bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomechanical Investigation of the Osseointegration of Titanium Implants With Different Surfaces Placed With Allogeneic Bone Transfer
Authors: Özcan Erhan Cahit , Aydin Melek Atille , Dundar Serkan , Tanrisever Murat , Bal Ali , Karasu Necmettin , Kirtay Mustafa
Published: May 2024

Allogeneic grafts can be preferred to autogenous grafts in plastic and oral-maxillofacial surgery for vertical and horizontal bone deficiencies. Implant surface properties are an important factor in osseointegration. This study aims to evaluate the osseointegration levels of titanium implants with machined, sand-blasted, and acid-etched (SLA) and resorbable blast material (RBM) surfaces placed together with allogeneic bone tissue transplantations obtained from the tibia bone using biomechanical method. Twenty-five female Sprague-Dawley rats were included in the study. The rats were divided into groups in which machined (n=7), SLA (n=7), and RBM (n=7) surface implants were placed with the transplantation of bone taken from the tibia. Four rats (both left and right tibias) were used as donors. Grafts and implants were surgically placed in the corticocancellous part of the metaphyseal area of the tibia bones of rats. At the end of the 4-week experimental setup, all rats were killed, and the implants and surrounding bone tissue were subjected to biomechanical reverse torque analysis (N/cm). Sand-blasted acid-etched surface implants were observed to have higher biomechanical osseointegration levels than RBM and machined surface implants (P<0.05). No statistical difference could be detected between the RBM and machined surface implants (P>0.05). On the basis of the limited results of this study, it can be concluded that the osseointegration levels of SLA surface implants placed with allogeneic bone transplantation may be better than those of machined and RBM surface implants.
Condylar Shave For the Treatment of Active Condylar Growth Excess
Authors: Obwegeser Joachim A. , Burkhard John-Patrik M.
Published: May 2024

The authors present a novel approach for addressing excessive condylar growth in individuals exhibiting asymmetric mandibular growth patterns.
Levodopa infusion therapies for Parkinson disease
Authors: Dean Marissa N. , Standaert David G.
Published: May 2024

Purpose of review

to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD).

Recent findings

Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing ‘off’ time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce ‘off’ time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site.

Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.
Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution
Authors: Gong Yun , Haeri Mohammad , Zhang Xiao , Li Yisu , Liu Anqi , Wu Di , Zhang Qilei , Jazwinski S. Michal , Zhou Xiang , Wang Xiaoying , Jiang Lindong , Chen Yi-Ping , Yan Xiaoxin , Swerdlow Russell H. , Shen Hui , Deng Hong-Wen
Published: May 2024

Aging significantly elevates the risk for Alzheimer’s disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.
Genome-wide association study reveals shared and distinct genetic architecture underlying fatty acid and bioactive oxylipin metabolites in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Downie Carolina G. , Highland Heather M. , Alotaibi Mona , Welch Barrett M. , Howard Annie Green , Cheng Susan , Miller Nick , Jain Mohit , Kaplan Robert C. , Lilly Adam G. , Long Tao , Sofer Tamar , Thyagarajan Bharat , Yu Bing , North Kari E. , Avery Christy L.
Published: May 2024

Bioactive fatty acid-derived oxylipin molecules play key roles in mediating inflammation and oxidative stress, which underlie many chronic diseases. Circulating levels of fatty acids and oxylipins are influenced by both environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biological pathways. Thus, we performed a genome wide association study (GWAS) of n=81 fatty acids and oxylipins in n=11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years, standard deviation = 13.8 years). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Heritability estimates ranged from 0% to 47.9%, and 48 of the 81oxylipins and fatty acids were significantly heritable. Moreover, 40 (49.4%) of the 81 oxylipins and fatty acids had at least one genome-wide significant (p< 6.94E-11) variant resulting in 19 independent genetic loci involved in fatty acid and oxylipin synthesis, as well as downstream pathways. Four loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including the desaturase-encodingFADSand the OATP1B1 transporter protein-encodingSLCO1B1, exhibited associations with four or more fatty acids and oxylipins. The majority of the 15 remaining loci (87.5%) (lead variant MAF range = 0.03-0.45, mean = 0.23) were only associated with one oxylipin or fatty acid, demonstrating evidence of distinct genetic effects. Finally, while most loci identified in two-degree-of-freedom tests were previously identified in our main effects analyses, we also identified an additional rare variant (MAF = 0.002) nearCARS2, a locus previously implicated in inflammation. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating future multi-omics work to characterize these compounds and elucidate their roles in disease pathways.
Frequency-Dependent Inter-Brain Synchrony is Modulated by Social Interaction in Freely Moving Mice
Authors: Scaglione Alessandro , Lucchesi Jessica , Mascaro Anna Letizia Allegra , Pavone Francesco Saverio
Published: May 2024

Social interaction, a pivotal aspect of human and animal behavior, involves a dynamic exchange of information that shapes behavioral responses, emotional states, and cognitive processes. To gain insights into the neural mechanisms underlying these processes, it is necessary to simultaneously investigate the brain activity of socially interacting subjects. Commonly, the simultaneous study of behavior and brain activity during the execution of social tasks is conducted through Hyperscanning in humans which limits the availability of interventions. Here we describe a new experimental platform that combines the development of a new miniaturized optical system, the “MiCe-μScope”, to monitor neural activity across the entire cortical mantle with a behavioral paradigm to perform a Hyperscanning study in freely moving mice engaged in social interaction. Our results revealed inter-brain synchrony across different frequency bands widespread over the entire cortical mantle, modulated by social behavior. This finding suggests that synchronization reflects the mutual prediction performed by the entire cortex in mice of interacting dyads. The presence of different synchronization maps in these frequency bands suggests a multiscale nature of interaction, extending the predictive nature of interaction to cortical areas beyond the medial prefrontal cortex. Our work provides an experimental framework to conduct Hyperscanning studies in an animal model that mirrors findings from human studies.
Functional MRI reveals that subcortical auditory push-pull interactions rely on intercollicular integrity
Authors: Severo Frederico , Valente Mafalda , Shemesh Noam
Published: May 2024

The role of subcortical structures in binaural integration is of great interest for auditory processing. The inferior colliculus (IC) is the main auditory midbrain center where ascending and descending auditory projections converge, which was suggested to encode auditory information via a push-pull mechanism between the two ICs. However, the origin of this push-pull mechanism in the brain and how it interacts with other upstream/downstream subcortical areas is still a matter of great debate. Here, we harness functional MRI (fMRI) in combination with IC lesions in the rat to dissect the push-pull interaction from a pathway-wide perspective. We find evidence for the push-pull mechanism in IC through negative/positive fMRI signals in the ipsilateral/contralateral ICs upon monaural stimulation. By unilaterally lesioning the corresponding contralateral IC, we demonstrate the necessity of collicular integrity and intercollicular interactions for the push-pull interaction. Using binaural stimulation and IC lesions, we show that the push-pull interaction is exerted also in binaural processing. Finally, we demonstrate that, at least at the population level revealed by fMRI, the main push-pull interactions occur first at the IC level, and not earlier, and that the outcome of the push-pull “calculation” is relayed downstream to MGB. This dissection of the push-pull interaction sheds light into subcortical auditory function.
Clockwork Orangutan: microRNAs, thermoregulatory tradeoffs, and the evolution of brain size
Authors: Fromm Bastian , Sorger Thomas
Published: May 2024

Models of brain size evolution have not accounted for the thermoregulatory adaptations underlying the 4-fold increase in brain metabolic rate (MR) in hominid apes. Like earlier increases in whole-bodyMR, the advent of placentation and permanent homeothermy, the divergence of Catarrhini coincided with an adaptive increase in the number of microRNA families (mirFam). We demonstrate in mammals that the size of the brain, the primary consumer of glucose, and the liver, the primary organ of gluconeogenesis, vary inversely relative to a thermogenic Core (kidney + heart + liver + brain). The cellularMR(cMR) of the liver, scaled in proportion tomirFam, varied inversely with body size and thecMRs of kidney, heart and brain. WithmirFamas a proxy for energy reliability, a logistic feedback model of relative brain size detected adaptation to a low-energy regime among the smallest primates and, among the largest primates, adaptation to the physiological limit on the rate of heat dissipation.
Using physiologically-based models to predictin vivoskeletal muscle energetics
Authors: Konno Ryan N. , Lichtwark Glen A. , Dick Taylor J. M.
Published: May 2024

Understanding how muscles use energy is essential for elucidating the role of skeletal muscle in animal locomotion. Yet, experimental measures ofin vivomuscle energetics are challenging to obtain, so physiologically-based muscle models are often used to estimate energy use. These predictions of individual muscle energy expenditure are not often compared to indirect whole body measures of energetic cost. Here, we examined and illustrated the capability of physiologically-based muscle models to predictin vivomeasures of energy use. To improve model predictions and ensure a physiological basis for model parameters, we refined our model to include data from isolated muscle experiments. Simulations were performed to capture three different experimental protocols, which involved varying contraction frequency, duty cycle, and muscle fascicle length. Our results demonstrated that these models are able capture the general features of whole body energetics across contractile conditions, but tended to under predict the magnitude of energetic cost. Our analysis revealed that when predictingin vivoenergetic rates across contractile conditions, the model was most sensitive to the force-velocity parameters and the data informing the energetic rates when predictingin vivoenergetic rates across contractile conditions. This work highlights it is the mechanics of skeletal muscle contraction that govern muscle energy use.
Enhanced dynamic covalent chemistry for the controlled release of small molecules and biologics from a nanofibrous peptide hydrogel platform
Authors: Pogostin Brett H. , Wu Samuel X. , Swierczynski Michael J. , Pennington Christopher , Li Si-Yang , Vohidova Dilrasbonu , Seeley Erin H. , Agrawal Anushka , Tang Chaoyang , Cabler Jacob , Dey Arghadip , Veiseh Omid , Nuermberger Eric L. , Ball Zachary T. , Hartgerink Jeffrey D. , McHugh Kevin J.
Published: May 2024

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventingMycobacterium tuberculosisgrowth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.
Autophagy suppression in DNA damaged cells occurs through a newly identified p53-proteasome-LC3 axis
Authors: Lieu D’Feau J. , Crowder Molly K. , Kryza Jordan R. , Tamilselvam Batcha , Kaminski Paul J. , Kim Ik-Jung , Li Yingxing , Jeong Eunji , Enkhbaatar Michidmaa , Chen Henry , Son Sophia B. , Mok Hanlin , Bradley Kenneth A. , Phillips Heidi , Blanke Steven R.
Published: May 2024

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and anex vivoorganoid model. Our data indicate that suppression of autophagy, through a newly identified p53-proteasome-LC3 axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could potentially be important for realigning proteostasis in cells undergoing DNA damage repair.
Cardiac hemodynamics computational modeling including chordae tendineae, papillaries, and valves dynamics
Authors: Crispino Andrea , Bennati Lorenzo , Vergara Christian
Published: May 2024

In the context of dynamic image-based computational fluid dynamics (DIB-CFD) modeling of cardiac system, the role of sub-valvular apparatus (chordae tendineae and papillary muscles) and the effects of different mitral valve (MV) opening/closure dynamics, have not been systemically determined. To provide a partial filling of this gap, in this study we performed DIB-CFD numerical experiments in the left ventricle, left atrium and aortic root, with the aim of highlighting the influence on the numerical results of two specific modeling scenarios: i) the presence of the sub-valvular apparatus, consisting of chordae tendineae and papillary muscles; ii) different MV dynamics models accounting for different use of leaflet reconstruction from imaging.

This is performed for one healthy and one MV regurgitant subjects. Specifically, a systolic wall motion is reconstructed from time-resolved Cine-MRI images and imposed as boundary condition for the CFD numerical simulation.

Analyzing the numerical results, we found that sub-valvular apparatus do not affect the global fluid dynamics quantities, although it creates local variations, such as the developing of vortexes or flow disturbances, which lead to different stress distributions on cardiac structures.

Moreover, different MV dynamics are considered starting from Cine-MRI MV segmentation at different temporal configurations, and then they are compared and managed numerically through a resistive approach. The obtained results highlight the importance of including a sophisticated diastolic model of MV dynamics, which accounts for MV geometries during diastasis and A-wave, in terms of describing the disturbed flow and ventricular turbulence.

Statements and Declarations

The authors have no relevant financial or non-financial interests to disclose.
Exploring changes in social spider DNA methylation profiles when succumbing to infection in CpG, CHG, and CHH contexts
Authors: Fisher David N. , Bechsgaard Jesper , Bilde Trine
Published: May 2024

Living at high density and with low genetic diversity are factors that should both increase the susceptibility of organisms to disease. Therefore, group living organisms, especially those that are inbred, should be especially vulnerable to infection and therefore have particular strategies to cope with infection. Phenotypic plasticity, underpinned by epigenetic changes, could allow group living organisms to rapidly respond to infection challenges. To explore the potential role of epigenetic modifications in the immune response to a group-living species with low genetic diversity, we compared the genome-wide DNA methylation profiles of five colonies of social spiders (Stegodyphus dumicola) in their natural habitat in Namibia at the point just before they succumbed to infection to a point at least six months previously where they were presumably healthier. We found increases in genome- and chromosome-wide methylation levels in the CpG, CHG, and CHH contexts, although the genome-wide changes were not clearly different from zero. These changes were most prominent in the CHG context, especially at a narrow region of chromosome 13, hinting at an as-of-yet unsuspected role of this DNA methylation context in phenotypic plasticity. However, there were few clear patterns of differential methylation at the base level, and genes with a known immune function in spiders had mean methylation changes close to zero. Our results suggest that DNA methylation may change with infection at large genomic scales, but that this type of epigenetic change is not necessarily integral to the immune response of social spiders.
Estimating full-field displacement in biological images using deep learning
Authors: Warsop Solomon J. E. T. , Caixeiro Soraya , Bischoff Marcus , Kursawe Jochen , Bruce Graham D. , Wijesinghe Philip
Published: May 2024

The estimation of full-field displacement between biological image frames or in videos is important for quantitative analyses of motion, dynamics and biophysics. However, the often weak signals, poor biological contrast and many noise processes typical to microscopy make this a formidable challenge for many contemporary methods. Here, we present a deep-learning method, termed Displacement Estimation FOR Microscopy (DEFORM-Net), that outperforms traditional digital image correlation and optical flow methods, as well as recent learned approaches, offering simultaneous high accuracy, spatial sampling and speed. DEFORM-Net is experimentally unsupervised, relying on displacement simulation based on a random fractal Perlin-noise process and optimised training loss functions, without the need for experimental ground truth. We demonstrate its performance on real biological videos of beating neonatal mouse cardiomyocytes and pulsed contractions inDrosophilapupae, and in various microscopy modalities. We provide DEFORM-Net as open source, including inference in the ImageJ/FIJI platform, for rapid evaluation, which will empower new quantitative applications in biology and medicine.
Disentangling acute motor deficits and adaptive responses evoked by the loss of cerebellar output
Authors: Sinha Nirvik , Israely Sharon , Ben Harosh Ora , Harel Ran , Dewald Julius , Prut Yifat
Published: May 2024

Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains uncertain. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing strategy designed to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered compensatory control strategy for managing impaired limb dynamics. Additionally, impaired feedforward control elevates motor noise, which cannot be entirely mitigated through compensatory strategies.
Analyzing high-throughput assay data to advance the rapid screening of environmental chemicals for human reproductive toxicity
Authors: Varshavsky Julia R. , Lam Juleen , Cooper Courtney , Allard Patrick , Fung Jennifer , Oke Ashwini , Kumar Ravinder , Robinson Joshua F. , Woodruff Tracey J.
Published: May 2024

While high-throughput (HTP) assays have been proposed as platforms to rapidly assess reproductive toxicity, there is currently a lack of established assays that specifically address germline development/function and fertility. We assessed the applicability domains of yeast (S. cerevisiae)and nematode(C. elegans)HTP assays in toxicity screening of 124 environmental chemicals, determining their agreement in identifying toxicants and their concordance with reproductive toxicityin vivo. We integrated data generated in the two models and compared results using a streamlined, semi-automated benchmark dose (BMD) modeling approach. We then extracted and modeled relevant mammalianin vivodata available for the matching chemicals included in the Toxicological Reference Database (ToxRefDB). We ranked potencies of common compounds using the BMD and evaluated correlation between the datasets using Pearson and Spearman correlation coefficients. We found moderate to good correlation across the three data sets, with r = 0.48 (95% CI: 0.28–1.00, p<0.001) and rs= 0.40 (p=0.002) for the parametric and rank order correlations between the HTP BMDs; r = 0.95 (95% CI: 0.76–1.00, p=0.0005) and rs= 0.89 (p=0.006) between the yeast assay and ToxRefDB BMDs; and r = 0.81 (95% CI: 0.28–1.00, p=0.014) and rs= 0.75 (p=0.033) between the worm assay and ToxRefDB BMDs. Our findings underscore the potential of these HTP assays to identify environmental chemicals that exhibit reproductive toxicity. Integrating these HTP datasets into mammalianin vivoprediction models using machine learning methods could further enhance the predictive value of these assays in future rapid screening efforts.
Characterizing the Role of EndocarpAandBCells Layers During Pod (silique) Development in Brassicaceae
Authors: Nichol Justin B. , Samuel Marcus A.
Published: May 2024

The process of silique dehiscence is essential for proper dispersal of seeds at the end of a plant’s lifecycle. Current research focuses on genetic manipulation to mitigate this process and enhance shatter tolerance in crop plants, which has significant economic implications. In this study, we have conducted a time-course analysis of cell patterning and development in valve tissues ofArabidopsis thalianaand closely related Triangle of U species from Brassicaceae. The goal was to decipher the detailed temporal developmental patterns of the endocarp a and b cell layers of the valve, specifically their degradation and lignification respectively. Additionally, we propose a new classification system for the lignification of the endocarp a cell layer: L1 indicates the cell closest to the replum, with L2 and L3 representing the second and third cells, respectively, each numerical increment indicating lignified cells farther from the replum. Our findings provide a foundational framework absent in current literature, serving as an effective blueprint for future genomic work aimed at modifying valve structures to enhance agronomic traits, such as reducing fiber (lignin) or increasing shatter tolerance.
Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality
Authors: Li Yue , Xie Long , Khandelwal Pulkit , Wisse Laura E. M. , Brown Christopher A. , Prabhakaran Karthik , Tisdall M. Dylan , Mechanic-Hamilton Dawn , Detre John A. , Das Sandhitsu R. , Wolk David A. , Yushkevich Paul A.
Published: May 2024

Background

Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer’s disease. However, image quality may vary in MRI. Poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as “modalities” here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poorquality images.

Method

MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer’s Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. To compare our proposed model with a baseline single-modality model in the full dataset with mixed high/poor image quality, we evaluated the ability of derived volume/thickness measures to discriminate Amyloid+ mild cognitive impairment (A+MCI) and Amyloid-cognitively unimpaired (A-CU) groups, as well as the stability of these measurements in longitudinal data.

Results

The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images.

Conclusion

The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.
Heterotrimeric Collagen Helix with High Specificity of Assembly Results in a Rapid Rate of Folding
Authors: Cole Carson C. , Walker Douglas R. , Hulgan Sarah A.H. , Pogostin Brett H. , Swain Joseph W.R. , Miller Mitchell D. , Xu Weijun , Duella Ryan , Misiura Mikita , Wang Xu , Kolomeisky Anatoly B. , Phillips George N. , Hartgerink Jeffrey D.
Published: May 2024

The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood and have not been studied. This work compares three heterotrimeric collagen mimics’ stabilities, specificities and folding rates. One of these was designed through a computational-assisted approach, resulting in a well-controlled composition and register, in addition to providing increased amino acid diversity and excellent specificity. The crystal structure of this heterotrimer elucidates the composition, register and geometry of pairwise cation-π and axial and lateral salt bridges. Complementary experimental methods of circular dichroism and NMR suggest the folding paradigm is frustrated by unproductive, competing heterotrimer species and these species must completely unwind to the monomeric state before refolding into the thermodynamically favored assembly. This collagen heterotrimer, which displays the best reported thermal specificity, was also found to fold much faster (hours vs days) than comparable, well-designed systems. The heterotrimeric collagen folding rate was observed to be both concentration and temperature-independent, suggesting a complex, multi-step mechanism. These results suggest heterotrimer folding kinetics are dominated by frustration of the energy landscape caused by competing triple helices.
Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points
Authors: Soelter Tabea M. , Howton Timothy C. , Wilk Elizabeth J. , Whitlock Jordan H. , Clark Amanda D. , Birnbaum Allison , Patterson Dalton C. , Cortes Constanza J. , Lasseigne Brittany N.
Published: May 2024

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-β plaque and intracellular neurofibrillary tangles of phosphorylated tau, along with neuronal loss. While neuronal loss is an AD hallmark, cell-cell communication between neuronal and non-neuronal cell populations maintains neuronal health and brain homeostasis. To study changes in cellcell communication during disease progression, we performed snRNA-sequencing of the hippocampus from female 3xTg-AD and wild-type littermates at 6 and 12 months. We inferred differential cell-cell communication between 3xTg-AD and wild-type mice across time points and between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) of interest. We also assessed the downstream effects of altered glia-neuron communication using pseudobulk differential gene expression, functional enrichment, and gene regulatory analyses. We found that glia-neuron communication is increasingly dysregulated in 12-month 3xTg-AD mice. We also identified 23 AD-associated ligand-receptor pairs that are upregulated in the 12-month-old 3xTg-AD hippocampus. Our results suggest increased AD association of interactions originating from microglia. Signaling mediators were not significantly differentially expressed but showed altered gene regulation and TF activity. Our findings indicate that altered glia-neuron communication is increasingly dysregulated and affects the gene regulatory mechanisms in neurons of 12-month-old 3xTg-AD mice.
Comparative and population genomics analyses of eared pheasants inhabiting highly varying altitudes
Authors: Wu Siwen , Wang Kun , Ge Xuehai , Yuan Sisi , Wu Dong-Dong , Ge Changrong , Jia Junjing , Su Zhengchang , Dou Tengfei
Published: May 2024

Oxygen pressure varies dramatically with altitudes on Earth; however, humans and animals thrive at almost all altitudes. To better understand genetic basis underlying adaptation of closely related species to varying altitudes, we annotated and compared the genome of a white eared pheasant (WT) (Crossoptilon crossoptilon) inhabiting high altitudes and the genome of a brown eared pheasant (BR) (C. mantchuricum) inhabiting low altitudes, and found that the WT genome harbors 967 more genes but 457 fewer pseudogenes than the BR genome. Moreover, we compared genetic variations in populations of WT and BR as well as of blue eared pheasants (BL) (C. auritum) inhabiting intermediate altitudes, and identified thousands of selective sweeps in each species. Intriguingly, the unique genes and pseudogenes in the two genomes converge on the same set of altitude adaptation-related pathways of four functional categories as genes in selective sweeps in each species. Thus, these species appear to adapt to highly varying altitudes by diverging selection on the same traits via loss-of-function mutations and fine-tuning genes in common pathways.
Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens
Authors: Wu Daichao , Yin Rui , Chen Guodong , Ribeiro-Filho Helder V. , Cheung Melyssa , Robbins Paul F. , Mariuzza Roy A. , Pierce Brian G.
Published: May 2024

T cell receptors (TCRs) that recognize cancer neoantigens are important for anti-cancer immune responses and immunotherapy. Understanding the structural basis of TCR recognition of neoantigens provides insights into their exquisite specificity and can enable design of optimized TCRs. We determined crystal structures of a human TCR in complex with NRAS Q61K and Q61R neoantigen peptides and HLA-A1 MHC, revealing the molecular underpinnings for dual recognition and specificity versus wild-type NRAS peptide. We then used multiple versions of AlphaFold to model the corresponding complex structures, given the challenge of immune recognition for such methods. Interestingly, one implementation of AlphaFold2 (TCRmodel2) was able to generate accurate models of the complexes, while AlphaFold3 also showed strong performance, although success was lower for other complexes. This study provides insights into TCR recognition of a shared cancer neoantigen, as well as the utility and practical considerations for using AlphaFold to model TCR–peptide–MHC complexes.
Soluble immune mediators orchestrate protective in vitro granulomatous responses across Mycobacterium tuberculosis complex lineages
Authors: Arbues Ainhoa , Schmidiger Sarah , Reinhard Miriam , Borrell Sonia , Gagneux Sebastian , Portevin Damien
Published: May 2024

The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise ten phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets - a phenotype associated with dormancy - that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B and TNF-alpha. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
Cardiolipin clustering promotes mitochondrial membrane dynamics
Authors: Zuccaro Kelly E. , Abriata Luciano A. , Meireles Fernando Teixeira Pinto , Moss Frank R. , Frost Adam , Dal Peraro Matteo , Aydin Halil
Published: May 2024

Cardiolipin (CL) is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which CL influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics (MD) simulations, we observed CL localize near the membrane-binding sites of the mitochondrial fusion protein Optic Atrophy 1 (OPA1). To validate these findings experimentally, we developed a bromine-labeled CL probe to enhance cryoEM contrast and characterize the structure of OPA1 assemblies bound to the CL-brominated lipid bilayers. Our images provide direct evidence of interactions between CL and two conserved motifs within the paddle domain (PD) of OPA1, which control membrane-shaping mechanisms. We further observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin (MLCL). Suggesting that the partial replacement of CL by MLCL accumulation, as observed in Barth syndrome-associated mutations of the tafazzin phospholipid transacylase, compromises the stability of protein-membrane interactions. Our analyses provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

Teaser

This study reveals how CL modulates the activity of OPA1 and how MLCL impacts its ability to govern mitochondrial function.
Turgor pressure affects transverse stiffness and resonant frequencies of buzz-pollinated poricidal anthers
Authors: Alvord Mitchell , McNally Jenna , Casey Cailin , Jankauski Mark
Published: May 2024

Several agriculturally valuable plants store their pollen in tube-like poricidal anthers, which release pollen through buzz pollination. In this process, bees rapidly vibrate the anther using their indirect flight muscles. The stiffness and resonant frequency of the anther are crucial for effective pollen release, yet the impact of turgor pressure on these properties is not well understood. Here, we perform three-point flexure tests and experimental modal analysis to determine anther transverse stiffness and resonant frequency, respectively. Dynamic nanoindentation is used to identify the anther’s storage modulus as a function of excitation frequency. We subsequently develop mathematical models to estimate how turgor pressure changes after the anther is removed from a flower, thereby emulating zero water availability. We find that 30 minutes post-ablation, anther stiffness decreases 60%. Anther resonant frequency decreases 20% 60 minutes post-ablation. Models indicate turgor pressure in the fresh anther is about 0.2 – 0.3 MPa. Our findings suggest that natural fluctuations in turgor pressure due to environmental factors like temperature and light intensity may require bees to adjust their foraging behaviors. Interestingly, anther storage modulus increased with excitation frequency, underscoring the need for more sophisticated mechanical models that consider viscous fluid transport through plant tissue moving forward.
Massively parallel screening of TIR-derived peptides reveals vast TLR-targeting immunomodulatory peptides
Authors: Lim Yun , Kang Tae Kyeom , Kim Meong Il , Kim Dohyeon , Kim Ji-Yul , Jung Sang Hoon , Park Keunwan , Lee Wook-Bin , Seo Moon-Hyeong
Published: May 2024

Toll-like receptors (TLRs) are critical regulators of the immune system, and altered TLR responses lead to a variety of inflammatory diseases. Interference of intracellular TLR signaling, which is mediated by multiple Toll/interleukin-1 receptor (TIR) domains on all TLRs and TLR adapters, is an effective therapeutic strategy against immune dysregulation. Peptides that inhibit TIR-TIR interactions by fragmenting interface residues have potential as therapeutic decoys. However, a systematic method for discovering TIR-targeting moieties has been elusive, limiting exploration of the vast unsequenced space of the TIR domain family. Here, we developed a comprehensive parallel screening method to uncover novel TIR-binding peptides derived from previously unexplored surfaces on a wide range of TIR domains. We constructed a large peptide library, named TIR surfacesome, by tiling surface sequences of the large TIR domain family and screening against MALTIRand MyD88TIR, TIRs of two major TLR adaptor proteins, resulting in the discovery of hundreds of TIR-binding peptides. The selected peptides inhibited TLR signaling, demonstrated anti-inflammatory effects in macrophages and therapeutic potential in mouse inflammatory models. This approach may facilitate the development of TLR-targeted therapeutics.
A pilot dose-finding study of Terazosin in humans
Authors: Schultz Jordan L. , Gander Phillip E. , Workman Craig D. , Ponto Laura L. , Cross Stephen , Nance Christopher S. , Groth Christopher L. , Taylor Eric B. , Ernst Sarah E. , Xu Jia , Uc Ergun Y. , Magnotta Vincent A. , Welsh Michael J. , Narayanan Nandakumar S.
Published: May 2024

Background

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects.

Methods

Eighteen healthy men and women (60 – 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels,31Phosphorous magnetic resonance spectroscopy for brain ATP levels,18F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics.

Results

Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral18F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response.

Conclusions

TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ’s efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.