bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the Volume of the Liposuction-Derived Adipose Tissue in Clinical Application
Authors: Yang Ruomeng , Song Zhen , Li Shengxu , Wang Jian , Liang Hongwei
Published: January 2025

Introduction:

The strategy of adipose component transplantation has been proposed and widely used in both reconstructive and aesthetic surgery. However, there is no uniform standard for the preparation of component fat, and the volume calculation of liposuction and injection in clinical applications is mostly based on experience. This study aims to analyze the volume of component fat obtained during clinical series.

Methods:

Patients undergoing abdominal or thigh liposuction and autologous component fat grafting from September 2020 to October 2024 were included. The high-density fat was harvested from the inferior one-third layer of the standard Coleman fat. The SVF-gel was obtained by mechanical emulsification and centrifugation of the oil layer and upper two-third layer of adipose tissue. Correlation analysis was conducted between the volume of SVF-gel and patient characteristics.

Results:

Sixty-five with an average age of 33.9 years were included. For breast augmentation, the volume of prepared high-density fat and SVF-gel were 331.7±70.8 and 60.3±13.1 mL, with the proportion of SVF in fat aspirated amounting to 6.4%±1.9%. For the treatment of temporal depression, the volume of prepared high-density fat and SVF-gel were 48.3±27.3 and 14.5±8.6 mL, respectively, with the proportion of SVF in fat aspirated amounting to 10.3%±2.0%. There was a significant difference between the proportion of SVF-gel in low-density fat and aspirated fat obtained from the abdomen and thigh.

Conclusion:

There is a significant negative correlation between the obtained SVF-gel proportion with BMI and the amount of fat aspirated. For the preparation of a large amount of SVF-gel, especially for individuals with high levels of BMI, the total volume of fat aspirated would be much higher.

Level of Evidence:

Level IV.
Prevalence and Incidence of Oral Benzodiazepine Use in Hospitalized Surgical Patients
Authors: Geensen Roos , Verhoeven Jorrit G. , Hendriks Johanna M. , Rietdijk Wim J.R. , Jeekel Johannes , Hunfeld Nicole G.M. , Klimek Markus
Published: January 2025

Objective:

To determine the prevalence of intrahospital oral benzodiazepine use in the surgical population of a tertiary care centre.

Summary of Background Data:

Oral benzodiazepines used for treating sleep disturbances and anxiety are widely used in the general population. Information regarding benzodiazepine use during hospitalization is scarce.

Methods:

A retrospective cohort study was conducted using routinely collected healthcare data in a university hospital in Rotterdam, the Netherlands. 10,896 patients representing 14,928 admissions were included in this cohort, corresponding to all adult surgical patients admitted between September 2018 and September 2022. Median age was 62 (50-72) and 8,761 out of 14928 (58.9%) were male. Main outcome measures were prevalence and incidence of oral benzodiazepines usage during hospitalization.

Results:

Prevalence of benzodiazepine administrations in the surgical department was 21.6% out of 14,928 admissions. Median number of tablets given during hospital stay was 3 (1-7). Temazepam (33%), oxazepam (24%) and zopiclone (19%) were prescribed most. Female patients were more likely to have been administered a benzodiazepine, with an adjusted odds ratio of 1.09 (95% confidence interval 1.002 to 1.19). Benzodiazepine administration during admission was positively associated with higher 30-day surgical readmission, with an adjusted odds ratio of 1.37 (1.22 to 1.54).

Conclusions:

In this study, one fifth of patients admitted to surgical departments were administered oral benzodiazepines for sleep disturbances and anxiety. Future research and policies should focus on finding and implementing effective non-pharmacological methods for perioperative sleep disturbances and anxiety.
Single-cell transcriptomics reveals the impact of sex and age in the healthy human liver
Authors: Rahman Raza Ur , Epstein Eliana T. , Murphy Shane , Amir-Zilberstein Liat , McCabe Cristin , Delorey Toni , Koene Hope , Fernandes Lilly , Tanabe Kenneth K. , Qadan Motaz , Ferrone Christina , Berger David L. , Shih Angela , Deguine Jacques , Mullen Alan C.
Published: January 2025

The liver is a vital organ composed of parenchymal, nonparenchymal, and immune cell populations, which are now being mapped at single cell resolution. Here we present a detailed map of the cellular composition of the human liver through single-nucleus RNA sequencing (snRNA-seq), incorporating insights from 32 healthy liver samples. The dataset contains cells from female and male donors spanning more than seven decades of age. Excluding the X and Y chromosome, we identified ∼500 genes uniquely enriched in cells of the female liver, and ∼600 genes enriched in cells of the male liver. These genes tend to be enriched across multiple cell types in females and are more restricted to individual cell types in males. These genes define unique circuitries within each cell type of the liver between females and males and their impact on cell-cell communication and response to external signals, including enrichment of cholesterol/lipid metabolism and associated angiopoietin-like protein (ANGPTL) signaling in female cells and bone morphogenic protein (BMP) signaling in male cells. With increased age, we observe a greater diversity in gene expression, including enrichment of genes that regulate neuregulin (NGR) signaling. While fewer genes are enriched within cell types of the younger liver, genes regulating insulin growth factor (IGF) signaling are in this group. Together, these results define the activities of healthy cell types within the liver across sex and age and provide a reference for future comparisons across different ancestries, geographies, and disease states.

One Sentence Summary

We applied single-nucleus RNA sequencing to define features influenced by sex and age across cell types and subtypes of the human liver.
Investigating the Mechanisms and Potential Therapeutic Targets of Vestibular Migraine
Authors: Yao Xiaotong , Liang Zhuoji , Liang Yanling
Published: January 2025

Background

Vestibular Migraine (VM) is a complex neurological disorder with recurrent headaches and various vestibular symptoms. Although it severely affects patients’ quality of life, its causes and pathophysiology are still unclear, and effective treatments are scarce. The lack of data emphasizes the need for bioinformatics to find key genes and pathways in VM, which could help develop new diagnostic and treatment methods.

Method

The GSE109558 dataset was acquired from the Gene Expression Omnibus (GEO) database. To identify VM - related differentially expressed genes, screening was carried out through limma and Weighted Correlation Network Analysis (WGCNA).The functional analysis of VM - related differentially expressed genes was conducted using three bioinformatics approaches: Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Feature selection was further refined using lasso regression and random forest. Also, CIBERSORT was utilized to analyze the infiltration of immune cells, and Spearman’s correlation analysis was employed to explore the correlations between diagnostic differentially expressed genes and immune cells.Finally, the Comparative Toxicogenomics Database (CTD) was utilized to search for corresponding drugs, and molecular docking was performed to explore potential therapeutic targets.

Result

Six key feature genes (CABIN1, IFIT3, HEATR1, ARHGDIA, RAB11FIP4, and ZNF444) were identified as potential diagnostic markers for VM. Among these, CABIN1 demonstrated the highest diagnostic potential based on ROC curve performance, highlighting its promise as a diagnostic biomarker.Functional annotation of DEGs revealed their enrichment in biological processes related to inflammation, calcium ion channel regulation, and other pathways likely involved in VM pathophysiology. Through the CTD, drugs like Acetaminophen, bisphenol A, and Phenylephrine were identified.

Molecular docking simulation was used to explore their potential therapeutic mechanisms for VM.

Conclusion

This study offers important insights into the molecular mechanisms of VM and identifies six key feature genes, with CABIN1 standing out as a potential diagnostic marker.These findings pave the way for further research to validate the diagnostic and therapeutic implications of these genes and pathways.
Divergent Effects ofAPOE3andAPOE4Human Astrocytes on Key Alzheimer’s Disease Hallmarks in Chimeric Mice
Authors: Cruz-Sese Joan , Mirón-Alcala Marta , Alfonso-Triguero Maria , Olalde Jon , Ruiz Leire , Galbis-Gramage Nuria , Cortes Lorea , Escobar Laura , Preman Pranav , Snellinx An , Saito Takashi , Saido Takaomi C , Saiz-Aúz Laura , Rábano-Gutiérrez Alberto , TCW Julia , Goate Alison , Strooper Bart De , Alberdi Elena , Arranz Amaia M
Published: January 2025

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimer’s disease (AD), the impact of astrocytes carrying differentAPOEvariants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenicAPOE3orAPOE4human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere.APOE3andAPOE4h-astrocytes differentially express and secrete the APOE protein, which binds to Aβ plaques with an isoform-dependent affinity. Remarkably,APOE3h-astrocytes ameliorate Aβ pathology, Tau pathology and neuritic dystrophy. In contrast,APOE4h-astrocytes aggravate these AD processes. Moreover,APOE3andAPOE4h-astrocytes modulate microglia responses to Aβ pathology in opposite ways.APOE4h-astrocytes enhance microglia clustering around Aβ plaques and exacerbate DAM state whereasAPOE3h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to Aβ pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with differentAPOEvariants and the different forms of APOE they secrete have a crucial role in AD progression.
Acquisition of ampliconic sequences marks a selfish mouset-haplotype
Authors: Swanepoel Callie M. , Wang Gaojianyong , Zhang Lucy , Brändl Björn , Bauer Hermann , Tsaytler Pavel , Müller Franz-Josef , Herrmann Bernhard G. , Mueller Jacob L.
Published: January 2025

Mendelian genetics posits equal transmission of alleles, but selfish alleles can bias the transmission of large genomic regions or entire chromosomes1–4. One long-standing question is how transmission bias evolves to encompass large genomic regions.Mus musculus(house mouse)t-haplotypes exhibit up to 99% transmission bias from heterozygous males5–14and harbor selfish alleles9–14genetically linked to large inversions spanning the proximal half of chromosome 1715–20. Here, by generating a high-quality, single-haplotype assembly of at- haplotype, we reveal the evolution of eight large amplicons with known11,13,21and candidate selfish alleles as a distinct genetic feature. Three amplicons are conserved in closely relatedMusspecies, and two have known selfish alleles in the oldest inversion, implicating amplicons and an inversion drove the origins of a selfish chromosome 17 ∼3MYA. The remainingt- haplotype amplicons harbor gene families expressed predominantly in haploid spermatids, newly acquired retrogenes, and the most differentially expressed genes in wild-type/t-haplotype spermatids. Targeted deletion of a ∼1.8Mb amplicon with candidate selfish alleles on thet- haplotype reduces selfish transmission in heterozygous males by 3%. Notably, the evolution of selfish allele-containing amplicons and inversions on thet-haplotype parallels mammalian sex chromosome evolution as signatures of selfish transmission. We propose amplicon acquisition and large inversions initiate evolutionary arms races between selfish haplotypes and serve as genome-wide signatures of selfish transmission.
Multimorbidity Management: A scoping review of comprehensive interventions for multimorbidity outcomes
Authors: Seakamela Kagiso P , Mashaba Reneilwe G , Ntimana Cairo B , Kabudula Chodziwadziwa W , Sodi Tholene
Published: January 2025

Background

Multimorbidity, defined as the co-occurrence of two or more chronic conditions in an individual, has emerged as a worldwide public health concern contributing to mortality and morbidity. With a prevalence estimated at 37% globally, this complex health phenomenon is increasingly affecting populations as they age. Despite the growing burden of multimorbidity, the development and implementation of interventions published by scholars are still in their early stages with significant variability in strategies and outcomes.

Objectives

The review aims to synthesize interventions designed to manage and mitigate multimorbidity and explore a range of approaches, including pharmacological treatments, lifestyle modifications, care coordination models, and technological innovations.

Methods

The scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. It included about 1,227,906 individuals with multimorbidity, with 199,413 being male (16.2%) and 1,028,493 (83.8%) female participants. Multimorbidity interventions were defined as strategies or programs designed to manage and improve the health and quality of life of individuals with multiple chronic conditions.

Results

The final analysis included 101 articles from 3119 published between 2012 and 2024. Themes on the need for lifestyle and behavioural interventions, patient empowerment and engagement, multimorbidity management, health integration, pharmacotherapy optimization, community and policy interventions, healthcare system improvements, technology and digital health, as well as research and evidence-based practice interventions, emerged.

Conclusion

The reviewed literature emphasizes the necessity of multidisciplinary approaches to effectively combat the escalating pandemic of multimorbidity.
Program Cost and Return on Investment of a Remote Patient Monitoring Program for Hypertension Management
Authors: Zhang Donglan Stacy , Millet Laure , Bellows Brandon K. , Lee Sarah , Mann Devin
Published: January 2025

Objective

To evaluate the program costs and financial sustainability of a remote patient monitoring for hypertension (RPM-HTN) program implemented in the cardiology practice of a large healthcare system.

Study Design

This economic evaluation utilized field observation, interviews, literature review, and quantitative analysis to assess RPM-HTN from March to June 2024 at New York University Langone Health

Methods

A costing tool was developed to quantify program costs, including personnel, start-up, equipment, and supply expenses, expressed in 2024 USD. Reimbursement rates were estimated using the 2024 Medicare Physician Fee Schedule. The return on investment (ROI) was calculated as the ratio of net return to program costs. Univariate sensitivity analyses evaluated the impact of varying a single parameter at a time on ROI.

Results

The average cost of RPM-HTN was $330 per patient (range: $208–$452), with an annual program cost of $33,000 (range: $20,785–$45,168) for 100 patients enrolled from the Cardiology Division. Key expenses included data review by nurse practitioners ($172/patient), blood pressure device costs ($48/patient), and nurse-patient communication ($36/patient). ROI averaged 22.2% at 55% patient compliance with the RPM-HTN program. This ROI ranged from-11.1% (assuming program costs of $452) to 93.3% (assuming program costs of $208) per patient. ROI was most sensitive to changes in data review costs, insurance reimbursement, patient compliance, and device setup.

Conclusions

The RPM-HTN program demonstrated positive ROI, indicating financial sustainability in a large urban healthcare system. Improving patient compliance with the program and reducing human resource costs are critical for scaling RPM-HTN programs effectively.
PP6 phosphatase and Elongator contribute to kinesin 5-dependent spindle assembly by controlling microtubule regulator levels
Authors: Marín Laura , Castro-Sangrador Jorge , Hoya Marta , Tello Shara , Coll Pedro M , Encinar del Dedo Javier , Fernández-Álvarez Alfonso , Ribas Juan C , Tran Phong T , Rincon Sergio A.
Published: January 2025

Eukaryotic chromosome segregation relies on the assembly of a bipolar machinery based on microtubules (MTs), named the mitotic spindle. Formation of the mitotic spindle follows a force balance mechanism that ensures the proper capture and separation of sister chromatids. Many proteins have been involved in the establishment of this force balance, although kinesin 5 is well recognized as the major outward pushing force generator, since its inactivation results in monopolar, non-functional spindles. In order to find additional players in the force balance mechanism, we have performed a suppressor screen using a conditional allele of the fission yeast kinesin 5 ortholog Cut7. This screen identified that the lack of the PP6 phosphatase partially suppresses cut7 phenotypes, at least by defective translation of MT regulators, impacting on the force balance mechanism. Additionally, our data show that the Elongator complex, a target regulated by PP6 involved in tRNA modification, also ensures the force balance, albeit to a lesser extent. Importantly, this complex has been recently involved in direct MT polymerization in metazoans, a role probably not shared by its fission yeast counterpart.
Lethal streptococcal infection is associated with widened lymph node bottlenecks
Authors: Xia Linya , Hullahalli Karthik , Tian Xingyu , Yuan Chen , Pan Fei , Fan Hongjie , Waldor Matthew K. , Ma Zhe
Published: January 2025

Streptococcus suisserotype 2 (SS2) infection causes streptococcal toxic shock-like syndrome (STSLS), which can be lethal in both pigs and humans. In mouse models, relatively subtle differences in the inoculum size result in drastically different infection outcomes, from clearance to acute death. Here, we leveraged barcoded SS2 in a murine model to define the bacterial population dynamics associated with death. Barcode sequencing analysis demonstrated that a 10-fold increase in inoculum size led to a 100-1,000-fold increase in the number of bacteria that initiated infection in certain lymph nodes, ultimately driving lethality. This lethal dose threshold was in part driven by suilysin (SLY), the major SS2 virulence factor. At higher doses, the clearance and replication kinetics of bacteria lacking SLY mimicked WT SS2 at sub-lethal doses. Our findings suggest that acute death in SS2 infection is caused by a wholesale failure of the immune system, enabling a large number of bacteria to initiate infection. These results demonstrate how subtle changes in inoculum size can have dramatic consequences for infection outcome and how lethal infection is driven by widened infection bottlenecks.

Author Summary

Lethal infections are often associated with a specific dose threshold, where increasing inoculum size is associated with an increased likelihood of death. However, a quantitative explanation how this numeric threshold is established is lacking. For example, lethal dose thresholds may reflect a dose where at least one microbe can pass through host-imposed barriers to infection. Alternatively, lethal dose thresholds may reflect a failure of the host immune system, leading to numerous microbes initiating infection. Here, using barcodedStreptococcus suisserotype 2 (SS2), we compare the within-host population dynamics associated between lethal and non-lethal infections. We find that lethal doses are associated with dramatic widening of infection bottlenecks, leading to a large number of bacteria that initiate infection. Lethal infection is also driven by suilysin, the major SS2 virulence factor. These observations demonstrate how lethal doses are quantitatively established by the relationship between host bottlenecks and bacterial virulence factors.
Clostridioides difficilemajor toxins remodel the intestinal epithelia, affecting spore adherence/internalization into intestinal tissue and their association with gut vitronectin
Authors: Castro-Cordova Pablo , Lopez-Garcia Osiris K. , Orozco Josué , Montes-Bravo Nicolás , Gil Fernando , Pizarro-Guajardo Marjorie , Paredes-Sabja Daniel
Published: January 2025

The most common cause of healthcare-associated diarrhea and colitis in the U.S., isClostridioides difficile, a spore-forming pathogen. Two toxins, TcdA and TcdB, are major virulence factors essential for disease manifestations, whileC. difficilespores are essential for disease transmission and recurrence. Both toxins cause major damage to the epithelial barrier, trigger massive inflammation, and reshape the microbiome and metabolic composition, facilitatingC. difficilecolonization.C. difficilespores, essential for transmission and recurrence of the disease, persist adhered and internalized in the intestinal epithelia. Studies have suggested that toxin-neutralization in combination with antibiotic during CDI treatment in humans significantly reduces disease recurrence, suggesting a link between toxin-mediated damage and spore persistence. Here, we show that TcdA/TcdB-intoxication of intestinal epithelial Caco-2 cells leads to remodeling of accessible levels of fibronectin (Fn) and vitronectin (Vn) and their cognate alpha-integrin subunits. While TcdB-intoxication of intestinal tissue had no impact in accessible levels of Fn and Vn, but significantly increased levels of intracellular Vn. We observed that Fn and Vn released to the supernatant readily bind toC. difficilesporesin vitro, while TcdB-intoxication of intestinal tissue led to increased association ofC. difficilespores with gut Vn. Toxin-intoxication of the intestinal tissue also contributes to increased adherence and internalization ofC. difficilespores. However, TcdB-intoxicated ligated loops infected of mice treated with Bezlotoxumanb (monoclonal anti- TcdB antibodies) did not prevent TcdB-mediated increased spore adherence and internalization into intestinal tissue. This study highlights the importance of studying the impact ofC. difficiletoxins of host tissues has inC. difficileinteraction with host surfaces that may contribute to increased persistence and disease recurrence.
Interface integrity in septin protofilaments is maintained by an arginine residue conserved from yeast to man
Authors: Grupp Benjamin , Graser Jano Benito , Seifermann Julia , Gerhardt Stefan , Lemkul Justin A. , Gehrke Jan Felix , Johnsson Nils , Gronemeyer Thomas
Published: January 2025

The septins are conserved, filament-forming, guanine nucleotide binding cytoskeletal proteins. They assemble into palindromic protofilaments which polymerize further into higher-ordered structures that participate in essential intracellular processes such as cytokinesis or polarity establishment. Septins belong structurally to the P-Loop NTPases but, unlike their relatives Ras or Rho, do not mediate signals to effectors through GTP binding and hydrolysis. Biochemical approaches addressing how and why septins utilize nucleotides are hampered by the lack of nucleotide free complexes. Using molecular dynamics simulations, we determined structural alterations and inter-subunit binding free energies in human and yeast septin dimer structures and in theirin silicogenerated apo forms.

An interchain saltbridge network in the septin unique β-meander, conserved across all kingdoms of septin containing species, is destabilized upon nucleotide removal, concomitant with disruption of the entire G-interface.

Within this network, we identified a conserved arginine residue, Arg(βb), as the central interaction hub.

The essential role of Arg(βb) for interface integrity was confirmed species-overlapping in human and yeast septins byin vitroandin vivoexperimentation.
Lysine-rich regions located in the C-terminal domain of DNA Topoisomerase 2-alpha act as polyphosphoinositide interaction sites and nucleolar localisation signals
Authors: Ardawatia Vandana V. , Jacobsen Rhîan G. , Turcu Diana C. , Ninzima Sandra , Decker Niclas P. , Edson Amanda J. , Lewis Aurélia E.
Published: January 2025

Polyphosphoinositides (PPIn) are lipid signalling molecules that regulate essential cellular processes in eukaryotic cells by regulating effector proteins not only in the cytoplasm, but also in the nucleus. To decipher PPIn nuclear functions, we have previously established quantitative proteomic methods in combination with PPIn pull-down to identify nuclear PPIn-binding proteins. We focused our analyses on one of these proteins, DNA Topoisomerase 2α (TOP2A), an enzyme known to resolve DNA topological problems occurring during replication, transcription and mitosis. In this study, we validated its direct interaction with PPIn and identified the binding site consisting of two lysine-rich polybasic regions (PBR) located within its C-terminal domain (CTD) at residues 1228-1237 and 1259-1276. Overexpression studies of the WT and PBR deletion mutants showed that these two PBR were required for TOP2A nucleolar localisation. TOP2A is localised to different sub-nuclear sites where PPIn have also been detected. We hence investigated the localisation of TOP2A by immunofluorescence microscopy and cell fractionation in relation to PPIn. We show that TOP2A colocalised with the PPIn phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2) in nuclear speckles of transcriptionally arrested HeLa cells. Inhibition of type II phosphatidylinositol-5-phosphate 4-kinase, which generates PtdIns(4,5)P2from PtdIns5P, led to an increase of TOP2A levels associated with the chromatin. Our results demonstrated TOP2A as a PPIn effector protein and a role for nuclear PPIn in regulating the subnuclear dynamic of TOP2A.
Speech-in-noise discriminability after noise exposure: Insights from a gerbil model of acoustic trauma
Authors: Jüchter Carolin , Beutelmann Rainer , Klump Georg Martin
Published: January 2025

Exposure to loud sounds can lead to hearing impairments. Speech comprehension, especially in the presence of background sounds, allegedly declines as a consequence of noise-induced hearing loss. However, the connection between noise overexposure and deteriorated speech-in-noise perception is not clear yet and potential underlying mechanisms are still under debate. This study investigates speech-in-noise discrimination in young-adult Mongolian gerbils before and after an acoustic trauma to reveal possible noise-induced changes in the perception of speech sounds and to examine the commonly suggested link between noise exposure and speech-in-noise perception difficulties. Nine young-adult gerbils were trained to discriminate a deviant consonant-vowel-consonant combination (CVC) or vowel-consonant-vowel combination (VCV) in a sequence of CVC or VCV standards, respectively. The logatomes were spoken by different speakers and masked by a steady-state speech-shaped noise. After the gerbils completed the behavioral baseline experiments, they underwent an acoustic trauma and collected data for the second time in the behavioral experiments. Applying multidimensional scaling, response latencies were used to generate perceptual maps reflecting the gerbils’ internal representations of the sounds pre- and post-trauma. To evaluate how the discrimination of vowels and consonants was altered after the acoustic trauma, changes in response latencies between phoneme pairs were investigated with regard to their articulatory features. Auditory brainstem responses were measured to assess peripheral auditory function. We found that the perceptual maps of vowels and consonants were very similar before and after noise exposure. Interestingly, the gerbils’ overall vowel discrimination ability was improved after the acoustic trauma, even though the gerbils suffered from noise-induced hearing loss. In contrast to the improvements in vowel discrimination, there were only minor changes in the gerbils’ ability to discriminate consonants. Moreover, the noise exposure showed a differential influence on the response latencies for vowel and consonant discriminations depending on the articulatory features of the specific phonemes.
Infection and herbicide exposure implicate c-Abl kinase in α-Synuclein Ser129 phosphorylation
Authors: Ehsani Marzieh , Sun Zeyang , Quevedo-Olmos Alvaro , Rösler Gesa , Rasa Mahdi , Holthaus David , Erttmann Saskia F. , Meyer Thomas F.
Published: January 2025

Background

Parkinson’s disease is a complex multifactorial neurodegenerative disorder characterized by α-Synuclein aggregation in Lewy bodies, with phosphorylation at serine 129 (pSer129) being a critical pathological hallmark. However, the exact mechanisms by which environmental triggers lead to this disease phenotype remain poorly understood. In this study we compare the effects of an exemplary infection and a certain pesticide exposure on the generation of pSer129 α-Synuclein, with a focus on the involvement of cellular kinases in this process.

Methods

Two distinct environmental stressors were applied to neuronal cells: the pesticide rotenone and the well-studied gastric bacteriumHelicobacter pylori (H. pylori). Phosphorylation of Ser129 α-Synuclein was assessed by immunofluorescent staining and Western blotting. Cells were treated with mechanistically distinct c-Abl inhibitors, and pSer129 α-Synuclein was detected using Western blotting and activities of the upstream serine-threonine kinase were predicted by kinase profiling and Western blotting, analyzed by one-way ANOVA followed by Tukey’s multiple comparisons test. Moreover, transcriptome analyses of treated cells were performed and ingenuity pathway analysis and Deseq2 were applied to unravel the affected neurodegenerative pathways.

Results

The functional analysis of our RNA sequence data demonstrated that bothH. pyloriand rotenone induced oxidative stress and neuroinflammation by stimulating neurodegenerative pathways. Rotenone andH. pyloriactivated c-Abl, likely through the induced oxidative stress and promoted α-Synuclein phosphorylation. The kinase inhibitors Ponatinib and Asciminib effectively prevented pSer129 α-Synuclein accumulation and reversed associated gene expression changes induced by rotenone orH. pylori. Moreover, GSK3β appeared to be involved in the induction of Ser129 phosphorylation via activated c-Abl. Furthermore,H. pylori’svacuolating cytotoxin appeared to play a crucial role in the phosphorylation of pSer129 α-Synuclein by c-Abl.

Conclusions

These findings highlight the pivotal role of c-Abl in α-Synucleopathies and provide insights into shared mechanisms between infection and pesticide exposure, offering potential therapeutic targets for Parkinson’s disease and related pathologies involving α-Synuclein modification.
Aggregated A-synuclein leads to corticostriatal synaptic dysfunction
Authors: Brzozowski Charlotte F. , Challa Harshita , Gcwensa Nolwazi Z. , Hall Dominic , Nabert Douglas , Chambers Nicole , Gallardo Ignacio , Millet Michael , Volpicelli-Daley Laura , Moehle Mark S.
Published: January 2025

Neuronal inclusions of α-synuclein (α-syn) are pathological hallmarks of Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). α-Syn pathology accumulates in cortical neurons which project to the striatum. To begin to understand how α-syn pathology effects cortico-striatal synapses, pre-formed α-syn fibrils (PFF) were injected into the striatum to induce robust α-syn aggregation in corticostriatal-projecting neurons. Electrophysiological recordings of striatal spiny projection neurons (SPNs) acute slices found a significant decrease in evoked corticostriatal glutamate release in mice with PFF-induced aggregates compared to monomer injected mice. Expansion microscopy, confocal microscopy and Imaris reconstructions were used to identify vGLUT1 positive presynaptic terminals juxtaposed to Homer-positive postsynaptic densities, termed synaptic foci. Quantitation of synaptic loci density revealed a loss of corticostriatal synapses. Immunoblots of the striatum show reductions in expression of pre-synaptic proteins with selective reduction in AMPA and NMDA receptor subunits in mice with α-syn aggregates compared to controls. Paradoxically, a small percentage of remaining VLGUT1+ synaptic loci with small, intrasynaptic α-syn aggregates showed enlarged volumes compared to nearby synapses without α-syn aggregates. Our combined physiology and high-resolution imaging data point to dysfunction of corticostriatal synapses in mice harboring □-synuclein inclusions, which may contribute to impaired basal ganglia circuitry in PD.

Highlights

- Corticostriatal glutamate drive is impaired in the presence of pathological α-syn

- α-Syn aggregation causes early loss of corticostriatal synapses

- Synaptic loci positive for small α-syn aggregates show volume increases

- Striatal expression of select synaptic proteins are reduced in animals with α-syn pathology
Profiling trait and state-like behaviour in pain modulation systems: a role for effective connectivity within endogenous pain control circuits
Authors: Medina Sonia , Clarke Sophie , Hughes Sam W.
Published: January 2025

Endogenous pain modulation systems can be assessed through distinct psychophysical paradigms such as conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA). Notably, the reliability of these measures has rarely been defined within the same participants, and measures to index the consistency of each measure across sessions and in the same participants are lacking. This study examined the test-retest reliability and intra-individual consistency of CPM, TSP, and OA and explored how CPM response status across sessions relates to neural dynamics within the descending pain modulation system. In 29 healthy participants, CPM, TSP, and OA responses were assessed across two sessions. The normalised session change index (NSCI) was introduced to evaluate consistency of each measure across sessions. Spectral dynamic causal modelling (DCM) of resting-state fMRI (rs-fMRI) investigated effective connectivity within the descending pain modulation network and its association with CPM response status. OA exhibited the highest test-retest reliability and had NSCI values closest to zero, indicating stable responses. CPM and TSP showed poor reliability and NSCI values deviating from zero, reflecting greater variability. Spectral DCM analysis revealed that effective connectivity within the descending pain modulation system explained CPM response variability across sessions. Specifically, consistent strong facilitatory or inhibitory CPM was associated with greater excitatory or inhibitory PAG-to-AI effective connectivity, respectively. These findings suggest that healthy participants either demonstrate stable (i.e. trait-like) or dynamic (i.e. state-like) endogenous pain modulation across repeated sessions which can be explained based on effective connectivity within the descending pain modulation system.
In-silico molecular enrichment and clearance of the human intracranial space
Authors: Causemann Marius , Kuchta Miroslav , Masri Rami , Rognes Marie E.
Published: January 2025

The mechanisms of intracranial solute transport are fundamental to human brain health, with alterations often linked to disease and functional impairment, and with distinct opportunities for personalized diagnostics and treatment. However, our understanding of these mechanisms and their interplay remains incomplete, in part due to the complexity of integrating insights across scales, between species and from different modalities. Here, we combine mixed-dimensional modelling, multi-modal magnetic resonance images, and high performance computing to construct and explore a high-fidelity in-silico model of human intracranial molecular enrichment. This model predicts the temporo-spatial spreading of a solute within an image-derived geometric representation of the subarachnoid space, ventricular system and brain parenchyma, including networks of surface perivascular spaces (PVSs). Our findings highlight the significant impact of cerebrospinal fluid (CSF) production and intracranial pulsatility on molecular enrichment following intrathecal tracer injection. We demonstrate that low-frequency vasomotion induces moderate CSF flow in surface PVS networks which substantially enhances tracer enrichment, and that impaired enrichment is a direct natural consequence of enlarged PVSs. This openly available technology platform thus provides an opportunity for integrating separate observations on diffusion in neuropil, vascular dynamics, intracranial pulsatility, CSF production, and efflux, and for exploring drug delivery and clearance in the human brain.
Investigating the influence of experimentally induced central sensitisation on pain prediction error encoding in healthy individuals: a novel virtual reality protocol
Authors: Palmisani Federico , Thiyagarajan Jawahar Sri Prakash , Horsey Joe , Hughes Sam , Medina Sonia
Published: January 2025

Persistent mismatches between predicted and actual pain-related signals, namely prediction errors (PEs), can cause maladaptive overestimation of pain intensity, a common feature of chronic pain states. Experimental protocols used to assess the contribution of central sensitisation (CS) to dysregulated prediction systems are lacking. To address this, we implemented a novel virtual reality (VR) paradigm to evoke PEs during mechanical stimulation following experimentally induced CS via the high-frequency stimulation (HFS) model. Twenty healthy volunteers underwent HFS on the right forearm. Mechanical pain sensitivity (MPS) was assessed through pinprick stimuli before and 30 minutes post-HFS to evaluate secondary hyperalgesia. Following this, participants received mechanical stimuli at proximal (sensitised area) and distal (non-sensitised area) points from the HFS site, with visual cues presented on their arm via VR alongside hand tracking technology indicating the stimulus location, allowing participants to make pain predictions. Cues were either congruent (matching) or incongruent (mismatching) with the actual stimulus site, to evoke PEs. Results showed that MPS significantly increased following HFS, confirming secondary hyperalgesia. Stimuli in sensitised areas induced more pain than in non-sensitised areas. Incongruent cues successfully elicited PEs across all locations, however, expectations modulated pain perception only in non-sensitised areas. Similarly, during incongruent trials, PEs diminished over time (reflecting adaptive learning) only in non-sensitised areas. These data demonstrate that pain expectations can influence pain perception differently in centrally sensitised and non-sensitised states. We propose this protocol as a good candidate to assess how cognitive and psychological manipulations influence PEs at various stages of CS.
Polymorphism in a secondary phosphine
Authors: Liu Mo , Izod Keith , Waddell Paul G.
Published: January 2025

Two crystal structures of bis(2,3,5,6-tetramethylphenyl)phosphine, C20H27P, are reported constituting the first recorded case of polymorphism in a secondary phosphine (R
2PH). The two structures differ in their conformation and, as a result, the steric hindrance experienced at the phosphorus centre is observed to be dependent on the packing environment. Each polymorph exhibits a distinct supramolecular structure; in polymorph I the molecules are arranged in columns in two directions, whereas polymorph II forms layers. There is a distinct lack of significant intermolecular interactions in either form, with the exception of some weak Me...π interactions observed in polymorph II. These interactions are likely the cause of the variation in the C—P—C angles observed between the two structures.
Young graduates’ satisfaction with university education: evidence from Chile
Authors: Espinoza Oscar , Miranda Catalina , McGinn Noel , Corradi Bruno , Sandoval Luis , González Luis
Published: January 2025

Purpose

This study seeks to assess the impact of three factors related to graduates’ situation in the labor market on their satisfaction with university education. The dimensions are: (1) the gender of the graduates; (2) the institutional features of the institution attended, such as the selectivity of the university, and (3) the work experiences of young graduates once employed.

Design/methodology/approach

Responses from a sample of 718 graduates from 11 Chilean universities surveyed in 2021 were used to estimate the association between sociodemographic and institutional characteristics and satisfaction. The data analysis was carried out in two steps. First, nonlinear principal component analysis (PCA) assessed the variance shared by the three ordinal variables measuring satisfaction. In the second step, ordinary least squares (OLS) regression analysis assessed the relative contribution of the independent variables to scores on the satisfaction variable.

Findings

The main results emphasize the relevance of two main influences on satisfaction with their university education. These were the selectivity of the university and the graduates’ experiences in the labor market. Graduates from the most selective universities tend to show a higher level of satisfaction with their university education. Satisfaction is also highest among those graduates who rapidly entered the workforce and secured employment closely aligned with their degree.

Originality/value

This is the first study in Chile on the satisfaction of graduates conducted in a representative number of universities.
Urban land values in Santiago: a time series assessment of the so-called “Chilean Miracle”
Authors: Garza Nestor , Gasic Ivo , Larrain Clemente
Published: January 2025

Purpose

This paper aims to build a set of long-term, geographically controlled land value indices for Santiago de Chile, with which to test land rent theory predictions regarding macroeconomic impacts.

Design/methodology/approach

This paper uses a geographic cluster approach to the Laspeyres estimator, weighted by the stock of available land plots and their market offers per zone, to create two quarterly land value indices for Gran Santiago during the period 1983Q4–2016Q2. Subsequently, this paper implements dynamic time series methods (Vector Error Correction) as a baseline to determine the effect of economic performance and interest rate on urban land values.

Findings

The two land value indices are correctly predicted by economic and interest rate shocks, as theoretically expected. In addition, this paper found that land values grew faster-than-predicted during the period of the so-called “Chilean Miracle” (1992–1998), a situation associated in the literature with worsened housing affordability and socio-spatial inequality.

Originality/value

The land value indices offer unprecedented time-series precision in tracking the long-term performance of real estate markets in a Latin American city, allowing us to produce short- and long-term (accumulative) time-series causality analyses.
The importance of ICT adoption on MSMEs performance: the mediating role of distinctive competencies
Authors: Yuwono Tri , Novandari Weni , Suroso Agus , Setyanto Refius Pradipta
Published: January 2025

Purpose

This study aims to examine and identify how the resource-based view and dynamic capability theory contribute to information and communication technology (ICT) adoption to improve micro, small and medium enterprise (MSME) performance, mediated by distinctive competencies. This research provides insight into how MSMEs can improve performance by strategically adopting ICT tools and developing distinctive competencies.

Design/methodology/approach

Data were collected through online questionnaires from creative industry MSMEs (fashion, culinary and crafts) in Indonesia. The results were analyzed using the partial least squares-structural equation method technique (Fornell and Cha, 1994) with Smart PLS 3.0 (Ringle et al., 2015).

Findings

The results show that ICT adoption significantly impacts the MSMEs marketing performance in the creative industry sector. In addition, adopting ICT tools influences the development of distinctive competencies among MSMEs, improving MSMEs marketing performance. Distinctive competencies were found to mediate the relationship between ICT adoption and MSMEs marketing performance, which underscores the importance of technology skills, organizational skills, environmental skills and entrepreneurial mindset in driving business success. These findings highlight the critical role of distinctive competencies as a key factor in leveraging ICT adoption to improve MSMEs marketing performance.

Research limitations/implications

The main limitation is that this research coverage area is less extensive due to the time constraints of this study. Future work could cover different regions and explore other mediators in the ICT–performance relationship.

Practical implications

This research assists MSMEs in improving performance by adopting ICT and developing distinctive competencies with targeted training in relevant skills.

Social implications

This research highlights the potential to improve MSMEs marketing performance and drive economic growth and resilience through ICT adoption.

Originality/value

This study contributes to the existing literature by providing empirical evidence of the relationship between ICT adoption, distinctive competencies and MSME marketing performance in the context of the creative industries sector. This study offers a new perspective on how MSMEs can use ICT tools and develop distinctive competencies to enhance their marketing performance competitive advantage and achieve sustainable growth. By emphasizing the mediating role of distinctive competencies, this study highlights how ICT adoption impacts positively MSME marketing performance, providing valuable insights for practitioners, policymakers and researchers in entrepreneurship and technology adoption.