A Structure-based B-cell Epitope Prediction Model Through Combing Local and Global Features

B-cell epitopes (BCEs) are a set of specific sites on the surface of an antigen that binds to an antibody produced by B-cell. The recognition of epitopes is a major challenge for drug design and vaccines development. Compared with experimental methods, computational approaches have strong potential for epitope prediction at much lower cost. Moreover, most of the currently computational methods focus on using local information around target amino acid residue for BCEs prediction without taking the global information of the whole antigen sequence into consideration. We propose a novel deep leaning method thorough combing local features and global features for BCEs prediction. In our model, two parallel modules are built to extract local and global features from the antigen separately. For local features, we use graph convolutional networks to capture information of spatial neighbors of a target amino acid residue. For global features, Attention based Bidirectional Long Short-Term Memory networks(Att-BLTM) are applied to extract information from the whole antigen sequence. Then the local and global features are combined to predict BCEs. The experiments show that the proposed method achieves superior performance over the state-of-the-art BCEs prediction methods on benchmark datasets. Also, we compare the performance differences between data with or without global features. The experimental results show that global features play an important role in BCEs prediction.

HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase

Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, histone PARylation factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to serine residues. Here we investigate the mechanism and specific consequences of HPF1-mediated PARylation using nucleosomes as both activators and substrates for PARP1. HPF1 provides that catalytic base Glu284 to substantially redirect PARylation by PARP1 such that the histones in nucleosomes become the primary recipients of PAR chains. Surprisingly, HPF1 partitions most of the reaction product to free ADPR, resulting in much shorter PAR chains compared to reactions in the absence of HPF1. This HPF1-mediated switch from polymerase to hydrolase has important implications for the PARP1-mediated response to DNA damage and raises interesting new questions about the role of intracellular ADPR and depletion of NAD+.

HPF1 and nucleosomes mediate a dramatic switch in activity of PARP1 from polymerase to hydrolase

Poly(ADP-ribose) polymerase 1 (PARP1) is an important player in the response to DNA damage. Recently, histone PARylation factor (HPF1) was shown to be a critical modulator of the activity of PARP1 by facilitating PARylation of histones and redirecting the target amino acid specificity from acidic to serine residues. Here we investigate the mechanism and specific consequences of HPF1-mediated PARylation using nucleosomes as both activators and substrates for PARP1. HPF1 provides that catalytic base Glu284 to substantially redirect PARylation by PARP1 such that the histones in nucleosomes become the primary recipients of PAR chains. Surprisingly, HPF1 partitions most of the reaction product to free ADPR, resulting in much shorter PAR chains compared to reactions in the absence of HPF1. This HPF1-mediated switch from polymerase to hydrolase has important implications for the PARP1-mediated response to DNA damage and raises interesting new questions about the role of intracellular ADPR and depletion of NAD+.

Leveraging Sequential and Spatial Neighbors Information by Using CNNs Linked With GCNs for Paratope Prediction

Antibodies consisting of variable and constant regions, are a special type of proteins playing a vital role in immune system of the vertebrate. They have the remarkable ability to bind a large range of diverse antigens with extraordinary affinity and specificity. This malleability of binding makes antibodies an important class of biological drugs and biomarkers. In this article, we propose a method to identify which amino acid residues of an antibody directly interact with its associated antigen based on the features from sequence and structure. Our algorithm uses convolution neural networks (CNNs) linked with graph convolution networks (GCNs) to make use of information from both sequential and spatial neighbors to understand more about the local environment of the target amino acid residue. Furthermore, we process the antigen partner of an antibody by employing an attention layer. Our method improves on the state-of-the-art methodology.

Scope of phytotherapeutics in targeting ACE2 mediated Host-Viral Interface of SARS‐CoV2 that causes COVID-19

<p>Severe acute respiratory syndrome coronavirus (SARS-CoV-2) that cause COVID-19 becomes a global threat and spread its pandemicity across the boundaries. Recent demography issued by WHO forecasting the severity of disease prevalence in more than 200 countries resulted in 16,96,588 laboratory confirmed cases excluding 1,05,952 deaths as on 12 April 2020. Countries like USA (4,92,881), Italy (1,52,271), Spain (1,61,852), Germany (1,20,479) are struggling hard to flatten their epidemic curve of COVID-19. Dynamic strategies are of utmost important in order to manage the crucial spread of SARS-CoV-2. Drug of herbal origin may offer reliable therapeutic opportunity in controlling widespread transmission. It was evident from the scientific outcomes that SARS‐CoV-2 gains access in to the host cell through angiotensin-converting enzyme 2 (ACE2) receptors. Hence drugs that reveals potential binding affinity with core amino acid of ACE-2 may expected to interfere the host-viral interaction. In our present investigation 28 lead molecules from well documented medicinal herbs were subjected to molecular docking analysis targeting ACE2 receptor and their potential of impeding host-viral interface were evaluated. Results of computational analysis signifies that out of 28 ligands nearly 11 bioactive lead molecules exhibit potential binding affinity of about 100% with the target amino acid residue (31 Lys and 353 Lys)<br></p>

Scope of phytotherapeutics in targeting ACE2 mediated Host-Viral Interface of SARS‐CoV2 that causes COVID-19

<p>Severe acute respiratory syndrome coronavirus (SARS-CoV-2) that cause COVID-19 becomes a global threat and spread its pandemicity across the boundaries. Recent demography issued by WHO forecasting the severity of disease prevalence in more than 200 countries resulted in 16,96,588 laboratory confirmed cases excluding 1,05,952 deaths as on 12 April 2020. Countries like USA (4,92,881), Italy (1,52,271), Spain (1,61,852), Germany (1,20,479) are struggling hard to flatten their epidemic curve of COVID-19. Dynamic strategies are of utmost important in order to manage the crucial spread of SARS-CoV-2. Drug of herbal origin may offer reliable therapeutic opportunity in controlling widespread transmission. It was evident from the scientific outcomes that SARS‐CoV-2 gains access in to the host cell through angiotensin-converting enzyme 2 (ACE2) receptors. Hence drugs that reveals potential binding affinity with core amino acid of ACE-2 may expected to interfere the host-viral interaction. In our present investigation 28 lead molecules from well documented medicinal herbs were subjected to molecular docking analysis targeting ACE2 receptor and their potential of impeding host-viral interface were evaluated. Results of computational analysis signifies that out of 28 ligands nearly 11 bioactive lead molecules exhibit potential binding affinity of about 100% with the target amino acid residue (31 Lys and 353 Lys)<br></p>

Renaissance Distribution for Statistically Failed Experiments

Much of the experimental data, especially in life sciences, is considered to be useless if it demonstrates a large standard deviation from the mean value. The Renaissance distribution, as presented in this study, allows one to extract true values from such statistical data with large noise. To obtain proof of the Renaissance distribution, high-throughput synthesis of deep substitutions for a target amino acid sequence was performed, and the known epitope was identified in assay with human serum antibodies. In addition, the Renaissance distribution was shown to approach the epitope affinity maturation by the deep alanine substitution. The Renaissance distribution may have an impact in the development of novel specific drugs.

Convenient Asymmetric Synthesis of Fmoc-(S)-6,6,6-Trifluoro-Norleucine

In this work we report a convenient asymmetric synthesis of Fmoc-(S)-6,6,6-trifluoro-norleucine via alkylation reaction of chiral glycine equivalent. The target amino acid of 99% enantiomeric purity was prepared with 82.4% total yield (three steps).

GNAQ and PMS1 Mutations Associated with Uveal Melanoma, Ocular Surface Melanosis, and Nevus of Ota

G protein mutations are common in uveal melanomas, and the vast majority target amino acid residue Q209 in either GNAQ or GNA11. The GNAQ R183Q mutation is found in a small fraction of uveal melanomas. We report a patient with an unusual presentation of uveal melanoma arising at an early age in the setting of congenital skin and ocular surface melanosis. A 34-year-old Hispanic female with congenital bilateral nevus of Ota and ocular surface melanosis presented with progressive loss of visual acuity and was found to have a juxtapapillary uveal melanoma. She was treated with brachytherapy, but the tumor relapsed. She underwent enucleation that revealed mixed spindle and epithelioid uveal melanoma cells with no extraocular or lymphovascular spread. Next-generation sequencing performed on DNA isolated from the enucleation specimen identified a GNAQ R183Q mutation and a PMS1 truncation mutation. Cytogenetic profiling revealed no monosomy 3. These findings raise the possibility that uveal melanomas bearing G protein R183 mutations may have distinct clinicopathologic profiles compared to those with Q209 mutations. Furthermore, this is the first reported case of a mutation in the mismatch repair gene PMS1 associated with uveal melanoma.