Miracle-dz/UniFAR-FTUs huggingface dataset:
How the 26S Proteasome Degrades Ubiquitinated Proteins in the Cell

The 26S proteasome is the central element of proteostasis regulation in eukaryotic cells, it is required for the degradation of protein factors in multiple cellular pathways and it plays a fundamental role in cell stability. The main aspects of proteasome mediated protein degradation have been highly (but not totally) described during three decades of intense cellular, molecular, structural and chemical biology research and tool development. Contributions accumulated within this time lapse allow researchers today to go beyond classical partial views of the pathway, and start generating almost complete views of how the proteasome acts inside the cell. These views have been recently reinforced by cryo-electron microscopy and mechanistic works that provide from landscapes of proteasomal populations distributed in distinct intracellular contexts, to detailed shots of each step of the process of degradation of a given substrate, of the factors that regulate it, and precise measurements of the speed of degradation. Here, we present an updated digest of the most recent developments that significantly contribute in our understanding of how the 26S proteasome degrades hundreds of ubiquitinated substrates in multiple intracellular environments.
Examination of a Subgroup of Patients With Chronic Low Back Pain Likely to Benefit More From Pilates-Based Exercises Compared to an Educational Booklet.

STUDY DESIGN Secondary analysis of a randomized controlled trial. BACKGROUND Pilates is recommended for the treatment of chronic low back pain (LBP). Currently, there are potential subgroups of patients with LBP that could potentially benefit more from Pilates. However, these subgroups of patients have not been tested as effect modifiers in a randomized controlled trial. OBJECTIVES To investigate whether two previously published classification approaches: updated treatment-based classification system (TBCS) and Pilates subgroup defined by a preliminary clinical prediction rule (CPR) can identify patients with LBP who benefit more from Pilates compared to an educational booklet. METHODS 222 patients received advice and were randomly allocated to an educational booklet group who did not receive additional treatment (n=74) or a Pilates group (n=148) who received treatment two or three times a week. At baseline patients were classified using a TBCS into having good prognosis (positive movement control) or not. Similarly using the Pilates CPR patients were classified as having a good (positive) or poor prognosis (negative). The analysis was conducted using interaction terms (interaction between characteristics of the subgroups and effect size of treatment) in linear regression models, considering the changes in pain and disability from baseline to six-week after randomization as dependent variables. RESULTS None of the interaction terms for pain and disability were statistically significant. Thus, the effect of treatment (Pilates versus an educational booklet) was similar in all subgroups. CONCLUSION The TBCS and the Pilates CPR were unable to identify subgroups of patients with chronic LBP who are likely to benefit more from Pilates compared to an educational booklet. J Orthop Sports Phys Ther, Epub 23 Aug 2019. doi:10.2519/jospt.2019. 8839.
The characterization of pc‐polylines representing protein backbones

The backbone of a protein is typically represented as either a C α‐polyline, a three‐dimensional (3D) polyline that passes through the C α atoms, or a tuple of ϕ,ψ pairs while its fold is usually assigned using the 3D topological arrangement of the secondary structure elements (SSEs). It is tricky to obtain the SSE composition for a protein from the C α‐polyline representation while its 3D SSE arrangement is not apparent in the two‐dimensional (2D) ϕ,ψ representation. In this article, we first represent the backbone of a protein as a pc‐polyline that passes through the centers of its peptide planes. We then analyze the pc‐polylines for six different sets of proteins with high quality crystal structures. The results show that SSE composition becomes recognizable in pc‐polyline presentation and consequently the geometrical property of the pc‐polyline of a protein could be used to assign its secondary structure. Furthermore, our analysis finds that for each of the six sets the total length of a pc‐polyline increases linearly with the number of the peptide planes. Interestingly a comparison of the six regression lines shows that they have almost identical slopes but different intercepts. Most interestingly there exist decent linear correlations between the intercepts of the six lines and either the average helix contents or the average sheet contents and between the intercepts and the average backbone hydrogen bonding energetics. Finally, we discuss the implications of the identified correlations for structure classification and protein folding, and the potential applications of pc‐polyline representation to structure prediction and protein design.
Advances of Metabolomics in Fungal Pathogen–Plant Interactions

Plant disease caused by fungus is one of the major threats to global food security, and understanding fungus–plant interactions is important for plant disease control. Research devoted to revealing the mechanisms of fungal pathogen–plant interactions has been conducted using genomics, transcriptomics, proteomics, and metabolomics. Metabolomics research based on mass spectrometric techniques is an important part of systems biology. In the past decade, the emerging field of metabolomics in plant pathogenic fungi has received wide attention. It not only provides a qualitative and quantitative approach for determining the pathogenesis of pathogenic fungi but also helps to elucidate the defense mechanisms of their host plants. This review focuses on the methods and progress of metabolomics research in fungal pathogen–plant interactions. In addition, the prospects and challenges of metabolomics research in plant pathogenic fungi and their hosts are addressed.
Large-Scale Networks for Auditory Sensory Gating in the Awake Mouse

Abstract The amplitude of the brain response to a repeated auditory stimulus is diminished as compared to the response to the first tone (T1) for interstimulus intervals (ISI) lasting up to hundreds of milliseconds. This adaptation process, called auditory sensory gating (ASG), is altered in various psychiatric diseases including schizophrenia and is classically studied by focusing on early evoked cortical responses to the second tone (T2) using 500-ms ISI. However, mechanisms underlying ASG are still not well-understood. We investigated ASG in awake mice from the brainstem to cortex at variable ISIs (125–2000 ms) using high-density EEG and intracerebral recordings. While ASG decreases at longer ISIs, it is still present at durations (500–2000 ms) far beyond the time during which brain responses to T1 could still be detected. T1 induces a sequence of specific stable scalp EEG topographies that correspond to the successive activation of distinct neural networks lasting about 350 ms. These brain states remain unaltered if T2 is presented during this period, although T2 is processed by the brain, suggesting that ongoing networks of brain activity are active for longer than early evoked-potentials and are not overwritten by an upcoming new stimulus. Intracerebral recordings demonstrate that ASG is already present at the level of ventral cochlear nucleus (vCN) and inferior colliculus and is amplified across the hierarchy in bottom-up direction. This study uncovers the extended stability of sensory-evoked brain states and long duration of ASG, and sheds light on generators of ASG and possible interactions between bottom-up and top-down mechanisms.
A Collaborative Multiagent Reinforcement Learning Method Based on Policy Gradient Potential

Gradient-based method has been extensively used in today’s multiagent reinforcement learning (MARL). In a gradient-based MARL algorithm, each agent updates its parameterized strategy in the direction of the gradient of some performance index. However, studies on the convergence of the existing gradient-based MARL algorithms for identical interest games are quite few. In this article, we propose a policy gradient potential (PGP) algorithm that takes PGP as the source of information for guiding the strategy update, as opposed to the gradient itself, to learn the optimal joint strategy that has a maximal global reward. Since the payoff matrix and the joint strategy are often unavailable to the learning agents in reality, we consider the probability of obtaining the maximal reward as the performance index. Theoretical analysis of the PGP algorithm on the continuous model involving an identical interest repeated game shows that if the component action of every optimal joint action is unique, the critical points corresponding to all optimal joint actions are asymptotically stable. The PGP algorithm is experimentally studied and compared against other MARL algorithms on two commonly used collaborative tasks—the robots leaving a room task and the distributed sensor network task, as well as a real-world minefield navigation problem where only local state and local reward information are available. The results show that the PGP algorithm outperforms the other algorithms in terms of the cumulative reward and the number of time steps used in an episode.
An exploratory spatial analysis of overweight and obesity among children and adolescents in Shandong, China

Objective Identifying the spatial patterns of childhood overweight/obesity (OW/OB) can help to guide resource allocation for preventive intervention in China. This study aims to estimate rates of childhood OW/OB across counties within Shandong Province, using geographic techniques to identify sex-specific spatial patterns of childhood OW/OB as well as the presence of spatial clusters. Design Cross-sectional study. Setting Shandong Province in China. Participants and methods Data on 6 216 076 children and adolescents aged 7–18 years from the Primary and Secondary Schoolchildren Physical Examination Database for Shandong Province were used in this study. Spatial patterns of sex-specific prevalence of childhood OW/OB were mapped. Global autocorrelation statistic (Moran’s I) and the Local Indicator of Spatial Association (LISA) were applied to assess the degree of spatial autocorrelation. Results The overall prevalence of childhood OW/OB in Shandong province were 15.05% and 9.23%, respectively. Maps of the sex-specific prevalence of OW/OB demonstrate a marked geographical variation of childhood OW/OB in different regions. Prevalence of childhood OW/OB had a significant positive spatial autocorrelation among both boys and girls. LISA analysis identified significant clusters (or ‘hot spots’) of childhood OW/OB in the eastern coastal region, central region and southwestern region. Conclusions The prevalence of childhood OW/OB is highly spatially clustered. Geographically focused appropriate intervention should be introduced in current childhood OW/OB prevention and control strategy.
Health Benefits of Indoor Cycling: A Systematic Review

Background and Objectives: Indoor cycling is one of the most practiced activities in fitness centers for most people regardless of their physical conditioning level. Several studies have analyzed the effect of indoor cycling on several parameters related to health, such as maximal oxygen consumption, blood pressure, body composition, as well as biochemical markers such as HDL or LDL. However, no study has synthesized all health benefits associated with the indoor cycling practice in the form of a systematic review and established guidelines or recommendations. Therefore, the aim of this manuscript was to conduct a systematic review of published studies about the benefits of indoor cycling training and to establish recommendations for coaches, researchers, and practitioners. Materials and Methods: The PRISMA guidelines were followed to conduct the current systematic review. A systematic search was performed to retrieve relevant published articles until January 2019 using the following keywords: ‘indoor cycling’, ‘indoor bicycle’, and ‘spinning exercise’. Information about participants, intervention, comparisons, outcomes, and study design (PICOS) was extracted. Results: A total of 300 studies were initially identified. After the revision process, 13 of them were included. The total sample size of the studies was 372 (306 women). Results revealed that indoor cycling may improve aerobic capacity, blood pressure, lipid profile, and body composition. These enhancements may be achieved as standalone intervention or combined with other physical exercises or diet. Conclusions: The combination of indoor cycling and diet is recommended to improve the lipid profile, lose weight, and reduce blood pressure. Furthermore, indoor cycling alone may also enhance aerobic capacity. Given the lack of randomized controlled trials, these conclusions should be taken with caution.
Deep Learning Diffuse Optical Tomography

Diffuse optical tomography (DOT) has been investigated as an alternative imaging modality for breast cancer detection thanks to its excellent contrast to hemoglobin oxidization level. However, due to the complicated non-linear photon scattering physics and ill-posedness, the conventional reconstruction algorithms are sensitive to imaging parameters such as boundary conditions. To address this, here we propose a novel deep learning approach that learns non-linear photon scattering physics and obtains an accurate three dimensional (3D) distribution of optical anomalies. In contrast to the traditional black-box deep learning approaches, our deep network is designed to invert the Lippman-Schwinger integral equation using the recent mathematical theory of deep convolutional framelets. As an example of clinical relevance, we applied the method to our prototype DOT system. We show that our deep neural network, trained with only simulation data, can accurately recover the location of anomalies within biomimetic phantoms and live animals without the use of an exogenous contrast agent.
Cyprinid herpesvirus 3 Evolves In Vitro through an Assemblage of Haplotypes that Alternatively Become Dominant or Under-Represented

Viruses are able to evolve in vitro by mutations after serial passages in cell cultures, which can lead to either a loss, or an increase, of virulence. Cyprinid herpesvirus 3 (CyHV-3), a 295-kb double-stranded DNA virus, is the etiological agent of the koi herpesvirus disease (KHVD). To assess the influence of serial passages, an isolate of CyHV-3 (KHV-T) was passaged 99 times onto common carp brain (CCB) cells, and virus virulence was evaluated during passages through the experimental infections of common carp. After 78 CCB passages, the isolate was much less virulent than the original form. A comparative genomic analysis of these three forms of KHV-T (P0, P78 and P99) revealed a limited number of variations. The largest one was a deletion of 1363 bp in the predicted ORF150, which was detected in P78, but not in P99. This unexpected finding was confirmed by conventional PCR and digital PCR. The results presented here primarily suggest that, CyHV-3 evolves, at least in vitro, through an assemblage of haplotypes that alternatively become dominant or under-represented.
Discriminating between viable and membrane-damaged cells of the plant pathogen Xylella fastidiosa

Xylella fastidiosa is a plant pathogenic bacterium with devastating consequences to several crops of economic importance across the world. While this pathogen has been studied for over a century in the United States, several aspects of its biology remain to be investigated. Determining the physiological state of bacteria is essential to understand the effects of its interactions with different biotic and abiotic factors on cell viability. Although X. fastidiosa is culturable, its slow growing nature makes this technique cumbersome to assess the physiological state of cells present in a given environment. PMA-qPCR, i.e. the use of quantitative PCR combined with the pre-treatment of cells with the dye propidium monoazide, has been successfully used in a number of studies on human pathogens to calculate the proportion of viable cells, but has less frequently been tested on plant pathogens. We found that the use of a version of PMA, PMAxx, facilitated distinguishing between viable and non-viable cells based on cell membrane integrity in vitro and in planta. Additional experiments comparing the number of culturable, viable, and total cells in planta would help further confirm our initial results. Enhancers, intended to improve the efficacy of PMAxx, were not effective and appeared to be slightly toxic to X. fastidiosa.
Ursolic Acid Derivatives as Potential Agents Against Acanthamoeba Spp.

The current chemotherapy of Acanthamoeba keratitis relies on few drugs with low potential and limited efficacy, for all this there is an urgent need to identify new classes of anti-Acanthamoeba agents. In this regard, natural products play an important role in overcoming the current need and medicinal chemistry of natural products represents an attractive approach for the discovery and development of new agents. Ursolic acid, a natural pentacyclic triterpenoid compound, possesses a broad spectrum of activities including anti-Acanthamoeba. Herein, we report on the development by chemical transformation of an ursolic acid-based series of seven compounds (2–8), one of them reported for the first time. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity revealed that acylation/ether formation or oxidation enhances their biological profile, suggesting that the hydrophobic moiety contributes to activity, presumably by increasing the affinity and/or cell membrane permeability. These ursolic acid derivatives highlight the potential of this source as a good base for the development of novel therapeutic agents against Acanthamoeba infections.
ShapeWordle: Tailoring Wordles using Shape-aware Archimedean Spirals

We present a new technique to enable the creation of shape-bounded Wordles, we call ShapeWordle, in which we fit words to form a given shape. To guide word placement within a shape, we extend the traditional Archimedean spirals to be shape-aware by formulating the spirals in a differential form using the distance field of the shape. To handle non-convex shapes, we introduce a multi-centric Wordle layout method that segments the shape into parts for our shape-aware spirals to adaptively fill the space and generate word placements. In addition, we offer a set of editing interactions to facilitate the creation of semantically-meaningful Wordles. Lastly, we present three evaluations: a comprehensive comparison of our results against the state-of-the-art technique (WordArt), case studies with 14 users, and a gallery to showcase the coverage of our technique.
Differential Impact of Subtherapeutic Antibiotics and Ionophores on Intestinal Microbiota of Broilers

Antimicrobial growth promoters (AGPs) are commonly used in the livestock industry at subtherapeutic levels to improve production efficiency, which is achieved mainly through modulation of the intestinal microbiota. However, how different classes of AGPs, particularly ionophores, regulate the gut microbiota remains unclear. In this study, male Cobb broiler chickens were supplemented for 14 days with or without one of five commonly used AGPs including three classical antibiotics (bacitracin methylene disalicylate, tylosin, and virginiamycin) and two ionophores (monensin and salinomycin) that differ in antimicrobial spectrum and mechanisms. Deep sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed that two ionophores drastically reduced a number of rare bacteria resulting in a significant decrease in richness and a concomitant increase in evenness of the cecal microbiota, whereas three antibiotics had no obvious impact. Although each AGP modulated the gut microbiota differently, the closer the antibacterial spectrum of AGPs, the more similarly the microbiota was regulated. Importantly, all AGPs had a strong tendency to enrich butyrate- and lactic acid-producing bacteria, while reducing bile salt hydrolase-producing bacteria, suggestive of enhanced metabolism and utilization of dietary carbohydrates and lipids and improved energy harvest, which may collectively be responsible for the growth-promoting effect of AGPs.
An Improved HILIC HPLC-MS/MS Method for the Determination of β-ODAP and Its α Isomer in Lathyrus sativus

β-N-Oxalyl-l-α,β-diaminopropionic acid (β-ODAP) is a non-protein amino acid present in Lathyrus sativus (grass pea) and other Lathyrus species, in parallel with its nontoxic isomer, α-ODAP. When consuming grass pea for several months as staple food, β-ODAP may cause neurolathyrism, a motor neuron degeneration syndrome. Therefore, the independent quantification of both ODAP isomers instead of only the total amount in grass pea allows the identification of less toxic varieties and the development of tools to support breeding for improving grass pea quality. In this work, a simple and fast HPLC-MS/MS method was developed without sample derivatization, using a hydrophilic interaction chromatography (HILIC) column and an isocratic gradient of eluents for 18 min, which allowed the determination of both α- and β-ODAP. The proposed method was fully validated and applied to the determination of α- and β-ODAP contents in a diverse collection of 107 grass pea accessions representative of the main grass pea-growing geographical regions in the world, with the prompt identification of contrasting accessions. β-ODAP content in the analyzed grass pea samples ranged from 0.45 ± 0.02 to 6.04 ± 0.45 mg g−1. The moderate correlation found between α- and β-ODAP contents (0.65) in this collection reinforces the importance of the independent quantification of both ODAP isomers.
α-Conotoxin TxIB: A Uniquely Selective Ligand for α6/α3β2β3 Nicotinic Acetylcholine Receptor Attenuates Nicotine-Induced Conditioned Place Preference in Mice

α-Conotoxin TxIB is a specific antagonist of α6/α3β2β3(α6β2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6β2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6β2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.