bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multiscale closed-loop neurotoxicity model of Alzheimer’s disease progression explains functional connectivity alterations
Authors: Cabrera-Álvarez Jesús , Stefanovski Leon , Martin Leon , Susi Gianluca , Maestú Fernando , Ritter Petra 
Published: September 2023

AbstractWhile the accumulation of amyloid-beta (Aβ) and hyperphosphorylated-tau (hp-tau) as two classical histopathological biomarkers are crucial in Alzheimer’s disease (AD), their detailed interaction with the electrophysiological changes at the meso- and macroscale are not yet fully understood. We developed a mechanistic mequltiscale model of AD progression, linking proteinopathy to its effects on neural activity and vice-versa. We integrated a heterodimer model of prion-like protein propagation, and a network of Jansen-Rit electrical oscillators whose model parameters varied due to neurotoxicity. Changes in inhibition guided the electrophysiological alterations found in AD, and bothAβand hp-tau-related inhibition changes were able to produce similar effects independently. Additionally, we found a causal disconnection between cellular hyperactivity and interregional hypersynchrony. Finally, we demonstrated that earlyAβand hp-tau depositions’ location determine the spatiotemporal profile of the proteinopathy. The presented model combines the molecular effects of bothAβand hp-tau together with a mechanistic protein propagation model and network effects within a unique closed-loop model. This holds the potential to enlighten the interplay between AD mechanisms on various scales, aiming to develop and test novel hypotheses on the contribution of different AD-related variables to the disease evolution.Significance StatementThis research presents a groundbreaking closed-loop model of AD mechanisms, bridging the gap between protein distribution and neural activity. Contrary to prior assumptions, the study reveals that interregional hyper-synchrony and cellular hyperactivity are not directly linked. Notably, the model identifies neural inhibition as a potential causal factor in neurophysiological AD alterations and posits early depositions ofAβas a determinant of the spatiotemporal profile of proteinopathy. The significance of this mechanistic disease framework lies in its potential to produce insights into AD evolution and to guide novel treatment strategies. It underscores the importance of further experiments and modelling efforts to refine our understanding of AD, offering hope for more effective treatments and personalized care in the fight against dementia.
Increased deformations are dispensable for cell mechanoresponse in engineered bone analogs mimicking aging bone marrow
Authors: Regner Alexander M , DeLeon Maximilien , Gibbons Kalin D. , Howard Sean , Nesbitt Derek Q. , Lujan Trevor J. , Fitzpatrick Clare K. , Farach-Carson Mary C , Wu Danielle , Uzer Gunes 
Published: September 2023

AbstractAged individuals and astronauts experience bone loss despite rigorous physical activity. Bone mechanoresponse is in-part regulated by mesenchymal stem cells (MSCs) that respond to mechanical stimuli. Direct delivery of low intensity vibration (LIV) recovers MSC proliferation in senescence and simulated microgravity models, indicating that age-related reductions in mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse. To answer this question, we developed a 3D bone marrow analog that controls trabecular geometry, marrow mechanics and external stimuli. Validated finite element (FE) models were developed to quantify strain environment within hydrogels during LIV. Bone marrow analogs with gyroid-based trabeculae of bone volume fractions (BV/TV) corresponding to adult (25%) and aged (13%) mice were printed using polylactic acid (PLA). MSCs encapsulated in migration-permissive hydrogels within printed trabeculae showed robust cell populations on both PLA surface and hydrogel within a week. Following 14 days of LIV treatment (1g, 100 Hz, 1 hour/day), type-I collagen and F-actin were quantified for the cells in the hydrogel fraction. While LIV increased all measured outcomes, FE models predicted higher von Mises strains for the 13% BV/TV groups (0.2%) when compared to the 25% BV/TV group (0.1%). Despite increased strains, collagen-I and F-actin measures remained lower in the 13% BV/TV groups when compared to 25% BV/TV counterparts, indicating that cell response to LIV does not depend on hydrogel strains and that bone volume fraction (i.e. available bone surface) directly affects cell behavior in the hydrogel phase independent of the external stimuli. Overall, bone marrow analogs offer a robust and repeatable platform to study bone mechanobiology.
A 3D Printed Ventilated Perfused Lung Model Platform to Dissect the Lung’s Response to Viral Infection in the Presence of Respiration
Authors: Derman I. Deniz , Alioglu Mecit Altan , Banerjee Dishary , Holton Sarah E. , Klunk Danielle Nicole , Nagamine Momoka , Rizvi Syed Hasan Askari , Mikacenic Carmen , Celik Nazmiye , Castaneda Diana Cadena , Prajakta Warang , Chen Phylip , Schotsaert Michael , Peeples Mark E. , Palucka Karolina , Koff Jonathan , Ozbolat Ibrahim T. 
Published: September 2023

AbstractIn this study, we developed a three-dimensionally (3D) printed lung model that faithfully recapitulates the intricate lung environment. This 3D model incorporated alveolar and vascular components that allow for a comprehensive exploration of lung physiology and responses to infectionin vitro. In particular, we investigated the intricate role of ventilation on formation of the alveolar epithelial layer and its response to viral infections. In this regard, we subjected our 3D printed, perfused lung model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days followed by infection with two viruses: influenza virus (Pr8) and respiratory syncytial virus (RSV), at two different concentrations for 24 or 48 h. The results revealed that ventilation induced increased tight-junction formation with better epithelial barrier function over time, facilitated higher expression of alveolar epithelial specific genes, enabled higher level of infection with an increased progression of viral spread and replication over time, and modulated the production of pro-inflammatory cytokines and chemokines. Our findings represent a critical step forward in advancing our understanding of lung-specific viral responses and respiratory infections in response to ventilation, which sheds light on vital aspects of pulmonary physiology and pathobiology.
SDC4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging spine
Authors: Sao Kimheak , Risbud Makarand V. 
Published: September 2023

AbstractSyndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of SDC4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that SDC4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in SDC4 KO mice. These changes in vertebral bone were due to elevated osteoclastic activity in KO mice. The histological assessment also showed subtle phenotypic changes in the intervertebral discs. Imaging-Fourier transform-infrared (FTIR) analyses showed a reduced relative ratio of mature collagen crosslink in young adult NP and AF compartments of KO compared to wildtype (WT) mice. Additionally, relative chondroitin sulfated glycosaminoglycan (GAG) levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, and endoplasmic reticulum to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the intervertebral disc.
Insect biomass of protected habitats under the impact of arable farming in Germany
Authors: Mühlethaler Roland , Köthe Sebastian , Hörren Thomas , Sorg Martin , Eichler Lisa , Lehmann Gerlind U. C. 
Published: September 2023

AbstractFive years after the well-known study on insect biomass decline in nature protected habitats in Germany over three decades, the project DINA (Diversity of Insects in Nature protected Areas) has investigated the status of insects in 21 selected nature reserves across Germany in the years 2020 and 2021. We used the same methods and protocols for trapping and measuring the biomass of flying insects as in the mentioned study. Across two seasons, we accumulated a comprehensive data set of 1621 data points of two-week emptying intervals. The measured overall insect biomass remained at low levels and corresponds to the published latest figures from the years 2007–2016. There were no significant regional differences, but biomass was negatively correlated with agricultural production area within 2 km of nature reserves. Differences between the two consecutive years were very likely due to well-known natural fluctuations of insect populations, changes in agricultural cultivation and local weather events. The results show that protected habitats are essential for insects, but not sufficient in their function, and that further steps need to be taken for a better protection and sustainment of insects, which fulfil key functions in many ecosystems.
A developmentally defined population of neurons in the lateral septum controls responses to aversive stimuli
Authors: García Miguel Turrero , Tran Diana N. , Peterson Ralph E. , Stegmann Sarah K. , Hanson Sarah M. , Reid Christopher M. , Xie Yajun , Vu Steve , Harwell Corey C. 
Published: September 2023

ABSTRACTWhen interacting with their environment, animals must balance exploratory and defensive behavior to evaluate and respond to potential threats. The lateral septum (LS) is a structure in the ventral forebrain that calibrates the magnitude of behavioral responses to stress-related external stimuli, including the regulation of threat avoidance. The complex connectivity between the LS and other parts of the brain, together with its largely unexplored neuronal diversity, makes it difficult to understand how defined LS circuits control specific behaviors. Here, we describe a mouse model in which a population of neurons with a common developmental origin (Nkx2.1-lineage neurons) are absent from the LS. Using a combination of circuit tracing and behavioral analyses, we found that these neurons receive inputs from the perifornical area of the anterior hypothalamus (PeFAH) and are specifically activated in stressful contexts. Mice lackingNkx2.1-lineage LS neurons display increased exploratory behavior even under stressful conditions. Our study extends the current knowledge about how defined neuronal populations within the LS can evaluate contextual information to select appropriate behavioral responses. This is a necessary step towards understanding the crucial role that the LS plays in neuropsychiatric conditions where defensive behavior is dysregulated, such as anxiety and aggression disorders.
PDZ Domains from the Junctional Proteins Afadin and ZO-1 Act as Mechanosensors
Authors: Vachharajani Vipul T. , DeJong Matthew P. , Dutta Soumya , Chapman Jonathan , Ghosh Eashani , Singharoy Abhishek , Dunn Alexander R. 
Published: September 2023

AbstractIntercellular adhesion complexes must withstand mechanical forces to maintain tissue cohesion while also retaining the capacity for dynamic remodeling during tissue morphogenesis and repair. Many cell-cell adhesion complexes contain at least one PSD95/Dlg/ZO-1 (PDZ) domain situated between the adhesion molecule and the actin cytoskeleton. However, PDZ-mediated interactions are characteristically nonspecific, weak, and transient, with multiple binding partners per PDZ domain, micromolar dissociation constants, and bond lifetimes of seconds or less. Here, we demonstrate that the bonds between the PDZ domain of the cytoskeletal adaptor protein afadin and the intracellular domains of the adhesion molecules nectin-1 and JAM-A form molecular catch bonds that reinforce in response to mechanical load. In contrast, the bond between the PDZ3-SH3-GUK (PSG) domain of the cytoskeletal adaptor ZO-1 and the JAM-A intracellular domain becomes dramatically weaker in response to ∼2 pN of load, the amount generated by single molecules of the cytoskeletal motor protein myosin II. Thus, physiologically relevant forces can exert dramatic and opposite effects on the stability of two of the major linkages between cell-cell adhesion proteins and the F-actin cytoskeleton. Our data demonstrate that that PDZ domains can serve as force-responsive mechanical anchors at cell-cell adhesion complexes. More broadly, our findings suggest that mechanical force may serve as a previously unsuspected regulator of the hundreds of PDZ-ligand interactions present in animal cells.
The impact of multiband and in-plane acceleration on white matter microstructure analysis
Authors: Zhang Zhengwu , Venkataraman Arun , Cole Martin , Ye Tianrui , Qiu Deqiang , Lin Feng V. , Risk Benjamin B. 
Published: September 2023

AbstractAccelerated imaging has been broadly adopted in diffusion MRI studies, yet little is known about its impacts. Acceleration can achieve higher spatial and q-space resolution in shorter time, reduce motion artifacts, and reduce patient burden. However, it leads to noise amplification, and its impacts in clinical cohorts are poorly understood. This study examined the impact of multiband (also called simultaneous multislice, or SMS) and in-plane acceleration (IPA, also called phase acceleration) in diffusion imaging in forty older adults differing in cognitive status. We evaluated a total of 400 scans from five acquisitions: no acceleration (S1P1); SMS=3 with no in-plane acceleration (S3P1); SMS=3 with IPA=2 (S3P2); S6P1; and S6P2. The number of diffusion directions and b-values was kept constant such that acquisition times varied from 21:28 to 3:56. We found that diffusion metrics were highly sensitive to acceleration factor, with a trend towards higher fractional anisotropy (FA) and lower orientation dispersion (OD) with acceleration. The differences between accelerated and unaccelerated acquisitions could be partly explained by the noise amplification (g-factor) and reduced motion. Intraclass correlations (ICCs) of FA and OD in white matter were excellent in both S1P1 and S3P1 (median >0.8), good but lower in S3P2 and S6P1 (medians around 0.70), and poor to fair in S6P2 (medians 0.46 and 0.57). In-plane acceleration decreased ICC, including areas of high susceptibility distortion. In a comparison of mild cognitive impairment versus healthy controls, acceleration tended to reduce group differences, particularly in the fornix, with greater costs in OD than FA. Our results provide guidance regarding the costs of acceleration (possible biases and reduced effect sizes) while also characterizing the benefits (reduced motion, good reliability at higher multiband with no in-plane).
Target gene regulatory network of miR-497 in angiosarcoma
Authors: Benton Annaleigh , Terwilliger Emma , Moriarty Noah M. , Liu Bozhi , Murphy Ant , Maluvac Hannah , Shu Mae , Gartenhaus Lauren E. , Janson Nimod D. , Pfeffer Claire M. , Utturkar Sagar M. , Parkinson Elizabeth I. , Lanman Nadia A. , Hanna Jason A. 
Published: September 2023

ABSTRACTAngiosarcoma (AS) is a vascular sarcoma that is highly aggressive and metastatic. Due to its rarity, treatment options for patients are limited, therefore more research is needed to identify possible therapeutic vulnerabilities. We previously found that conditional deletion ofDicer1drives AS development in mice. Given the role of DICER1 in canonical microRNA (miRNA) biogenesis, this suggests that miRNA loss is important in AS development. After testing miRNAs previously suggested to have a tumor-suppressive role in AS, microRNA-497-5p (miR-497) suppressed cell viability most significantly. We also found that miR-497 overexpression led to significantly reduced cell migration and tumor formation. To understand the mechanism of miR-497 in tumor suppression, we identified clinically relevant target genes using a combination of RNA-sequencing data in an AS cell line, expression data from AS patients, and target prediction algorithms. We validated miR-497 direct regulation of CCND2, CDK6, and VAT1. One of these genes, VAT1, is an understudied protein that has been suggested to promote cell migration and metastasis in other cancers. Indeed, we find that pharmacologic inhibition of VAT1 with the natural product Neocarzilin A reduces AS migration. This work provides insight into the mechanisms of miR-497 and its target genes in AS pathogenesis.
The determinants of the rarity of nucleic and peptide short sequences in nature
Authors: Chantzi Nikol , Mouratidis Ioannis , Mareboina Manvita , Konnaris Maxwell A. , Montgomery Austin , Georgakopoulos-Soares Ilias 
Published: September 2023

AbstractThe prevalence of nucleic and peptide short sequences across organismal genomes and proteomes has not been thoroughly investigated. Here we examined 45,785 reference genomes and 21,871 reference proteomes, spanning archaea, bacteria, viruses and eukaryotes to calculate the rarity of short sequences in them. To capture this, we developed a metric of the rarity of each sequence in nature, the Anti-Kardashian index. We find that the frequency of certain dipeptides in rare oligopeptide sequences is hundreds of times lower than expected, which is not the case for any dinucleotides. We also generate predictive regression models that infer the rarity of nucleic and proteomic sequences in nature. For six-mer peptide kmers the R2performance of the regression models based on amino acid and dipeptide content is 0.816, whereas models based on physicochemical features achieve an R2of 0.788. For twelve-mer nucleic kmers the R2performance of our models based on mono and dinucleotides is 0.481. Our results indicate that the mono and dinucleotide composition of nucleic sequences and the amino acids, dipeptides and physicochemical properties of peptide sequences can explain a significant proportion of the variance in their frequencies between organisms in nature.
The genetic architecture of polygenic local adaptation and its role in shaping barriers to gene flow
Authors: Zwaenepoel Arthur , Sachdeva Himani , Fraïsse Christelle 
Published: September 2023

AbstractWe consider how the genetic architecture underlying locally adaptive traits determines the strength of a barrier to gene flow in a mainland-island model. Assuming a general life cycle, we derive an expression for the effective migration rate when local adaptation is due to a polygenic trait under directional selection on the island, allowing for arbitrary fitness and dominance effects across loci. We show how the effective migration rate can be combined with classical single-locus diffusion theory to accurately predict multilocus differentiation between the mainland and island at migration-selection-drift equilibrium and determine the migration rate beyond which local adaptation collapses, while accounting for genetic drift and weak linkage. Using our efficient numerical tools, we then present a detailed study of the effects of dominance on barriers to gene flow, showing that when total selection is sufficiently strong, more recessive local adaptation generates stronger barriers to gene flow. We show that details of the haplodiplontic life cycle can be captured using a set of effective parameters, and consider how the relative strength of selection in the two phases affects barriers to gene flow. We then study how heterogeneous genetic architectures of local adaptation affect barriers to gene flow, characterizing adaptive differentiation at migration-selection balance for different distributions of fitness effects. We find that a more heterogeneous genetic architecture generally yields a stronger genome-wide barrier to gene flow and that the detailed genetic architecture underlying locally adaptive traits can have an important effect on observable differentiation when divergence is not too large. Lastly, we study the limits of our approach as loci become more tightly linked, showing that our predictions remain accurate over a large biologically relevant domain.
ASBAR: an Animal Skeleton-Based Action Recognition framework. Recognizing great ape behaviors in the wild using pose estimation with domain adaptation
Authors: Fuchs Michael , Genty Emilie , Zuberbühler Klaus , Cotofrei Paul 
Published: September 2023

AbstractTo date, the investigation and classification of animal behaviors have mostly relied on direct human observations or video recordings with posthoc analysis, which can be labor-intensive, time-consuming, and prone to human bias. Recent advances in machine learning for computer vision tasks, such as pose estimation and action recognition, thus have the potential to significantly improve and deepen our understanding of animal behavior. However, despite the increased availability of open-source toolboxes and large-scale datasets for animal pose estimation, their practical relevance for behavior recognition remains under-explored. In this paper, we propose an innovative framework,ASBAR, forAnimal Skeleton-Based Action Recognition, which fully integrates animal pose estimation and behavior recognition. We demonstrate the use of this framework in a particularly challenging task: the classification of great ape natural behaviors in the wild. First, we built a robust pose estimator model leveraging OpenMonkeyChallenge, one of the largest available open-source primate pose datasets, through a benchmark analysis on several CNN models from DeepLabCut, integrated into our framework. Second, we extracted the great ape’s skeletal motion from the PanAf dataset, a large collection of in-the-wild videos of gorillas and chimpanzees annotated for natural behaviors, which we used to train and evaluate PoseConv3D from MMaction2, a second deep learning model fully integrated into our framework. We hereby classify behaviors into nine distinct categories and achieve a Top 1 accuracy of 74.98%, comparable to previous studies using video-based methods, while reducing the model’s input size by a factor of around 20. Additionally, we provide an open-source terminal-based GUI that integrates our full pipeline and release a set of 5,440 keypoint annotations to facilitate the replication of our results on other species and/or behaviors. All models, code, and data can be accessed at:https://github.com/MitchFuchs/asbar.Author summaryThe study of animal behaviors has mostly relied on human observations and/or video analysis traditionally. In this paper, we introduce a new framework calledASBAR(forAnimal Skeleton-Based Action Recognition) that integrates recent advances in machine learning to classify animal behaviors from videos. Compared to other methods that use the entire video information, our approach relies on the detection of the animal’s pose (e.g., position of the head, eyes, limbs) from which the behavior can be recognized. We demonstrate its successful application in a challenging task for computers as it classifies nine great ape behaviors in their natural habitat with high accuracy. To facilitate its use for other researchers, we provide a graphical user interface (GUI) and annotated data to replicate our results for other animal species and/or behaviors.