bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-Concussion Assessment as a diagnostic and mechanistic framework for treating patients with Long COVID
Authors: Davidson Bradley S. , Noteboom Lily , Pierro Hannah , Kantor Cayce , Stoot Daniel , Stoot Fred , Linseman Daniel , Hale Troy , Gorgens Kim 
Published: September 2022

AbstractIntroductionDespite first coming into view over two years ago, effective diagnostic and treatment pathways for Long COVID continue to evade the medical community. The overlap in neurological-based symptoms and neuroinflammatory origin indicates that the framework of post-concussion syndrome may provide insight into new diagnostics and treatment for patients with Long COVID. The objective of this investigation was to determine whether tools from the four common domains of concussion assessment were sensitive to differentiate between patients with Long COVID from a reference group who was infected with Sars-CoV-2 and does not have Long COVID.MethodsIn this prospective cohort design, each participant self reported their group (Acute, n=28) and Long COVID Group (n=33). Each participant underwent an examination in four assessment categories: symptoms, vestibular nystagmography, Automated Neuropsychological Assessment Metrics (ANAM), and a series of balance tasks.ResultsTotal Symptom scores were separated into functional classifications and showed clear success as a tool to differentiate between Acute and Long COVID. Five of the 33 people in the Long COVID had detectable central lesions, which increases the risk of developing long COVID by 64% (Relative Risk=1.64). A wide variety of objective and quantitative measures from post-concussion care are sensitive to the Long COVID condition. Prolonged latency during random saccades eye tracking was present (p<0.01, d=0.87) in the Long COVID group corresponding to the King-Devick rapid reading test, which was highly sensitive to Long COVID (p<0.01, d=1.34). ANAM reaction time subtests had similarly large effects (p<0.01, d=0.93-1.09). Balance performance with corrupted sensory feedback was also sensitive (p<0.01, d=0.96).DiscussionOur results indicate that long-standing and validated post-concussion symptom questionnaires may be used for quantifying the severity of Long COVID. Some of the most sensitive measures (especially the King-Devick rapid reading test) are easy to implement clinically and may be effective at tracking patient progress in the context of Long COVID treatment. The results point to wide deficits in motor integration and provide a rationale for treating the subset of Long COVID patients with similar rehabilitation strategies as patients with post-concussion syndrome.
Contractile work and biarticular mechanisms of the triceps surae muscles facilitate net ankle mechanical work at high walking speeds
Authors: Kharazi Mohamadreza , Bohm Sebastian , Theodorakis Christos , Mersmann Falk , Arampatzis Adamantios 
Published: September 2022

AbstractIncreasing walking speed is accompanied by an enhancement of the mechanical power and work performed at the ankle joint despite the decrease of the intrinsic muscle force potential. We measured Achilles tendon (AT) elongation and, based on an experimentally determined AT-force-elongation relationship; we quantified AT-force as a proxy of the triceps surae muscle force at four walking speeds (slow 0.7 m.s-1, preferred 1.4 m.s-1, transition 2.0 m.s-1 and maximum 2.6±0.3 m.s-1). Further, we investigated the mechanical power and work of the triceps surae muscles at the ankle joint (TSA) and the mechanical power and work of the biarticular gastrocnemii at the ankle and knee joint. We found a ~21% decrease of maximum AT-force at the two higher speeds compared to the preferred; however, the net TSA-work increased as a function of walking speed. An earlier plantarflexion accompanied by increased activation of the triceps surae muscles and a knee-to-ankle energy transfer via the biarticular gastrocnemii enhanced the net TSA-mechanical work by 1.7 and 2.4-fold in the transition and maximum walking speeds, respectively. Our findings provide first time evidence for different mechanistic participation of the monoarticular soleus muscle and the biarticular gastrocnemii for the speed-related enhancement of net TSA-work.
Hydraulic tradeoffs underlie enhanced performance of polyploid trees under soil water scarcity
Authors: Losada JM , Blanco-Moure N , Fonollá A , Martínez-Ferrí E , Hormaza JI 
Published: September 2022

SummaryPolyploid trees are excellent candidates to reduce crop water footprint and mitigate the increasingly reduced availability of freshwater for irrigation in many regions of the world due to climate change. Yet, the relationships between aerial organ morpho-anatomy of woody polyploids with their functional hydraulics under water stress remain understudied.We evaluated growth-associated traits, aerial organ xylem anatomy, and physiological parameters of diploid, triploid, and tetraploid genotypes of the woody perennial genus Annona (Annonaceae), testing their performance under long-term soil water reduction.Polyploids displayed contrasting phenotypes, vigorous triploids and dwarf tetraploids, but consistently showed stomatal size-density trade-off. The vessel elements in aerial organs were ∼1.5 times wider in polyploids compared with diploids, but triploids displayed the lowest vessel density. Sap flow velocity, measured in vivo through a novel method, was 10-fold faster in flower carpels than in second leaf vein orders. Triploid leaves displayed the slowest velocity in the leaves but the fastest in the carpels. Plant hydraulic conductance was higher in well-irrigated diploids at the cost of consuming more belowground water, but diploids showed less tolerance than polyploids to soil water deficit.The phenotypic disparity of atemoya polyploids associates with contrasting leaf and stem xylem porosity traits that coordinate to regulate water balances between the trees and the belowground and aboveground environment. Polyploid trees displayed a better performance under soil water scarcity, opening the possibility for deeper research on the factors underlying this behaviour and use them for a more sustainable agricultural and forestry production.
End-to-End Differentiable Blind Tip Reconstruction for Noisy Atomic Force Microscopy Images
Authors: Matsunaga Yasuhiro , Fuchigami Sotaro , Ogane Tomonori , Takada Shoji 
Published: September 2022

AbstractObserving the structural dynamics of biomolecules is vital to deepening our understanding of biomolecular functions. High-speed (HS) atomic force microscopy (AFM) is a powerful method to measure biomolecular behavior at near physiological conditions. In the AFM, measured image profiles on a molecular surface are distorted by the tip shape through the interactions between the tip and molecule. Once the tip shape is known, AFM images can be approximately deconvolved to reconstruct the surface geometry of the sample molecule. Thus, knowing the correct tip shape is an important issue in the AFM image analysis. The blind tip reconstruction (BTR) method developed by Villarrubia1 is an algorithm that estimates tip shape only from AFM images using mathematical morphology operators. While the BTR works perfectly for noise-free AFM images, the algorithm is susceptible to noise, or it is difficult to determine a threshold parameter against noise. To overcome this issue, we here propose an alternative BTR method, called end-to-end differentiable BTR, based on a modern machine learning approach. In the method, we introduce a loss function and a regularization term to prevent overfitting to noise, and the tip shape is optimized with automatic differentiation and backpropagations developed in deep learning frameworks. Using noisy pseudo-AFM images of myosin V motor domain as test cases, we show that our end-to-end differentiable BTR is robust against noise in AFM images. The method can also detect a double-tip shape and deconvolve doubled molecular images. Finally, application to real HS-AFM data of myosin V walking on an actin filament shows that the method can reconstruct the accurate surface geometry of actomyosin consistent with the structural model. Our method serves as a general post-processing for reconstructing hidden molecular surfaces from any AFM images. Codes are available at https://github.com/matsunagalab/differentiable_BTR.
A helminth mimic of TGF-β, TGM, enhances regenerative cutaneous wound healing and modulates immune cell recruitment and activation
Authors: Lothstein Katherine E. , Chen Fei , Mishra Pankaj , Smyth Danielle J. , Wu Wenhui , Lemenze Alexander , Kumamoto Yosuke , Maizels Rick M. , Gause William C. 
Published: September 2022

AbstractIntestinal helminth parasites express excretory/secretory (ES) molecules, which modulate the type-2 immune response including anti-inflammatory and tissue repair pathways. TGF-β mimic (TGM), an ES molecule secreted byHeligmosomoides polygyrus(Hp), binds TGF-β receptors yet lacks structural homology to TGF-β and exhibits distinct receptor interactions. We demonstrate TGM treatment enhanced wound healing and tissue regeneration in anin vivowound biopsy model. TGM, in a 1.5% carboxymethylcellulose solution, was topically administered beneath a Tegaderm layer. Through histological analysis, increased restoration of normal tissue structure in the wound beds of TGM-treated mice was observed during mid- to late-stage wound healing. These observations included accelerated re-epithelialization and hair follicle regeneration, without increased scarring. Flow cytometric and gene expression analysis showed differential expansion of myeloid populations at different stages of wound healing. This included enhanced early accumulation and persistence of macrophages in TGM-treated wounds during the initial inflammatory phase. Additionally, the percentage of alternatively activated (M2) macrophages expressing CD206 was reduced with TGM treatment during early and mid-stage wound healing. scRNAseq analysis of TGM-treated wounds indicate upregulation of multiple wound healing-associated genes without expression of CD206 within macrophage subsets. Experiments with truncated TGM constructs revealed that the TGFβ-R binding domain was essential in enhancing the wound healing response. In summary, TGM can accelerate skin wound healing and pro-restorative maturation through its interaction with the TGF-β receptor and stimulate the recruitment and reprogramming of specific macrophage subsets. This study indicates a role for TGM as a potential novel therapeutic option for enhanced wound healing.One-Sentence SummaryA helminth-derived protein leads to rapid wound closure, skin regeneration, and reprogramming of macrophage activation through TGF-βR binding.
Design principles of 3D epigenetic memory systems
Authors: Owen Jeremy A. , Osmanović Dino , Mirny Leonid A. 
Published: September 2022

AbstractThe epigenetic state of a cell is associated with patterns of chemical modifications of histones (“marks”) across the genome, with different marks typical of active (euchromatic) and inactive (heterochromatic) genomic regions. These mark patterns can be stable over many cell generations—a form of epigenetic memory—despite their constant erosion due to replication and other processes. Enzymes that place histone marks are often stimulated by the same marks, as if “spreading” marks between neighboring histones. But this positive feedback may not be sufficient for stable memory, raising the question of what is. In this work, we show how 3D genome organization—in particular, the compartmental segregation of euchromatin and heterochromatin— could serve to stabilize an epigenetic memory, as long as (1) there is a large density difference between the compartments, (2) the modifying enzymes can spread marks in 3D, and (3) the enzymes are limited in abundance relative to their histone substrates. We introduce a biophysical model stylizing chromatin and its dynamics through the cell cycle, in which enzymes spread self-attracting marks on a polymer. We find that marks localize sharply and stably to the denser compartment, but over several cell generations, the model generically exhibits uncontrolled spread or global loss of marks. Strikingly, imposing limitation of the modifying enzymes—a plausible but oft-neglected element—totally changes this picture, yielding an epigenetic memory system, stable for hundreds of cell generations. Our model predicts a rich phenomenology to compare to experiments, and reveals basic design principles of putative epigenetic memory systems relying on compartmentalized 3D genome structure for their function.
Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in a Mouse Model of Parkinsonism
Authors: Chen Liqiang , Daniels Samuel , Dvorak Rachel , Chu Hong-Yuan 
Published: September 2022

AbstractDegeneration of midbrain dopaminergic (DA) neurons causes a reduced motor output from the primary motor cortex (M1), underlying the motor symptoms of Parkinson’s disease (PD). However, cellular and circuitry mechanisms of M1 dysfunction in PD remain undefined. Using multidisciplinary approaches, we found that DA degeneration induces cell-subtype- and inputs-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. Physiological and anatomical analyses suggest that DA degeneration induces a loss of thalamocortical synapses to M1 PT neurons, resulting in an impaired thalamic driving of their activities. Moreover, we showed that the decreased thalamocortical connectivity are mediated by an excessive activation of NMDA receptors of M1 PT neurons. Further, the decreased thalamocortical transmission in parkinsonism can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that the reduced motor cortical outputs in parkinsonism are not only an immediate consequence of basal ganglia inhibition but also involves specific local circuitry adaptations within M1. This study reveals novel insight in the pathophysiology of parkinsonian motor deficits.
The Effect of Repeat Length on Marcal1-Dependent Single-Strand Annealing in Drosophila
Authors: Dewey Evan B. , Holsclaw Julie Korda , Saghaey Kiyarash , Wittmer Mackenzie E. , Sekelsky Jeff 
Published: September 2022

AbstractProper repair of DNA double strand breaks (DSBs) is essential to maintenance of genomic stability and avoidance of genetic disease. Organisms have many ways of repairing DSBs, including use of homologous sequences through homology-directed repair (HDR). While HDR repair is often error-free, in single-strand annealing (SSA) homologous repeats flanking a DSB are annealed to one another, leading to deletion of one repeat and the intervening sequences. Studies in yeast have shown a relationship between the length of the repeat and SSA efficacy. We sought to determine the effects of homology length on SSA in Drosophila, as Drosophila uses a different annealing enzyme (Marcal1) than yeast. Using an in vivo SSA assay, we show that 50 base pairs (bp) is insufficient to promote SSA and that 500-2000 bp is required for maximum efficiency. Loss of Marcal1 generally followed the same homology length trend as wild-type flies, with SSA frequencies reduced to about a third of wild-type frequencies regardless of homology length. Interestingly, we find a difference in SSA rates between 500 bp homologies that align to the annealing target either nearer or further from the DSB, a phenomenon that may be explained by Marcal1 dynamics. This study gives insights into Marcal1 function and provides important information to guide design of genome engineering strategies that use SSA to integrate linear DNA constructs into a chromosomal DSB.
Regulation of phage lambda packaging motor-DNA interactions: Nucleotide independent and dependent gripping and friction
Authors: Rawson Brandon , Ordyan Mariam , Yang Qin , Sippy Jean , Feiss Michael , Catalano Carlos E. , Smith Douglas E. 
Published: September 2022

AbstractMany dsDNA viruses utilize ATP-powered “terminase” motors to package their genomes into procapsid shells. Here we use a single-molecule DNA grip/slip assay with rapid solution exchange to probe effects of nucleotide binding/dissociation in phage lambda motors containing both the large (TerL) and small (TerS) terminase subunits. Both subunits are required for packaging in vivo, but for some viruses (e.g., phages T4, HK97) packaging can be measured in vitro with only the catalytic TerL subunit. TerS facilitates initiation of packaging in vivo, but it has remained unclear if it plays any role during translocation. Surprisingly we measure frequent DNA gripping and high motor-DNA friction even in the absence of nucleotide. Such behavior was not observed in phage T4 motors containing only TerL, for which motor-DNA interactions were measured to be much weaker and significant gripping and friction was only observed with nucleotide present. For the lambda TerL/TerS holoenzyme, binding of nucleotide (ATP analogs or ADP) further increases gripping and friction, indicating there are both nucleotide independent and dependent interactions. Our findings suggest that TerS plays an important role in motor processivity, and that ATP-independent DNA gripping explains pausing observed during lambda packaging. We propose TerS acts as a “sliding clamp” to limit back slipping when TerL loses grip. Additionally, we show that the lambda packaging complex has a “DNA end clamp” mechanism that prevents the viral genome from completely exiting the capsid once packaging has initiated.
Impact of sample clarification by size exclusion on virus detection and diversity in wastewater-based epidemiology
Authors: Faleye Temitope O.C. , Skidmore Peter , Elyaderani Amir , Adhikari Sangeet , Kaiser Nicole , Smith Abriana , Yanez Allan , Perleberg Tyler , Driver Erin M. , Halden Rolf U. , Varsani Arvind , Scotch Matthew 
Published: September 2022

ABSTRACTThe use of wastewater-based epidemiology (WBE) for early detection of virus circulation and response during the SARS-CoV-2 pandemic increased interest in and use of virus concentration protocols that are quick, scalable, and efficient. One such protocol involves sample clarification by size fractionation using either low-speed centrifugation to produce a clarified supernatant or membrane filtration to produce an initial filtrate depleted of solids, eukaryotes and bacterial present in wastewater (WW), followed by concentration of virus particles by ultrafiltration of the above. While this approach has been successful in identifying viruses from WW, it assumes that majority of the viruses of interest should be present in the fraction obtained by ultrafiltration of the initial filtrate, with negligible loss of viral particles and viral diversity.We used WW samples collected in a population of ∼700,000 in southwest USA between October 2019 and March 2021, targeting three non-enveloped viruses (enteroviruses [EV], canine picornaviruses [CanPV], and human adenovirus 41 [Ad41]), to evaluate whether size fractionation of WW prior to ultrafiltration leads to appreciable differences in the virus presence and diversity determined.We showed that virus presence or absence in WW samples in both portions (filter trapped solids [FTS] and filtrate) are not consistent with each other. We also found that in cases where virus was detected in both fractions, virus diversity (or types) captured either in FTS or filtrate were not consistent with each other. Hence, preferring one fraction of WW over the other can undermine the capacity of WBE to function as an early warning system and negatively impact the accurate representation of virus presence and diversity in a population.
Stitched peptides as potential cell permeable inhibitors of oncogenic DAXX protein
Authors: Jelinska Clare , Kannan Srinivasaraghavan , Frosi Yuri , Ramlan Siti Radhiah , Winnerdy Fernaldo , Lakshminarayanan Rajamani , Brown Christopher J , Phan Anh-Tuan , Rhodes Daniela , Verma Chandra 
Published: September 2022

AbstractThe death domain associated protein 6 (DAXX) is frequently upregulated in a number of common cancers where its suppression has been linked to reduced tumour progression. As a master regulator protein, with >70 reported protein interaction partners, the role of DAXX in its oncogenecity remains unclear. We designed and developed a set of novel stapled/stitched peptides that target a surface on the N-terminal helical bundle domain of DAXX which is the anchor-point for binding to multiple interaction partners (including Rassf1C, P53, Mdm2 and ATRX) and also for the auto regulation of the DAXX N-terminal SUMO interaction motif (SIM). We demonstrate that these peptides bind to and inhibit DAXX with an affinity higher than those reported for the known interaction partners and release the auto-inhibited SIM for interaction with SUMO-1. NanoBret assays show that the peptides enter cells and that their intracellular concentrations remain at nanomolar levels even after 24 hours, without causing membrane perturbation. Together our data suggest that these peptides are both tools for probing the molecular interactions of DAXX and potential precursors to the development of therapeutics.
Structural and Dynamical Properties of Elastin-Like Peptides near their Lower Critical Solution Temperature
Authors: Morozova Tatiana I. , García Nicolás A. , Matsarskaia Olga , Roosen-Runge Felix , Barrat Jean-Louis 
Published: September 2022

AbstractElastin-like peptides (ELPs) are artificially derived intrinsically disordered proteins (IDPs) mimicking the hydrophobic repeat unit in the protein elastin. ELPs are characterized by a lower critical solution temperature (LCST) in aqueous media. Here, we investigate the sequence GVG(VPGVG)3over a wide range of temperatures (below, around, and above the LCST) and peptide concentrations employing all-atom molecular dynamics simulations, where we focus on the role of intra- and inter-peptide interactions. We begin by investigating the structural properties of a single peptide that demonstrates a hydrophobic collapse with temperature, albeit moderate, as the sequence length is short. We observe a change in the interaction between two peptides from repulsive to attractive with temperature by evaluating the potential of mean force, indicating an LCST-like behaviour. Next, we explore dynamical and structural properties of peptides in multi-chain systems. We report the formation of dynamical aggregates with coil-like conformation, in which Val central residues play an important role. Moreover, the lifetime of contacts between chains strongly depends on the temperature and can be described by a power-law decay that is consistent with the LCST-like behaviour. Finally, the peptide translational and internal motion are slowed down by an increase in the peptide concentration and temperature.