Miracle-dz/UniFAR-FTUs huggingface dataset:
PAK1 and NF2/Merlin jointly drive myelination by remodeling actin cytoskeleton in oligodendrocytes

In the central nervous system (CNS), myelin formation by oligodendrocytes (OLs) relies on actin dynamics. Actin polymerization supports the ensheathment step, when the OL process contacts the axon, while a drastic shift to actin depolymerization is required to enable the following step of wrapping and expansion of myelin membranes. The molecular mechanisms triggering this switch, essential for proper myelination, have yet to be elucidated. Here, we identify P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. We show that PAK1 accumulates in OLs in a kinase inhibited form, triggering actin disassembly and, consequently, myelin expansion. Remarkably, we identify NF2/Merlin as an endogenous inhibitor of PAK1 by proteomics analysis of its binding partners. We found that Nf2 knockdown in OLs results in PAK1 activation and impairs myelin formation, and that pharmacological inhibition of PAK1 in Nf2-knockdown OLs rescues these defects. Moreover, we demonstrate that modulating PAK1 activity in OLs controls myelin expansion and provide compelling evidence indicating that specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that PAK1-NF2/Merlin duo plays a key role in actin cytoskeleton remodeling in OLs, required for proper myelin formation. These findings have broad mechanistic and therapeutic implications for demyelinating diseases and neurodevelopmental disorders. Significance Remodeling actin cytoskeleton plays a crucial role in myelin formation by oligodendrocytes (OLs). Recent studies have shown that expansion and wrapping of myelin membranes around axons depends on actin depolymerization. However, the molecular mechanisms triggering this key step in myelination are not fully elucidated. Using genetic and pharmacological tools as well as proteomics analyses, we found that PAK1 (P21 Activated Kinase 1) kinase activity is maintained inhibited by NF2/Merlin in OLs to allow actin depolymerization and, consequently, myelin membrane expansion. Pak1 loss-of-function in OLs leads to an increase in myelin thickness in the white matter of adult mice, confirming the role of PAK1 inactivation in myelin membrane expansion.
Active regulatory elements recruit cohesin to establish cell-specific chromatin domains

As the structure of the genome is analysed at ever increasing resolution it is becoming clear that there is considerable variation in the 3D chromatin architecture across different cell types. It has been proposed that this may, in part, be due to increased recruitment of cohesin to activated cis-elements (enhancers and promoters) leading to cell-type specific loop extrusion underlying the formation of new subTADs. Here we show that cohesin correlates well with the presence of active enhancers and this varies in an allele-specific manner with the presence or absence of polymorphic enhancers which vary from one individual to another. Using the alpha globin cluster as a model, we show that when all enhancers are removed, peaks of cohesin disappear from these regions and the erythroid specific subTAD is no longer formed. Re-insertion of the major alpha globin enhancer (R2) is associated with the appearance of a new peak of cohesin at the site of insertion. In complementary experiments insertion of R2 into a “neutral” region of the genome recruits cohesin, induces transcription and creates a new large (75kb) erythroid specific domain. Together these findings support the proposal that active enhancers recruit cohesin, stimulate loop extrusion and promote the formation of cell specific subTADs.
Age-related disparities in oscillatory dynamics within scene-selective regions during spatial navigation

Position is a key property that allows certain objects in the environment to attain navigational relevance. Symmetrical processing of object position across the horizontal meridian remains an unchallenged assumption of the spatial navigation literature. Nonetheless, a growing body of research reports vertical inhomogeneities in perceptual tasks, and recent evidence points towards a lower visual field preference in healthy aging. Factoring in the vertical position of objects to better apprehend spatial navigation abilities across the lifespan is essential. The occipital place area (OPA), parahippocampal place area (PPA), and medial place area (MPA) are ideal candidates to support the processing of the vertical location of navigational cues. Indeed, they are implicated in scene processing and spatial cognition, functions that may interact with their underlying retinotopic codes. This study aimed to elucidate whether young and older participants adjusted their gaze patterns and EEG activity within scene-selective regions in response to the vertical arrangement of landmarks. A sample of 21 young and 21 older participants completed a desktop-based task requiring them to navigate using objects at different vertical locations. We equipped them with an eye tracker and a high-density EEG cap. We used a fMRI-informed source-reconstruction algorithm to study the OPA, PPA and MPA with high spatial and temporal precision. Older adults exhibited a higher number of errors compared to young adults during reorientation. This age-related decline in accuracy was accompanied by a tendency among older participants to fixate objects in the lower half of the screen. This gaze bias was absent in young participants, who instead adapted their oculomotor behaviour based on the position of navigationally-relevant information. Another primary finding pertains to the differential pattern of theta and beta band activity in the OPA, PPA and RSC for environments that only contained relevant cues in the upper visual field. It thus appears that scene-selective regions process some aspect of the vertical position of information, irrespectively of their inherent retinotopic biases. Moreover, we revealed striking disparities between age groups in beta/gamma band synchronization in all scene-selective regions, indicating compromised top-down attentional mechanisms during spatial navigation in ageing. These age-related disparities in attentional dynamics might account for performance deficits in older participants. This study sheds light on a systematic downward gaze bias and altered attentional dynamics within scene-selective regions during spatial navigation in older age. It also emphasises the importance of considering vertical positioning as a fundamental property of objects within scenes.
Revealing the spatial pattern of brain hemodynamic sensitivity to healthy aging through sparse DCM

Age-related changes in the BOLD response could reflect neuro-vascular coupling modifications rather than simply impairments in neural functioning. In this study, we propose the use of a generative dynamic causal model (DCM) to decouple neuronal and vascular factors in the BOLD signal, with the aim of characterizing the whole-brain spatial pattern of hemodynamic sensitivity to healthy aging, as well as to test the role of hemodynamic features as independent predictors in an age-classification model.In this view, DCM was applied to the resting-state fMRI data of a cohort of 126 healthy individuals in a wide age range, providing reliable estimates of the hemodynamic response function (HRF) for each subject and each region of interest. Then, some features characterizing each HRF curve were extracted and used to fit a multivariate logistic regression model to predict the age class of each individual. Ultimately, we tested the final predictive model on an independent dataset of 338 healthy subjects selected from the Human Connectome Project Aging (HCP-A) and Development (HCP-D) cohorts. Our results entail the spatial heterogeneity of the age effects on the hemodynamic component, since its impact resulted to be strongly region- and population-specific, discouraging any space-invariant corrective procedures that attempt to correct for vascular factors when carrying out functional studies involving groups with different ages. Moreover, we demonstrated that a strong interaction exists between some specific hemodynamic features and age, further supporting the essential role of the hemodynamic factor as independent predictor of biological aging, rather than a simple confounding variable. Significance statement By inferring region-wise hemodynamic profiles at the individual level, this is the first study providing an exhaustive whole-brain characterization of the hemodynamic sensitivity to healthy aging, reporting further evidence of the vascular changes across the adult lifespan. Using a predictive framework, we analysed the statistical influence of advancing age on individual regional hemodynamic attributes, offering a quantitative evaluation of the diverse hemodynamic bias across different brain regions. We unveiled a specific set of hemodynamic predictors to discriminate young from elderly people, mainly describing vascular properties of right-hemispheric areas. This suggests the asymmetric nature of vascular degeneration processes affecting the human brain at the latest stage of life, other than a potential biomarker that could be relevant for brain-age prediction.
Length measurement of cholinergic innervation in the tunica albuginea of rat testis

The testicular albuginea is not a simple receptacle that contains the testis parenchyma. It is a biologically active structure involved, among other things, in the progression of sperm from the seminiferous tubules to the rete testis. This function, attributed to the albuginea myofibroblasts’ contractile properties, is mediated by its vegetative innervation. Therefore, the quantification of innervation seems relevant to deepen the knowledge of the testicular envelope’s physiology. The albuginea contains cholinergic nerve fibers that are not very evident and with a marked directional arrangement (anisotropy). These structural characteristics require that the quantification of the fibers’ length be carried out using stereological measurements, which ensure the absence of bias in the process. The authors have developed stereological tools usually carried out on vertical VUR (vertical uniform random) sections in the present work. This approach’s novelty is that the albuginea is treated "in toto" as if it were a thick section (slice) on which a cycloid grid is applied through different optical planes. Thus, on a pilot study of three specimens, cholinergic nerve fibers’ length density was estimated, as well as the estimates of the coefficient of error of measurements and the biological variability of the sample. Furthermore, after estimating the albuginea volume, the mean of the fibers’ absolute length can be obtained. This stereological approach can be used after visualization of the immunostained nerve fibers for various markers, as long as the reagents’ penetration into the tissue is ensured. Moreover, it can be used in other biological structures, such as the intestine of small animals, which can also be processed as whole mounts and treated as thick VUR sections.
Functional analysis of chromatin-associated proteins in Sordaria macrospora reveals similar roles for RTT109 and ASF1 in development and DNA damage response

We performed a functional analysis of two potential partners of ASF1, a highly conserved histone chaperone that plays a crucial role in the sexual development and DNA damage resistance in the ascomycete Sordaria macrospora. ASF1 is known to be involved in nucleosome assembly and disassembly, binding histones H3 and H4 during transcription, replication and DNA repair and has direct and indirect roles in histone recycling and modification as well as DNA methylation, acting as a chromatin modifier hub for a large network of chromatin-associated proteins. Here, we functionally characterized two of these proteins, RTT109 and CHK2. RTT109 is a fungal-specific histone acetyltransferase, while CHK2 is an ortholog to PRD-4, a checkpoint kinase of Neurospora crassa that performs similar cell cycle checkpoint functions as yeast RAD53. Through the generation and characterization of deletion mutants, we discovered striking similarities between RTT109 and ASF1 in terms of their contributions to sexual development, histone acetylation and protection against DNA damage. Phenotypic observations revealed a developmental arrest at the same stage in Δrtt109 and Δasf1 strains, accompanied by a loss of H3K56 acetylation, as detected by western blot analysis. Deletion mutants of rtt109 and asf1 are sensitive to the DNA damaging agent MMS (methylmethane sulfonate), but not HU (hydroxyurea). In contrast, chk2 mutants are fertile and resistant to MMS, but not HU. Our findings suggest a close functional association between ASF1 and RTT109 in the context of development, histone modification and DNA damage response, while indicating a role for CHK2 in separate pathways of the DNA damage response. Article summary In the filamentous fungus Sordaria macrospora, the conserved histone chaperone ASF1, which interacts with histones H3 and H4, was previously shown to be required for multicellular development and DNA damage response. Here, we have analyzed two additional chromatin-associated proteins. rtt109 encodes a histone acetyltransferase, and deletion of the gene in S. macrospora results in a phenotype similar to that of a Δasf1 mutant, whereas chk2 is involved in different aspects of the DNA damage response, but not in development.
Two complementary circuits for spatial navigation in mouse: evidence from Fos mapping

We designed and implemented a novel spatial behavioral protocol based on the figure 8 maze paradigm. This solution employs a fully automated closed-loop system using visual contexts for guiding behavior. It allows high throughput testing of large cohorts of animals. This automated approach highly reduces the effect of stress, but also eliminates the influence of rule learning and the involvement of working memory. Here, we show that training mice in the apparatus leads to change in strategy from internal tendency to alternate into navigation based exclusively on visual cues. This effect could be achieved using two different protocols: prolonged alternation training, or a flexible protocol with unpredictable turn succession. We provide evidence of opposing levels of engagement of hippocampus and retrosplenial cortex after training mice in these two different regimens. This supports the hypothesis of the existence of parallel circuits supporting navigation, one based on the well described hippocampal representation, and another, RSC-dependent.
hkb is required for DIP-α expression and target recognition in the Drosophila neuromuscular circuit

Our nervous system contains billions of neurons that form precise connections with each other through interactions between cell surface proteins (CSPs). In Drosophila, the Dpr and DIP immunoglobulin protein subfamilies form homophilic or heterophilic interactions to instruct synaptic connectivity, synaptic growth and cell survival. However, the upstream regulation and downstream signaling mechanisms of Dprs and DIPs are not clear. In the Drosophila larval neuromuscular system, DIP-α is expressed in the dorsal and ventral type-Is motor neurons (MNs). We conducted an F1 dominant modifier genetic screen to identify regulators of Dprs and DIPs. We found that the transcription factor, huckebein (hkb), genetically interacts with DIP-α and is important for target recognition specifically in the dorsal Is MN, but not the ventral Is MN. Loss of hkb led to complete removal of DIP-α expression. We then confirmed that this specificity is through the dorsal Is MN specific transcription factor, even-skipped (eve), which acts downstream of hkb. Genetic interaction between hkb and eve revealed that they act in the same pathway to regulate dorsal Is MN connectivity. Our study provides insight into the transcriptional regulation of DIP-α and suggests that distinct regulatory mechanisms exist for the same CSP in different neurons.
How motivational interviewing shifts food choices and craving-related brain responses to healthier options

Changing one’s habits is challenging. Motivational interviewing (MI) has been proposed as a communication-based approach to overcome this challenge. Here, we tested how change and sustain talk suggestions, elicited by MI, influenced value-based dietary decision-making and responses of a recently developed neurobiological craving signature (NCS) in female adults. We found that following change talk, compared to sustain talk, participants’ food choices and activity in the ventromedial prefrontal cortex were more driven by the healthiness and less by the tastiness of food. These findings were paralleled by lower NCS responses to tasty food after change compared to sustain talk. Further, following change talk, participants’ body mass indices moderated the NCS decoding of healthy and tasty food choices. These results show that MI can shift value-based decision-making and reduce craving-related brain marker responses to highly palatable food items. The findings contribute to a better understanding of behavioral change interventions toward healthier eating.
Network level enrichment provides a framework for biological interpretation of machine learning results

Machine learning algorithms are increasingly used to identify brain connectivity biomarkers linked to behavior and clinical outcomes. However, non-standard methodological choices in neuroimaging datasets, especially those with families or twins, have prevented robust machine learning applications. Additionally, prioritizing prediction accuracy over biological interpretability has made it challenging to understand the biological processes behind psychopathology. In this study, we employed a linear support vector regression model to study the relationship between resting-state functional connectivity networks and chronological age using data from the Human Connectome Project. We examined the effect of shared variance from twins and siblings by using cross-validation, either randomly assigning or keeping family members together. We also compared models with and without a Pearson feature filter and utilized a network enrichment approach to identify predictive brain networks. Results indicated that not accounting for shared family variance inflated prediction performance, and the Pearson filter reduced accuracy and reliability. Enhancing biological interpretability was achieved by inverting the machine learning model and applying network-level enrichment on the connectome, while directly using regression coefficients as feature weights led to misleading interpretations. Our findings offer crucial insights for applying machine learning to neuroimaging data, emphasizing the value of network enrichment for comprehensible biological interpretation.
Evaluation of erosion control products using natural rainfall events

ABSTRACT: Five different erosion control products were tested on the slopes of a newly constructed highway sedimentation basin to determine their impact on vegetative growth, runoff and soil erosion. The five tested treatments were a wood fiber blanket, a straw/coconut blanket, a straw blanket, a bonded-fiber matrix (hydraulically applied) and disk-anchored straw mulch. Three replicates of each treatment were used. The site was seeded with native prairie seeds and the establishment of vegetation was monitored over time. Early in the study, a large runoff event from the area above the plots overtopped them and caused a failure of the bonded-fiber matrix product. These plots were reclassified as a bare treatment. For the season of plant growth, the straw mulch plots had the greatest biomass, and the bare treatment had the least. There was little difference among treatments after the second growing season. Runoff and sediment yield were analyzed for five storm events. The largest runoff and sediment yields were observed from the bare treatment. The soil erosion was approximately ten times greater than that from the straw-mulch plots. The blanket treatments had less erosion than straw-mulch plots. There was, however, little difference between blanket types.
Fluvial-Sandstone Architecture and Thrust-Induced Subsidence, Northern Green River Basin, Wyoming

: Facies analysis of the Lenticular Sandstone and Shale Sequence in the northern Green River basin, Wyoming provides the basis for testing the concept that subsidence controls fluvial-sandstone architecture. This sequence consists of three genetic facies including (1) low sinuosity fluvial channel sandstones of both ribbon and multistory geometries, (2) levee and splay complexes, and (3) interfluve swamp, bog, and lake deposits. The fluvial channels are thick (>5 m), lenticular bodies consisting of fine- to medium-grained sandstone with basal scour lags. The absence of point bar lateral accretion surfaces and the low variance of paleocurrent directions suggest low sinuosity. Ubiquitous levee and splay sandstones are thin (0.5 m) and contain small-scale trough crossbedding and microtrough cross-lamination. The interfluve rocks consist of dark gray mudstone, carbonaceous shale, thin coal beds, and thin, nonmarine micritic limestone. We interpret these deposits to be the products of a fixed-channel fluvial system that developed in a rapidly subsiding foreland basin. High subsidence rates are indicated by the large proportion of overbank mudstone, ribbon to multistory channel geometries and lack of paleosol horizons. Subsidence analysis (backstripping) also shows that basin subsidence was rapid during the Campanian and therefore that the architecture of the Lenticular Sandstone and Shale Sequence may have been tectonically controlled. We attribute this subsidence to regional flexure induced by tectonic loading during major thrust emplacement to the west.