bluuebunny/crossref_metadata_2025 huggingface dataset:
Second language learning in older adults modulates Stroop task performance and brain activation
Authors: Schultz DH , Gansemer A , Allgood K , Gentz M , Secilmis L , Deldar Z , Savage CR , Ghazi Saidi L
Published: March 2024

Numerous studies have highlighted cognitive benefits in lifelong bilinguals during aging, manifesting as superior performance on cognitive tasks compared to monolingual counterparts. Yet, the cognitive impacts of acquiring a new language in older adulthood remain unexplored. In this study, we assessed both behavioral and fMRI responses during a Stroop task in older adults, pre- and post language-learning intervention.

A group of 41 participants (age:60-80) from a predominantly monolingual environment underwent a four-month online language course, selecting a new language of their preference. This intervention mandated engagement for 90 minutes a day, five days a week. Daily tracking was employed to monitor progress and retention. All participants completed a color-word Stroop task inside the scanner before and after the language instruction period.

We found that performance on the Stroop task, as evidenced by accuracy and reaction time, improved following the language learning intervention. With the neuroimaging data, we observed significant differences in activity between congruent and incongruent trials in key regions in the prefrontal and parietal cortex. These results are consistent with previous reports using the Stroop paradigm. We also found that the amount of time participants spent with the language learning program was related to differential activity in these brain areas. Specifically, we found that people who spent more time with the language learning program showed a greater increase in differential activity between congruent and incongruent trials after the intervention relative to before.

Future research is needed to determine the optimal parameters for language learning as an effective cognitive intervention for aging populations. We propose that with sufficient engagement, language learning can enhance specific domains of cognition such as the executive functions. These results extend the understanding of cognitive reserve and its augmentation through targeted interventions, setting a foundation for future investigations.
Brain-Penetrant NF-κB and NLRP3 Targeting Nanoligomers are Therapeutic in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD) Human Organoid and Mouse Models
Authors: Sharma Sadhana , Wahl Devin , Risen Sydney , Gilberto Vincenzo S. , Chatterjee Anushree , Moreno Julie A. , LaRocca Thomas J. , Nagpal Prashant
Published: March 2024

Millions of people suffer worldwide from neurodegenerative diseases ranging from rapidly progressing and fatal motor neuron diseases like Amyotrophic Lateral Sclerosis (ALS) to more chronic illnesses such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD). A growing number of studies have implicated neuroinflammation as a key and causative phenomenon and an important target for novel therapeutics for these diseases. Neuroinflammation is characterized by reactive glial cells that produce pro-inflammatory neurotoxic cytokines. Our previous studies have shown a brain-penetrant Nanoligomer cocktail (NI112) inhibiting the neuroinflammation mediators nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) is a safe, targeted, and effective neurotherapeutic drug. Here, we show that a four-week NI112 treatment is therapeutic using: 1) an ALS-FTD 3D human motor neuron organoid model of tar DNA binding protein 43 (TDP-43, a key contributor to ALS pathology) overexpression (knock-in); 2) an AD model of APOE4/APOE4 (AD risk allele) double mutation in human neurons comprising a 3D human prefrontal cortex (PFC) organoid; and 3) multiplein vivo(mouse models) of the same/related conditions. In 3D organoids made from healthy motor neurons (HMN negative control) and TDP-43 overexpressing (or ALS organoids), we monitored the mean firing rate using calcium signaling as a functional output, while measuring TDP-43 and other key neurodegeneration biomarkers. After 4 weeks, we observed a massive improvement in the mean firing rate of NI112-treated ALS organoids compared to untreated ALS organoids, which was more comparable to healthy HMN organoids. Similarly, we found a significant decrease in neurodegeneration markers like amyloid beta 42 (Aβ42) in NI112-treated AD organoids compared to untreated AD organoids (Aβ42 comparable to healthy PFC organoids). In the mouse ALS (SOD1-G93A) model, we observed behavioral improvements and restoration of motor function (e.g., grip strength) in NI112-treated mice, and in mouse AD model mice (radiation-induced accelerated neuropathology in APP/PS1, and rTg4510 phospho-tau), we observed improved cognition. In both models, we also found an accompanying reduction in neuroinflammation and reduced neuropathology. These results show the promise for further testing and development of neuroinflammation-targeting Nanoligomers to benefit patients suffering from debilitating neurodegenerative diseases like ALS, FTD, and AD.
Demographic history and the efficacy of selection in the globally invasive mosquitoAedes aegypti
Authors: Kent Tyler V. , Schrider Daniel R. , Matute Daniel R.
Published: March 2024

Aedes aegyptiis the main vector species of yellow fever, dengue, zika and chikungunya. The species is originally from Africa but has experienced a spectacular expansion in its geographic range to a large swath of the world, the demographic effects of which have remained largely understudied. In this report, we examine whole-genome sequences from 6 countries in Africa, North America, and South America to investigate the demographic history of the spread ofAe. aegyptiinto the Americas its impact on genomic diversity. In the Americas, we observe patterns of strong population structure consistent with relatively low (but probably non-zero) levels of gene flow but occasional long-range dispersal and/or recolonization events. We also find evidence that the colonization of the Americas has resulted in introduction bottlenecks. However, while each sampling location shows evidence of a past population contraction and subsequent recovery, our results suggest that the bottlenecks in America have led to a reduction in genetic diversity of only ∼35% relative to African populations, and the American samples have retained high levels of genetic diversity (expected heterozygosity of ∼0.02 at synonymous sites) and have experienced only a minor reduction in the efficacy of selection. These results evoke the image of an invasive species that has expanded its range with remarkable genetic resilience in the face of strong eradication pressure.
Cell Marker Accordion: interpretable single-cell and spatial omics annotation in health and disease
Authors: Busarello Emma , Biancon Giulia , Cimignolo Ilaria , Lauria Fabio , Ibnat Zuhairia , Ramirez Christian , Tomè Gabriele , Ciuffreda Marianna , Bucciarelli Giorgia , Pilli Alessandro , Marino Stefano Maria , Bontempi Vittorio , Aass Kristin R. , VanOudenhove Jennifer , Mione Maria Caterina , Standal Therese , Macchi Paolo , Viero Gabriella , Halene Stephanie , Tebaldi Toma
Published: March 2024

Single-cell technologies offer a unique opportunity to explore cellular heterogeneity in health and disease. However, reliable identification of cell types and states represents a bottleneck. Available databases and analysis tools employ dissimilar markers, leading to inconsistent annotations and poor interpretability. Furthermore, current tools focus mostly on physiological cell types, limiting their applicability to disease.

We developed the Cell Marker Accordion, a user-friendly platform providing automatic annotation and unmatched biological interpretation of single-cell populations, based on consistency weighted markers. We validated our approach on multiple single-cell and spatial datasets from different human and murine tissues, improving annotation accuracy in all cases. Moreover, we show that the Cell Marker Accordion can identify disease-critical cells and pathological processes, extracting potential biomarkers in a wide variety of disease contexts.

The breadth of these applications elevates the Cell Marker Accordion as a fast, flexible, faithful and standardized tool to annotate and interpret single-cell and spatial populations in studying physiology and disease.
Cell extrusion - a novel mechanism driving neural crest cell delamination
Authors: Moore Emma , Zhao Ruonan , McKinney Mary C , Yi Kexi , Wood Christopher , Trainor Paul
Published: March 2024

Neural crest cells (NCC) comprise a heterogeneous population of cells with variable potency, that contribute to nearly every tissue and organ system throughout the body. Considered unique to vertebrates, NCC are transiently generated within the dorsolateral region of the neural plate or neural tube, during neurulation. Their delamination and migration are crucial events in embryo development as the differentiation of NCC is heavily influenced by their final resting locations. Previous work in avian and aquatic species has shown that NCC delaminate via an epithelial-mesenchymal transition (EMT), which transforms these stem and progenitor cells from static polarized epithelial cells into migratory mesenchymal cells with fluid front and back polarity. However, the cellular and molecular drivers facilitating NCC delamination in mammals are poorly understood. We performed live timelapse imaging of NCC delamination in mouse embryos and discovered a group of cells that exit the neuroepithelium as isolated round cells, which then halt for a short period prior to acquiring the mesenchymal migratory morphology classically associated with most delaminating NCC. High magnification imaging and protein localization analyses of the cytoskeleton, together with measurements of pressure and tension of delaminating NCC and neighboring neuroepithelial cells, revealed these round NCC are extruded from the neuroepithelium prior to completion of EMT. Furthermore, we demonstrate that cranial NCC are extruded through activation of the mechanosensitive ion channel, PIEZO1, a key regulator of the live cell extrusion pathway, revealing a new role for PIEZO1 in neural crest cell development. Our results elucidating the cellular and molecular dynamics orchestrating NCC delamination support a model in which high pressure and tension in the neuroepithelium results in activation of the live cell extrusion pathway and delamination of a subpopulation of NCC in parallel with EMT. This model has broad implications for our understanding of cell delamination in development and disease.
DNA-based ForceChrono Probes for Deciphering Single-Molecule Force Dynamics in Living Cells
Authors: Hu Yuru , Li Hongyun , Zhang Chen , Feng Jingjing , Wang Wenxu , Chen Wei , Yu Miao , Zhang Xinghua , Liu Zheng
Published: March 2024

Accurate measurement of mechanical forces in cells is key to understanding how cells sense and respond to mechanical stimuli, a central aspect of mechanobiology. However, accurately quantifying dynamic forces at the single-molecule level in living cells is a significant challenge. Here, we’ve developed the DNA-based ForceChrono probe to enable in-depth studies of integrin force dynamics at the single-molecule level in living cells. By illuminating two distinct mechanical points and circumventing the inherent fluctuations of single-molecule fluorescence, the ForceChrono probe enables analysis of the complex dynamics of mechanical forces at the single-molecule level, such as loading rates and durations. Our results refine previous broad estimates of cellular loading rates to a more precise range of 0.5 to 2 pN/s, shedding light on the specifics of cellular mechanics. In addition, this study reveals a critical link between the magnitude and duration of integrin forces, consistent with the catch-bond behavior demonstrated in vitro. The ForceChrono probe has distinct advantages, such as precise analysis of single-molecule force dynamics and robust resistance to fluorescence fluctuations, which will significantly advance our understanding of cell adhesion and mechanotransduction at the single-molecule level.
Structural and biophysical characterisation of ubiquitin variants that specifically inhibit the ubiquitin conjugating enzyme Ube2d2
Authors: McAlpine Jeffery M.R.B. , Zhu Jingyi , Pudjihartono Nicholas , Teyra Joan , Currie Michael J. , Dobson Renwick C.J. , Sidhu Sachdev S. , Day Catherine L. , Middleton Adam J.
Published: March 2024

The ubiquitin conjugating E2 enzymes play a central role in ubiquitin transfer. Disruptions to the ubiquitin system are implicated in multiple diseases and as a result, molecules that modulate the activity of the ubiquitin system are of interest. E2 enzyme function is reliant on interactions with partner proteins and disruption of these is an effective way of modulating activity. Here, we report the discovery of ubiquitin variants (UbVs) that inhibit the E2 enzyme, Ube2d2 (UbcH5b). The six UbVs identified inhibit ubiquitin chain building, and structural and biophysical characterisation of two of these demonstrate they bind to Ube2d2 with low micromolar affinity and high specificity within the Ube2d family of E2 enzymes. Both characterised UbVs bind at a site that overlaps with E1 binding, while the more inhibitory UbV blocks a critical non-covalent ubiquitin binding site on the E2 enzyme. The discovery of novel protein-based ubiquitin derivatives that inhibit protein-protein interactions is an important step towards discovery of small molecules that inhibit the activity of E2 enzymes. Furthermore, the specificity of the UbVs within the Ube2d family suggests that it may be possible to develop tools to selectively inhibit highly related E2 enzymes.
Fertilization-induced synergid cell death by RALF12-triggered ROS production and ethylene signaling
Authors: Chen Junyi , Wang Huan , Wang Jinlin , Zheng Xixi , Qu Wantong , Fang Huijian , Wang Shuang , He Le , Hao Shuang , Dresselhaus Thomas
Published: March 2024

Fertilization-dependent elimination of the persistent synergid cell is essential to block supernumerary pollen tubes and thus to avoid polyspermy in flowering plants. Little is known about the molecular mechanisms ensuring timely induction and execution of synergid cell death. We analysed manually isolated maize synergid cells along their degeneration and show that they are gland cells expressing batteries of genes encoding small secreted proteins under control of the MYB98 transcription factor. This network is down-regulated after fertilization, while genes involved in reactive oxygen species (ROS) production, ethylene biosynthesis and response, senescence, and oxidative stress regulation are induced before synergid elimination and its ultimate fusion with the endosperm. We further show that fertilization-induced RALF12 peptide specifically triggers mitochondrial ROS and apoptosis, while ethylene promotes synergid degeneration. In conclusion, this study sheds light on developmental programmed cell death (dPCD) in plants and provides a unique resource to discover novel PCD regulators.
Tipping-point transition from transient to persistent inflammation in pancreatic islets
Authors: Holst-Hansen Thomas , Yde Pernille , Jensen Mogens H. , Mandrup-Poulsen Thomas , Trusina Ala
Published: March 2024

Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however it is unknown if and how the two opposing modes may emerge at single islet level.

We investigated the duality of IL-1β with a quantitative in-silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses, when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NFκ-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway – IL-1 receptor antagonist and A20 among others. A transient response ensues when the two feedbacks are balanced. When positive feedback is dominating over the negative islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode.

Our results are likely not limited to IL-1β but general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedbacks of opposing nature and acting on different time scales provides a number of testable predictions, which call for dynamic monitoring of pro-inflammatory cytokines at the single islet level.

AUTHOR SUMMARY

Different expression or activity dynamics of the same proteins or signaling molecules can lead to opposing fates in cells and tissues. While it is known that brief and prolonged exposure to pro-inflammatory cytokine IL-1β have opposing effects on the functionality and viability of pancreatic β-cells, it is unclear if and how these differences in dynamics may arise at the single islet level. We use a mathematical model of the core feedback loops in the IL-1β regulatory network to show that transient and persistent responses are the two characteristic dynamic modes of the IL-1β response. The likelihood of each mode depends on systemic inflammation and elevated glycaemia and free fatty acids levels. We find that large islets are more prone to transit into the persistent mode, which may provide an explanation for why large islets are underrepresented in type 2 diabetes patients.
Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV
Authors: Obare Laventa M. , Priest Stephen , Ismael Anas , Mashayekhi Mona , Zhang Xiuqi , Stolze Lindsey K. , Sheng Quanhu , Vue Zer , Neikirk Kit , Beasley Heather , Gabriel Curtis , Temu Tecla , Gianella Sara , Mallal Simon , Koethe John R. , Hinton Antentor , Bailin Samuel , Wanjalla Celestine N.
Published: March 2024

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.
Mechanistic insights into transport models of the sphingolipid transport protein, Spinster homolog 2 (Spns2), using MD simulations
Authors: Sharp Amanda K. , LoPresti Marion Q. , Brown Anne M.
Published: March 2024

Sphingosine-1-phosphate (S1P) is a sphingolipid signaling molecule that when elevated results in multiple disease states including metastatic cancers. Modulating the extracellular concentrations of S1P has been an evolving strategy in drug development for metastatic cancers due to its role in angiogenesis and cell migration. Research has shown that Spns2, the S1P transport protein, is an important microenvironment regulatory gene in metastatic lung cancer colonization and has demonstrated that Spns2 inhibition is a powerful suppressor of metastatic cancers. Spns2 transports and regulates cellular levels of S1P but has unresolved aspects related to mechanism of transport. Here, molecular modeling strategies including, homology modeling and molecular dynamics (MD) simulations, were used to determine structural mechanisms of action related to S1P transport and exploitable for inhibition. Results indicate Spns2 contains a unique salt-bridge network essential for structural stability that is disrupted by the R119A mutation. Additionally, we observe that Spns2 follows a rocker-switch transport model and that S1P translocation is initialized by interacting with residues such as Thr216, Arg227, and Met230. This work provides initial insight into structural morphologies sampled by Spns2, the role of a complex salt bridge network, and residues engaged in structural state transition that can be targeted with inhibitors to control extracellular concentrations of S1P.
SARS-CoV-2 Omicron BA.2.87.1 Exhibits Higher Susceptibility to Serum Neutralization Than EG.5.1 and JN.1
Authors: Wang Qian , Guo Yicheng , Schwanz Logan T. , Mellis Ian A. , Sun Yiwei , Qu Yiming , Urtecho Guillaume , Valdez Riccardo , Stoneman Emily , Gordon Aubree , Wang Harris H. , Liu Lihong , Ho David D.
Published: March 2024

As SARS-CoV-2 continues to spread and mutate, tracking the viral evolutionary trajectory and understanding the functional consequences of its mutations remain crucial. Here, we characterized the antibody evasion, ACE2 receptor engagement, and viral infectivity of the highly mutated SARS-CoV-2 Omicron subvariant BA.2.87.1. Compared with other Omicron subvariants, including EG.5.1 and the current predominant JN.1, BA.2.87.1 exhibits less immune evasion, reduced viral receptor engagement, and comparable infectivity in Calu-3 lung cells. Intriguingly, two large deletions (Δ15-26 and Δ136-146) in the N-terminal domain (NTD) of the spike protein facilitate subtly increased antibody evasion but significantly diminish viral infectivity. Collectively, our data support the announcement by the USA CDC that the public health risk posed by BA.2.87.1 appears to be low.
cGAS-STING is responsible for aging of telomerase deficient zebrafish
Authors: Şerifoğlu Naz , Allavena Giulia , Bastos-Lopes Bruno , Marzullo Marta , Bousounis Pavlos , Trompouki Eirini , Ferreira Miguel Godinho
Published: March 2024

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA damage responses and p53 stabilization, leading to apoptosis or replicative senescence.In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type I interferon inflammation and senescence. However, the consequences of these events to the organism are not yet understood. Here, we show thatstingis responsible for premature aging of telomerase-deficient zebrafish. We generatedsting-/- tert-/-double mutants and observed a thorough rescue oftert-/-phenotypes. At the cellular level, lack of cGAS-STING inter tmutants resulted in reduced senescence, increased cell proliferation, and low inflammation despite similar short telomeres. Critically, absence ofstingfunction resulted in dampening of the DNA damage response and low p53 levels. At the organism level,sting-/- tert-/-zebrafish regained fertility, delayed cachexia, and cancer incidence, resulting in increased healthspan and lifespan of telomerase mutants.
Helicobacter pyloriγ-glutamyltransferase relates to proteomic adaptions important for gastric colonization
Authors: Fuchs Sonja , Fiedler Michaela K. , Heiduk Nicole , Wanisch Andreas , Debowski Aleksandra W. , Marshall Barry J. , Sieber Stephan A. , Gerhard Markus , Mejías-Luque Raquel
Published: March 2024

Helicobacter pyloriγ-glutamyltransferase (gGT) is a virulence factor that promotes bacterial colonization and immune tolerance. Although some studies addressed potential functional mechanisms, the supportive role of gGT forin-vivocolonization remains unclear. Additionally, it is unknown how different gGT expression levels may lead to compensatory mechanisms ensuring infection and persistence. Hence, it is crucial to unravel thein-vivofunction of gGT. We assessed acid survival under conditions mimicking the human gastric fluid and elevated the pH in the murine stomach prior toH. pyloriinfection to link gGT-mediated acid resistance to colonization. By comparing proteomes of gGT-proficient and -deficient isolates before and after infecting mice, we investigated proteomic adaptations of gGT-deficient bacteria during infection. Our data indicate that gGT is crucial to sustain urease activity in acidic environments, thereby supporting survival and successful colonization. Absence of gGT triggers expression of proteins involved in the nitrogen and iron metabolism and boosts the expression of adhesins and flagellar proteins during infection, resulting in increased motility and adhesion capacity. In summary, gGT-dependent mechanisms confer a growth advantage to the bacterium in the gastric environment, which renders gGT a valuable target for the development of new treatments againstH. pyloriinfection.

Author Summary

H. pyloriγ-glutamyltransferase (gGT) is a virulence factor that strongly supports bacterial colonization. Despite considerable research on the function of gGT, the exact role of this enzyme in ensuringin-vivoinfection remained elusive. We developed a novel system that allowed us to selectively inhibit gGT-activity and used this model to assess the function of gGT in the gastric environment. We found that gGT sustains urease activity in acidic environments thereby facilitating survival and effective colonization. In addition, we identified several compensatory mechanisms triggered by the loss of gGT which ensure colonization and persistence. These mechanisms included increased flagellar motility, adhesion capacity and expression of proteins involved in the nitrogen and iron metabolism. These findings unraveled novel functional roles of gGT important for bacterial colonization and thereby confirmed gGT as a promising target for novel treatments againstH. pyloriinfection. By comprehensively addressing the compensatory mechanisms resulting from the loss of gGT-activity, the success of such new treatments can be improved.
miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma
Authors: Hong Ellen S. , Wang Sabrina Z. , Ponti András K. , Hajdari Nicole , Lee Juyeun , Mulkearns-Hubert Erin E. , Volovetz Josephine , Kay Kristen E. , Lathia Justin D. , Dhawan Andrew
Published: March 2024

Background

Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown.

Methods

We leveraged previously published paired miRNA and mRNA sequencing of 39 GBM patients (22 male, 17 female) to identify sex-biased miRNAs. We further interrogated a separate single-cell RNA sequencing dataset of 110 GBM patients to examine whether differences in miRNA target gene expression were tumor cell intrinsic or tumor cell extrinsic. Results were validated in a panel of patient-derived cell models.

Results

We identified 10 sex-biased miRNAs (adjusted<0.1), of which 3 were more highly expressed in males and 7 more highly expressed in females. Of these, miR-644a was higher in females, and increased expression of miR-644a target genes was significantly associated with decreased overall survival (HR 1.3,p= 0.02). Furthermore, analysis of an independent single-cell RNA sequencing dataset confirmed sex-specific expression of miR-644a target genes in tumor cells (p< 10-15). Among patient derived models, miR-644a was expressed a median of 4.8-fold higher in females compared to males.

Conclusions

Our findings implicate miR-644a as a candidate tumor cell-intrinsic regulator of sex-biased gene expression in GBM.

Key Points

miR-644a is more highly expressed in female GBM patients.

Lower miR-644a target gene expression is associated with improved overall survival.

miR-644a target genes are higher in male GBM cells but not in other cell types.

Importance of the Study

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level and were previously linked to glioblastoma (GBM) growth and therapeutic resistance. miRNAs play a role in the sex bias of various cell types and diseases, but how miRNAs contribute to sex differences in GBM is not well elucidated. We show that 10 miRNAs are differentially expressed between males and females and identify miR-644a as more highly expressed in female GBM patients. Using single-cell RNA-seq data, we demonstrate that sex differences in miR-644a target gene expression are tumor cell-intrinsic. Likewise, decreased miR-644a target gene expression is associated with improved overall patient survival. Our findings reveal miR-644a as a novel sex-biased miRNA in GBM, and a possible target for sex-specific precision therapies with limited collateral damage.
Distinct intersecting pathways link homolog pairing to initiation of meiotic chromosome synapsis
Authors: Blazickova Jitka , Trivedi Shalini , Bowman Richard , Geetha Sowmya Sivakumar , Subah Silma , Smolikove Sarit , Jantsch Verena , Zetka Monique , Silva Nicola
Published: March 2024

Faithful meiotic segregation requires pairwise alignment of the homologous chromosomes and Synaptonemal Complex assembly (SC) at their interface. Here, we investigate on new factors that promote and coordinate these events duringC. elegansmeiosis. We identify BRA-2 (BMPReceptorAssociated family member2)as an interactor of HIM-17, previously shown to promote double-strand break formation. We found that loss ofbra-2specifically impairs synapsis licensing without affecting homologs recognition, SC maintenance or chromosome movement. Double mutant analysis revealed a previously unrecognized role for HIM-17 in promoting homolog pairing under dysfunctional SC assembly, without perturbing nuclear envelope recruitment of factors required for chromosome movement. We provide evidence thatbra-2andhim-17act in distinct pathways, exerting partially redundant functions in SC licensing, as well as separable roles in regulating homologs pairing. Altogether, our findings unveil novel mechanisms that ensure stabilization of homologous chromosome interaction via SC licensing upon homology assessment.
High-throughput determination of RNA tertiary contact thermodynamics by quantitative DMS chemical mapping
Authors: Lange Bret , Gil Ricardo G. , Yesselman Joseph D.
Published: March 2024

Structured RNAs often contain long-range tertiary contacts that are critical to their function. Despite the importance of tertiary contacts, methods to measure their thermodynamics are low throughput or require specialized instruments. Here, we introduce a new quantitative chemical mapping method (qDMS-MaPseq) to measure Mg2+-induced formation of tertiary contact thermodynamics in a high-throughput manner using standard biochemistry equipment. With qDMS-MaPseq, we measured the ΔG of 98 unique tetraloop/tetraloop receptor (TL/TLR) variants in a one-pot reaction. These results agree well with measurements from specialized instruments (R2=0.64). Furthermore, the DMS reactivity of the TL directly correlates to the stability of the contact (R2=0.68), the first direct evidence that DMS reactivity reports on thermodynamics. Combined with structure prediction, DMS reactivity allowed the development of experimentally accurate 3D models of TLR mutants. These results demonstrate that qDMS-MaPseq is broadly accessible, high-throughput, and directly links DMS reactivity to thermodynamics.
Establishing a method for the cryopreservation of viable peripheral blood mononuclear cells in the International Space Station
Authors: Ishii Hiroto , Endo Rin , Hamanaka Sanae , Hidaka Nobuyuki , Miyauchi Maki , Hagiwara Naho , Miyao Takahisa , Yamamori Tohru , Aiba Tatsuya , Akiyama Nobuko , Akiyama Taishin
Published: March 2024

The analysis of cells frozen within the International Space Station (ISS) will provide crucial insights into the impact of the space environment on cellular functions and properties. The objective of this study was to develop a method for cryopreserving blood cells under the specific constraints of the ISS. In a ground experiment, mouse blood was directly mixed with a cryoprotectant and gradually frozen at -80 °C. Thawing the frozen blood sample resulted in the successful recovery of viable mononuclear cells when using a mixed solution of dimethylsulfoxide and hydroxyethyl starch as a cryoprotectant. Additionally, we developed new freezing cases to minimize storage space utilization within the ISS freezer. Finally, we confirmed the recovery of major mononuclear immune cell subsets from the cryopreserved blood cells through a high dimensional analysis of flow cytometric data using 13 cell surface markers. Consequently, this ground study lays the foundation for the cryopreservation of viable blood cells on the ISS, enabling their analysis upon return to Earth. The application of this method in ISS studies will contribute to understanding the impact of space environments on human cells. Moreover, this method may find application in the cryopreservation of blood cells in situations where research facilities are inadequate.
Pyruvate kinase M2 regulates Japanese encephalitis virus replication by interacting with NS1 protein
Authors: Bohara Vijay Singh , Deshmukh Atharva , Kumar Sachin
Published: March 2024

Pyruvate kinase isoform M2 (PKM2) is a key modulator of glucose metabolism. While the major role of PKM2 is to facilitate the breakdown of glucose, it is potentially associated with other additional non-glycolytic functions as well. The role of PKM2 in the autoimmune response and inflammatory process is increasingly being acknowledged as a crucial modulator of cellular pathophysiological activity. However, its role in modulating viral replication has not been explored in detail. In the present study, we have shown a significant increase in endogenous PKM2 expression in JEV-infected mouse neuroblastoma cells. Furthermore, overexpression of PKM2 significantly reduced JEV replication, suggesting a negative effect of PKM2 on JEV replication. This was further confirmed by siRNA-mediated downregulation of endogenous PKM2 expression, which resulted in enhanced JEV replication. In silicostudies revealed the potential interaction between PKM2 and NS1 protein of JEV. The microscopic studies also showed cellular colocalization of PKM2 and NS1 in the ER of infected cells. The interaction was further validatedin vitroby co-immunoprecipitation assay. The present study suggests that PKM2 negatively regulates the JEV replication by its possible interaction with NS1.

Importance

Japanese encephalitis (JE) is a neuroinflammatory disease caused by the Japanese encephalitis virus (JEV). JE is a major threat to public health not only because it causes many deaths but also for its permanent neuropsychiatric sequelae in children. Out of all non-structural proteins of JEV, NS1 is highly immunogenic. A wide range of possible interactive partners has been identified for the NS1, many of those have been linked to immune evasion and regulating viral replication. In the current study, we have described a novel host cell factor, PKM2 modulating JEV replication by interacting with NS1 protein. Considering PKM2’s central role in regulating host cell metabolism, our findings suggest a previously unrecognized role for PKM2 in JEV neuropathogenesis. The identification and characterization of previously unknown host factors, as well as the elucidation of their regulatory mechanisms, are of utmost importance in the development of innovative treatments and antivirals against JEV.
General model and toolkit for the ionization of three or more electrons in strongly driven molecules using an effective Coulomb potential for the interaction between bound electrons
Authors: Katsoulis G. P. , Peters M. B. , Emmanouilidou A.
Published: March 2024

We formulate a general three-dimensional semiclassical model for the study of correlated multielectron escape during fragmentation of molecules driven by intense infrared laser pulses. We do so in the context of triple ionization of strongly driven HeH2+. Our model fully accounts for the singularity in the Coulomb potentials of a recolliding electron with the core and a bound electron with the core as well as for the interaction of a recolliding electron with a bound electron. This model also accounts for the magnetic field of the laser pulse. To avoid artificial autoionization, our model employs effective potentials to treat the interaction between bound electrons. We focus on triple and double ionization as well as frustrated triple and frustrated double ionization. In these processes, we identify and explain the main features of the sum of the kinetic energies of the final ion fragments. We find that frustrated double ionization is a major ionization process, and we identify the different channels and hence different final fragments that are obtained through frustrated double ionization. Also, we discuss the differences between frustrated double and triple ionization.

Published by the American Physical Society
2024
Spectral analysis of solar-irradiance fluctuations
Authors: Bel G. , Bandi M.M.
Published: March 2024

Solar-irradiance fluctuations possess a power-law spectrum with two different slopes in the intermediate (1/day <f<1/h) and high [1/h <f<1/(2 min)] frequency (f) regimes. This spectrum is a combination of a deterministic (latitude-dependent) variation of daylight duration and a stochastic component arising from various environmental attenuation factors. We propose a principled approach to decompose the solar-irradiance time series into the deterministic location-dependent clear sky and the stochastic environmental attenuation signals. Such decomposition permits one to systematically analyze the solar photovoltaic power-fluctuation spectra after accounting for the strong geographic dependence, failing which no baseline standard exists with which to compare spectra between disparate geographic locations. Our analysis for two different locations shows that the stochastic environmental factors determine the spectral power-law slope in the high-frequency range, while the deterministic clear-sky signal plays a role in the intermediate frequency range. We close by discussing its implications for solar photovoltaic power production, in particular, for the geographic smoothing of fluctuations.

Published by the American Physical Society
2024
Photoinduced Electronic and Spin Topological Phase Transitions in Monolayer Bismuth
Authors: Peng Bo , Lange Gunnar F. , Bennett Daniel , Wang Kang , Slager Robert-Jan , Monserrat Bartomeu
Published: March 2024

Ultrathin bismuth exhibits rich physics including strong spin-orbit coupling, ferroelectricity, nontrivial topology, and light-induced structural dynamics. We use calculations to show that light can induce structural transitions to four transient phases in bismuth monolayers. These light-induced phases exhibit nontrivial topological character, which we illustrate using the recently introduced concept of spin bands and spin-resolved Wilson loops. Specifically, we find that the topology changes via the closing of the electron and spin band gaps during photoinduced structural phase transitions, leading to distinct edge states. Our study provides strategies to tailor electronic and spin topology via ultrafast control of photoexcited carriers and associated structural dynamics.

Published by the American Physical Society
2024
Dynamic capabilities of global and local humanitarian organizations with emergency response and long-term development missions
Authors: Son Byung-Gak , Roscoe Samuel , Sodhi ManMohan S.
Published: March 2024

Purpose

This study aims to answer the question: What dynamic capabilities do diverse humanitarian organizations have?

Design/methodology/approach

We examine this question through the lens of dynamic capabilities with sensing, seizing and reconfiguring capacities. The research team interviewed 15 individuals from 12 humanitarian organizations that had (a) different geographic scopes (global versus local) and (b) different missions (emergency response versus long-term development aid). We also gathered data from secondary sources, including standard operating procedures, company websites, and news databases (Factiva, Reuters and Bloomberg).

Findings

The findings identify the operational and dynamic capabilities of global and local humanitarian organizations while distinguishing between their mission to provide long-term development aid or emergency relief. (1) The global organizations, with their beneficiary responsiveness, reconfigured their sensing and seizing capacities throughout the COVID-19 pandemic by pivoting quickly to local procurement or regional supply chains. The long-term development organizations pivoted to multi-year supplier agreements with fixed pricing to counter price uncertainty and accessed social capital with government bodies. In contrast, emergency response organizations developed end-to-end supply chain visibility to sense changes in supply and demand. (2) Local humanitarian organizations developed the capacity to sense demand and supply changes to reconfigure based on their experiential learning working with the local community. The long-term-development local organizations used un-owned and scalable relief infrastructure to seize opportunities to rebuild affected areas. In contrast, emergency response organizations developed their capacity to seize opportunities to provide aid stemming from their decentralized decision-making, a lack of structured procedures, and the authority for increased expenditure.

Originality/value

We propose a theoretical framework to identify humanitarian organizations' operational and dynamic capabilities, distinguishing between global and local organizations and their emergency response and long-term aid missions.
Impact of educating faculty on student assessment: beyond satisfaction level
Authors: Mohamed Wessam
Published: March 2024

Purpose

This study evaluated the impact of a faculty training program on student assessment using the Kirkpatrick model.

Design/methodology/approach

A self-reported survey assessed 111 Saudi and non-Saudi participants' satisfaction. Subjective and objective measures (self-reported measures, assessment literacy inventory and performance-based assessment tasks) gauged participants' learning level. Pre- and post-training data were collected from 2020 to 2022.

Findings

A highly significant effect on satisfaction (>80%) and learning levels was observed, as manifested by workplace practices of student assessment (>70%, the cut-off score). Pre- and post-training comparisons of participants' satisfaction and assessment literacy scores showed significant improvements following training. Multiple regression analyses showed no significant effects for gender and educational attainment but a substantial impact of academic cluster on participants' student assessment skills.

Research limitations/implications

Long-term effects of training faculty on assessment practices and student achievement will be studied at the institutional level in future research.

Practical implications

The current study contributes to human capital investment via faculty training on student assessment, helping them comply with assessment best practices. This assures the quality, fairness and consistency of assessment processes across disciplines in higher education institutions, enhances assessment validity and trust in educational services and may support institutional accreditation.

Social implications

This study provides opportunities for sharing best practices and helps establish a community of practice. It enhances learning outcomes achievement and empowers higher education graduates with attributes necessary to succeed in the labor market. The human capital investment may have a long-term impact on overall higher education quality.

Originality/value

This study contributes to the scarce literature investigating the impact of training faculty from different clusters on student assessment using subjective and objective measures. It provides developing and evaluating a long-term student assessment program following the Kirkpatrick model.
What is known about Australian child protection practitioners’ participation in the health care of children living in out of home care: a scoping review
Authors: Sanders Rachael Elizabeth , Modderman Corina , Bracksley-O'Grady Stacey , Harley Fiona , Spencer Jacquelin , Molloy Jacinta
Published: March 2024

Purpose

There is a growing recognition of the urgency to enhance health outcomes for children and young people residing in out-of-home care (OOHC). Research underscores the need to establish effective pathways to quality health care for children and young people who have been exposed to trauma. Child protection (CP) practitioners should play a vital role in proactively improving health outcomes and navigating the intricacies of healthcare systems. Their involvement in initiating and collaborating on healthcare interventions is pivotal for the well-being of these vulnerable children and young people. However, challenges associated with poor health literacy and the complexities of healthcare systems hinder collaborative service delivery in the Australian context. This review explores how CP practitioners support the health care of children and young people in their care.

Design/methodology/approach

A scoping review followed Arksey and O’Malley’s framework, employing a narrative synthesis to assess the selected studies.

Findings

Health outcomes for children and young people in OOHC remain under-researched and potentially under-resourced within the realm of CP practice. There is room for enhanced practices and system integration in CP service delivery to better address health needs and prevent further health and well-being disparities.

Originality/value

Through this scoping review and involving industry experts in the discussion of findings, this study contributes valuable insights to the existing knowledge base regarding the active participation of CP practitioners in addressing the healthcare needs of vulnerable children.