bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies
Authors: Infante-Tadeo Sonia , Barber Diane L. 
Published: December 2024

ABSTRACTThe neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD, however, remain unresolved. Diverse disease models including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including CNTFR (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics.SIGNIFICANCE STATEMENTUnderstanding the cellular pathology of Frontotemporal Dementia linked to a GGGGCC expansion in the C9orf72 gene remains a challenge.This study shows that undifferentiated patient-derived iPSCs exhibit hallmark FTD characteristics, including lysosome dysfunction and TDP-43 proteinopathy, and identifies dysregulated genes related to neurodegeneration.These findings highlight patient-derived iPSCs as a valuable model for studying FTD pathology and for drug screening, potentially guiding future research in therapeutic development.
Contrasting impacts of invasiveOpuntiacacti on mammal habitat use
Authors: Stewart Peter S. , Hill Russell A. , Oduor Ayub M. O. , Stephens Philip A. , Whittingham Mark J. , Dawson Wayne 
Published: December 2024

AbstractBiological invasions impact ecosystems worldwide, including through changing the behaviour of native species. Here, we used camera traps to investigate the effects of invasiveOpuntiacacti on the habitat use of twelve mammal species in Laikipia County, Kenya, an internationally important region of mammalian biodiversity. We found thatOpuntiaimpacted mammal occupancy and activity, but the strength and direction of the effects varied among species and between seasons, and depended on the spatial scale at whichOpuntiawas considered. Notably, we observed consistent positive effects for olive baboons and elephants, two major consumers ofOpuntiafruit. We also observed seasonally varying effects on the occupancy of two key grazers: Grevy’s zebra and plains zebra. As well as having important implications for mammal conservation, ecosystem functioning, and the future spread ofOpuntia, our findings highlight behavioural changes in large mammals as a potentially important pathway through which invasive species impact ecosystems.
Kolmogorov-Smirnov and Shapiro-Wilk single distribution analysis methods in examining sample structure, strength of genetic background, and effects of interventions in lifespan and aging studies
Authors: Konopatov Alexander V. , Shidlovsky Yuli V. , Shtil Alexander A. , Bylino Oleg V. 
Published: December 2024

AbstractThe analysis of lifespan and ageing involves a variety of calculations based on survival data. One of these is the comparison of survival curves. However, inspection of survival curves provides little information about the frequency of phenotypes within samples. Here we propose to divide the distribution into intervals to obtain information about the sample structure. Then, we apply the normality criterion to the distributions using the Kolmogorov-Smirnov and Shapiro-Wilk tests. Using this approach, we reveal the destabilising effect of mutations on ontogenesis and lifespan, and estimate the strength of the genetic background of the lines. The proposed methodology allows effective estimation of sample structure and adds a new layer of information to longevity studies.
Stress-actuated Flexible Microelectrode Arrays for Activity Recording in 3D Neuronal Cultures
Authors: Serra João , Mateus José C. , Cardoso Susana , Ventura João , Aguiar Paulo , Leitao Diana C. 
Published: December 2024

ABSTRACTMicroelectrode arrays (MEAs) are instrumental in monitoring electrogenic cell populations, such as neuronal cultures, allowing high precision measurements of electrical activity. Although three-dimensional neuronal cultures replicate the behavior ofin vivosystems better than two-dimensional models, conventional planar MEAs are not well suited to capture activity within such networks. Novel MEA geometries can overcome this difficulty, but often at the cost of increased fabrication complexity. Here, we used the stress mismatch between thin film layers to fabricate MEAs with vertical electrodes, using methods compatible with established microfabrication protocols. A micrometric SiO2hinge enables control over the bending angle of flexible polyimide structures with embedded electrodes. The performance of the patterned electrodes was assessed before and after stress actuation, through impedance measurements, voltage noise mapping, and neuronal activity recordings. 3D MEAs with 30×30 µm2electrodes showed an impedance of 0.96 ± 0.07 MΩ per electrode and detected neuronal activity spikes with amplitudes as high as 400 µV. These results demonstrate the potential of the developed methods to provide a scalable approach to fabricate 3D MEAs, enabling enhanced recording capabilities forin vitroneuronal cultures.
NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway
Authors: Magaña-Ávila Germán , Carbajal-Contreras Héctor , Amnekar Ramchandra , Dite Toby , Téllez-Sutterlin Michelle , García-Ávila Kevin , Marquina-Castillo Brenda , Lopez-Saavedra Alejandro , Vazquez Norma , Rojas-Ortega Eréndira , Delpire Eric , Ellison David H. , Alessi Dario R. , Gamba Gerardo , Castañeda-Bueno María 
Published: December 2024

AbstractThe With No lysine (WNK) kinases regulate processes such as cell volume and epithelial ion transport through the modulation of Cation Chloride Cotransporters such as the NaCl cotransporter, NCC, present in the distal convoluted tubule (DCT) of the kidney. Recently, the interaction of WNKs with Nuclear Receptor Binding Protein 1 (NRBP1) and Transforming Growth Factor β-Stimulated Clone 22 Domain (TSC22D) proteins was reported. Here we explored the effect of NRBP1 and TSC22Ds on WNK signaling in vitro and in the DCT. TSC22D1.1, TSC22D2, and NRBP1 are localized in DCT WNK bodies, which are cytoplasmic biomolecular condensates associated with WNK activation. In HEK293 cells, long TSC22D isoforms and NRBP1 increase WNK4 activity. DCT-specific NRBP1 knockout mice have reduced NCC phosphorylation and activate a compensatory response. Thus, NRBP1 and long TSC22D proteins are positive modulators of WNK signaling and modulate Na+reabsorption in the kidney. NRBP1 and TSC22Ds likely influence WNK signaling in other tissues, impacting various physiological processes.TeaserThe pseudokinase NRBP1 and its associated TSC22D proteins modulate WNK kinases to regulate sodium reabsorption in the kidney.
Mechanisms of host exploitation by a microsporidian parasite
Authors: Silva Luís M. , Vallat Armelle , Koella Jacob C. 
Published: December 2024

AbstractParasites are masters at exploiting their hosts. In doing so, they often affect the development of co-infecting parasites. Such is the case of microsporidia andPlasmodium spp., which have been shown to have their development within the mosquito repressed in the presence of the former. Therefore, microsporidia hold significant potential as biological control agents for malaria. However, the mechanisms behind this repression remain unclear. Here, we characterised the mechanisms underpinning the infection by using evolved lines of the microsporidianVavraia culicisdiffering in their virulence upon infecting the mosquitoAnopheles gambiae, the main malaria vector. Through the use of host metallomics and energy quantification throughout infection progression, we were able to identify important parasite mechanisms of host exploitation of general and virulence-specific interest, namely iron. Our findings advance the fundamental understanding of microsporidia infections and provide important insights into the design of effective malaria control strategies.
Mechanisms for plastic landmark anchoring in zebrafish compass neurons
Authors: Tanaka Ryosuke , Portugues Ruben 
Published: December 2024

AbstractVision is a sensory modality particularly important for navigation, as it can inform animals of their current heading (i.e. visual landmarks) as well as its changes (i.e. optic flow). It has been shown that head direction (HD) neurons in various species incorporate the visual cues into their heading estimates. However, circuit mechanisms underlying this process remain still elusive in vertebrates. Here, we asked if and how the recently identified HD cells in the larval zebrafish – one of the smallest vertebrate models – incorporate visual information. By combining two-photon microscopy with a panoramic virtual reality setup, we demonstrate that the zebrafish HD cells can reliably track the orientation of multiple visual scenes, exploiting both landmark and optic flow cues. The mapping between landmark cues and the heading estimates is idiosyncratic across fish, and experience-dependent. Furthermore, we show that the landmark tracking requires the lateralized projection from the habenula to the interpeduncular nucleus (IPN), where the HD neuron processes innervate. The physiological and morphological parallels suggest that a Hebbian mechanism similar to the fly ring neuron is at work in the habenula axons. Overall, the observations that the hindbrain HD cells of the larval zebrafish lacking an elaborate visual telencephalon shed new light on the evolution of the navigation circuitry in vertebrates.
The inner integument controls embryo sac development and seed shape inArabidopsis thaliana
Authors: Mody Tejasvinee Atul , Schneitz Kay 
Published: December 2024

AbstractThe angiosperm ovule is characterized by the close association of the two generations, with the haploid female gametophyte or embryo sac being encapsulated by the diploid sporophyte, which usually forms two integuments. How the gametophyte and sporophyte coordinate their development has long been of interest. However, the function of the inner integument in embryo sac development has remained elusive. Here, we addressed this question. We applied a genetic ablation strategy to achieve an early block in inner integument outgrowth. We generated plants expressingBARNASEunder the control of an early acting endothelium-specific promoter. Corresponding lines carried ovules lacking most of the inner integument. The genetic and cell biological data revealed that in the near absence of an inner integument embryo sac development is blocked at the mono-nuclear embryo sac stage in most pre-fertilization ovules. Approximately 10 percent of the ovules developed a functional embryo sac and underwent fertilization. Subsequent embryo and endosperm development appeared unperturbed and viable seeds were produced albeit of altered shape. Our results show that the inner integument plays an important role in early embryo sac development as well as ovule and seed shape, but is dispensable for embryo and endosperm development. Key words: embryo sac, embryo, endothelium, female gametophyte, integument, seed developmentHighlightGenetic ablation of the inner integument demonstrates its role in embryo sac development and its irrelevance for embryogenesis.
The striatal compartments, striosome and matrix, are embedded in largely distinct resting state functional networks
Authors: Sadiq Alishba , Funk Adrian T. , Waugh Jeff L. 
Published: December 2024

AbstractThe striatum is divided into two interdigitated tissue compartments, the striosome and matrix. These compartments exhibit distinct anatomical, neurochemical, and pharmacological characteristics and have separable roles in motor and mood functions. Little is known about the functions of these compartments in humans. While compartment-specific roles in neuropsychiatric diseases have been hypothesized, they have yet to be directly tested. Investigating compartment-specific functions is crucial for understanding the symptoms produced by striatal injury, and to elucidating the roles of each compartment in healthy human skills and behaviors. We mapped the functional networks of striosome and matrix in humansin vivo. We utilized a diverse cohort of 674 healthy adults, derived from the Human Connectome Project, including all subjects with complete diffusion and functional MRI data and excluding subjects with substance use disorders. We identified striatal voxels with striosome-like and matrix-like structural connectivity using probabilistic diffusion tractography. We then investigated resting state functional connectivity (rsFC) using these compartment-like voxels as seeds. We found widespread differences in rsFC between striosome-like and matrix-like seeds (p< 0.05, FWE corrected for multiple comparisons), suggesting that striosome and matrix occupy distinct functional networks. Slightly shifting seed voxel locations (<4 mm) eliminated these rsFC differences, underscoring the anatomic precision of these networks. Striosome-seeded networks exhibited ipsilateral dominance; matrix-seeded networks had contralateral dominance. Next, we assessed compartment-specific engagement with the triple-network model (default mode, salience, and frontoparietal networks). Striosome-like voxels dominated rsFC with the default mode network bilaterally. The anterior insula (a primary node in the salience network) had higher rsFC with striosome-like voxels. The inferior and middle frontal cortices (primary nodes, frontoparietal network) had stronger rsFC with matrix-like voxels on the left, and striosome-like voxels on the right. Since striosome-like and matrix-like voxels occupy highly segregated rsFC networks, striosome-selective injury may produce different motor, cognitive, and behavioral symptoms than matrix-selective injury. Moreover, compartment-specific rsFC abnormalities may be identifiable before disease-related structural injuries are evident. Localizing rsFC differences provides an anatomic substrate for understanding how the tissue-level organization of the striatum underpins complex brain networks, and how compartment-specific injury may contribute to the symptoms of specific neuropsychiatric disorders.
Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy chain locus
Authors: Gornitzka Mari B. , Røsjø Egil , Jana Uddalok , Ford Easton E. , Tourancheau Alan , Lees William D. , Vanwinkle Zachary , Smith Melissa L. , Watson Corey T. , Lossius Andreas 
Published: December 2024

AbstractGenetic diversity within the human immunoglobulin heavy chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive sequences and complex structural variation pose significant challenges for large-scale characterization. Here, we introduce a method using Oxford Nanopore ultra-long sequencing and adaptive sampling, coupled with a bioinformatic pipeline, to generate haplotype-resolved single-contig IGH assemblies. We compared our method to a well-established IGH characterization framework using Pacific Biosciences HiFi sequencing in four donors and observed almost complete sequence congruence between our haplotype-resolved assemblies and the HiFi reads. Applying our approach to the HG002 reference material revealed no base differences to the Telomere-to-Telomere genome benchmark over the IGH locus. Importantly, among the four donors, our approach uncovered 30 novel alleles and previously uncharacterized large structural variants, including a 120 kb segmental duplication spanning IGHE to IGHA1 and an expanded seven-copy IGHV3-23 gene haplotype.
Predictive value of preclinical models for CAR-T cell therapy clinical trials: a systematic review and meta-analysis
Authors: Andreu-Sanz David , Gregor Lisa , Carlini Emanuele , Scarcella Daniele , Marr Carsten , Kobold Sebastian 
Published: December 2024

AbstractExperimental mouse models are indispensable for the preclinical development of cancer immunotherapies, whereby complex interactions in the tumor microenvironment (TME) can be somewhat replicated. Despite the availability of diverse models, their predictive capacity for clinical outcomes remains largely unknown, posing a hurdle in the translation from preclinical to clinical success. This study systematically reviews and meta-analyzes clinical trials of chimeric antigen receptor (CAR-) T cell monotherapies with their corresponding preclinical studies. Adhering to PRISMA guidelines, a comprehensive search of PubMed andClinicalTrials.govwas conducted, identifying 422 clinical trials and 3157 preclinical studies. From these, 105 clinical trials and 180 preclinical studies, accounting for 44 and 131 distinct CAR constructs, respectively, were included.Patientś responses varied based on the target antigen, expectedly with higher efficacy and toxicity rates in hematological cancers. Preclinical data analysis revealed homogenous and antigen-independent efficacy rates. Our analysis revealed that only 4 % (n = 12) of mouse studies used syngeneic models, highlighting their scarcity in research. Three logistic regression models were trained on CAR structures, tumor entities, and experimental settings to predict treatment outcomes. While the logistic regression model accurately predicted clinical outcomes based on clinical or preclinical features (Macro F1 and AUC > 0.8), it failed in predicting preclinical outcomes from preclinical features (Macro F1 < 0.5, AUC < 0.6), indicating that preclinical studies may be influenced by experimental factors not accounted for in the model.These findings underscore the need for better understanding the experimental factors enhancing the predictive accuracy of mouse models in preclinical settings.
Modulating Cellular Deformability via 3D Dextran Hydrogel Cultivation to Regulate the Microcirculation of Mesenchymal Stem Cells in Murine Spleen and Liver
Authors: Zhu Xiaolu , Wang Zheng , Shi Yuanping , Yao Shuang , He Fengliang , Teng Fang 
Published: December 2024

AbstractFor mesenchymal stem cell (MSC) therapy to be effective, the vascular system may be used to deliver and steer the cells to the target tissue. However, the expanded MSCs in petri dishes are usually have a limited deformability and commonly excluded by the capillary networks when homing to the downstream organs via microcirculation. Here, we propose to utilize specially designed 3D dextran hydrogels and tuning the microscopic heterogeneity of hydrogel composition to make the administrated cells mechanically comply with the structure and mechanics of the capillary. The cell deformability in petri dishes, microcosmically homogeneous (HOM) and heterogeneous (HET) dextran hydrogels were investigated in vitro by measuring cell moduli through atomic force microscope (AFM), analyzing the expression of cytoskeletal protein via flow cytometry and fluorescent imaging. The in vitro experimental results demonstrate a progressive increase in cell deformability from 2D dishes, to HOM-hydrogel derived cells, and then to HET-hydrogel derived cells. The in vivo mouse experiment indicates the cells could deform accordingly and pass through easily with reduced resistance inside the mouse organs. It is suggested that the main destination of hMSC microcirculation could be selected between the spleen and liver of mice, by tuning cell mechanics that depends on the stimulus from microcosmically HOM or HET hydrogel, which lays a potential foundation for the mechanically modified MSC therapy for lesions in the organs.
Living in Endemic Area for Infectious Diseases is Associated to Differences in Immunosenescence Signatures
Authors: Coelho Monique Macedo , Moreira Felipe Caixeta , Zuccherato Luciana Werneck , Ventura Lucas Haniel de Araújo , Camatta Giovanna Caliman , Starling-Soares Bernardo , Torres Lícia , Durso Danielle Fernandes , Sato Hugo Itaru , da Costa Murilo Soares , Guimarães Henrique Cerqueira , Barbuto Rafael Calvão , O. Júnior Mauro Lúcio , Speziali Elaine , Tupinambas Unaí , Teixeira Santuza Maria Ribeiro , Silveira-Nunes Gabriela , Teixeira-Carvalho Andrea , Maioli Tatiani Uceli , Faria Ana Maria Caetano 
Published: December 2024

AbstractResearch on aged individuals from developed countries show that lifestyle factors such as diet, physical activity, stress, smoking, and sleep quality impact aging. However, other relevant factors may influence aging in less-studied populations, such as Brazilian cohorts. This study aimed to analyze immunosenescence profile of individuals living in an endemic area for several infectious diseases in Brazil. We showed that these individuals exhibited accelerated epigenetic aging and increased production of IL-12p70, IL-17A, and IL-9. Production of inflammatory mediators IL-12p70, IL-6, IL-1β, IL-2, and IL-1ra in individuals with flu-like symptoms and those with COVID-19 was higher among residents in endemic areas than in residents from a control non-endemic area. Furthermore, residents of the endemic area had a more prominent inflammatory profile during viral infection and a different pattern of plasma mediators when compared to residents of a non-endemic area. It suggests that these two cohorts had specific immune signatures regardless of the presence or the type of infection at study. Therefore, we demonstrated that there were distinct patterns of immune responses and epigenetic aging depending on the environment the individuals live in. These observations add a layer of diversity to the studies of human aging by including less represented individuals.