Miracle-dz/UniFAR-FTUs huggingface dataset:
Towards Unraveling the Histone Code by Fragment Blind Docking

Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD).
Viscoelastic shear stress relaxation in two-dimensional glass-forming liquids

Significance A phase transition from a liquid to an ordered solid state in two dimensions is different from that in three dimensions. In two dimensions, the appearance of quasi–long-range orientational correlations is decoupled from the that of quasi–long-range translational correlations, which is correlated with the emergence of a nonzero shear modulus. Here, we show that a similar decoupling also exists in 2D glassy phenomena, albeit with transitions replaced by crossovers. The onset of slow dynamics is signaled by the appearance of a two-step decay in orientational correlations, but a glassy viscoelastic response develops at a lower temperature. Translational dynamics of 2D glass-forming fluids is strongly influenced by soft, long-wavelength fluctuations first recognized by D. Mermin and H. Wagner. As a result of these fluctuations, characteristic features of glassy dynamics, such as plateaus in the mean-squared displacement and the self-intermediate scattering function, are absent in two dimensions. In contrast, Mermin–Wagner fluctuations do not influence orientational relaxation, and well-developed plateaus are observed in orientational correlation functions. It has been suggested that, by monitoring translational motion of particles relative to that of their neighbors, one can recover characteristic features of glassy dynamics and thus disentangle the Mermin–Wagner fluctuations from the 2D glass transition. Here we use molecular dynamics simulations to study viscoelastic relaxation in two and three dimensions. We find different behavior of the dynamic modulus below the onset of slow dynamics (determined by the orientational or cage-relative correlation functions) in two and three dimensions. The dynamic modulus for 2D supercooled fluids is more stretched than for 3D supercooled fluids and does not exhibit a plateau, which implies the absence of glassy viscoelastic relaxation. At lower temperatures, the 2D dynamic modulus starts exhibiting an intermediate time plateau and decays similarly to the 2D dynamic modulus. The differences in the glassy behavior of 2D and 3D glass-forming fluids parallel differences in the ordering scenarios in two and three dimensions.
PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms

Poly (ADP‐ribose) polymerase (PARP) inhibitors have provided great clinical benefits to ovarian cancer patients. To date, three PARP inhibitors, namely, olaparib, rucaparib and niraparib have been approved for the treatment of ovarian cancer in the United States. Homologous recombination deficiency (HRD) and platinum sensitivity are prospective biomarkers for predicting the response to PARP inhibitors in ovarian cancers. Preclinical data have focused on identifying the gene aberrations that might generate HRD and induce sensitivity to PARP inhibitors in vitro in cancer cell lines or in vivo in patient‐derived xenografts. Clinical trials have focused on genomic scar analysis to identify biomarkers for predicting the response to PARP inhibitors. Additionally, researchers have aimed to investigate mechanisms of resistance to PARP inhibitors and strategies to overcome this resistance. Combining PARP inhibitors with HR pathway inhibitors to extend the utility of PARP inhibitors to BRCA‐proficient tumours is increasingly foreseeable. Identifying the population of patients with the greatest potential benefit from PARP inhibitor therapy and the circumstances under which patients are no longer suited for PARP inhibitor therapy are important. Further studies are required in order to propose better strategies for overcoming resistance to PARP inhibitor therapy in ovarian cancers.
A role for affectivity in rapid facial mimicry: An electromyographic study

ABSTRACT Emotional expressions evoke rapid facial reactions in the perceiver that are consistent with the valence of the observed expression. We aimed to investigate whether this robust facial reaction is purely a motor matching response or instead represents underlying affective processes. Participants’ (N = 60) corrugator supercilii and zygomaticus major muscle activity was quantified using facial electromyography (EMG) while they viewed three sets of images; (i) upright happy and angry facial expressions, (ii) inverted happy and angry facial expressions, and (iii) sad and happy eyes and mouth expressions. Participants displayed patterns of EMG responding that were consistent with the affective valence of the emotional expression, as opposed to merely matching the observed stimuli (i.e. a motor matching response). Using a novel methodological approach, these findings provide evidence for the contention that affective processing underlies rapid facial mimicry reactions.
Saturated bioisosteres of benzene: where to go next?

The replacement of para-substituted benzenes with saturated bi- and polycyclic bioisosteres - bicyclo[1.1. 1]pentane, bicyclo[2.2. 2]octane and cubane, - often increases the potency, selectivity and metabolic stability of bioactive compounds. The currently remaining challenge for chemists, however, is to rationally design, synthesize and validate the saturated bioisosteres for ortho- and meta-substituted benzenes.
Current and emerging biologic and small molecule therapies for atopic dermatitis

ABSTRACT Introduction: Atopic dermatitis (AD) is the most common inflammatory skin disease, yet until recently there were no safe systemic therapies approved for the long-term management of AD in adult patients. A deeper understanding of disease pathogenesis and identification of molecular and cellular changes has resulted in a rapidly evolving pipeline of therapeutics that holds promise for safer long-term control. Areas covered: In this review, we highlight the growing arsenal of biologic and small molecule antagonists that target pathways implicated in AD pathogenesis. Evidence that AD is driven by multiple immune axes extending beyond the Th2 polarization has resulted in therapies targeting additional pathways, including the Th22, Th17/IL-23, and JAK-STAT pathways. Pruritus, a hallmark of AD, has been linked to multiple mechanisms and various therapeutics have emerged in response to alternative hypotheses. Expert opinion: Despite the assumption that AD has a common disease mechanism, recent studies indicate that the disorder is characterized by several phenotypes and therapy may need to be tailored to the unique immune traits of specific phenotypes. Targeted therapy should complement and expand our molecular map of AD across the various phenotypic iterations and help push AD pharmacotherapy into a new era of personalized medicine.
Reconstituting the reticular ER network – mechanistic implications and open questions

ABSTRACT The endoplasmic reticulum (ER) is a major membrane-bound organelle in all eukaryotic cells. This organelle comprises morphologically distinct domains, including the nuclear envelope and peripheral sheets and tubules. The tubules are connected by three-way junctions into a network. Several membrane proteins have been implicated in network formation; curvature-stabilizing proteins generate the tubules themselves, and membrane-anchored GTPases fuse tubules into a network. Recent experiments have shown that a tubular network can be formed with reconstituted proteoliposomes containing the yeast membrane-fusing GTPase Sey1 and a curvature-stabilizing protein of either the reticulon or REEP protein families. The network forms in the presence of GTP and is rapidly disassembled when GTP hydrolysis of Sey1 is inhibited, indicating that continuous membrane fusion is required for its maintenance. Atlastin, the ortholog of Sey1 in metazoans, forms a network on its own, serving both as a fusion and curvature-stabilizing protein. These results show that the reticular ER can be generated by a surprisingly small set of proteins, and represents an energy-dependent steady state between formation and disassembly. Models for the molecular mechanism by which curvature-stabilizing proteins cooperate with fusion GTPases to form a reticular network have been proposed, but many aspects remain speculative, including the function of additional proteins, such as the lunapark protein, and the mechanism by which the ER interacts with the cytoskeleton. How the nuclear envelope and peripheral ER sheets are formed remain major unresolved questions in the field. Here, we review reconstitution experiments with purified curvature-stabilizing proteins and fusion GTPases, discuss mechanistic implications and point out open questions. Summary: This Review focuses on the ongoing efforts to recapitulate the formation of a tubular ER network using purified proteins such as the curvature-stabilizing proteins and the fusion GTPases.
Adaptive Fuzzy Control With High-Order Barrier Lyapunov Functions for High-Order Uncertain Nonlinear Systems With Full-State Constraints

This paper focuses on the practical output tracking control for a category of high-order uncertain nonlinear systems with full-state constraints. A high-order tan-type barrier Lyapunov function (BLF) is constructed to handle the full-state constraints of the control systems. By the BLF and combining a backstepping design technique, an adding a power integrator, and a fuzzy control, the proposed approach can control high-order uncertain nonlinear system with full-state constraints. A novel controller is designed to ensure that the tracking errors approach to an arbitrarily small neighborhood of zero, and the constraints on system states are not violated. The numerical example demonstrates effectiveness of the proposed control method.
Contralaterally controlled functional electrical stimulation improves wrist dorsiflexion and upper limb function in patients with early-phase stroke: A randomized controlled trial.

OBJECTIVES To investigate the effectiveness of contralaterally controlled functional electrical stimulation (CCFES) on the recovery of active wrist dorsiflexion and upper limb function in patients with early-phase stroke (<15 days post-stroke). METHODS Patients in the CCFES group were treated with routine rehabilitation combined with CCFES, while those in the conventional neuromuscular electrical stimulation (NMES) group were treated with routine rehabilitation combined with NMES. Time intervals from stroke onset to appearance of wrist dorsiflexion, and from onset of treatment to appearance of wrist dorsiflexion were recorded (in days). Functional assessments were also performed at baseline and endpoint. RESULTS Nineteen out of 21 patients in the CCFES group and 12 out of 20 patients in the NMES group regained active wrist dorsiflexion during the treatment and follow-up period (90.5% vs 60%, p = 0.025). The mean time interval from onset of treatment to appearance of active wrist dorsiflexion was signifcantly shorter in the CCFES group than in the NMES group (p < 0.001). The CCFES group had signifcantly higher scores for upper extremity function (p = 0.001), strength of extensor carpi (p = 0.002), active ROM for wrist dorsiflexion (p = 0.003), activities of daily living score (p = 0.023) and ICF score (p < 0.001) than the NMES group at the endpoint. CONCLUSION CCFES signifcantly shortened the time for regaining wrist dorsiflexion, and improved the upper extremity function and general health of patients with early-phase stroke. CCFES therefore has potential as a clinical intervention.
HEALPix-IA: A Global Registration Algorithm for Initial Alignment

Methods of point cloud registration based on ICP algorithm are always limited by convergence rate, which is related to initial guess. A good initial alignment transformation can sharply reduce convergence time and raise efficiency. In this paper, we propose a global registration method to estimate the initial alignment transformation based on HEALPix (Hierarchical Equal Area isoLatitude Pixelation of a sphere), an algorithm for spherical projections. We adopt EGI (Extended Gaussian Image) method to map the normals of the point cloud and estimate the transformation with optimized point correspondence. Cross-correlation method is used to search the best alignment results in consideration of the accuracy and robustness of the algorithm. The efficiency and accuracy of the proposed algorithm were verified with created model and real data from various sensors in comparison with similar methods.
Varicella-zoster virus infections – antiviral therapy and diagnosis

Varicella-zoster virus is an important human pathogen that causes varicella after primary infection and zoster after recurrence. Following primary infection, the virus remains latently for life in dorsal root and cranial nerve ganglia. Varicella and zoster are worldwide widespread diseases and may be associated with significant complications. This manuscript presents a short overview about the fundamental knowledge including the most important clinical signs, the capabilities for antiviral treatment and the spectrum of methods for laboratory diagnosis.
Effects of Tea Saponin Supplementation on Nutrient Digestibility, Methanogenesis, and Ruminal Microbial Flora in Dorper Crossbred Ewe

Simple Summary Greenhouse gas emissions are a serious cause of global warming and climate change, and have become a common focus for all countries. Methane has been proven the second most commonly occurring greenhouse gas. Ruminants have been blamed for substantially contributing to methane emissions. Supplementation with tea saponin (TS) effectively decreased methane emissions and nitrogen emissions. It is not only beneficial for environmental protection, but also has potential economic benefits. Abstract Two experiments were conducted using Dorper × thin-tailed Han crossbred ewes. In experiment 1, eighteen ewes were randomly assigned to two dietary treatments (a basal diet, or the same basal diet supplemented with 2.0 g tea saponin (TS)/head/day) to investigate the effects of TS supplementation on nutrient digestibility and methane emissions. In experiment 2, six ewes with ruminal cannulae were assigned to the same two dietary treatments as in experiment 1 to investigate the effects of TS supplementation on rumen fermentation and microbial flora. TS supplementation increased the apparent digestibility of organic matter (OM) (p = 0.001), nitrogen (N) (p = 0.036), neutral detergent fibre (NDF) (p = 0.001), and acid detergent fibre (ADF) (p < 0.001). Urinary N (p = 0.001) and fecal N (p = 0.036) output were reduced, and N retention (p = 0.001) and nitrogen retention/nitrogen intake (p = 0.001) were increased. Supplementary TS did not decrease absolute methane emissions (p = 0.519) but decreased methane emissions scaled to metabolic bodyweight by 8.80% (p = 0.006). Ammonia levels decreased (p < 0.001) and total volatile fatty acid levels increased (p = 0.018) in response to TS supplementation. The molar proportion of propionate increased (p = 0.007), whereas the acetate:propionate ratio decreased (p = 0.035). Supplementation with TS increased the population of Fibrobacter succinogenes (p = 0.019), but the population of protozoans tended to decrease (p = 0.054). Supplementation with TS effectively enhanced the apparent digestibility of OM, N, NDF, and ADF, and decreased methane emissions scaled to metabolic bodyweight.
Comparison of treadmill trip-like training versus Tai Chi to improve reactive balance among independent older adult residents of senior housing: a pilot controlled trial.

Background There is growing interest in using perturbation-based balance training to improve the reactive response to common perturbations (e.g., tripping and slipping). The goal of this study was to compare the efficacy of treadmill-based reactive balance training versus Tai Chi performed at, and among independent residents of, older adult senior housing. Methods Thirty-five residents from five senior housing facilities were allocated to either treadmill-based reactive balance training or Tai Chi training. Both interventions were performed three times per week for four weeks, with each session lasting approximately 30 minutes. A battery of balance tests was performed at baseline, and again one week, one month, three months, and six months post-training. The battery included six standard clinical tests of balance and mobility, and a test of reactive balance performance. Results At baseline, no significant between-group differences were found for any balance tests. After training, reactive balance training participants had better reactive balance than Tai Chi participants. Maximum trunk angle was 13.5 degrees smaller among reactive balance training participants one week after training (p = .01), and a reactive balance rating was 24-31% higher among reactive balance training participants one week to six months after training (p < .03). Clinical tests showed minimal differences between groups at any time point after training. Conclusion Trip-like reactive balance training performed at senior housing facilities resulted in better rapid balance responses compared to Tai Chi training.
Effect of a Multicomponent Intervention on Lifestyle Factors among Brazilian Adolescents from Low Human Development Index Areas: A Cluster-Randomized Controlled Trial

Promoting healthy lifestyle factors (e.g., physical activity, healthy eating, less screen time) among young people is a relevant and challenging step toward reducing non-communicable diseases. This study aimed to evaluate the effect of a multicomponent intervention on lifestyle factors among adolescents from schools in low Human Development Index (HDI < 0.500) areas. The Fortaleça sua Saúde program was conducted with 548 adolescents aged 11–18 years old in the intervention group and 537 in the control group. The four-month intervention included strategies focused on training teachers, new opportunities for physical activity in the school environment, and health education strategies for the school community (including parents). Moderate- to-vigorous physical activity level (≥420 min/week), TV watching and computer use/gaming (<2 h/day), daily consumption of fruit juice, fruit, vegetables, soft drinks, savory foods and sweets, and current alcohol and tobacco use were measured before and after intervention. McNemar’s test and logistic regression (odds ratio [OR] and a 95% confidence interval [95% CI]) were used, considering p < 0.05. In the intervention schools, a significant increase occurred in the number of adolescents who met physical activity guidelines (5.3%; 95% CI = 0.8; 9.8) and who reported using computer for <2 h a day (8.6%; 95% CI = 3.8; 13.4) after intervention. No changes were observed in the control schools. At the end of the intervention, adolescents from intervention schools were more likely to practice physical activity at recommended levels (OR = 1.44; 95% CI = 1.00; 2.08) than adolescents from control schools. No significant change was observed for the other lifestyle factors. In conclusion, this multicomponent intervention was effective in promoting physical activity among adolescents from vulnerable areas. However, other lifestyle factors showed no significant change after intervention. This study is registered at Clinicaltrials.gov NCT02439827.
Quetiapine associated Central Serous Chorioretinopathy: Implicit role of serotonin and dopamine pathways

A 30-year-old insomniac, an off-label user of quetiapine, presented with blurring of central vision, eventually diagnosed as central serous chorioretinopathy. A potential association was suspected based on the drug's actions on the autonomic nervous system. He showed improvement on drug withdrawal; then he unwittingly resumed quetiapine and had a recurrence. Possible underlying mechanisms that include alteration in choroidal perfusion through serotonin and dopamine receptors are discussed. Although retinal vein occlusions and pigment epithelial detachment have been described with quetiapine, to the author's knowledge, this is the first case report of quetiapine-associated central serous chorioretinopathy.
Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update

The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients.
Geographical variation in life-history traits suggests an environmental-dependent trade-off between juvenile growth rate and adult lifespan in a moth

Abstract Life-history theory predicts a trade-off between the juvenile growth rate and adult traits related to survival. However, this hypothesized negative correlation is difficult to test robustly because many trade-offs are mild, and environmental variables, such as changes in nutrient availability, can ameliorate the trade-off or make it more pronounced. Thus, it is reasonable to expect that the expression of the trade-off can be condition-dependent. In the present study, we first examined the pre-adult life-history traits of the cotton bollworm, Helicoverpa armigera, collected from northern, central, and southern China at different temperatures. We found that the northern China population has a significantly shorter pre-adult developmental time and higher growth rate than the southern China population as a result of adaptation to the decreased seasonal length. Then, we tested for a trade-off between the juvenile growth rate and adult lifespan in different temperature and nutrient conditions. We found a negative relationship between juvenile growth rate and adult lifespan under starvation or desiccation conditions; however, a continuous supply of sugar can diminish or obviate the apparent negative relationship, in which the adult lifespan did not show a significant difference in most of the comparisons. These results suggested a resource-mediated trade-off may exist between juvenile growth rate and adult lifespan. However, the adult size may have some positive effect on the lifespan under starvation and desiccation conditions, which may affect the expression of trade-off.