bluuebunny/crossref_metadata_2025 huggingface dataset:
PNEUMATIC RETINOPEXY FOR GIANT RETINAL TEAR–ASSOCIATED RETINAL DETACHMENT
Authors: Cruz-Pimentel Miguel , Alfalah Mohammed , Lee Wei Wei , Martins-Melo Isabela , Wong Jovi C. , Pirouzmand Neda , Pecaku Aurora , Demian Sueellen , Maniyali Faryal , Kertes Peter J. , Muni Rajeev H.
Published: December 2024

Purpose:

To report the technique and long-term outcomes of patients with giant retinal tear–associated retinal detachment treated with pneumatic retinopexy (PnR).

Methods:

Retrospective cohort study. All patients presenting with giant retinal tear–associated retinal detachment with tears in the superior ten-clock hours who underwent primary PnR were included in this study.

Results:

Thirty-one patients were included in the study. Of these, 61.2% (19 of 31) achieved primary reattachment rate (PARR) with PnR at 3 months and 58.0% (18 of 31) at the final follow-up. Patients included in this study had a median follow-up of 24 months (interquartile range 46.5 months). The absence of retinal tears elsewhere at baseline was associated with a final PARR of 80% (16 of 20) (P = 0.007). Thirteen eyes required pars plana vitrectomy after a failed PnR. Two eyes required the intraoperative use of perfluorocarbon liquids. No eyes required silicone oil. Visual acuity improved significantly from baseline to the last follow-up. Final anatomical reattachment rate was 100% (31 of 31).

Conclusion:

For selected cases of giant retinal tear associated retinal detachments affecting the superior ten-clock hours, PnR could be a possible treatment option when patients consent to extra visits and the surgeon has substantial expertise. When lacking this extensive experience and comfort with PnR, pars plana vitrectomy remains the treatment that is most likely to result in a primary anatomical reattachment. Although this study provides guidance on PnR technique for giant retinal tear associated retinal detachment, it is essential to note that the reported PARR may be contingent on the expertise of the surgeon/center, and the authors recommend that those new to PnR first gain substantial experience in cases meeting clinical trial criteria.
Double-Suture Scleral-Fixated Intraocular Lens With 2 Polypropylene Sutures
Authors: Lam Christine C. Y. , Kam Ka Wai , Young Alvin L.
Published: December 2024

Purpose:

We present a modified technique in performing scleral fixation of a posterior chamber intraocular lens (IOL) using 2 pairs of double-armed 9-O polypropylene sutures and an ab-externo technique, in 2 patients with surgical aphakia after complicated cataract surgery.

Methods:

Two eyes of 2 patients underwent this modified technique by an experienced cataract surgeon (A.L.Y.) in 2022. We evaluated pre- and postoperative best-corrected visual acuity, perioperative complications, corneal endothelial cell density by specular microscopy, and IOL position by anterior segment optical coherence tomography and ultrasound biomicroscopy.

Results:

Both patients achieved an improvement in best-corrected visual acuity from 20/50 to 20/30 and 20/80 to 20/50, respectively. There was a loss in endothelial cell count in both cases (8% and 23%, respectively). No complications were noted in both cases, and postoperative anterior segment optical coherence tomography and ultrasound biomicroscopy showed a stable scleral fixation of IOL at more than 20 months postoperatively.

Conclusions:

The utilization of 2 pairs of double-armed 9-O Prolene suture may provide a stronger alternative than conventional scleral fixation of IOL with single suture.
Assessment of Structural Progression in Glaucoma Through Automated Optic Nerve Head Hemoglobin Measurements
Authors: Rocha Janaina Andrade Guimarães , Goytacaz Thaíssa Cristina Affonso Nazareth , Calzavara Lemos Maria Betânia , Paranhos Augusto , Teixeira Sérgio Henrique , Kanadani Fábio Nishimura , Gracitelli Carolina Pelegrini Barbosa , Prata Tiago Santos
Published: December 2024

Précis:

Automated optic nerve head hemoglobin measurements through change over time in the Globin Individual Pointer (GIP) index, provided by the Laguna ONhE software, can be useful to evaluate structural progression in glaucoma.

Purpose:

To assess the performance of automated optic nerve head hemoglobin measurements (ONH Hb) for detection of structural progression in glaucoma patients using event analysis.

Patients and Methods:

Treated glaucoma patients were included in this cross-sectional study. Two experienced examiners classified patients into progressors and non-progressors (controls) based on serial color retinographies (CR). Progressors were then subdivided in structural changes of the neuroretinal rim (NR) or retinal nerve fiber layer (RNFL). Globin individual pointer (GIP) index, derived from ONH Hb measurements, was calculated for each CR using the Laguna ONhE software. Differences in GIP values, ​​between baseline and last visit CRs, were used to assess structural progression. Sensitivity at a fixed specificity (50%; median GIP difference in controls) and areas under receiver operating characteristic curves (AUROC) were calculated.

Results:

Eight-seven eyes (35 progressors and 52 controls) from 64 patients were enrolled. Mean GIP reduction over time was greater in progressors (−13.0±18.6) than controls (−2.9±10.4; P=0.001). In progressors, mean GIP reduction was greater in patients with NR changes (−19.6±19.5) than RNFL changes (−3.1±12.1; P=0.008). GIP difference correctly identified 69% of the progressors (AUROC: 0.66), being 76% of these progressions related to NR changes (AUROC: 0.76) and 57% to RNFL changes (AUROC: 0.52).

Conclusions:

The GIP index, based on automated ONH Hb measurements demonstrated good sensitivity to differentiate progressors from controls, especially in cases in which progression was documented through structural NR changes. Using only 2 CRs and event analysis, GIP changes over time can be a useful screening tool to evaluate structural progression.
Oncogenic KRAS Promotes Ferroptosis in Pancreatic Cancer Through Regulation of the Fosl1-Tfrc Axis
Authors: Zhao Huijia , Huang Qi , Liu Ying-ao , Wu Wenming
Published: December 2024

Mutant KRAS activation occurs in most of pancreatic ductal adenocarcinoma (PDAC), which induce the sensitivity to ferroptosis of PDAC cells, but the underlying mechanism is still poorly understood. Here, we show how KRAS acts in signaling to activate transcription factor FOSL1, which promotes the expression of the iron uptake receptor TFRC. In PDAC cells, repression of TFRC by KRAS/FOSL1 signaling inhibited intracellular iron levels, thereby restricting the occurrence of ferroptosis. Furthermore, the KRAS/FOSL1/TFRC axis can make the PDAC cells vulnerable to alteration of the iron level in the tumor microenvironment. Our study highlights a pivotal mechanism of PDAC ferroptosis through iron metabolism and supports a new therapeutic strategy for PDAC with superior potential.
Brief Report: The Implications of Removing Race From Interpretation of Pulmonary Function Among Persons With or Without HIV
Authors: Wang Richard J. , Kunisaki Ken M. , Morris Alison , Drummond M. Bradley , Nouraie Mehdi , Huang Laurence , Tien Phyllis C. , Baugh Aaron D. , Barjaktarevic Igor , Bhandari Neha , Bhatt Surya P. , D'Souza Gypsamber , Fischl Margaret A. , Foronjy Robert F. , Jensen Robert L. , Lazarous Deepa G. , Ofotokun Ighovwerha , Reddy Divya , Stosor Valentina , McCormack Meredith C. , Raju Sarath
Published: December 2024

Background:

Studies suggest that the use of race-specific pulmonary function reference equations may obscure racial inequities in respiratory health. Whether removing race from the interpretation of pulmonary function would influence analyses of HIV and pulmonary function is unknown.

Setting:

Pulmonary function measurements from 1067 men (591 with HIV) in the Multicenter AIDS Cohort Study and 1661 women (1175 with HIV) in the Women's Interagency HIV Study were analyzed.

Methods:

Percent-of-predicted values for spirometry and single-breath diffusing capacity of carbon monoxide (DLCO) measurements were generated with race-specific reference equations derived from the National Health and Nutrition Examination Survey and with the race-neutral application of reference equations derived from the Global Lung Function Initiative database. Regression models were used to evaluate the association between HIV and percent-of-predicted measures of pulmonary function. Alpaydin's F test was used to compare how well these values predicted self-reported respiratory health-related quality of life.

Results:

Persons with HIV were observed to have significantly lower percent-of-predicted diffusing capacity for carbon monoxide (DLCO) than those without HIV but no significant differences in spirometric measures of pulmonary function, regardless of whether a race-specific or race-neutral approach was used. Among men, but not women, the race-neutral application of reference equations to generate percent-of-predicted DLCO values performed better for predicting respiratory-related quality of life.

Conclusions:

The race-neutral application of pulmonary function reference equations continues to identify lung function impairment in persons with or at risk for HIV and, for DLCO, may be superior to the use of race-specific reference equations in identifying clinically relevant impairments.
18F-AlF-NOTA-FAPI-04 Superior to 18F-FDG PET/CT in Detecting Primary Tumor and Metastatic Lymph Nodes in a Cervical Cancer Patient
Authors: Wei Jinhui , Feng Qiaochu , Liu Haodong , Zheng Hongna , Li Longjie
Published: December 2024

A 41-year-old woman with an enlarged right supraclavicular lymph node underwent a fine-needle biopsy, which confirmed the presence of metastatic squamous cell carcinoma. To identify the primary tumor, an 18F-FDG PET/CT scan was performed, revealing multiple metabolically active lymph nodes throughout the body, but no primary lesion was identified. Subsequently, an 18F-AlF-NOTA-FAPI-04 PET/CT scan was conducted, which demonstrated increased abnormal uptake in the cervix and revealed additional metabolically active lymph nodes. Thus, a biopsy of the uterine cervical region was performed, and the results confirmed cervical squamous cell carcinoma.
Celebrating a scientist: Josué A. Núñez’s passion for insect physiology, engineering and evolution
Authors: De Marco Rodrigo J.
Published: December 2024

On the tenth anniversary of his passing and the hundredth anniversary of his birth, this article honours Josué A. Núñez (1924–2014), a pioneering Argentine biologist remembered for his groundbreaking work in insect physiology and behaviour. Núñez’s seminal papers are recognized for their rigorous experimentation and his skill in crafting instruments. Known for his humility and sense of humour, he taught and conducted research at prestigious institutions worldwide. The article traces Núñez’s career through key milestones, beginning with his foundational studies in insect anatomy and physiology. It then explores his formative years in Buenos Aires, where he conducted innovative independent experiments, and his influential early career research in Germany. Núñez’s initial interest in the relationship between flowers and honeybees developed into a profound exploration at the intersection of biology, evolutionary theory, and engineering principles. A major focus of this tribute is his integration of engineering concepts to examine the roles of honeybees as both nectar carriers and information channels. By emphasizing Núñez’s meticulous data analysis and systemic approach, the article not only highlights his significant contributions but also challenges traditional Eurocentric perspectives, advocating for a more inclusive understanding of global scientific achievements.
Development of a Novel Hybprinter-SAM for Functionally Graded Tissue Engineering Constructs with Patterned and Localized Biochemical Signals
Authors: Li Jiannan , Kim Carolyn , Alizadeh Hossein V. , Garg Shreya , Bruyas Arnaud , Zhao Peng , Passos Isadora S. D. , Pérez Andrea S. Flores , Yang Yunzhi P.
Published: December 2024

Engineering native-mimetic tissue constructs is challenging due to their intricate biological and structural gradients. To address this, Hybprinter-SAM was developed by integrating three bioprinting technologies: syringe extrusion (SE), acoustic droplet ejection (ADE) and molten material extrusion (MME). This system enables not only the creation of mechanical gradients by combining soft and rigid materials but also precise patterning and controlled localization of biochemical signals within printed scaffolds. This capability is beneficial in replicating the complexity of native tissues to enhance functionality. Both the printing process and biomaterials were optimized to balance printability, mechanical integrity, and biocompatibility. As a proof of concept, Hybprinter-SAM was used in a bone-tendon regeneration study to engineer a multi-material construct with patterned fibroblast growth factor 2 (FGF-2), resulting in markers indicative of fibrocartilage development. These findings highlight the potential of Hybprinter-SAM as a versatile platform for diverse tissue engineering applications that require complex, functionally graded tissue constructs.
Structural Convergence and Water-Mediated Substrate Mimicry Enable Broad Neuraminidase Inhibition by Human Antibodies
Authors: Lederhofer Julia , Borst Andrew J. , Nguyen Lam , Gillespie Rebecca A. , Williams Connor J. , Walker Emma L. , Raab Julie E. , Yap Christina , Ellis Daniel , Creanga Adrian , Tan Hyon-Xhi , Do Thi H. T. , Ravichandran Michelle , McDermott Adrian B. , Sage Valerie Le , Andrews Sarah F. , Graham Barney S. , Wheatley Adam K. , Reed Douglas S. , King Neil P. , Kanekiyo Masaru
Published: December 2024

Influenza has been responsible for multiple global pandemics and seasonal epidemics and claimed millions of lives. The imminent threat of a panzootic outbreak of avian influenza H5N1 virus underscores the urgent need for pandemic preparedness and effective countermeasures, including monoclonal antibodies (mAbs). Here, we characterize human mAbs that target the highly conserved catalytic site of viral neuraminidase (NA), termed NCS mAbs, and the molecular basis of their broad specificity. Cross-reactive NA-specific B cells were isolated by using stabilized NA probes of non-circulating subtypes. We found that NCS mAbs recognized multiple NAs of influenza A as well as influenza B NAs and conferred prophylactic protections in mice against H1N1, H5N1, and influenza B viruses. Cryo-electron microscopy structures of two NCS mAbs revealed that they rely on structural mimicry of sialic acid, the substrate of NA, by coordinating not only amino acid side chains but also water molecules, enabling inhibition of NA activity across multiple influenza A and B viruses, including avian influenza H5N1 clade 2.3.4.4b viruses. Our results provide a molecular basis for the broad reactivity and inhibitory activity of NCS mAbs targeting the catalytic site of NA through substrate mimicry.
Improving the integration of AI into existing ecological inference workflows
Authors: Cowans Amber , Lambin Xavier , Hare Darragh , Sutherland Chris
Published: December 2024

Artificial Intelligence (AI) has revolutionised the process of identifying species and individuals in audio recordings and camera trap images. However, despite developments in sensor technology, machine learning, and statistical methods, a general AI-assisted data-to-inference pipeline has yet to emerge.

We argue that this is, in part, due to a lack of clarity around several decisions in existing workflows, including: the choice of classifier used (e.g., semi- vs. fully automated); how classifier confidence scores are used and interpreted; and the availability and selection of appropriate statistical methods for drawing ecological inferences.

Here, we attempt to conceptualise a general workflow associated with automated tools in ecology. We motivate this perspective using our experiences with occupancy modelling using monitoring data collected through passive acoustic monitoring and camera trapping, identifying priority areas for future developments.

We offer an accessible guide to support the ecological community in navigating and capitalising on rapid technological and methodological advances. We describe how different error types arise from both sensor-based monitoring and from classifiers themselves; how different error types are handled at each stage of the workflow; and finally, implications and opportunities associated with deciding on methods used at each step of the pipeline.

We recommend that “black box” tools like neural network classification algorithms should be embraced in ecology, but widespread uptake requires more formal integration of AI into the existing ecological inference workflows. Like ecological AI more broadly, however, successful development of new data-to-inference pipelines is a multidisciplinary endeavour that requires input from everyone invested in collecting, processing, analysing, and using ecological monitoring data.
Feasibility of intravenous injections of pig plasma extracellular particles into rats — an acute study
Authors: Cherñavsky Nicolás , de Campos Zani Stepheny C. , Mori Marcelo A. , Zanvettor Nina T.
Published: December 2024

Background

Extracellular particles (EPs), especially small extracellular vesicles (EVs), extracted from young animals are increasingly being studied in animal models as agents for regeneration and rejuvenation, with studies using EPs from one species injected into another showing no immune reaction. In this study, we aimed to investigate if the injection of Pig Plasma Extracellular Particles (PPEPs) into rats would produce an acute immune or toxic reaction.

Methods

Blood from a young pig was collected, PPEPs were isolated by size exclusion chromatography and injected into young male Sprague-Dawley rats, while the control group received a sterile saline injection. After 9 days, the animals were euthanized and their organs were histologically analyzed for signs of cellular damage or immune infiltration.

Results

The treated rats showed no signs of acute immunological reaction, behaving normally immediately after the injections and during the 9 days since the first injection. Throughout the trial period, the animals continued gaining weight normally and the histological analysis of their liver, kidney and spleen showed no signs of acute toxicity.

Conclusions

PPEPs from young animals do not cause an acute immune or toxic response when injected intravenously into young male Sprague-Dawley rats.
Exploring the Impact of Apocarotenoids on PathogenicFusarium oxysporumf.sp.liniand Endophytic Fo47 strains
Authors: Kochneva Yelyzaveta , Burgberger-Stawarz Marta , Boba Aleksandra , Preisner Marta , Mierziak-Derecka Justyna , Kulma Anna
Published: December 2024

TheFusarium oxysporum species complex(FOSC) contains highly specific plant pathogens and some nonpathogenic strains, such as Fo47. In our work we concentrated onFusarium oxysporumf.sp.lini(Foln), the specific flax pathogen and the endophytic strainFusarium oxysporum47 (Fo47), which is possibly protective for flax against pathogens. We investigated the influence of apocarotenoids like ionones and abscisic acid (ABA) on growth and development of these fungal strains considering possible fungicidal abilities of mentioned substances and comparing responses of fungi. The study shows inhibitory effect of ionones on mycelium growth of both Foln and Fo47. Our results also show the differences in apocarotenoid’s effect on studied strains in regards of sporulation,FUBgenes cluster activity and fusaric acid (FA) production.

Author summary

In this study, we investigated the interaction betweenFusarium oxysporum, a fungus that can either harm or potentially benefit plants, and natural plant-derived compounds known as apocarotenoids. We focused on two fungal strains: one that specifically infects flax plants, causing disease, and a nonpathogenic strain that may protect flax from pathogens. By examining the effects of apocarotenoids like ionones and abscisic acid, we aimed to understand how these compounds influence fungal growth, sporulation, toxin production, and gene activity related to pathogenicity. Our findings reveal that ionones inhibit the growth of both strains, suggesting their potential as antifungal agents. Interestingly, the two strains showed distinct responses to these compounds, particularly in their production of fusaric acid and activation of toxin-related genes. These results highlight the complexity of fungal interactions with plant-derived molecules and suggest that apocarotenoids could play a role in modulating fungal behavior. This work contributes to our understanding of plant-fungal interactions and may inform future strategies for managing crop diseases sustainably.
SS-31 protects against bleomycin-induced lung injury and fibrosis
Authors: Gu Quankuan , Wang Yunlong , Zhang Haichao , Yang Wei , Meng Xianglin , Zhao Mingyan
Published: December 2024

Objective

The aim of this research was to investigate if the mitochondria-targeting peptide SS-31 could serve as a protective measure against bleomycin-induced pulmonary fibrosis in mice.

Method

Mice were split into four groups named CON group, SS-31 group, BLM group, and the BLM+ SS-31 group. SS-31 was administered daily from the day prior to the experiment for the control and model groups. Mice were euthanized after 28 days of the experiment, following which blood, bronchoalveolar lavage fluid, and lung tissue were collected for analysis.

Results

The study demonstrated that SS-31 could potentially mitigate the reduction in mice. It was observed through HE and Masson staining, immunohistochemistry, hydroxyproline detection, and fibrosis index measurement via Western blot that SS-31 could alleviate pulmonary fibrosis caused by BLM. Electron microscopy and ATP detection further suggested that SS-31 might help protect mitochondrial structure and function. It was also found that SS-31 could reduce reactive oxygen species and myeloperoxidase, thereby alleviating the reduction of antioxidant factor MPO and SOD, as well as diminishing the inflammatory factors TNF-α, IL-1 β, and IL-6.

Conclusion

The mitochondria-targeting drug SS-31 exhibited potential in mitigating bleomycin-induced pulmonary fibrosis, improving mitochondrial structural and functional damage, stabilizing the balance between oxidative and antioxidant systems, reducing inflammatory factor expression, and improving apoptosis in lung tissue.
CGMFinder Identifies Correlated Gene Modules from 3H scRNA-seq Data
Authors: Ma Wenping , Xie Xiaoliang Sunney
Published: December 2024

Correlated gene modules (CGMs) contain genes whose expression fluctuates together. Genes in CGMs are often functionally related and regulated by shared transcription factors. CGMs can be identified under steady-state conditions in populations of cells using single-cell RNA sequencing (scRNA-seq). Here, we introduce CGMFinder, a tool for CGM identification using “3H” scRNA-seq data (High mRNA capture efficiency, High cell numbers, and High sequencing depth). CGMFinder employs a graph-based filtering approach, first identifying CGM cores from highly-expressed genes and then linking noisy low-abundance genes to these cores. In lymphoblastoid cell line 3H datasets generated by in-lab and commercial protocols, CGMFinder accurately identifies CGMs enriched for gene ontologies or pathways. In cells grown under hypoxic conditions, CGMFinder successfully identified hypoxia-specific “glycolysis” and “response to oxygen levels” modules. Evaluations using ground truth correlation modules demonstrate that CGMFinder outperforms other CGM identification methods such as WGCNA and FastICA in scRNA-seq data.
PAG orchestrates T cell immune synapse function by binding to actin
Authors: Moore Emily K. , Strazza Marianne , Hu Xizi , Tymm Carly , Paiola Matthieu , Shannon Michael J. , Xie Xinping , Bukhari Shoiab , Lerrer Shalom , Mace Emily M. , Winchester Robert , Mor Adam
Published: December 2024

Many immunotherapies impact T cell function by impacting the immune synapse. While immunotherapy is extremely successful in some patients, in many others, it fails to help or causes complications, including immune-related adverse events. Phosphoprotein Associated with Glycosphingolipid Rich Microdomains 1 (PAG) is a transmembrane scaffold protein with importance in T cell signaling. PAG has 10 tyrosine phosphorylation sites where many kinases and phosphatases bind. PAG is palmitoylated, so it localizes in lipid rafts of the membrane, and contains a C-terminal PDZ domain to link to the actin cytoskeleton. As a link between signaling-protein-rich membrane regions and the actin cytoskeleton, PAG is an exciting and novel target for manipulating immune function. Here, we sought to determine if PAG works with actin to control T cell synapse organization and function. We found that PAG and actin dynamics are tightly coordinated during synapse maturation. A PDZ domain mutation disrupts the PAG-actin interaction, significantly impairing synapse formation, stability, and function. To assess the impact of the PDZ mutation functionally in vivo, we employed a mouse model of type IV hypersensitivity and an OVA-tumor mouse model. In both systems, mice with T cells expressing PDZ-mutant PAG had diminished immune responses, including impaired cytotoxic function. These findings highlight the importance of the PAG-actin link for effective T cell immune synapse formation and function. The results of our study suggest that targeting PAG is a promising approach for modulating immune responses and treating immune-related diseases.

One Sentence Summary

Adaptor protein PAG links to the actin cytoskeleton, and this link is essential for T cell synapse formation and cytotoxic function.
Semaglutide Analogues Enhancing GLP-1R Activation: A Dynamic Structural & Electrostatic Perspective
Authors: Li Wei
Published: December 2024

On December 5, 2017, the U.S. FDA approved Novo Nordisk A/S’s diabetes drug Ozempic, whose active ingredient, semaglutide, represents a major advancement in the class of glucagon-like peptide-1 (GLP-1) analogues. These analogues mimic the action of an intestinal hormone that promotes insulin secretion, thereby playing a pivotal role in metabolic regulation. Since then, semaglutide has profoundly transformed the treatment landscape for type 2 diabetes and obesity, demonstrating efficacy in glycemic control, weight management and cardiovascular risk mitigation. Yet, it remains an open question whether semaglutide is the best GLP-1 receptor (GLP-1R) agonist either as of now or in future. Given GLP-1R as the therapeutic target, a structural basis of the GLP-1-GLP-1R interaction is paramount for the design of GLP-1 analogues that fully harness the therapeutic potential of GLP-1R activation. Thus, this study employs a structural biophysical approach to enhance GLP-1R activation through the rational design of semaglutide analogues. By incorporating an electrostatic scaffold of interfacial salt bridges, site-specific missense mutations were engineered into the semaglutide backbone to establish additional stabilizing interactions with the extracellular domain (ECD) of GLP-1R, thereby enhancing ligand-receptor binding and activation. In addition to 564 semaglutide analogues, the structural biophysical analysis here also reveal the presence of an electrostatic scaffold comprising four salt bridges at the semaglutide-GLP-1R binding interface. Drawing parallels with the continued optimization of insulin analogues, this articles proposes that the electrostatic scaffold offers a robust framework for the continued development of next-generation GLP-1R agonists, enabling more precise and effective therapies for managing metabolic diseases.
Moving beyond the motor cortex: a brain-wide evaluation of target locations for intracranial speech neuroprostheses
Authors: Verwoert Maxime , Ottenhoff Maarten C. , Tousseyn Simon , van Dijk Johannes P. , Kubben Pieter L. , Herff Christian
Published: December 2024

Speech is the fastest and most natural form of communication, which can be impaired in certain disorders. Speech brain- computer interfaces (BCIs) offer a solution by decoding brain activity into speech. Current neuroprosthetic devices focus on the motor cortex, which might not be usable in all patient populations. Fortunately, many other brain regions have been associated with the speech production process. Here, we investigate which regions are potential (alternative) targets for a speech BCI across a brain-wide distribution within a single study. The distribution includes sulci and subcortical areas, sampled with both a high temporal and a high spatial resolution. Thirty participants were recorded with intracranial electroencephalography during speech production, resulting in 3249 recorded contacts across the brain. We trained machine learning models to continuously predict speech from a brain-wide global to a single-channel local scale. Within each scale we examined a variation of selected electrode contacts based on anatomical features within participants. We found significant speech detection in both gray and white matter tissue, no significant difference between gyri and sulci at any of the analysis scales and limited contribution from subcortical areas. The best potential targets in terms of decoding accuracy and consistency are located within the depth of and surrounding the lateral fissure bilaterally, such as the (sub)central sulcus, transverse temporal gyrus (Heschls’ gyrus), the supramarginal cortex and parts of the insula. These results highlight the potential benefits of extending beyond the motor cortex and reaching the sulcal depth for speech neuroprostheses.
C. eleganshuntingtin,htt-1,promotes robust autophagy induction and survival under stress conditions
Authors: Chung Christine Hyein , Lee Hanee , Park Kyumin , Park Young Seo , Jung Roy , Seong Ihnsik , Lee Junho
Published: December 2024

Huntingtin (HTT) is the gene responsible for Huntington’s disease (HD), a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion mutation. While HD pathogenesis has traditionally been attributed to the toxic gain-of-function effects of mutant huntingtin (mHTT), increasing evidence underscores the critical role of wild-type HTT loss-of-function. Understanding the physiological roles of HTT is essential for elucidating HD mechanisms and developing effective therapeutic strategies. TheC. elegans htt-1gene, an ortholog of human HTT, remains largely uncharacterized. Here, we demonstrate thathtt-1promotes survival under stress conditions that requires autophagy as a defense mechanism. Specifically, we identify intestinalhtt-1as a key regulator ofC. eleganssurvival duringPseudomonas aeruginosaPA14 infection. Our findings reveal thathtt-1functions downstream of the MPK-1/ERK pathway to induce systemic autophagy and enhance host defense during immune challenges. Moreover, expression of wild-type human HTT inhtt-1mutant worms rescues the survival defect during PA14 infection. Expression of mutant human HTT, on the other hand, exacerbates survival deficits, underscoring the conserved function of HTT across species. Additionally, we found thathtt-1affects survival and autophagy under heat shock stress conditions. These results establishhtt-1as a critical regulator of survival and autophagy in response to both pathogenic bacterial infection and thermal stress.

Author summary

Huntingtin plays essential roles in selective autophagy across various organisms, includingDrosophila,mice, and humans. Notably, theC. eleganshuntingtin ortholog,htt-1,remains largely uncharacterized. Here, we describe a novel pro-survival rolehtt-1in stress resistance. We show thathtt-1mutants exhibit significantly reduced survival duringPseudomonas aeruginosainfection. Expression of wild-type human HTT rescues the reduced survival ofhtt-1mutants, whereas mutant HTT further exacerbates the phenotype. These findings establishC. elegans htt-1as a valuable model for studying huntingtin biology and its roles in stress resistance. Downregulation of ERK inhtt-1mutants had no additional effect on survival, suggesting thathtt-1functions downstream of ERK. Interestingly,htt-1mutants display reduced autophagy, indicating thathtt-1functions in the ERK-autophagy signaling cascade during infection. Mechanistically, we propose thathtt-1regulates autophagy at the protein level. HTT-1 remains cytoplasmic, and autophagy-related gene transcripts remain stable, without downregulation, inhtt-1mutants following infection. Additionally,htt-1mutants exhibit reduced survival and impaired autophagy under heat stress. These results suggest thathtt-1may have a broader role in stress resilience extending beyond immune defense.
Striatal Astrocytes Influence Dopamine Dynamics and Behavioral State Transitions
Authors: Lazaridis Iakovos , Ahn Gun , Hirokane Kojiro , Choi Wonchang , Graybiel Ann M.
Published: December 2024

We demonstrate here that astrocytes in the striatum interact with striatal dopamine in bidirectional signaling with dopamine release actively driving surges in astrocytic Ca++, which in turn modulate and reduce subsequent dopamine release. These Ca++surges accurately predict behavioral state changes from task-engaged to task-disengaged states, but fail to predict detailed action parameters. We propose that interactions between striatal astrocytes and dopamine are strong candidates to modulate nigro-striato-nigral loop function underlying on-going behavioral state dynamics.
Invisible Spectrum: A model for minority community public engagement in cancer research
Authors: O’Grady Shane , Ralston Jessica C. , McKiernan Eadaoin , Lanigan Fiona , Salauddin Md , Sharmin Shayla , McVeigh Terri , Gallagher William M. , Guerin Suzanne , Rahman Arman , Kolch Walter
Published: December 2024

Background

Ethnic minority communities are often recognised as experiencing decreased accessibility to vital medical services as well as increased barriers to participation in research studies. These issues stem from a variety of social, cultural and economic factors, all of which must be taken into consideration when designing engagement initiatives for a particular community.Invisible Spectrumis an annual engagement initiative which seeks to promote effective communication and outreach to often-overlooked ethnic minority communities within Ireland, primarily those of Bangladeshi origin. The programme was developed in response to the traditionally low levels of engagement with healthcare services observed within these communities and seeks to empower communities in their own healthcare decision making.

Methods

This study reports a programme of community participation activity with an embedded empirical research component based on participatory action research. The team included researchers and leaders within the Bangladeshi and Arabic Muslim communities in Ireland. Over the course of four years, feedback polls, pre- and post-event surveys and in-depth interviews gathered the views and recommendations of attendees.

Results

Four annual events were held as part of theInvisible Spectrumprogramme, from 2019 to 2023. Feedback from participants consistently demonstrated high levels of satisfaction within the target communities while quantitative survey data also indicated improvements in key areas such as recognition of potential cancer symptoms and greater awareness of available screening services.

Conclusion

There is a significant need to continually promote patient involvement and minority inclusion in healthcare and research initiatives. In line with this goal and after 4 successful years of running theInvisible Spectrumprogramme, we have developed a set of recommendations and guidelines for the successful development and organisation of minority community engagement initiatives. It is our hope that theInvisible Spectrumprogramme could be used as a model for future endeavours of a similar nature.
A foundation model for generalized brain MRI analysis
Authors: Tak Divyanshu , Garomsa Biniam A. , Chaunzwa Tafadzwa L. , Zapaishchykova Anna , Climent Pardo Juan Carlos , Ye Zezhong , Zielke John , Ravipati Yashwanth , Vajapeyam Sri , Mahootiha Maryam , Smith Ceilidh , Familiar Ariana M. , Liu Kevin X. , Prabhu Sanjay , Bandopadhayay Pratiti , Nabavizadeh Ali , Mueller Sabine , Aerts Hugo JWL , Huang Raymond Y. , Poussaint Tina Y. , Kann Benjamin H.
Published: December 2024

Artificial intelligence (AI) applied to brain magnetic resonance imaging (MRI) has the potential to improve disease diagnosis and management but requires algorithms with generalizable knowledge that can perform well in a variety of clinical scenarios. The field has been constrained, thus far, by limited training data and task-specific models that do not generalize well across patient populations and medical tasks. Foundation models, by leveraging self-supervised learning, pretraining, and targeted adaptation, present a promising paradigm to overcome these limitations. Here, we present Brain Imaging Adaptive Core (BrainIAC), a novel foundation model designed to learn generalized representations from unlabeled brain MRI data and serve as a core basis for diverse downstream application adaptation. Trained and validated on 48,519 brain MRIs across a broad spectrum of tasks, we demonstrate that BrainIAC outperforms localized supervised training and other pretrained models, particularly in low-data settings and high-difficulty tasks, allowing for application in scenarios otherwise infeasible. BrainIAC can be integrated into imaging pipelines and multimodal frameworks and may lead to improved biomarker discovery and AI clinical translation.
Reflective Learning from Implementing Care Pathways for Vulnerable Infants and Their Mothers: Case Studies from Pakistan, South Sudan and Yemen.
Authors: Deconinck Hedwig , Wrottesley Stephanie V , Shahid Saba , Boi Angelina Nasira , Luka Pascal Mane , Hebie Marlene Traore , Dearden Kirk , Aljabi Ahmed , Hirata Emily , McGrath Marie
Published: December 2024

Many infants are born vulnerable or become vulnerable in the first 6 months of life, putting them at risk of poor growth and development, long-term ill-health, and increased mortality. Many policies and practitioners aim to integrate care across services for at-risk mother infant pairs, but this is challenging in practice given individual, setting, and policy complexities. The MAMI Care Pathway, an integrated care pathway approach, frames and guides implementation of WHO nutrition and health guidelines within health and nutrition systems. Local contextualization is a pre-requisite for evidencing national policy uptake of relevant global recommendations. To gain insight into such contextualization, we undertook three in-depth country case studies to investigate planning, implementation, adoption, and scalability of the approach with practitioners in Pakistan, South Sudan, and Yemen. Our mixed methods using theoretical frameworks explored planning, implementation, normalization, and sustainable scalability of the care pathway. We explored healthcare workers' perspectives through in- and cross-country reflective learning discussion. Initiatives were prompted by perceived but unmeasured need. Planning and starting implementation required substantial time and stakeholder consultation. Healthcare workers needed skills to perform existing tasks (reflecting shortfalls in routine care capacity and quality) as well as new ones (e.g. maternal mental health). Shifting from disease-focused to person-centred care required (and did not always get) buy-in from healthcare workers (where it was not embedded in service duties and pay), and from communities and mothers to adopt it (practical and competing priorities). It was possible to be system-supportive and scale-sensitive in emergency contexts. Identified commonalities in implementation realities heighten transferable learning potential. Health system strengthening is needed for impactful scale. A paradigm shift towards person-centred care is needed in policy framing and implementation guidance. Deeper localized case study development is a critical type of evidence to inform policy navigation, development and practice.
CETP inhibition Reduces Cardiovascular Events by Lowering of Cumulative LDL Exposure: Reconciling Evidence from Human Genetics and Clinical Trials
Authors: Landfors Fredrik , Kastelein John J.P. , Chorell Elin
Published: December 2024

Background

Genetic studies consistently demonstrate that individuals born with reduced Cholesteryl Ester Transfer Protein (CETP) activity experience lower rates of atherosclerotic vascular disease throughout their lives. In contrast, short-term randomized controlled trials of CETP inhibitors have yielded mixed results, with only one of four trials reporting a reduction in clinical events. Several theories have been proposed to explain this discrepancy, but none fully account for the central mechanism of atherosclerosis: the cumulative lifetime exposure to circulating low-density lipoprotein (LDL) particles in the arterial walls.

Objectives

We aimed to reconcile these conflicting findings by examining the relationship between cumulative LDL exposure and atherosclerosis risk across both genetic studies and clinical trials.

Methods

We analyzed 679 carriers ofCETPprotein-truncating variants (resulting in reduced or non-functional CETP protein) and 505,837 non-carriers in a population with 95,568 atherosclerosis events. Additionally, we assessed treatment effects relative to cumulative LDL reductions in 34 cardiovascular prevention trials involving 328,036 participants and 53,161 events.

Results

HeterozygousCETPprotein-truncating variant carrier status reduced atherosclerotic disease risk (odds ratio, 0.70; 95% confidence interval, 0.57– 0.85;P=5×10-4). In clinical trials, we observed a significant interaction between the magnitude and duration of LDL lowering on treatment effects (hazard ratio, 0.69 per 10– mmol/L×years; 95% confidence interval, 0.52–0.90;P=0.007), supporting that reducing cumulative LDL exposure is key to lowering cardiovascular risk. When comparing genetics with trial outcomes, accounting for differences in timing, duration, and follow-up, we observed consistent effects on atherosclerosis-related events per LDL years across genetic and pharmacological CETP inhibition, as well as with statins, ezetimibe, PCSK9 inhibitors, and familial hypercholesterolemia-associated variants (hazard ratio, 0.74 and 0.69 per 10–mmol/L×years, respectively). This suggests that CETP inhibition reduces cardiovascular risk primarily through LDL. Notably, several trials failed to achieve sufficient cumulative LDL reduction to impact clinical events, and this was not unique to CETP inhibitors.

Conclusion

Our findings indicate that future CETP inhibitor trials achieving substantial and sustained LDL reduction will demonstrate efficacy in preventing cardiovascular events. These results highlight the importance of long-term LDL lowering and support further investigation of CETP inhibition as a strategy for cardiovascular prevention.

GRAPHICAL ABSTRACT
Frequency dynamics predict viral fitness, antigenic relationships and epidemic growth
Authors: Figgins Marlin D , Bedford Trevor
Published: December 2024

During the COVID-19 pandemic, SARS-CoV-2 variants drove large waves of infections, fueled by increased transmissibility and immune escape. Current models focus on changes in variant frequencies without linking them to underlying transmission mechanisms of intrinsic transmissibility and immune escape. We introduce a frame- work connecting variant dynamics to these mechanisms, showing how host population immunity interacts with viral transmissibility and immune escape to determine relative variant fitness. We advance a selective pressure metric that provides an early signal of epidemic growth using genetic data alone, crucial with current underreporting of cases. Additionally, we show that a latent immunity space model approximates immunological distances, offering insights into population susceptibility and immune evasion. These insights refine real-time forecasting and lay the groundwork for research into the interplay between viral genetics, immunity, and epidemic growth.
Similarity in Early Life Stress Exposure is Associated with Similarity in Neural Representations in Early Adulthood
Authors: Ilomäki Miro , Lindblom Jallu , Flykt Marjo , Vänskä Mervi , Punamäki Raija-Leena , Wikman Patrik
Published: December 2024

Early life stress (ELS) has profound implications for developmental trajectories, yet the neural mechanisms underlying its long-term effects remain incompletely understood. In the present study, we examined whether interindividual similarity in ELS exposure aligns with similarity in neural representations and behavioral task performance in early adulthood. Leveraging a 20-year longitudinal dataset of Finnish families, we evaluated 87 young adults who underwent functional magnetic resonance imaging (fMRI) during an emotional go/no-go task. Intersubject representational similarity analysis (IS-RSA) was used to assess the associations between pairwise similarities in prospectively or retrospectively measured ELS, neural representations in 360 cortical regions, and task performance. We incorporated multidimensional scaling and Procrustes alignment to visualize interindividual differences in representational spaces. Prospective ELS, but not Retrospective ELS, was significantly associated with neural representational similarity across 40 cortical regions, including the anterior insula, frontal operculum, and anterior cingulate cortex. Higher Prospective ELS was also linked to reduced detection sensitivity, mediated by neural responses to angry facial expressions. These findings highlight the systematic and chronic effects of more moderate ELS on brain development and emphasize the value of prospective measurements and advanced similarity analyses in capturing the nuanced influences of ELS. By integrating spatial and shape analytical techniques, the present study provides new insights into the long-term neurobiological correlates of ELS and introduces novel methodological tools for neurodevelopmental research.
Environmental exposures and familial background alter the induction of neuropathology and inflammation after SARS-CoV-2 infection
Authors: Chatterjee Debotri , Kurup Drishya , Smeyne Richard Jay
Published: December 2024

Abstract

Basal ganglia disease has been reported as a post-infection sequela of several viruses, with documentation of this phenomenon from the H1N1 Spanish flu to the recent COVID-19 (SARS-CoV-2) pandemic. SARS-CoV-2 infection leads to multisystem deficits, including those affecting the nervous system. Here, we investigated whether a SARS-CoV-2 infection alone increases the susceptibility to develop parkinsonian phenotypes in C57BL/6J mice expressing the human ACE2 receptor, or in addition to two well-known toxin exposures, MPTP and paraquat. Additionally, we examined mice carrying a G2019S mutation in the LRRK2 gene. We also examined if vaccination with either an mRNA- or protein-based vaccine can alter any observed neuropathology. We find that the infection with the WA-1/2020 (alpha) or omicron B1.1.529 strains in ACE2 and G2019S LRRK2 mice both synergize with a subtoxic exposure to the mitochondrial toxin MPTP to induce neurodegeneration and neuroinflammation in the substantia nigra. This synergy appears toxin-dependent since we do not observe this following exposure to the direct redox-inducing compound paraquat. This synergistic neurodegeneration and neuroinflammation is rescued in WT mice that were vaccinated using either mRNA- and protein- based vaccines directed against the Spike protein of the SARS-CoV-2 virus. However, in the G2019S LRRK2 mutant mice, we find that only the protein-based vaccine but not the mRNA- based vaccine resulted in a rescue of the SARS-CoV-2 mediated neuropathology. Taken together, our results highlight the role of both environmental exposures and familial background on the development of parkinsonian pathology secondary to viral infection and the benefit of vaccines in reducing these risks.