bluuebunny/crossref_metadata_2025 huggingface dataset:
Small-molecule inhibitor of C-terminal HSP90 dimerization modulates autophagy and functions synergistically with mTOR inhibition to kill cisplatin-resistant cancer cells
Authors: David Céline , Sun Yadong , Woloschin Vitalij , Vogt Melina , Dienstbier Niklas , Schlütermann David , Berning Lena , Lungerich Beate , Friedrich Annabelle , Akgün Seda , Mendiburo María José , Gertzen Christopn G.W. , Borkhardt Arndt , Wesselborg Sebastian , Gohlke Holger , Bhatia Sanil , Kurz Thomas , Stork Björn
Published: December 2024

Background

A major obstacle for the successful treatment of cancer is the primary presence or development of resistance mechanisms toward therapeutic intervention. In urothelial cancer, cisplatin-based regimens are still routinely employed, and multiple cellular pathways contribute to chemoresistance. Since the identification of heat shock protein 90 (HSP90) as potential cancer target, various HSP90 inhibitors (HSP90i) have been developed and evaluated in clinical trials. However, limited efficacy has been observed, mainly caused by dose-limiting toxicity and the concomitant induction of a cytoprotective heat shock response (HSR). To avoid this effect, inhibitors targeting the C-terminal domain (CTD) of HSP90 that do not elicit an HSR have been put forward. Additionally, the crosstalk between autophagy and HSP90 is currently being explored, since both processes work together in proteostasis, and the modulation of autophagic responses might be helpful in order to improve the efficacy of HSP90 inhibitors.

Methods

The second-generation small-molecule inhibitor VWK147 targeting HSP90 CTD dimerization was synthesized and characterized in detail by biochemical cell-free and cellular assays and molecular modeling. Specifically, HSP90 inhibition, cell viability, and autophagy were monitored in mono- and combined treatments.

Results

We demonstrate that VWK147 induces cell death in both cisplatin-sensitive and cisplatin-resistant urothelial carcinoma cells. The treatment with VWK147 in these cells led to the destabilization of classical HSP90 client proteins without triggering an HSR. Additionally, we observe that VWK147 re-sensitizes resistant urothelial carcinoma cells to cisplatin and—in combination with mTOR inhibition—synergistically kills cisplatin-sensitive and -resistant cells, in contrast to what is observed upon treatment with the N-terminal domain-targeting HSP90 inhibitor 17-AAG. This synergy may be explained by VWK147-mediated inhibition of late autophagy events, and thus a blockade of autophagic flux. Finally, we also observed that VWK147 induces non-canonical LC3 lipidation, indicating that this compound possibly exerts a broader effect on ion balance or pH of the endolysosomal system.

Conclusion

VWK147 is a promising inhibitor that targets the C-terminal dimerization of HSP90 and simultaneously exhibits autophagy-modulating effects. This compound could potentially be an effective option for improving anti-cancer therapies and/or overcoming treatment resistance.
Time-Resolved Neural Oscillations Across Sleep Stages: Associations with Sleep Quality and Aging
Authors: Passaro Antony D , Poltorak Alexander
Published: December 2024

Sleep is a fundamental physiological process critical to cognitive function, memory consolidation, emotional regulation, and overall health. This study investigates the relationship between EEG spectral power dynamics and key sleep metrics, including percentage of N3, biological age, percentage of REM, and total sleep time (TST). Using high-resolution spectral analysis, we examine how power across multiple frequency bands (0.1–50 Hz) evolves temporally across sleep stages and influences sleep architecture. Our results reveal an inverse relationship between high-frequency power (sigma, beta, and gamma) during the N1 and N2 stages and the subsequent percentage of N3, suggesting that excessive low-frequency power in N2 may disrupt the smooth progression into deep sleep. Additionally, we identify a negative correlation between low delta power (0.1–0.5 Hz) during N2 and both percentages of N3 and TST, challenging traditional views on the role of delta activity in sleep regulation. These findings advance the understanding of how brain activity across frequencies modulates sleep depth and duration, with implications for addressing age-related sleep declines.
How bats exit a crowded colony when relying on echolocation only - a modeling approach
Authors: Mazar Omer , Yovel Yossi
Published: December 2024

Bats face a complex navigation challenge when emerging from densely populated roosts, where vast numbers take off at once in dark, confined spaces. Each bat must avoid collisions with walls and conspecifics while locating the exit, all amidst overlapping acoustic signals. This crowded environment creates the risk of acoustic jamming, in which the calls of neighboring bats interfere with echo detection, potentially obscuring vital information. Despite these challenges, bats navigate these conditions with remarkable success. Although bats have access to multiple sensory cues, here we focused on whether echolocation alone could provide sufficient information for orientation under such high-interference conditions. To explore whether they manage this challenge, we developed a sensorimotor model that mimics the bats’ echolocation behavior under high-density conditions. Our findings suggest that the problem of acoustic jamming may be less severe than previously thought. Bats can compensate for potential interference by emitting frequent calls with short inter-pulse intervals (IPI), creating a redundancy in the sensory information that allows them to aggregate echoes over multiple calls. This redundancy, combined with simple pathfinding strategies, such as following walls and avoiding nearby obstacles, enables bats to exit the roost effectively, even when faced with significant sensory interference. Our model indicates that bats’ echolocation strategies are robust enough to mitigate the effects of jamming and demonstrates the critical role of signal redundancy in successful navigation. These insights not only enhance our understanding of bat behavior but also offer implications for swarm robotics and collective movement in complex environments.
Characterization of theTuta absolutavirome reveals higher viral diversity in field populations
Authors: Becerra-García Rosa Esmeralda , Hernández-Pelegrín Luis , Crava Cristina , Herrero Salvador
Published: December 2024

A significant number of insect-specific viruses (ISVs) have been discovered in agriculturally important insect pests, facilitated by high-throughput sequencing (HTS). Despite its global impact on tomato crops, the RNA virome of the South American tomato pinworm,Tuta absoluta, remains uncharacterized. In this study, we utilized meta-transcriptomics and bioinformatic approaches to discover the RNA virome ofT. absolutaacross worldwide populations. We identified ten novel ISVs, classified into six groups: Nidovirales, Bunyavirales, Mononegavirales,Virgaviridae,Iflaviridae,Nodaviridae,Solemoviridae, andPhasmaviridae. Notably, no core virus was consistently present across the studied populations, and field-collected samples revealed a greater diversity of ISVs compared to those from laboratory samples. In addition, we detected plant-infecting viruses and mycoviruses associated with the pest. This study represents the first description of the RNA virome associated withT. absoluta, providing valuable insights into its biological and ecological interactions. It also lay the foundation for future studies aimed to clarify the biological roles of ISVs.
Maf1 Cooperates with Progesterone Receptor to Repress RNA Polymerase III Transcription of Select tRNAs
Authors: Finlay-Schultz Jessica , Paul Kiran V. , Erickson Benjamin , Fettig Lynsey M. , Hastings Benjamin S. , Johnson Deborah L. , Bentley David L. , Kabos Peter , Sartorius Carol A.
Published: December 2024

Progesterone receptors (PR) can regulate transcription by RNA Polymerase III (Pol III), which transcribes small non-coding RNAs, including all transfer RNAs (tRNAs). We have previously demonstrated that PR is associated with the Pol III complex at tRNA genes and that progestins downregulate tRNA transcripts in breast tumor models. To further elucidate the mechanism of PR-mediated regulation of Pol III, we studied the interplay between PR, the Pol III repressor Maf1, and TFIIIB, a core transcription component. ChIP-seq was performed for PR, the Pol III subunit POLR3A, the TFIIIB component Brf1, and Maf1 in breast cancer cells with or without progestin treatment. Upon progestin exposure, PR localized to approximately half of POLR3A-occupied tRNA genes, with Maf1 co-recruited to many of these PR-POLR3A sites. While progestin treatment did not significantly alter the number of tRNA genes occupied by Pol III or Brf1, Brf1 occupancy was stabilized, as indicated by increased peak amplitudes. Analysis of nascent tRNA transcription revealed a specific progestin-induced downregulation of approximately one-third of highly expressed tRNA genes. This repression was significantly reduced by Maf1 knockdown, indicating that Maf1 is necessary for PR-mediated tRNA transcription downregulation. Overall, these findings demonstrate a ligand-dependent PR-mediated repression of tRNA transcription through Maf1.
Pyrophosphate-containing Calcium Phosphates Negatively Impact Heterotopic Bone Quality
Authors: Jolic Martina , Åberg Isabella , Omar Omar , Engqvist Håkan , Engstrand Thomas , Palmquist Anders , Thomsen Peter , Shah Furqan A.
Published: December 2024

In bone, critical size defects pose substantial challenge in maxillofacial and orthopaedic reconstructions as they are incapable of spontaneous regeneration. Autologous bone grafts remain the “gold standard” in bone repair but their limitations and associated morbidities drive the development of bone graft substitute materials. Assessing the osteoinductive properties of these substitutes can help predict their success in bone regeneration applications. Calcium phosphates (CaP) are widely used bone graft substitutes due to their biocompatibility, osteoconductive properties, and potential for osteoinductivity. CaP materials containing monetite, beta-tricalcium phosphate (β-TCP), and a small amount of calcium pyrophosphate (Ca-PP) possess both osteoconductive and osteoinductive properties. However, the role of Ca-PP in osteoinduction and material degradation remains unexplored. This study investigates heterotopic bone formation in response to five CaP material compositions, maintaining a constant monetite and β-TCP ratio, with varying amounts of Ca-PP (0 – 12.5%). Twelve adult female sheep (Ovis aries) were subcutaneously implanted with constructs made of six CaP tiles interconnected by a Ti6Al4V frame and a control implant. Histological analysis, backscattered electron scanning electron microscopy, and Raman spectroscopy of samples retrieved at 12- and 52 weeks reveal that Ca-PP does not hinder heterotopic bone formation and minimally impacts CaP degradation. While monetite and β-TCP transform into apatite, the Ca-PP phase remains unchanged. The addition of Ca-PP to the CaP material influences heterotopic bone quality and inflammatory response during tissue regeneration.
Relationships between wellbeing polygenic scores, brain structure, and psychopathology in children
Authors: Tamnes Christian K. , Dahl Andreas , van der Meer Dennis , Agartz Ingrid , Alnaes Dag , Andreassen Ole A. , Mills Kathryn L. , Norbom Linn B. , Richard Geneviève , Dahl Ronald E. , Røysamb Espen , Westlye Lars T. , Ferschmann Lia
Published: December 2024

Wellbeing is shaped by an interplay of genetic and environmental factors and is associated with both health and functioning. It remains unclear whether genetic influences on wellbeing are linked to brain structure and, in turn, early-life psychopathology. Here, we investigated associations between wellbeing polygenic scores (PGS), magnetic resonance imaging (MRI)-derived measures of brain structure, and parent-reported measures of child psychopathology in a large cross-sectional sample of children from the Adolescent Brain Cognitive Development (ABCD) Study (n = 10,471; 8.9-11.1 years old). Preregistered analyses revealed no significant associations between wellbeing PGS and regional cortical surface area, cortical thickness, or subcortical volumes, while an exploratory analysis identified a small positive association with intracranial volume (ICV; β = 0.03, p<.001). Preregistered analyses showed small negative associations between wellbeing PGS and general psychopathology (β = −0.08, p<.001) and both internalizing (β = −.08, p<.001) and externalizing problems (β = −0.07, p<.001). ICV partially mediated the relationships between wellbeing PGS and psychopathology, accounting for 3-7% of these relationships. The findings suggest that while wellbeing PGS have limited associations with regional brain structure in children, they exhibit small protective effects against psychopathology.
Brain maps of general cognitive function and spatial correlations with neurobiological cortical profiles
Authors: Moodie Joanna E. , Buchanan Colin , Furtjes Anna , Conole Eleanor , Stolicyn Aleks , Corley Janie , Ferguson Karen , Hernandez Maria Valdes , Maniega Susana Munoz , Russ Tom C. , Luciano Michelle , Whalley Heather , Bastin Mark E. , Wardlaw Joanna , Deary Ian , Cox Simon
Published: December 2024

In this paper, we attempt to answer two questions: 1) which regions of the human brain, in terms of morphometry, are most strongly related to individual differences in domain-general cognitive functioning (g)? and 2) what are the underlying neurobiological properties of those regions? We meta-analyse vertex-wiseg-cortical morphometry (volume, surface area, thickness, curvature and sulcal depth) associations using data from 3 cohorts: the UK Biobank (UKB), Generation Scotland (GenScot), and the Lothian Birth Cohort 1936 (LBC1936), with the meta-analyticN= 38,379 (age range = 44 to 84 years old). Theseg-morphometry associations vary in magnitude and direction across the cortex (|β| range = -0.12 to 0.17 across morphometry measures) and show good cross-cohort agreement (mean spatial correlationr =0.57,SD= 0.18). Then, to address (2), we bring together existing -and derive new -cortical maps of 33 neurobiological characteristics from multiple modalities (including neurotransmitter receptor densities, gene expression, functional connectivity, metabolism, and cytoarchitectural similarity). We discover that these 33 profiles spatially covary along four major dimensions of cortical organisation (accounting for 65.9% of the variance) and denote aspects of neurobiological scaffolding that underpin the spatial patterning of MRI-cognitive associations we observe (significant |r| range = 0.21 to 0.56). Alongside the cortical maps from these analyses, which we make openly accessible, we provide a compendium of cortex-wide and within-region spatial correlations among general and specific facets of brain cortical organisation and higher order cognitive functioning, which we hope will serve as a framework for analysing other aspects of behaviour-brain MRI associations.
An Exploratory EEG Comparison of Good and Bad Readers
Authors: Álvarez-Alonso María José , de la Peña Cristina , Scott Ricardo
Published: December 2024

Reading is a crucial skill for critical thinking and cognitive development, yet many individuals experience difficulties that impact their daily lives. This study examines the neurophysiological differences between proficient and struggling readers using electroencephalography (EEG). The analysis focuses on the alpha (8-12 Hz) and beta (13-30 Hz) frequency bands, which are prominently involved in cognitive and language-related processes, although other frequency bands also contribute significantly to language comprehension and cognitive control. Eighteen participants (9 good readers and 9 poor readers) were selected based on standardized reading assessments. Resting-state EEG recordings were collected with a 64-channel system while participants were at rest with their eyes closed. After preprocessing to remove artifacts, the power spectra were analyzed, emphasizing relative power and alpha peak activity. Functional connectivity was measured using the corrected imaginary part of the phase-locking value (ciPLV), ensuring accuracy by minimizing volume conduction effects. Results revealed that good readers displayed increased beta power in frontal regions and enhanced synchronization within fronto-central-parietal networks compared to poor readers. Alpha band activity showed complex associations with factors such as age, reading skills, and verbal fluency, indicating nuanced relationships between neural development and literacy. The heightened beta activity in good readers is consistent with its role in cognitive control and language processing, while their stronger network connectivity suggests more efficient neural communication. These findings provide valuable insights into the neural basis of reading proficiency and emphasize the importance of distributed brain networks in skilled reading. Future research should replicate these results with larger samples and longitudinal designs to better understand the neural mechanisms underlying literacy development.
OST component RPN1 is a novel regulator of IRE1 RNase activity that interacts with multiple distinct IRE1 and PERK complexes
Authors: Larburu Natacha , Storer Freya , Ben-Khoud Yassin , Chen Chao-Sheng , Adams Christopher J , Southall Tony D , Ali Maruf MU
Published: December 2024

The unfolded protein response (UPR) is an essential cell signalling system that regulates ER protein homeostasis. IRE1 and PERK are receptor proteins that propagate the UPR signal from the ER to the cytosol. Both receptors are suggested to interact with various proteins from different biological pathways, although the scale and scope of such interactions are unclear. Previous reconstitution experiments have utilized purified isolated domains of IRE1 and PERK to understand mechanism. Here, we affinity purify full length IRE1 and PERK from mammalian cells and characterise the complexes they form by biochemical techniques and assess RNase function in vivo. We identify RPN1 as a novel interacting protein present in complexes with IRE1 and PERK. In the Drosophila eye, RNAi knockdown of RPN1 results in loss of IRE1 RNase activity. This work provides a basis for understanding of protein interaction networks for IRE1 and PERK and identifies OST subunit RPN1 as a novel regulator of IRE1 RNase activity.
METTL7A improves bovine IVF embryo competence by attenuating oxidative stress
Authors: Zhu Linkai , Ming Hao , Scatolin Giovanna N. , Xiao Andrew , Jiang Zongliang
Published: December 2024

In vitro fertilization (IVF) is a widely used assisted reproductive technology to achieve a successful pregnancy. However, the acquisition of oxidative stress in embryo in vitro culture impairs its competence. Here, we demonstrated that a nuclear coding gene, methyltransferase- like protein 7A (METTL7A), improves the developmental potential of bovine embryos. We found that exogenous METTL7A modulates expression of genes involved in embryonic cell mitochondrial pathways and promotes trophectoderm development. Surprisingly, we discovered that METTL7A alleviates mitochondrial stress and DNA damage and promotes cell cycle progression during embryo cleavage. In summary, we have identified a novel mitochondria stress eliminating mechanism regulated by METTL7A that occurs during the acquisition of oxidative stress in embryo in vitro culture. This discovery lays the groundwork for the development of METTL7A as a promising therapeutic target for IVF embryo competence.

Summary statement (Graphic abstract)

We describe a molecule acts in the pre-implantation period to attenuate oxidative stress that enhances embryo development to the blastocyst stage and subsequent pregnancy in cattle.
Mathematical bounds onr2and the effect size in case-control genome-wide association studies
Authors: Paye Sanjana M. , Edge Michael D.
Published: December 2024

Case-control genome-wide association studies (GWAS) are often used to find associations between genetic variants and diseases. When case-control GWAS are conducted, researchers must make decisions regarding how many cases and how many controls to include in the study. Depending on differing availability and cost of controls and cases, varying case fractions are used in case-control GWAS. Connections between variants and diseases are made using association statistics, includingχ2. Previous work in population genetics has shown that LD statistics, includingr2, are bounded by the allele frequencies in the population being studied. Since varying the case fraction changes sample allele frequencies, we extend use the known bounds onr2to explore how variation in the fraction of cases included in a study can impact statistical power to detect associations. We analyze a simple mathematical model and use simulations to study a quantity proportional to theχ2noncentrality parameter, which is closely related tor2, under various conditions. Varying the case fraction changes theχ2noncentrality parameter, and by extension the statistical power, with effects depending on the dominance, penetrance, and frequency of the risk allele. Our framework explains previously observed results, such as asymmetries in power to detect risk vs. protective alleles, and the fact that a balanced sample of cases and controls does not always give the best power to detect associations, particularly for highly penetrant minor risk alleles that are either dominant or recessive. We show by simulation that our results can be used as a rough guide to statistical power for association tests other thanχ2tests of independence.
The transcriptomic signature of age and sex is not conserved in human primary myocytes
Authors: Lamon Séverine , Soria Megan , Williams Ross , Critchlow Annabel , Garnham Andrew , Varshney Akriti , Beillharz Traude , Hiam Danielle , Ziemann Mark
Published: December 2024

Human primary muscle cell (HPMC) lines derived from skeletal muscle biopsies are potentially powerful tools to interrogate the molecular pathways underlying fundamental muscle mechanisms. HPMCs retain their genome in culture, but many endogenous circulating factors are not present in thein vitroenvironment or at concentrations that do not mirror physiological levels. To address the assumption that HPMCs are valid models of age and sex-specificity in human muscle research, we examined to what extent HPMC lines maintain their source phenotypes in culture. A comparison of the transcriptomic signature of 30 human muscle biopsies (N = 10 young males, N = 10 young females, N = 10 old males) and their corresponding HPMCs indicated a near-complete lack of retention of the genes and pathways that were differentially regulatedin vivowhen compared to theirin vitroequivalent, except for some genes encoded on the Y-chromosome. The diversity of the muscle cell population and the lack of sex- and age-dependent factors in the cellular milieu likely contribute to these observations, which call for caution when using HPMCs as an experimental model of human muscle sex or age. Nuclear single cell sequencing or HMPCs grown in 3D culture as organoids under strain might therefore provide a closer alternative to human muscle tissue.
Naturalistic language comprehension engages a cascade of widespread brain networks in the one second following comprehension
Authors: Hong Min Kyung , Janson Andrew , Koirala Prasanna , Fotidzis Tess , Polyn Sean , Aboud Katherine
Published: December 2024

Language comprehension (LC) is a cornerstone of human cognition, enabling the extraction of meaning from written and spoken communication with remarkable efficiency. Decades of neuroimaging research have identified the brain networks associated with LC, but limitations in spatial and temporal resolution have hindered a comprehensive characterization of the whole-brain (millimeter scale), real-time (millisecond precision) dynamics underlying this process. To overcome these constraints, we applied a fusion of multimodal brain imaging techniques (fMRI and EEG) in healthy adults (n = 30) to map the spatiotemporal progression of neural network engagement during LC in the one second following comprehension. Our findings reveal a cascade of brain network activations, beginning with the occipitotemporal perceptual word processing network (250 ms), followed by the temporoparietal semantic retrieval network (400 ms), the posterior default mode inferential network (500 ms), the frontotemporal semantic integration network (600 ms), and finally, a distributed goal-directed comprehension network (700 ms). Crucially, inferential processing emerged as a “hinge point,” linking early word processing to later higher-order networks. Efficient LC was associated with greater mediation by this inferential network and reduced reliance on top-down semantic integration. These findings provide evidence that naturalistic LC relies on rapid, dynamic interactions across widespread brain networks, with individual differences in LC reflecting specific subnetwork interactions. This work offers a framework for investigating the temporal evolution of distributed brain network dynamics in complex cognition across domains and clinical populations.
Widespread annual rhythms in pediatric emergencies
Authors: Tachinardi Patricia , Witt Rochelle M , Wu Gang , Paulose Jiffin K , Koritala Bala S C , Wong Hector R , Mendonca Eneida A , Smith David F , Hogenesch John B , Ruben Marc D
Published: December 2024

Assessments of emergency department (ED) utilization for specific medical conditions reveal distinct annual rhythms, providing valuable insights into risk factors and optimal clinical staffing. However, focusing on a single condition in isolation can lack essential context. Such rhythms may (i) depend on co-occurrence with other conditions, (ii) be obscured by systemic factors that influence all conditions similarly, or (iii) offer limited clinical utility without understanding their rhythmic effect sizes relative to other emergencies. Using a unified framework for analysis, we studied the annual variation in incidences of all chief complaints (CCs) from 1.5 million admissions to our pediatric ED and urgent care centers from 2010 to 2021, enabling comparison of seasonality, effect sizes, and interactions across all types of emergencies. Most CCs (∼80%) had annual rhythms, with a range of phases. Specific patterns, such as spring and fall peaks in neurologic-, injury-, and psychiatric-related CCs, have immediate significance. For example, psychiatric emergencies, which the American Academy of Pediatrics has designated a national crisis, were among the largest rhythmic effect sizes of all CCs. Further evaluation integrating ICD-10 diagnoses identified patient subtypes for psychiatric and other CCs, suggesting distinct annual influences. Using counterpart data from across Brazil, we identified marked global differences in annual patterns of ED utilization, including psychiatric emergencies. Lastly, we identified CCs with largeweekdayeffects, impacting care and staffing needs, especially when combined with annual rhythms.
Subregional analysis of the amygdala, thalamus, and hypothalamus at the pre-decline stage in Parkinson’s disease groups with later cognitive impairment
Authors: Seo Kazuhide , Oyama Genko , Yamamoto Toshimasa
Published: December 2024

While cognitive decline in Parkinson’s disease (PD) significantly impacts patients’ quality of life, early detection remains challenging. Recent advances in magnetic resonance imaging analysis have enabled detailed examination of subcortical structures. This study aimed to investigate subtle changes in specific subregions of the amygdala, thalamus, and hypothalamus in PD patients before they developed cognitive decline. Magnetic resonance imaging data of 163 participants (97 healthy controls [HC], 45 PD patients with normal cognition [PDNC], and 21 PD patients who show cognitive impairment [PDCI]) from the Parkinson’s Progression Markers Initiative database were analyzed. Detailed subregional analyses of brain structures were performed. Cognitive function was assessed using the Montreal Cognitive Assessment and domain-specific tests. The PDCI group exhibited significantly lower intracranial occupancy rates in specific subregions of the amygdala, thalamus, and hypothalamus than the HC group; however, these changes did not correlate significantly with cognitive test scores. Conversely, significant structural changes were observed in extensive cortical regions, subcortical gray matter areas, and white matter areas, which correlated with various cognitive functions including memory, attention, executive function, and visuospatial abilities. Nevertheless, no significant associations were found between changes in individual brain regions and the risk of mild cognitive impairment progression. This study elucidates early brain structural changes associated with cognitive decline in PD. While structural alterations were observed in the amygdala, thalamus, and hypothalamus, widespread cortical changes demonstrated stronger associations with cognitive decline. These findings suggest that cognitive impairment in PD results from extensive cortical network alterations rather than changes in specific subcortical regions. This insight emphasizes the need for a comprehensive approach, considering multiple brain regions and their interactions, in early diagnosis and intervention strategies for PD-related cognitive impairment.
Structural Insights into the Assembly and Regulation of 2’-ORNA Methylation by SARS-CoV-2 nsp16/nsp10
Authors: Misra Anurag , Rahisuddin R. , Parihar Manish , Arya Shailee , Viswanathan Thiruselvam , Jackson Nathaniel , Qi Shan , Chan Siu-Hong , Harris Reuben S. , Martinez-Sobrido Luis , Gupta Yogesh K.
Published: December 2024

2’-O-ribose methylation of the first transcribed base (adenine or A1in SARS-CoV-2) of viral RNA mimics the host RNAs and subverts the innate immune response. How nsp16, with its obligate partner nsp10, assembles on the 5’-end of SARS-CoV-2 mRNA to methylate the A1has not been fully understood. We present a ∼ 2.4 Å crystal structure of the heterotetrameric complex formed by the cooperative assembly of two nsp16/nsp10 heterodimers with one 10-mer Cap-1 RNA (product) bound to each. An aromatic zipper-like motif in nsp16 and the N-terminal regions of nsp10 and nsp16 orchestrate an oligomeric assembly for efficient methylation. The front catalytic pocket of nsp16 stabilizes the upstream portion of the RNA while the downstream RNA remains unresolved, likely due to its flexibility. An inverted nsp16 dimer extends the positively charged surface area for longer RNA to influence the catalysis. Additionally, a non-specific nucleotide-binding pocket on the backside of nsp16 plays a critical role in catalysis, further contributing to its enzymatic activity.
The inhibitory effects of Remodelin on murine myoblasts differentiation
Authors: Sian Veronica , Hentschel Andreas , Sarparanta Jaakko , Roos Andreas , Jonson Per Harald , Gayathri Swethaa Natraj , Mai Antonello , Rotili Dante , Altucci Lucia , Udd Bjarne , Savarese Marco , Nebbioso Angela
Published: December 2024

Myoblasts differentiation is a highly regulated and complex process leading to the formation of fused and aligned mature myotubes. Growing interest in the role of epigenetics in muscle differentiation has highlighted epi-modulators as crucial regulators of this process. Ourin vitrostudy aimed to explore the potential effects of Remodelin, a selective inhibitor of the acetyltransferase Nat10, on myoblasts differentiation.

We cultivated and differentiated murine C2C12 myoblasts on ultra-compliant gelatin for up to 16 days, and treated them with Remodelin. We used confocal microscopy, together with RNAseq and proteomics analyses, to examine the impact of Remodelin on myotube formation.

Remodelin impaired myotube organization and maturation, and proper morphology compared to untreated cells. Additionally, no significant twitching was observed upon Remodelin treatment. Intersection of transcriptomics and proteomics analyses confirmed that Remodelin effectively slowed myotube formation. Overall, these results suggest that Remodelin broadly affects the regulatory networks involved in skeletal muscle differentiation.
Chemical degradation identified Human p38-MAPK as a host target to combat parasitic infections
Authors: Singhal Jhalak , Rawat Neha , Bansal Ruby , Srivastava Pallavi , Peer Gajala Deethamvali Ghouse , Pandey Ramendra Pati , Ranganathan Anand , Singh Shailja
Published: December 2024

The interplay between host and parasite determines parasite burden and disease outcome. Parasite exploits host signaling pathways like p38-MAPK for its survival and pathogenesis. NR-7h, a proteolysis-targeting chimera (PROTAC) targeting human p38-MAPK was used to assess p38-MAPK’s role inLeishmania donovaniandPlasmodium falciparuminfection in their respective hosts. NR-7h degraded host p38-MAPK in a time- and dose-dependent manner. Degradation of host p38-MAPK by NR-7h reduced parasite load in host cells dose-dependently, implicating the role of p38-MAPK in parasite survival. The modulation of cytokine profiling and oxidative burst upon NR-7h mediated degradation of host p38-MAPK was further correlated with parasite death. The synergistic effect of host p38-MAPK degradation by NR-7h with Amphotericin B enhances the efficacy of parasite-directed therapy. This study underscores the importance of host p38-MAPK forL. donovaniandP. falciparumprogression and highlights NR-7h’s potential in antiparasitic therapy by targeting this pathway.
The ‘Janus A’ gene encodes a polo-kinase whose loss creates a dorsal/ventral intracellular homeosis in the ciliate,Tetrahymena
Authors: Cole Eric S. , Maier Wolfgang , Huynh Huy Vo , Reister Benjamin , Sowunmi Deborah Oluwabukola , Chukka Uzoamaka , Lee Chinkyu , Gaertig Jacek
Published: December 2024

Genetic studies on the protist,Tetrahymena thermophilaprovide a glimpse into the unexpectedly rich world of intracellular patterning that unfolds within the ciliate cell cortex. Ciliate pattern studies provide a useful counterpoint to animal models of pattern formation in that the unicellular model draws attention away from fields of cells (or nuclei) as the principal players in the metazoan pattern paradigm, focusing instead on fields of ciliated basal bodies serving as sources of positional information. In this study, we identifyJANA, a Polo kinase ofTetrahymena, that serves as an important factor driving global, circumferential pattern. Loss of function of JanA results in global, mirror-duplication of ventral organelles on the dorsal surface: a kind of intracellular homeosis that has been named the ‘janus’ phenotype. Gain of function (over-expression) reduces or even eliminates cortical organelles within the ventral ‘hemi-cell’. GFP-tagging reveals that JanA decorates basal bodies predominantly within the left-dorsal hemi-cell. These results led us to propose a model in which the default state of cortical patterning is a mirror-image assemblage of cortical organelles including oral apparatus, contractile vacuole pores and cytoproct. JanA normally suppresses organelle assembly in the dorsal hemi-cellular cortex, resulting in a simple, ventral assemblage of these organelles, a ‘half-pattern’ as it were. PLK inhibitors produce a janus phenocopy, but reveal other unanticipated roles for PLK activities involving more local patterning events that control organelle dimensions and organization. We discuss results in light of metazoan studies in which PLK activity links cell cycle control to intracellular symmetry breaking.
Quantum-Limited Generalized Measurement for Tunnel-Coupled Condensates
Authors: Prüfer Maximilian , Minoguchi Yuri , Zhang Tiantian , Kuriatnikov Yevhenii , Ramana M. Venkat , Schmiedmayer Jörg
Published: December 2024

The efficient readout of the relevant information is pivotal for quantum simulation experiments. Often only single observables are accessed by performing standard projective measurements. In this work, we implement an atomic beam splitter by controlled outcoupling that enables a generalized measurement scheme. This gives us simultaneous access to number imbalance and relative phase in a system of two tunnel-coupled 1D Bose gases, which realize a quantum simulator of the sine-Gordon field theory. We demonstrate that the scheme is quantum limited by accessing number squeezing as a sensitive probe for added noise; further, we show that we can track Josephson oscillation dynamics with the generalized measurements. Finally, we show that the scheme allows the extraction of atoms while maintaining the system’s coherent dynamics, which opens up the door to accessing multitime correlation functions. Our scheme constitutes a step towards accessing quantum properties of the sine-Gordon field theory and, in the future, studying spatially extended systems under continuous monitoring.

Published by the American Physical Society
2024
Inferring Nonlinear Dynamics of Cell Migration
Authors: Zadeh Pedrom , Camley Brian A.
Published: December 2024

The motility of eukaryotic cells is strongly influenced by their environment, with confined cells often developing qualitatively different motility patterns from those migrating on simple two-dimensional substrates. Recent experiments, coupled with data-driven methods to extract a cell's equation of motion, showed that cancerous MDA-MB-231 cells persistently hop in a limit cycle when placed on two-state adhesive micropatterns (two large squares connected by a narrow bridge), while they remain stationary on average in rectangular confinements. In contrast, healthy MCF10A cells migrating on the two-state micropattern are bistable, i.e., they settle into either basin on average with only noise-induced hops between the two states. We can capture all these behaviors with a single computational phase field model of a crawling cell, under the assumption that contact with nonadhesive substrate inhibits the cell front. Our model predicts that larger and softer cells are more likely to persistently hop, while smaller and stiffer cells are more likely to be bistable. Other key factors controlling cell migration are the frequency of protrusions and their magnitude of noise. Our results show that relatively simple assumptions about how cells sense their geometry can explain a wide variety of different cell behaviors, and show the power of data-driven approaches to characterize both experiment and simulation.

Published by the American Physical Society
2024
Diffractometer for element-specific analysis on local structures using a combination of X-ray fluorescence holography and anomalous X-ray scattering
Authors: Tajiri Hiroo , Kohara Shinji , Kimura Koji , Halubai Sekhar , Morimoto Haruto , Happo Naohisa , Stellhorn Jens R. , Onodera Yohei , Qiao Xvsheng , Urushihara Daisuke , Hu Peidong , Wakihara Toru , Kinoshita Toyohiko , Hayashi Koichi
Published: December 2024

To tackle disorder in crystals and short- and intermediate-range order in amorphous materials, such as glass, we developed a carry-in diffractometer to utilise X-ray fluorescence holography (XFH) and anomalous X-ray scattering (AXS), facilitating element-specific analyses with atomic resolution using the wavelength tunability of a synchrotron X-ray source. Our diffractometer unifies XFH and AXS configurations to determine the crystal orientation via diffractometry. In particular, XFH was realised even for a crystal with blurred emission lines by a standing wave in a hologram, and high-throughput AXS with sufficient count statistics and energy resolution was achieved using three multi-array detectors with crystal analysers. These features increase tractable targets by XFH and AXS, which have novel functionalities.
The role of leadership, continuous improvement and benchmarking on organizational performance: the mediating mechanism of EOC
Authors: Al-Dhaafri Hassan Saleh , Alosani Mohammed Saleh
Published: December 2024

Purpose

The main purpose of this study is to examine the collective effect of leadership, continuous improvement and benchmarking on organizational performance. In addition, the study also investigates the intervening mechanism of EOC as a mediator between leadership, continuous improvement and benchmarking from one side and organizational performance on the other side.

Design/methodology/approach

Hypotheses for testing have been generated using primary data gathered through a survey questionnaire. A total of 355 questionnaires were returned from amongst 565 when data was gathered from the Dubai police organization. The data was analyzed using the Structural Equation Modelling (SEM) method and SmartPLS.

Findings

Most of the hypotheses in the study’s model were found to have a significant effect on organizational performance. Statistical findings using SEM-PLS also confirmed the mediating role of EOC as a mechanism between leadership, continuous improvement, benchmarking and organizational performance.

Practical implications

Findings reported many valuable implications. The study has theoretical implications to close the gap in the existing body of knowledge and practical implications to consider the study’s variables to enhance the overall performance through considering entrepreneurial culture as an intervening mechanism.

Originality/value

The collective role of leadership, continuous improvement, benchmarking, EOC and organizational performance is studied as one of the most important empirical studies which bring original contribution to the existing body of knowledge.
Crisis-induced career shock and entrepreneurial intention among employees: what is the role of layoff, job insecurity and perceived employability during COVID-19?
Authors: Hamouche Salima , Bani-Melhem Shaker , Demir Ahmet , Kammogne Christiane Liliane
Published: December 2024

Purpose

Crises significantly affect the “people” dimension of the triple bottom line, disrupting careers through economic consequences, reducing organizational trust and altering career choices. Entrepreneurial careers may emerge as an alternative to secure income and career control. Crises can generate career shocks, prompting transitions from traditional employment to entrepreneurship. This study aims to investigate how crises influence career transitions, particularly entrepreneurial intentions, focusing on the effects of layoffs, job insecurity and perceived employability during COVID-19. It explores both direct and indirect impacts of these factors through career shock, contributing to career and entrepreneurship research.

Design/methodology/approach

Cross-sectional data were collected in the United Arab Emirates (UAE) using snowball sampling during the COVID-19 health crisis. The final sample consisted of 211 working individuals. An online questionnaire was distributed to participants. The study hypotheses were tested using Partial Least Squares (PLS) analysis conducted with SmartPLS 3.0.

Findings

The obtained results showed that the layoff of others, job insecurity and low perceived employability are significantly associated with career shock. And that career shock mediates the relationship between these variables and entrepreneurial intention in times of crisis, except for job insecurity.

Practical implications

This research provides insights for employees, managers, organizations and policymakers. It is necessary to carefully address employee expectations and experiences to identify career decisions resulting from career shocks and determine the needed interventions and support.

Originality/value

Very few studies examined the relationship between career shock and entrepreneurial intention. This cannot help human resources management practitioners understand how career shock can trigger the transition from paid employment to an entrepreneurial career. This study broadens the scope of research on human resource management, entrepreneurship and career by examining the direct effects of layoff, job insecurity and perceived employability on career shock as well as on entrepreneurial intention, in addition to their direct effects on the latter through career shock during a crisis.
The curious case of one-dollar CEO salaries: evidence from market reaction to salary decision announcements
Authors: Danielova Anna , Liao Wei-Ju
Published: December 2024

Purpose

This study investigates the motivations for and compensation structure changes behind $1 CEO salary decisions.

Design/methodology/approach

Using a hand-collected sample, we relied on an event study framework and regression analysis to decipher the informational content of $1 CEO salary announcements.

Findings

The results show that the market reacts positively to $1 CEO salary announcements that indicate aligning the interests of CEOs and shareholders.

Practical implications

A lot of academic and professional attention has been given to the components of executive compensation packages as tools for incentivizing managers. Our findings will help executive board members tasked with determining CEO compensation packages.

Originality/value

This study adds to the literature on CEO compensation by deciphering the market reaction to $1 salary decision announcements. Our study contributes to the literature on executive compensation by providing evidence consistent with efficient contracting.
Embracing emojis: prototyping mood enhanced information systems for fiction readers
Authors: Lee Wan-Chen , Huang Li-Min Cassandra , Hirt Juliana
Published: December 2024

Purpose

This study aims to understand fiction readers’ perspectives on the strengths and concerns of incorporating emojis into information systems for fiction. To solicit readers’ feedback, the authors adopted Cho et al.’s (2023) model of three families of fiction mood categories as the theoretical framework. Based on this framework, prototypes of interface designs that implemented textual mood descriptors and/or emojis were developed.

Design/methodology/approach

Eighteen adult fiction readers at a US public university were recruited for online interviews. The participants shared their insights into the prototypes and their fiction search and review experiences.

Findings

Most participants preferred designs that support both mood terms and emojis. The findings highlighted the potential of emojis to improve metadata inclusivity and serve diverse users’ needs. Technical challenges and accessibility issues for blind or visually impaired users were noted as limitations of emoji implementation.

Originality/value

Based on established theoretical frameworks and emoji mappings for mood categories, this study advances the progress of implementing emojis into information systems for fiction. The findings will inform user-centered interface designs that support the description, search and review of fiction.