Rajesh Adarsh , Evensen K. Garrett , Varanasi Siva Karthik , Shang Linshan , Schmidt Elizabeth , Lee Jin , Kim Kenneth , Teneche Marcos Garcia , Hoffmann Filipe , LaPorte Michael , Davis Andrew , Grier Abby , Reisz Julie A. , Tharp Kevin , Gandhi Armin , Lei Xue , Proulx Jessica , Miller Karl N. , Sacco Alessandra , Shadel Gerald S. , Niedernhofer Laura , Feng Gen-Sheng , D’Alessandro Angelo , Kaech Susan , Williams April , Adams Peter D.
Published: August 2024

Age is a major risk factor for liver cancer, as is the case for most adult human cancers. However, the underlying mechanisms are not well defined. A better understanding of the role of aging in liver and other cancers can facilitate approaches for risk assessment, early detection and prevention. We hypothesize that age-driven changes render aged liver more sensitive to oncogenic stress and hence tumorigenesis. To investigate how the liver changes with age, we documented the immune profile, transcriptome and epigenome of healthy livers from both young and aged mice, revealing pronounced alterations with aging. Notably, in aged hepatocytes, we identified heightened interferon (IFN) signaling, as well as simultaneous tumor suppressor and oncogene signaling at both bulk and single cell level, suggestive of an aged liver that is poised for neoplasia. To challenge this seemingly poised state, we employed adeno-associated virus (AAV)-mediated expression of a c-Myc oncogene in young and aged mouse liver hepatocytesin vivo. Analysis of aged hepatocytes expressing c-Myc revealed further elevated expression of IFN Stimulated Genes (ISGs). This ISG upregulation was evident in multiple models of oncogenic stress and transformation in older mice and also observed in aged humans with Metabolic dysfunction-Associated Steatohepatitis (MASH). We determined that Stat1 is both necessary and sufficient for the age specific elevated ISG expression in old wild type mice. Remarkably, inhibiting Jak/Stat signaling alongside ectopic c-Myc expression led to high-grade hepatocyte dysplasia and tumor formation, selectively in aged mice. Together, these results suggest that an aged liver is in a state of “precarious balance”, due to concurrent activation of oncogenic and tumor suppressor pathways, but protected against neoplastic progression by IFN-signaling. Age-dependent activation of IFN signaling has been observed in many tissues and recent studies have demonstrated its detrimental consequences on aging, raising the question as to why IFN-signaling is activated during aging. We propose that aged tissues are intrinsically at higher risk of cancer and age-dependent activation of IFN-signaling is an adaptive process to protect from tumorigenesis, but one that also has maladaptive consequences.
Using virtual patient cohorts to uncover immune response differences in cancer and immunosuppressed COVID-19 patients
Authors: Gazeau Sonia , Deng Xiaoyan , Brunet-Ratnasingham Elsa , Kaufmann Daniel E. , Larochelle Catherine , Morel Penelope A. , Heffernan Jane M. , Davis Courtney L. , Smith Amber M. , Jenner Adrianne L. , Craig Morgan
Published: August 2024

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in millions of deaths globally. Adults with immunosuppression (e.g., solid organ transplant recipients) and those undergoing active cancer treatments experience worse infections and more severe COVID-19. It is difficult to conduct clinical studies in these populations, resulting in a restricted amount of data that can be used to relate mechanisms of immune dysfunction to COVID-19 outcomes in these vulnerable groups. To study immune dynamics after infection with SARS-CoV-2 and to investigate drivers of COVID-19 severity in individuals with cancer and immunosuppression, we adapted our mathematical model of the immune response during COVID-19 and generated virtual patient cohorts of cancer and immunosuppressed patients. The cohorts of plausible patients recapitulated available longitudinal clinical data collected from patients in Montréal, Canada area hospitals. Our model predicted that both cancer and immunosuppressed virtual patients with severe COVID-19 had decreased CD8+ T cells, elevated interleukin-6 concentrations, and delayed type I interferon peaks compared to those with mild COVID-19 outcomes. Additionally, our results suggest that cancer patients experience higher viral loads (however, with no direct relation with severity), likely because of decreased initial neutrophil counts (i.e., neutropenia), a frequent toxic side effect of anti-cancer therapy. Furthermore, severe cancer and immunosuppressed virtual patients suffered a high degree of tissue damage associated with elevated neutrophils. Lastly, parameter values associated with monocyte recruitment by infected cells were found to be elevated in severe cancer and immunosuppressed patients with respect to the COVID-19 reference group. Together, our study highlights that dysfunction in type I interferon and CD8+ T cells are key drivers of immune dysregulation in COVID-19, particularly in cancer patients and immunosuppressed individuals.
Thermodynamic modeling of Csr/Rsm- RNA interactions capture novel, direct binding interactions across thePseudomonas aeruginosatranscriptome
Authors: Lukasiewicz Alexandra J , Leistra Abigail N , Hoefner Lily , Monzon Erika , Gode Cindy J , Zorn Bryan T , Janssen Kayley H , Yahr Timothy L , Wolfgang Matthew C , Contreras Lydia M
Published: August 2024

Background

Pseudomonas aeruginosa(PA) is a ubiquitous, Gram-negative, bacteria that can attribute its survivability to numerous sensing and signaling pathways; conferring fitness due to speed of response. Post-transcriptional regulation is an energy efficient approach to quickly shift gene expression in response to the environment. The conserved post-transcriptional regulator RsmA is involved in regulating translation of genes involved in pathways that contribute to virulence, metabolism, and antibiotic resistance. Prior high-throughput approaches to map the full regulatory landscape of RsmA have estimated a target pool of approximately 500 genes; however, these approaches have been limited to a narrow range of growth phase, strain, and media conditions. Computational modeling presents a condition-independent approach to generating predictions for binding between the RsmA protein and highest affinity mRNAs. In this study, we draft a two-state thermodynamic model to predict the likelihood of RsmA binding to the 5’ UTR sequence of genes present in the PA genome.

Results

Our modeling approach predicts 1043 direct RsmA-mRNA binding interactions, including 457 novel mRNA targets. We then perform GO term enrichment tests on our predictions that reveal significant enrichment for DNA binding transcriptional regulators. In addition, quorum sensing, biofilm formation, and two-component signaling pathways were represented in KEGG enrichment analysis. We confirm binding predictions usingin vitrobinding assays, and regulatory effects usingin vivotranslational reporters. These reveal RsmA binding and regulation of a broader number of genes not previously reported. An important new observation of this work is the direct regulation of several novel mRNA targets encoding for factors involved in Quorum Sensing and the Type IV Secretion system, such asrsaLandmvaT.

Conclusions

Our study demonstrates the utility of thermodynamic modeling for predicting interactions independent of complex and environmentally-sensitive systems, specifically for profiling the post-transcriptional regulator RsmA. Our experimental validation of RsmA binding to novel targets both supports our model and expands upon the pool of characterized target genes in PA. Overall, our findings demonstrate that a modeling approach can differentiate direct from indirect binding interactions and predict specific sites of binding for this global regulatory protein, thus broadening our understanding of the role of RsmA regulation in this relevant pathogen.
Clearing the air on pollutant disruptions of the gut-brain axis: Developmental exposure to Benzo[a]pyrene disturbs zebrafish behavior and the gut microbiome in adults and subsequent generations
Authors: Alexiev Alexandra , Stretch Ebony , Kasschau Kristin D. , Wilson Lindsay B. , Truong Lisa , Tanguay Robyn L. , Sharpton Thomas J.
Published: August 2024

Developmental exposure to benzo[a]pyrene (BaP), a ubiquitous environmental pollutant, has been linked to various toxic effects, including neurodegenerative disorders and, most recently, multigenerational behavioral impairment. While the specific mechanisms driving BaP neurotoxicity are not fully understood, recent work highlights two important determinants of developmental BaP neurotoxicity: (1) the aryl hydrocarbon receptor (AHR), which is responsible for inducing host metabolism of BaP, and (2) the gut microbiome, which may interact with BaP to affect its metabolism, or be perturbed directly by BaP to yield disruptions to the gut-brain axis. To explore the role of AHR, the gut microbiome, and their interaction on BaP-induced neurotoxicity, we utilized the zebrafish model. We sought to determine (1) how exposure to BaP and developmental expression of AHR2, a key gene in the zebrafish AHR pathway, link to adult zebrafish behavior, (2) how these same variables associated with the structure and function of the adult zebrafish gut metagenome, and (3) whether these associations were multigenerational. This finding revealed a reticulated axis of association between BaP exposure, developmental AHR2 expression, the zebrafish gut metagenome, and behavior. Our results also indicate that AHR2 is a key mediator of how BaP elicits neurotoxicity and microbiome dysbiosis. Additionally, this axis of association manifests inter- and transgenerationally, suggesting that exposure to BaP may yield dysbiotic and neurodevelopmental impacts on subsequent generations. These findings demonstrate the power of utilizing the zebrafish model to study pollutant-metagenome interactions and elucidate the role of specific host genes in the neurotoxicity and dysbiosis.

Importance

Benzo[a]pyrene (BaP) is a toxic chemical that is especially ubiquitous in industrialized nations, as it is produced in large quantities by burning coal, oil, and other organic compounds. Early-life andin uteroexposure to this chemical can induce adverse behavior changes in model animals, like mice and zebrafish. In humans, developmental exposure is linked to symptoms of ADHD, anxiety, and depression. This study found BaP affects zebrafish behavior and the gut microbiome throughout their life and across subsequent generations. We further discovered that a host regulatory pathway called the aryl hydrocarbon receptor is a key component of how benzo[a]pyrene, the gut microbiome, and behavior interconnect. The aryl hydrocarbon receptor binds many toxicants, as well as microbial metabolites associated with maintaining gut homeostasis, and regulates the gut-brain connection. This receptor presents a new potential mechanism of how gut microbiota relate to BaP exposure and behavior for future studies to investigate.
Evaluation of vectors for gene expression inPseudovibriomarine bacteria
Authors: Dai Yitao , Eustáquio Alessandra S.
Published: August 2024

α-Proteobacteria belonging to thePseudovibriogenus have been isolated from different marine organisms including marine sponges, corals and algae. This genus was first described in 2004 and has since garnered attention due to the potential ecological relevance and biotechnological application of its metabolites. For instance, we recently reported specialized metabolites we named pseudovibriamides fromPseudovibrio brasiliensisAb134. The pseudovibriamide encodingpppgene cluster is found in two thirds ofPseudovibriogenomes. Pseudovibriamides coordinate motility and biofilm formation, behaviors that are known to be important for host colonization. Although we previously established reverse genetics methods to delete genes via homologous recombination, no self-replicative vectors have been reported forPseudovibrio. We show that plasmid vectors containing two different broad-host-range replicons, RSF1010 and pBBR1, can be used inP. brasiliensis. The efficiency of vector transfer by electroporation averaged ∼ 3 × 103CFU/µg plasmid DNA whereas the conjugation frequency fromE. coliranged from 10-3to 10-6. We then tested the vectors for fluorescent protein expression and consequent labeling, which allowed us to observe their effects on swarming motility and to compare plasmid stability. This study expands the genetic toolbox available forPseudovibriowhich is expected to enable future ecological and biotechnological studies.

Importance

The genusPseudovibrioof α-Proteobacteria has consistently been isolated from marine sponges and other marine organisms such as corals and algae.Pseudovibriobacteria are a source of antibiotics and other secondary metabolites with the potential to be developed into pharmaceuticals. Moreover, the secondary metabolites they produce are important for their physiology and for interactions with other organisms. Here we expand the genetic tool box available forPseudovibriobacteria by establishing self-replicative vectors that can be used for the expression of e.g., fluorescent proteins. The availability of genetic tools is important to enable us to explore the emerging ecological and biotechnological potential ofPseudovibriobacteria.
Dysbiosis-associated gut bacteriumRuminococcus gnavusvaries at the strain level in ability to utilize key mucin component sialic acid
Authors: Sokolovskaya Olga M. , Uzunovic Jasmina , Peng Yutian , Okumura Mikiko , Wang Lingjue Mike , Zhou Yuhui , Lai Zijuan , Skippington Elizabeth , Tan Man-Wah
Published: August 2024

Ruminococcus gnavusis a prevalent human gut commensal bacterium with known roles in intestinal mucus degradation, including by catabolism of the terminal mucin sugar sialic acid. WhileR. gnavusis not considered a pathogen, overabundance of this species is correlated with Inflammatory Bowel Disease (IBD), and its sialic acid metabolism may play a role in the dysbiotic state. Interestingly, liberation of mucin-bound sialic acid byR. gnavusyields the distinct product of 2,7-anhydro-N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), in contrast to other known mucin-degrading bacteria, which generate Neu5Ac. This prompted us to look for 2,7-anhydro-Neu5Ac metabolism proteins in the genomes of 77R. gnavusclinical isolates. We found that 2,7-anhydro-Neu5Ac metabolism is sporadically distributed in this species with respect to phylogeny and strain origin. We measured sialic acid-dependent growth of 12 sequenced isolates, finding that the presence of 2,7-anhydro-Neu5Ac catabolism proteins was predictive of growth on this substrate. Our analysis also uncovered “partial” 2,7-anhydro-Neu5Ac catabolism pathways in twoR. gnavusstrains, which we determined constitute the canonical Neu5Ac catabolism pathway, previously unreported in this species. These results reveal a notable diversity of sialic acid catabolism across theR. gnavusspecies, an essential consideration for further investigations into the importance of this metabolism in mucin degradation and in roles ofR. gnavusin IBD and other gut dysbioses.
Effects of short-term isolation on vocal and non-vocal social behaviors in prairie voles
Authors: Madrid Jesus E. , Pranic Nicole M. , Chu Samantha , Bergstrom Johanna J. D. , Singh Rhea , Rabinovich Joclin , Lopez Kaycee Arias , Ophir Alexander G. , Tschida Katherine A.
Published: August 2024

Social isolation affects the brain and behavior in a variety of animals, including humans. Studies in traditional laboratory rodents, including mice and rats, have supported the idea that short-term social isolation promotes affiliative social behaviors, while long-term isolation promotes anti-social behaviors, including increased aggression. Whether the effects of isolation on the social behaviors of mice and rats generalize to other rodents remains understudied. In the current study, we characterized the effects of short-term (3-days) social isolation on the vocal and non-vocal social behaviors of adult prairie voles (Microtus ochrogaster) during same-sex and opposite-sex social interactions. Our experiments revealed that short-term isolation did not affect rates of ultrasonic vocalizations or time spent in non-aggressive social behaviors and huddling. In contrast, short-term isolation affected aggression in a sex- and context-specific manner during male-male interactions. Our findings highlight the importance of comparative work across species and the consideration of social context to understand the diverse ways in which social isolation can impact social behavior.
Genomic and phenotypic characterization of an Oropouche virus strain implicated in the 2023-24 large-scale outbreak in Brazil
Authors: Azevedo Elisa de Almeida Neves , da Silva Alexandre Freitas , da Silva Verônica Gomes , Machado Lais Ceschini , de Lima Gustavo Barbosa , Ishigami Bruno Issao Matos , Silva Keilla Maria Paz e , da Costa Mayara Matias de Oliveira Marques , Falcão Diego Arruda , Vasconcelos Andreza Pâmela , da Silva Clintiano Curvêlo , Naveca Felipe Gomes , Bezerra Matheus Filgueira , de Lima Campos Tulio , Acioli-Santos Bartolomeu , Paiva Marcelo Henrique Santos , Morais Clarice Neuenschwander Lins de , Wallau Gabriel Luz
Published: August 2024

TheOrthobunyavirus oropoucheensein a arthropod borne zoonotic pathogen known to infect sylvatic animals and humans by means of biting midges transmission. Several large-scale human outbreaks of Oropouche virus (OROV), primarily confined to the Amazon region, were documented over the decades. However, since 2022, more widespread OROV outbreaks have been unfolding in Brazil and across South America, with cases exported to Cuba, Italy, and Germany. I In Brazil, the virus has reached and established communitary transmission in states from all major regions of the country. Here we isolated, characterized the cytopathic effect and the full genomic sequence of two OROV isolates from the current outbreak. Our data shows that OROV can readily infect and replicate in non-human primate cells, supporting the role of non-human primates as important reservoirs. Phylogenetic data supports a direct introduction of the same lineages causing the 2022-24 outbreak in Brazil from the Amazonas state, the epicenter of the epidemics in Brazil. Lastly, as case counts accumulate in the state and the Northeast region, clear evidence supports established and sustained transmission. Continued studies are critical to understand the transmission cycle in this region, the most important vectors and reservoirs, to appropriately deploy control measures.
Endocytic dynamin deficiency impairs the host colonization of phytopathogenic fungi
Authors: Chen Xin , Chen Xiaomin , Long Yunfei , Fang Zhenyu , Abubakar Yakubu Saddeeq , Zheng Huawei , Wang Zonghua , Zheng Wenhui
Published: August 2024

Abstract

During host-pathogen interactions, pathogens employ endolysosomal trafficking to fine-tune host and environmental cues, facilitating disease progression. Inhibiting the functions of the endolysosomal network could be promising for the control of plant fungal diseases. Herein, we showed that inhibition of the endocytic dynamin FgVps1 by the phenothiazines chlorpromazine (CPZ) and prochlorperazine (PCZ) leads to endolysosomal dysfunction. Further analyses revealed that the phenothiazines directly bind the GTPase domain of FgVps1 to inhibit its activity. Moreover, our results showed that FgVps1 is recruited to the endosome by the Rab GTPases FgRab51 and FgRab7 to facilitate the release of retromer- and sorting nexin-coated vesicles, thereby ensuring the proper recycling of some cargos and promoting fungal development and pathogenicity. Direct treatment of the phytopathogensF. graminearum,Magnaporthe oryzaeandFusarium oxysporum f. sp. cubensewith CPZ and PCZ also impairs their growth, development and virulence. These results unveil the underlying mechanisms of endocytic dynamin actions and provide a potential strategy for broad-spectrum control of phytopathogenic fungi.
Membrane bound geranylated RNAs establish a primitive peptide synthesis system
Authors: Chan Chun-Yin , Singer Johannes , Carell Thomas
Published: August 2024

The origin of an RNA-based translation system necessitates a specific interaction of certain RNAs with defined amino acids. This must have happened in a protocellular environment where these molecules were concentrated so that a connection between the encoding RNA and the amino acids could be established that allowed the formation of peptides. A model of how such a system could have evolved does not exist. Here we show that geranylated non-canonical nucleotides that are potential fossils in an early RNA world, allow RNA to anchor to lipid membranes. This creates RNA-geranylating lipids on which a primitive peptide synthesis can then operate with rudimentary chemoselectivity. The system creates a protocellular model of how RNAs and amino acids could have been mutually selected based on their physicochemical properties.
Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders
Authors: Newton Fay , Halachev Mihail , Nguyen Linda , McKie Lisa , Mill Pleasantine , Megaw Roly
Published: August 2024

Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.
Monoacylglycerol acyltransferase maintains ionotropic receptor expression for cool temperature sensing and avoidance inDrosophila
Authors: Deng Xiangmei , Suito Takuto , Tominaga Makoto , Sokabe Takaaki
Published: August 2024

Sensory inputs of temperature dynamics in the environment are essential for appropriate physiological outputs. The responsiveness of sensory neurons is maintained by functional thermosensor expression. However, the mechanism by which their expression is regulated is unclear. In this study, we identified a monoacylglycerol acyltransferase-coding gene namedbishu-1that contributes to maintaining the responsiveness of cool temperature sensing neurons inDrosophila.bishu-1mutation led to abnormal thermal avoidance in a cool temperature range. Cooling-induced responses in dorsal organ cool cells were weakened by the absence ofbishu-1, and this was associated with reduced transcription of the ionotropic receptorsIR25aandIR21athrough the transcription factorbroad. Our findings unveil a novel link between lipid metabolism and thermosensor function, thus providing new insights into mechanisms underlying the appropriate maintenance of sensory inputs.
Predatory aggression evolved through adaptations to noradrenergic circuits
Authors: Eren Güniz Goze , Böger Leonard , Roca Marianne , Hiramatsu Fumie , Liu Jun , Alvarez Luis , Goetting Desiree , Zorn Nurit , Han Ziduan , Okumura Misako , Scholz Monika , Lightfoot James W.
Published: August 2024

Behaviors are adaptive traits evolving through natural selection. Crucially, the genetic, molecular, and neural modifications that shape behavioral innovations are poorly understood. Here, we identify specialized adaptations linked to the evolution of aggression in the predatory nematodePristionchus pacificus. Using machine learning, we identified robust behavioral states associated with aggressive episodes. These depend on modifications to the invertebrate noradrenergic pathway, with octopamine promoting predatory bouts, and tyramine antagonistically suppressing predation. Strikingly, aggression coincides with rewiring of key circuits across nematode evolution. We find additional octopaminergic neurons with morphological adaptations, including neurites extending to teeth-like structures, and expanded receptor expression throughout head sensory neurons gating prey detection. Thus, evolutionary adaptations in noradrenergic circuits facilitated the emergence of aggressive behavioral states associated with complex predatory traits.
Identification of anthelmintic activity in a small chemical library through random screening using the wormCaenorhabditis elegansas a model helminth
Authors: Gajera Gemini , Kothari Vijay
Published: August 2024

Parasitic helminths contribute notably to the global infection burden, particularly in developing and underdeveloped nations. Anthelmintic agents currently available for therapeutic purpose are not many in number, and owing to development of resistance against them among parasitic worms, their utility spectrum is also shrinking. Hence, there is an urgent need for discovery of new anthelmintic compounds. This study subjected a small library of 181 compounds to a random screening for identification of compounds with anthelmintic activity against the model wormCaenorhabditis elegans. This screening effort identified 50 compounds capable of killing 100% of the worm population in less than 24 hours, at 25-50 ppm. Further investigation on these ‘hits’ is warranted to identify potential anthelmintic ‘leads’.
Structural mechanism of MUC5AC mucin net-like polymer formation and its SNP variability that affect risk of the lung diseases COPD and IPF
Authors: Trillo-Muyo Sergio , Ermund Anna , Magnusson Jesper M. , Hansson Gunnar C.
Published: August 2024

Gel-forming mucins MUC5AC and MUC5B constitute the main structural component of the mucus in the respiratory system. Secreted mucins interact specifically with each other and other molecules giving mucus specific properties. We determined the cryoEM structures of the wild type MUC5AC-D3 assembly and the structural SNP variants R996Q and R1201W. Our structures explain the basis of MUC5AC N-terminal non-covalent oligomerization upon secretion. The MUC5AC-D3 assembly forms covalent dimers in two alternative conformations, open and closed. The closed conformation dimers interact through an arginine rich loop in the TIL3 domain forming tetramers. Moreover, we found a positive disease correlation between the SNP (R996Q, rs878913005), Chronic Obstructive Pulmonary Disease (COPD), and Idiopathic Pulmonary Fibrosis (IPF). The well-known MUC5B promotor SNP (rs35705950) association with IPF is much stronger when combined with the MUC5AC SNP. Our study provides a model to explain the formation of MUC5AC net-like structures and how both SNPs will affect mucus organization and increase risk of lung disease.
Word-selective EEG/MEG responses in the English language obtained with Fast Periodic Visual Stimulation (FPVS)
Authors: Hauk O , Marchive M , Volfart A , Schiltz C , Rossion B , Lambon Ralph MA , Lochy A
Published: August 2024

Fast periodic visual stimulation (FPVS) allows the recording of objective brain responses of human word discrimination (i.e., reproducible word-category-selective responses) with a high signal-to-noise ratio. This approach has been successfully employed over the last decade in a number of scalp electroencephalography (EEG) studies. Three important advances were achieved in this study: (1) robust measures of written word-selective responses with this approach have not been reported in English; (2) responses have only been reported in EEG but not with MEG, and (3) without source localization. Thus, we presented English words periodically (2 Hz) among different types of letter strings (10Hz; consonant strings, non-words, pseudowords) whilst recording simultaneous EEG and MEG in 25 participants who performed a simple non-linguistic color detection task. Data were analyzed in sensor and in source space (L2-minimum-norm estimation, MNE). With only 4 minutes of stimulation we observed a robust word discrimination response in each condition including, importantly, even when words were embedded in word-like pseudowords. This response was larger in nonwords and largest in consonant strings. We observed left-lateralized responses in all conditions in the majority of our participants. Cluster-based permutation tests revealed that these responses were left-lateralized in sensor as well as in source space, with peaks in left posterior regions. Our results demonstrate that the FPVS paradigm can elicit robust English word-discrimination responses in EEG and MEG within only a few minutes of recording time. Together with source estimation, this can provide novel insights into the neural basis of visual word recognition in healthy and clinical populations.
E2F3-dependent activation of FAM111B restricts mouse cytomegalovirus replication in primate cells
Authors: Ostermann Eleonore , Luoto Laura-Marie , Clausen Michaela , Virdi Sanamjeet , Brune Wolfram
Published: August 2024

Cytomegaloviruses are highly species-specific as they replicate only in cells of their own or a closely related species. For instance, human cytomegalovirus cannot replicate in rodent cells, and mouse cytomegalovirus (MCMV) cannot replicate in human and monkey cells. However, the mechanisms underlying the host species restriction remain poorly understood. We have previously shown that passaging MCMV in human retinal pigment epithelial cells allows the virus to replicate to high titers in these cells due to the accumulation of adaptive mutations, such as loss-of-function mutations in the viral M117 gene. The M117 protein interacts with E2F transcription factors and activates E2F-dependent transcription. Here we show that activation of E2F3 is primarily responsible for MCMV’s inability to replicate in human cells. By transcriptome analysis, we identified two E2F3-induced serine proteases, FAM111A and FAM111B, as potential host restriction factors. By using shRNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout, we demonstrated that FAM111B, but not its paralog FAM111A, suppresses MCMV replication in human and rhesus macaque cells. By immunofluorescence, we detected FAM111B predominantly in the nucleus of infected cells with enrichment in viral replication compartments, suggesting that it might play a role during viral replication. The fact that the FAM111B gene is conserved in primates but absent in rodents suggests that MCMV has not evolved to evade or counteract this restriction factor, which is not present in its natural host.

Importance

Viruses must counteract host cell defenses to facilitate viral replication. Viruses with a narrow host range, such as the cytomegaloviruses, are unable to counteract cellular defenses in cells of a foreign species. However, little is known about the cellular host range factors restricting cytomegalovirus replication. Here we show that MCMV induces the expression of the FAM111 proteases and that FAM111B, but not FAM111A that has previously been shown to restrict the replication of polyomavirus and orthopoxvirus host range mutants, acts as a cellular factor suppressing MCMV replication in human and rhesus monkey cells. The identification of FAM111B as a host range factor should provide new insight into the physiological functions of this poorly characterized protein.
Development of a latency model based on HIV-1 subtype C to study how long terminal repeat genetic variation impacts viral persistence and latency reversal
Authors: Maikoo Shreyal , Palstra Robert-Jan , Dong Krista L. , Mahmoudi Tokameh , Ndung’u Thumbi , Madlala Paradise
Published: August 2024

Most people living with HIV (PLWH) reside in sub-Saharan Africa. South Africa is the epicentre where 98% of HIV-1 infections are subtype C. However, partially due to unavailability of non-subtype B latency models, most studies of HIV-1 latency and cure have focused on HIV-1 subtype B (HIV-1B) which predominates Europe and USA. Moreover, the effect of inter- and intra-subtype genetic variation of the viral promoter, long terminal repeat (LTR), from PLWH on latency reversal is unknown. We constructed a retroviral vector expressing green fluorescent protein and HIV-1 subtype C (HIV-1C) consensus Tat protein under the control of either HIV-1C consensus or PLWH-derived transmitted/founder (T/F) LTR, produced respective LTR pseudotyped viruses, infected Jurkat E6 and primary CD4+ T cellsin vitro, enriched for latently infected cells, and treated these cells with different latency reversing agents. We show that the HIV-1C LTR exhibited lower reactivation compared to HIV-1B. Furthermore, HIV-1C T/F LTR pseudotyped proviral variants with four NF-κB motifs exhibited lower reactivation compared to those with three NF-κB motifs. Our data indicate that inter- and intra-subtype HIV-1 LTR genetic variation in combination with host variation modulates latency reversal.

Author summary

Antiretroviral therapy (ART) suppresses HIV-1 replication, but it is not curative due to a persistent latent reservoir established early in infection. Although HIV-1 subtype C (HIV-1C) is responsible for about 50% of global and 98% of southern Africa infections, it is underrepresented in HIV-1 cure studies. The unavailability of non-subtype B latency models has led to most studies on HIV-1 latency and cure focusing on HIV-1 subtype B (HIV-1B) which predominates in western countries. The viral promoter, long terminal repeat (LTR) drives viral gene transcription and is important for the HIV-1 life cycle. In this study we undertook to develop a latency model based on HIV-1 subtype C to investigate the effect of inter- and intra- LTR genetic variation on viral persistence and latency reversal. Our data show that the HIV-1C LTR exhibited lower reactivation compared to HIV-1B. Furthermore, HIV-1C T/F LTR pseudotyped proviral variants with four NF-κB motifs exhibited lower reactivation compared to those with three NF-κB motifs. Taken together, our data suggest that inter- and intra-subtype HIV-1 LTR genetic variation in combination with host variation modulates latency reversal.
TheStreptococcus agalactiaeLytSR two-component regulatory system promotes vaginal colonisation and virulencein vivo
Authors: AlQadeeb Hajar , Baltazar Murielle , Cazares Adrian , Poonpanichakul Tiraput , Kjos Morten , French Neil , Kadioglu Aras , O’Brien Marie
Published: August 2024

Streptococcus agalactiae(or Group BStreptococcus, GBS) is a leading cause of neonatal sepsis and meningitis globally. To sense and respond to variations in its environment, GBS possesses multiple two-component regulatory systems (TCSs) such as LytSR. Here, we aimed to investigate the role of LytSR in GBS pathogenicity. We generated an isogeniclytSknockout mutant in a clinical GBS isolate and used a combination of phenotypic in vitro assays and in vivo murine models to investigate the contribution oflytSto the colonisation and invasive properties of GBS. Deletion of thelytSgene in the GBS chromosome resulted in significantly higher survival rates in mice during sepsis, accompanied by reduced bacterial loads in blood, lung, spleen, kidney and brain tissue compared to infection with the wild-type strain. In a mouse model of GBS vaginal colonisation, we also observed that thelytSknockout mutant was cleared more readily from the vaginal tract compared to its wild-type counterpart. Interestingly, lower levels of proinflammatory cytokines were found in the serum of mice infected with thelytSmutant. Our results demonstrate that the LytSR TCS plays a key role in GBS tissue invasion and pathogenesis, and persistence of mucosal colonisation.

Importance

Streptococcus agalactiae (Group B strep, or GBS)is a common commensal of the female urogenital tract and one of WHO’s priority pathogens. The bacterium has evolved mechanisms to adapt and survive in its host, many of which are regulated via two-component signal transduction systems (TCSs), however, the exact contributions of TCSs towards GBS pathogenicity remain largely obscure.

We have constructed a TCSlytS-deficient mutant in a CC-17 hypervirulent GBS clinical isolate. Using murine models, we showed that LytSR regulatory system is essential for vaginal colonisation via promoting biofilm production. We also observed thatlytSdeficiency led to significantly attenuated virulence properties and lower levels of proinflammatory cytokines in blood. Our findings are of significant importance in that they unveil a previously unreported role for LytSR in GBS and pave the way towards a better understanding of its ability to transition from an innocuous commensal to a deadly pathogen.
Design of passive radiative heating nanocomposite films by managing natural radiation energy
Authors: Kaplan Sibel , Demirbek Dilara Melek , Korkmaz Memis Nazife
Published: August 2024

Purpose

Personal thermal management by controlling the radiation energies of both the body and the sun can be used in all environments and contributes to sustainability components with the advantages of energy saving, low chemical usage and comfort enhancements under dynamic conditions. In this study, passive radiative heating nanocomposite films were produced using sodium alginate as the matrix and zinc oxide (ZnO) and aluminum oxide (Al2O3) nanoparticles as nanofillers having far infrared radiation reflecting, hence passive heating functions.

Design/methodology/approach

Nanocomposite film solutions were prepared by stirring sodium alginate powder, deionized water, ZnO and Al2O3 nanoparticles (20% wt of matrix polymer) with surfactant using magnetic and ultrasonic stirrers in turn. Films produced within Petri dishes after drying at room temperature were analyzed by FT-IR, UV-VIS-NIR spectroscopy and SEM for chemical, radiation management and morphological characteristics, respectively. Emissivity values giving idea about the heating performances of the films were determined with an IR camera and a hotplate system. Moreover, direct heating performances were measured by the hotplate system including a far-infrared lamp.

Findings

Results showed that the emissivity of the films increased by approximately 18% and 16% with ZnO and Al2O3 nanoparticles, respectively. Moreover, NaAlg–Al2O3 nanocomposite film exhibited passive radiative heating performance of 3.58 °C, higher than the heating performance of NaAlg–ZnO nanocomposite film which is 2.97 °C when compared to the reference NaAlg film. These results indicate that both NaAlg–ZnO and especially NaAlg–Al2O3 nanocomposite films have excellent far-infrared emission and absorption properties ensuring a significant heating effect.

Originality/value

In addition to other clothing types, the heating performance obtained with the produced nanocomposite structures may be applied to different types of cosmetic/medical applications (beauty mask, wound dresses, etc.) enabling skincare/healing with the advantage of the sodium alginate matrix.
Human surface morphology representation and shape subdivision driven by space vector on female “waist-to-thigh” zone
Authors: Li Tao , Ma Jing , Wu Jinying , Lin Xiyan , Zou Fengyuan
Published: August 2024

Purpose

The human body has the same basic size data but has different surface morphology, resulting in the unfitness even under the same size specification. The purpose of this study was to solve the local fitness problems by representing and quantifying the human surface morphological difference.

Design/methodology/approach

Firstly, the 3D point cloud for 323 female students was scanned, and the cross-section layers of the “waist-to-thigh” zone were determined. Secondly, the space vector based on the space Euclidean distance was extracted to represent and quantify the surface morphological difference. And the Principal Component Analysis and K-means were adopted to subdivide the target zone. Thirdly, the pattern based on the subdivision results and surface flattening was generated. Additionally, the fitness was evaluated by the subjective and objective assessments, separately.

Findings

The space vector could represent and quantify the shape morphology of the “waist-to-thigh” zone. It had successfully achieved the human body subdivision and corresponding pattern generation for the “waist-to-thigh” zone. And the pattern based on the shape subdivision and surface flattening of the space vector could effectively improve the wearing fitness. Particularly in the waist and crotch area of trousers, the obvious wrinkles had been solved because the space vector is more in line with the shape morphology characteristics.

Originality/value

The proposed method could represent and quantify the difference in human surface morphology in a 3D manner. It solved the unfitness problem caused by the same body size but different shape surface morphology. And it will contribute to the fitness improvement of the trousers.
Empowering small farmers for sustainable agriculture: a human resource approach to SDG-driven training and innovation
Authors: Pandey Satyendra C. , Modi Pratik , Pereira Vijay , Fosso Wamba Samuel
Published: August 2024

Purpose

Amid the growing global emphasis on sustainable agriculture, organizations and governments face a pressing need to equip farmers with the knowledge and tools necessary for the adoption of sustainable farming practices, aligning with the Sustainable Development Goals (SDGs). However, understanding the complex relationship between training programs and the adoption of sustainable practices among small-scale farmers remains a critical challenge. Taking a human resource approach, this paper attempts to understand the interrelationships between training effectiveness, farmers’ psychological and demographic characteristics in explaining the adoption of sustainable farming practices.

Design/methodology/approach

We employed a multi-stage random sampling method and administered a structured questionnaire to collect data from 331 small farmers who were part of a government-led, large-scale intervention aimed at training them in sustainable farming practices.

Findings

Our research findings not only emphasize the critical role of HR approach through training but also underscore its importance in the broader mission of aligning with the SDGs. Specifically, we demonstrate that sustained exposure to training, intrinsic motivation to acquire knowledge, and the innovative capacity of farmers collectively enhance the effectiveness of training programs, thereby contributing significantly to the widespread adoption of sustainable farming practices in line with SDGs.

Originality/value

Drawing from self-determination theory, training effectiveness literature, and the call for improved alignment with the SDGs, this study presents a model that explains how psychological characteristics, combined with the quality and quantity of training influence the adoption of sustainable farming practices among small-scale farmers.
Linguistic landscape and multilingualism in tourist destinations: a sociolinguistic analysis
Authors: Al-Sofi Bakr Bagash Mansour Ahmed
Published: August 2024

Purpose

This site-based study employed a sociolinguistic approach to investigate the linguistic landscape and multilingualism displayed on signs in Marib, a historical and tourist city in Yemen. The study focused on the types and functions of these signs, as well as people's perceptions of the status quo of the linguistic landscape.

Design/methodology/approach

A mixed-methods approach was used to collect data. Signs in tourist areas were photographed, and subsequent semi-structured interviews were conducted with relevant individuals to achieve the study's objectives.

Findings

The results revealed that both multilingual and monolingual signs coexist, with multilingual signs being more prevalent. Multilingual signs, which were official (top-down), served informational and symbolic functions, while monolingual signs, which were informal (bottom-up), served purely informational purposes. Bilingual signs were not present at the research sites. Interviewees generally expressed their satisfaction with multilingualism, as both national (Arabic and Musnad) and international (English) languages coexisted. However, they highlighted a deficiency in the number of signs at the research sites.

Practical implications

This study suggested intensifying efforts to include more signs, augmented with QR codes, to convey an appealing image of the linguistic landscape and provide visitors with information about these sites. Exposing students to the linguistic landscape can significantly enhance their English learning.

Originality/value

This study contributes to existing literature by providing further insights into the linguistic landscape in tourist destinations in Marib city. It offers the local and global community a better understanding of why and how the linguistic landscape should be improved and presented more appropriately.