Miracle-dz/UniFAR-FTUs huggingface dataset:
Multi-task deep learning for concurrent prediction of protein structural properties

Protein structural properties are diverse and have the characteristics of spatial hierarchy, such as secondary structures, solvent accessibility and backbone angles. Protein tertiary structures are formed in close association with these features. Separate prediction of these structural properties has been improved with the increasing number of samples of protein structures and with advances in machine learning techniques, but concurrent prediction of these tightly related structural features is more useful to understand the overall protein structure and functions. We introduce a multi-task deep learning method for concurrent prediction of protein secondary structures, solvent accessibility and backbone angles (ϕ, ψ). The new method has main two deep network modules: the first one is designed as a DenseNet architecture a using bidirectional simplified GRU (GRU2) network, and the second module is designed as an updated Google Inception network. The new method is named CRRNN2. CRRNN2 is trained on 14,100 protein sequences and its prediction performance is evaluated by testing on public benchmark datasets: CB513, CASP10, CASP11, CASP12 and TS1199. Compared with state-of-the-art methods, CRRNN2 achieves similar, or better performance on the prediction of 3- and 8-state secondary structures, solvent accessibility and backbone angles (ϕ, ψ). Online CRRN-N2 applications, datasets and standalone software are available at http://qianglab.scst. suda.edu. cn/crrnn2/.
A Novel Rubi-Like Virus in the Pacific Electric Ray (Tetronarce californica) Reveals the Complex Evolutionary History of the Matonaviridae

Rubella virus (RuV) is the causative agent of rubella (“German measles”) and remains a global health concern. Until recently, RuV was the only known member of the genus Rubivirus and the only virus species classified within the Matonaviridae family of positive-sense RNA viruses. Other matonaviruses, including two new rubella-like viruses, Rustrela virus and Ruhugu virus, have been identified in several mammalian species, along with more divergent viruses in fish and reptiles. To screen for the presence of additional novel rubella-like viruses we mined published transcriptome data using genome sequences from Rubella, Rustrela, and Ruhugu viruses as baits. From this, we identified a novel rubella-like virus in a transcriptome of Tetronarce californica (Pacific electric ray) that is more closely related to mammalian Rustrela virus than to the divergent fish matonavirus and indicative of a complex pattern of cross-species virus transmission. Analysis of host reads confirmed that the sample analysed was indeed from a Pacific electric ray, and two other viruses identified in this animal, from the Arenaviridae and Reoviridae, grouped with other fish viruses. These findings indicate that the evolutionary history of the Matonaviridae is more complex than previously thought and highlights the vast number of viruses still to be discovered.
Establishing regulated unconventional secretion for production of heterologous proteins

Heterologous protein production is a highly demanded biotechnological process. Secretion of the product to the culture broth is advantageous because it drastically reduces downstream pro-cessing costs. We exploit unconventional secretion for heterologous protein expression in the fungal model microorganism Ustilago maydis. Proteins of interest are fused to carrier chitinase Cts1 for export via the fragmentation zone of dividing yeast cells in a lock-type mechanism. Here, we are first to develop regulatory systems for unconventional protein secretion. This enables uncoupling the accumulation of biomass and protein synthesis of a product of choice from its export. Regulation was successfully established at two different levels using transcriptional and post-translational induction strategies. As a proof-of-principle, we applied autoinduction based on transcriptional regulation for the production and secretion of functional anti-Gfp nanobodies. The presented developments comprise tailored solutions for differentially prized products and thus constitute another important step towards a competitive protein production platform.
High Affinity Chimeric Antigen Receptor with Cross-Reactive scFv to Clinically Relevant EGFR Oncogenic Isoforms

Tumor heterogeneity is a key reason for therapeutic failure and tumor recurrence in glioblastoma (GBM). Our chimeric antigen receptor (CAR) T cell (2173 CAR T cells) clinical trial (NCT02209376) against Epidermal growth factor receptor (EGFR) variant III (EGFRvIII) demonstrated successful trafficking of T cells across the blood brain barrier into GBM active tumor sites. However, CAR T cell infiltration was associated only with a selective loss of EGFRvIII+ tumor, demonstrating little to no effect on EGFRvIII- tumor cells. Post-CAR T treated tumor specimens showed continued presence of EGFR amplification and oncogenic EGFR extracellular domain (ECD) missense mutations, despite loss of EGFRvIII. To address tumor escape, we generated an EGFR-specific CAR by fusing monoclonal antibody (mAb) 806 to a 4-1BB co-stimulatory domain. The resulting construct was compared to 2173 CAR T cells in GBM, using in vitro and in vivo models. 806 CAR T cells specifically lysed tumor cells and secreted cytokines in response to amplified EGFR, EGFRvIII, and EGFR-ECD mutations in U87MG cells, GBM neurosphere-derived cell lines, and patient-derived GBM organoids. 806 CAR T cells did not lyse fetal brain astrocytes or primary keratinocytes to a significant degree. They also exhibited superior antitumor activity in vivo when compared to 2173 CAR T cells. The broad specificity of 806 CAR T cells to EGFR alterations gives us the potential to target multiple clones within a tumor and reduce opportunities for tumor escape via antigen loss.
TNF signalling fine-tunes Langerhans cell transcriptional programmes mediating adaptive immunity

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.
Uncovering Differences in Hydration Free Energies and Structures for Model Compound Mimics of Charged Sidechains of Amino Acids

Free energies of hydration are of fundamental interest for modeling and understanding conformational and phase equilibria of macromolecular solutes in aqueous phases. Of particular relevance to systems such as intrinsically disordered proteins are the free energies of hydration and hydration structures of model compounds that mimic charged sidechains of Arg, Lys, Asp, and Glu. Here, we deploy a Thermodynamic Cycle based Proton Dissociation (TCPD) approach in conjunction with data from direct measurements to obtain estimates for the free energies of hydration for model compounds that mimic the sidechains of Arg+, Lys+, Asp-, and Glu-. Irrespective of the choice made for the hydration free energy of the proton, the TCPD approach reveals clear trends regarding the free energies of hydration for Arg+, Lys+, Asp-, and Glu-. These trends include asymmetries between the hydration free energies of acidic (Asp- and Glu-) and basic (Arg+ and Lys+) residues. Further, the TCPD analysis, which relies on a combination of experimental data, shows that the free energy of hydration of Arg+ is less favorable than that of Lys+. We sought a physical explanation for the TCPD derived trends free energies of hydration. To this end, we performed temperature dependent calculations of free energies of hydration and analyzed hydration structures from simulations that use the polarizable AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) forcefield and water model. At 298 K, the AMOEBA model generates estimates of free energies of hydration that are consistent with TCPD values with a free energy of hydration for the proton of ≈ -259 kcal / mol. Analysis of temperature dependent simulations leads to a structural explanation for the observed differences in free energies of hydration of ionizable residues and reveals that the heat capacity of hydration is positive for Arg+ and Lys+ and negative for Asp- and Glu-.
Mechanically induced localization of SECONDARY WALL INTERACTING bZIP is associated with thigmomorphogenic and secondary cell wall gene expression

Plant growth requires the integration of internal and external cues, perceived and transduced into a developmental program of cell division, elongation, and wall thickening. Mechanical forces contribute to this regulation, and thigmomorphogenesis typically includes reducing stem height, increasing stem diameter, and a canonical transcriptomic response. We present data on a bZIP transcription factor involved in this process in grasses. Brachypodium distachyon SECONDARY WALL INTERACTING bZIP (SWIZ) protein translocated into the nucleus following mechanostimulation. Classical touch responsive genes were upregulated in B. distachyon roots following touch, including significant induction of the glycoside hydrolase 17 family, which may be unique to grass thigmomorphogenesis. SWIZ protein binding to an E-box variant in exons and introns was associated with immediate activation followed by repression of gene expression. SWIZ overexpression resulted in plants with reduced stem and root elongation. These data further define plant touch-responsive transcriptomics and physiology, offering insights to grass mechanotranduction dynamics.
An innovative microwave-assisted extraction and antioxidant potential of polyphenols from different parts of Ocimum basilicum

Microwave-assisted extraction technique is widely used for the extraction of polyphenols from plant material due to high extraction efficiency, short time for extraction and less energy consumption. Due to such advantageous properties of this technique, microwave-assisted extraction was used for the extraction of polyphenols from different parts (seed, stem, and flower) of Ocimum basilicum by using three solvents of different polarities and results were compared with other conventional techniques (heat reflux extraction and soxhlet extraction). Highest polyphenols (980 mg GAE/g) were observed in stem extract of O. basilicumprepared using microwave assisted extraction technique. Methanol was found to be most effective solvent for the extraction of polyphenols from plant parts irrespective of the technique used. Antioxidant potential was evaluated by employing five different antioxidant assays. Highest antioxidant potential was found in stem extract of O. basilicum followed by flower and seed extract. Key words: Ocimum basilicum, microwave-assisted extraction technique, polyphenols, antioxidant potential.
Hybrid Multisite Silicon Neural Probe with Integrated Flexible Connector for Interchangeable Packaging

Multisite neural probes are a fundamental tool to study brain function. Hybrid silicon/polymer neural probes, in particular, allow the integration of complex probe geometries, such as multi-shank designs, with flexible biocompatible cabling. Despite these advantages and benefiting from the highly reproducible fabrication methods on both silicon and polymer substrates, they have not been widely available. This paper presents the development, fabrication, characterization, and in vivo electrophysiological assessment of a hybrid multisite multi-shank silicon probe with a monolithically integrated polyimide flexible interconnect cable. The fabrication process was optimized on wafer level and several neural probes with 64 gold electrode sites equally distributed along 8 shanks with an integrated 8 μm-thick highly flexible polyimide interconnect cable were produce. To avoid the time-consuming bonding of the probe to definitive packaging, the flexible cable was designed to terminate in a connector pad that can mate with commercial zero-insertion force (ZIF) connectors for electronics interfacing. This allows great experimental flexibility since interchangeable packaging can be used according to experimental demands. High-density distributed in vivo electrophysiological recordings were obtained from the hybrid neural probes with low intrinsic noise and high signal-to-noise ratio (SNR).
Impact of Compression on Effective Thermal Conductivity and Diffusion Coefficient of Woven Gas Diffusion Layers in Polymer Electrolyte Fuel Cells

The contrasting effect of compression on the ability of gas diffusion layer (GDL) in polymer electrolyte membrane fuel cell to conduct fluid, heat and electron implies that there is an optimal clamping force for cell performance. For a given GDL, understanding its associated optimal compression needs to know how its conductive ability changes with compressive pressure. In this paper we investigated the impact of compression on the effective diffusion coefficient and thermal conductivity of a carbon‐cloth GDL. The interior microstructures of the GDL under different compressions were acquired using X‐ray tomography; microscopic models were then developed to simulate gas diffusion and heat transfer in the microstructures in both in‐plane and through‐plane directions. The effective diffusion coefficient and thermal conductivity were calculated by volumetrically averaging the simulated gas diffusive and thermal flux rates at micron scale. The results show that both effective diffusion coefficient and thermal conductivity were anisotropic and their values in the in‐plane direction were higher than in the through‐plane direction. With porosity decreasing under the compression, the effective diffusion coefficient decreased faster in the through‐plane direction than in the in‐plane direction; the formula derived by Nam and Kaviany was capable of describing the change of the effective diffusion coefficient with porosity in the in‐plane direction but not in the through‐plane direction. For heat transfer, as the porosity decreased, the thermal conductivity increased faster in the through‐plane direction than in the in‐plane direction, and the increase in both directions could fit to the formula of Das et al.
Little Evidence the Standard Genetic Code Is Optimized for Resource Conservation

Selection for resource conservation can shape the coding sequences of organisms living in nutrient-limited environments. Recently, it was proposed that selection for resource conservation, specifically for nitrogen and carbon content, has also shaped the structure of the standard genetic code, such that the missense mutations it allows tend to cause small increases in the number of nitrogen and carbon atoms in amino acids. Moreover, it was proposed that this optimization is not confounded by known optimizations of the standard genetic code, such as for polar requirement or hydropathy. We challenge these claims. We show the proposed optimization for nitrogen conservation is highly sensitive to choice of null model and the proposed optimization for carbon conservation is confounded by the known conservative nature of the standard genetic code with respect to the molecular volume of amino acids. There is therefore little evidence the standard genetic code is optimized for resource conservation.
Identification of novel inner membrane complex and apical annuli proteins of the malaria parasite Plasmodium falciparum

The inner membrane complex (IMC) is a defining feature of apicomplexan parasites, which confers stability and shape to the cell, functions as a scaffolding compartment during the formation of daughter cells and plays an important role in motility and invasion during different life cycle stages of these single celled organisms. To explore the IMC proteome of the malaria parasite Plasmodium falciparum we applied a proximity-dependent biotin identification (BioID)-based proteomics approach, using the established IMC marker protein Photosensitized INA-Labelled protein 1 (PhIL1) as bait in asexual blood-stage parasites. Subsequent mass spectrometry-based peptide identification revealed enrichment of twelve known IMC proteins and several uncharacterized candidate proteins. We validated nine of these previously uncharacterized proteins by endogenous GFP-tagging. Six of these represent new IMC proteins, while three proteins have a distinct apical localization that most likely represent structures described as apical annuli in Toxoplasma gondii. Additionally, various Kelch13 interacting candidates were identified, suggesting an association of the Kelch13 compartment and the IMC in schizont and merozoite stages. This work extends the number of validated IMC proteins in the malaria parasite and reveals for the first time the existence of apical annuli proteins in P. falciparum. Additionally, it provides evidence for a spatial association between the Kelch13 compartment and the IMC in late blood-stage parasites.
Suppression of miR-199a-5p alleviates ulcerative colitis by upregulating endoplasmic reticulum stress component XBP1

Aims: This study aimed to explore the biological activities of miR-199a-5p in dextran sulphate sodium (DSS)-induced ulcerative colitis and apoptosis and identify the direct target of miR-199a-5p in this process. Main methods: HT-29 cells and C57BL/6 mice were used to examine the function of miR-199a-5p in vitro and in vivo, respectively. Expression of miRNA and mRNA was measured using quantitative real-time PCR and western blotting was used to measure the change in protein expression. Flow cytometry was subsequently employed to determine cell apoptosis, and a luciferase assay was used to confirm the direct target of miR-199a-5p. Results: Expression of miR-199a-5p was increased by DSS treatment in mice. In parallel, miR-199a-5p is found to be involved in endoplasmic reticulum stress (ERS) and cell apoptosis in HT-29 cells, and its upregulation induced ERS, apoptosis, weight loss, and ulcerative colitis in mice in vivo, which could be prevented by the suppression of miR-199a-5p. Luciferase assay confirmed that the 3′ untranslated region (3′-UTR) of XBP1 is the target binding site of miR-199a-5p. Conclusion: miR-199a-5p promotes ulcerative colitis and cell apoptosis by targeting the 3′-UTR of XBP1. Our findings reveal a new regulatory mechanism for ERS signaling and suggest that miR-199a-5p might be a potential target for UC therapy.
The Human walking kinematic model combined with upper and lower limb movement

The purpose of this study is to build a relatively complete human walking kinematic model. This model is combined with the rolling-foot model (lower limb) and multi-rod swinging model (upper limb) connected by COM. We calculated the velocity of COM and other critical joints of the upper limb by marker point capture experiment using the high-speed camera. This research shows that the hand joint velocity measured through the experiment can achieve high coincidence with that calculated by the theoretical model given specific inputs. Moreover, the common pattern of upper limb angles is also studied for an accurate description. The proposed kinematic model is expected to forecast desired motion intention for better compliance by the rehabilitation and assistive robots.
Mechanism of the Chemoselective and Stereoselective Ring Opening of Oxathiaphospholanes: An Ab Initio Study

Ab initio investigations of the reaction profiles for the base-catalyzed methanolysis of amino-2-thiono-1,3,2-oxathiaphospholane suggested that ring opening with a retention of configuration at phosphorus would be energetically favorable, which provides a reasonable interpretation for the chemo- and stereoselectivity that have been determined experimentally for the reaction of diastereomerically pure 2-[(1-(α-naphthyl)ethyl)amino]-2-thiono-1,3,2-oxathiaphospholane. Nucleophilic attack at phosphorus will lead to a trigonal bipyramidal (TBP) pentacoordinate phosphorane intermediate, and pseudorotation will then occur concomitantly with collapse of the TBP intermediate. Thus, pseudorotation is strongly coupled with the reaction coordinate for the substitution pathway. This finding suggests that substitution with a retention of configuration can occur even though a TBP species resulting from pseudorotation fails to exist as an intermediate.
Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was surprisingly low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Available methods to control Winner’s Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.