pwc-archive/papers-with-abstracts huggingface dataset:
Cancer driver gene detection in transcriptional regulatory networks using the structure analysis of weighted regulatory interactions
Authors: Mostafa Akhavan Safar, Babak Teimourpour, Abbas Nozari-Dalini
Date: 2021-01-19 00:00:00

Identification of genes that initiate cell anomalies and cause cancer in humans is among the important fields in the oncology researches. The mutation and development of anomalies in these genes are then transferred to other genes in the cell and therefore disrupt the normal functionality of the cell. These genes are known as cancer driver genes (CDGs). Various methods have been proposed for predicting CDGs, most of which based on genomic data and based on computational methods. Therefore, some researchers have developed novel bioinformatics approaches. In this study, we propose an algorithm, which is able to calculate the effectiveness and strength of each gene and rank them by using the gene regulatory networks and the stochastic analysis of regulatory linking structures between genes. To do so, firstly we constructed the regulatory network using gene expression data and the list of regulatory interactions. Then, using biological and topological features of the network, we weighted the regulatory interactions. After that, the obtained regulatory interactions weight was used in interaction structure analysis process. Interaction analysis was achieved using two separate Markov chains on the bipartite graph obtained from the main graph of the gene network. To do so, the stochastic approach for link-structure analysis has been implemented. The proposed algorithm categorizes higher-ranked genes as driver genes. The efficiency of the proposed algorithm, regarding the F-measure value and number of identified driver genes, was compared with 23 other computational and network-based methods.
Accurate Evaluation on the Interactions of SARS-CoV-2 with Its Receptor ACE2 and Antibodies CR3022/CB6
Authors: Hong-ming Ding, Yue-wen Yin, Song-di Ni, Yan-jing Sheng, Yu-qiang Ma
Date: 2021-01-17 00:00:00

The spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global health crisis. The binding affinity of SARS-CoV-2 (in particular the receptor binding domain, RBD) to its receptor angiotensin converting enzyme 2 (ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19. In this work, we propose a new method based on molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to ACE2 and antibodies. The calculated binding free energy of SARS-CoV-2 RBD to ACE2 is -13.3 kcal/mol, and that of SARS-CoV RBD to ACE2 is -11.4 kcal/mol, which agrees well with experimental result (-11.3 kcal/mol and -10.1 kcal/mol, respectively). Moreover, we take two recently reported antibodies as the example, and calculate the free energy of antibodies binding to SARS-CoV-2 RBD, which is also consistent with the experimental findings. Further, within the framework of the modified MM/PBSA, we determine the key residues and the main driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational alanine scanning method. The present study offers a computationally efficient and numerically reliable method to evaluate the free energy of SARS-CoV-2 binding to other proteins, which may stimulate the development of the therapeutics against the COVID-19 disease in real applications.
Glutathione conjugates of the mercapturic acid pathway and guanine adduct as biomarkers of exposure to CEES, a sulfur mustard analog
Authors: Marie Roser, David Béal, Camille Eldin, Leslie Gudimard, Fanny Caffin, Fanny Gros-Désormeaux, Daniel Léonço, François Fenaille, Christophe Junot, Christophe Piérard, Thierry Douki
Date: 2021-01-11 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Sulfur mustard (SM), a chemical warfare agent, is a strong alkylating compound that readily reacts with numerous biomolecules. The goal of the present work was to define and validate new biomarkers of exposure to SM that could be easily accessible in urine or plasma. Because investigations using SM are prohibited by the Organization for the Prohibition of Chemical Weapons, we worked with 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM. We developed an ultra-high-pressure liquid chromatography - tandem mass spectrometry approach (UHPLC-MS/MS) to the conjugate of CEES to glutathione and two of its metabolites, the cysteine and the N-acetyl-cysteine conjugates. The N7-guanine adduct of CEES (N7Gua-CEES) was also targeted. After synthesizing the specific biomarkers, a solid phase extraction protocol and a UHPLC-MS/MS method with isotopic dilution were optimized. We were able to quantify N7Gua-CEES in the DNA of HaCaT keratinocytes and of explants of human skin exposed to CEES. N7Gua-CEES was also detected in the culture medium of these two models, together with the glutathione and the cysteine conjugates. In contrast, the N-acetyl-cysteine conjugate was not detected. The method was then applied to plasma from mice cutaneously exposed to CEES. All four markers could be detected. Our present results thus validate both the analytical technique and the biological relevance of new, easily quantifiable biomarkers of exposure to CEES. Because CEES behaves very similarly to SM, the results are promising for application to this toxic of interest.
An enzymatic hormesis box
Authors: Michael Grinfeld
Date: 2021-01-08 00:00:00

We present a simple enzymatic system that is capable of a biphasic response under competitive inhibition. This is arguably the simplest system that can be said to be hormetic
Exploring the Regulatory Function of the N-terminal Domain of SARS-CoV-2 Spike Protein Through Molecular Dynamics Simulation
Authors: Yao Li, Tong Wang, Juanrong Zhang, Bin Shao, Haipeng Gong, Yusong Wang, Siyuan Liu, Tie-Yan Liu
Date: 2021-01-06 00:00:00

SARS-CoV-2 is what has caused the COVID-19 pandemic. Early viral infection is mediated by the SARS-CoV-2 homo-trimeric Spike (S) protein with its receptor binding domains (RBDs) in the receptor-accessible state. We performed molecular dynamics simulation on the S protein with a focus on the function of its N-terminal domains (NTDs). Our study reveals that the NTD acts as a "wedge" and plays a crucial regulatory role in the conformational changes of the S protein. The complete RBD structural transition is allowed only when the neighboring NTD that typically prohibits the RBD's movements as a wedge detaches and swings away. Based on this NTD "wedge" model, we propose that the NTD-RBD interface should be a potential drug target.
State dependent effects on the frequency response of prestin real and imaginary components of nonlinear capacitance
Authors: Joseph Santos-Sacchi, Dhasakumar Navaratnam, Winston Tan
Date: 2020-12-15 00:00:00

The outer hair cell (OHC) membrane harbors a voltage-dependent protein, prestin (SLC26a5), in high density, whose charge movement is evidenced as a nonlinear capacitance (NLC). NLC is bell-shaped, with its peak occurring at a voltage, Vh, where sensor charge is equally distributed across the plasma membrane. Thus, Vh provides information on the conformational state of prestin. Vh is sensitive to membrane tension, shifting to positive voltage as tension increases and is the basis for considering prestin piezoelectric (PZE). NLC can be deconstructed into real and imaginary components that report on charge movements in phase or 90 degrees out of phase with AC voltage. Here we show in membrane macro-patches of the OHC that there is a partial trade-off in the magnitude of real and imaginary components as interrogation frequency increases, as predicted by a recent PZE model (Rabbitt, 2020). However, we find similar behavior in a simple kinetic model of prestin that lacks piezoelectric coupling, the meno presto model. At a particular frequency, Fis, the complex component magnitudes intersect. Using this metric, Fis, which depends on the frequency response of each complex component, we find that initial Vh influences Fis; thus, by categorizing patches into groups of different Vh, (above and below -30 mV) we find that Fis is lower for the negative Vh group. We also find that the effect of membrane tension on complex NLC is dependent, but differentially so, on initial Vh. Whereas the negative group exhibits shifts to higher frequencies for increasing tension, the opposite occurs for the positive group. Despite complex component trade-offs, the low-pass roll-off in absolute magnitude of NLC, which varies little with our perturbations and is indicative of diminishing total charge movement, poses a challenge for a role of voltage-driven prestin in cochlear amplification at very high frequencies.
Docking study for Protein Nsp-12 of SARS-CoV with Betalains and Alfa-Bisabolol
Authors: Isaac Lucas-Gómez, Abelardo López-Fernández, Brenda Karen González-Pérez, M. Rivas-Castillo Andrea, A. Valdez Calderón, Manuel A. Gayosso-Morales
Date: 2020-12-28 00:00:00

The present Health Crisis tests the response of modern science and medicine to finding treatment for a new COVID-19 disease. The presentation on the world stage of antivirals such as remdesivir, obeys to the continuous investigation of biologically active molecules with multiple theoretical, computational and experimental tools. Diseases such as COVID:19 remind us that research into active ingredients for therapeutic purposes should cover all available sources, such as plants. In the present work, in silico tools, specifically docking study, were used to evaluate the binding and inhibition capacity of an antiviral such as remdesivir on the NSP-12 protein of SARS-CoV, a polymerase that is key in the replication of the SARS-COV virus. The results are then compared with a docking analysis of two natural products (Alpha-Bisabolol and betalain) with SARS-CoV protein, in order to find more candidates for COVID-19 virus replication inhibitors. in addition to increasing studies that help explain the specific mechanisms of the SARs-CoV-2 virus, remembering that we will have to live with the virus for an indefinite time from now on. Finally, natural products such as betalains may have inhibitory effects of a small order but in conjunction with other synergistic active ingredients they may increase their inhibition effect on NSP-12 protein of SARS-CoV.
FMO Interaction Energy between 17$β$-Estradiol, 17$α$-Estradiol and Human Estrogen Receptor $α$
Authors: Ricardo Ugarte
Date: 2020-12-20 00:00:00

The estrogen receptor is a nuclear hormone receptor activated by the natural steroid hormone 17$\beta$-estradiol (E2). Fragment molecular orbital (FMO) calculations were performed which allowed us to obtain the interaction energy ($E_{int}$) between E2, 17$\alpha$-estradiol (17$\alpha$-E2) and the human estrogen receptor $\alpha$ ligand-binding domain. In aqueous media the MP2/6-31G(d) $E_{int}$ was of -88.52 kcal/mol for E2 and -78.73 kcal/mol for 17$\alpha$-E2. Attractive dispersion interactions were observed between ligands and all surrounding hydrophobic residues. Water molecules were found at the binding site and strong attractive electrostatic interactions were observed between the ligands and the Glu 353 and His 524 residues. The essential dynamics revealed that E2 adapts to the binding site and its motion, in a sense, synchronizes with the whole receptor; while 17$\alpha$-E2, with its motion of greater amplitude compared to E2, disturbs the binding site. Perhaps this feature of the normal substrate is a necessary condition for biological function. Another important requirement relates to the number of water molecules at the binding site. Therefore, negative values in $E_{int}$ is a necessary but not sufficient condition since, it is also necessary to consider the conformers population that fulfill all the requirements that ensure a biological response.
The impact of physiological stress conditions on protein structure and trypsin inhibition of serine protease inhibitor Kazal type 1 (SPINK1) and its N34S variant
Authors: Ina Buchholz, Felix Nagel, Annelie Klein, Preshit R. Wagh, Ujjwal M. Mahajan, Andreas Greinacher, Markus M. Lerch, Julia Mayerle, Mihaela Delcea
Date: 2020-12-18 00:00:00

One of the most common mutations in the serine protease inhibitor Kazal type 1 (SPINK1) gene is the N34S variant which is strongly associated with chronic pancreatitis. Although it is assumed that N34S mutation constitutes a high-risk factor, the underlying pathologic mechanism is still unknown. In the present study, we investigated the impact of physiological stress factors on SPINK1 protein structure and trypsin inhibitor function using biophysical methods. Our circular dichroism spectroscopy data revealed differences in the secondary structure of SPINK1 and N34S mutant suggesting protein structural changes induced by the mutation as an impairment that could be disease-relevant. We further confirmed that both SPINK1 (KD of 0.15 +/- 0.06 nM) and its N34S variant (KD of 0.08 +/- 0.02 nM) have similar binding affinity and inhibitory effect towards trypsin as shown by surface plasmon resonance and trypsin inhibition assay studies, respectively. We found that stress conditions such as altered ion concentrations (i.e. potassium, calcium), temperature shifts, as well as environmental pH lead to insignificant differences in trypsin inhibition between SPINK1 and N34S mutant. However, we have shown that the environmental pH induces structural changes in both SPINK1 constructs in a different manner. Our findings suggest protein structural changes in the N34S variant as an impairment of SPINK1 and environmental pH shift as a trigger that could play a role in disease progression of pancreatitis.
Homochirality: a prerequisite or consequence of life?
Authors: Axel Brandenburg
Date: 2020-12-15 00:00:00

Many of the building blocks of life such as amino acids and nucleotides are chiral, i.e., different from their mirror image. Contemporary life selects and synthesizes only one of two possible handednesses. In an abiotic environment, however, there are usually equally many left- and right-handed molecules. If homochirality was a prerequisite of life, there must have been physical or chemical circumstances that led to the selection of a certain preference. Conversely, if it was a consequence of life, we must identify possible pathways for accomplishing a transition from a racemic to a homochiral chemistry. After a discussion of the observational evidence, I will review ideas where homochirality of any handedness could emerge as a consequence of the first polymerization events of nucleotides in an emerging RNA world. These mechanisms are not limited to nucleotides, but can also occur for peptides, as a precursor to the RNA world. The question of homochirality is, in this sense, intimately tied to the origin of life. Future Mars missions may be able to detect biomolecules of extant or extinct life. We will therefore also discuss possible experimental setups for determining the chirality of primitive life forms in situ on Mars.
Calotropin from milk of Calotropis gigantean a potent inhibitor of COVID 19 corona virus infection by Molecular docking studies
Authors: Arun Dev Sharma, Inderjeet Kaur
Date: 2020-12-11 00:00:00
Tasks: Drug Design, Molecular Docking

SARS-CoV-2 (COVID-19), a positive single stranded RNA virus, member of corona virus family, is spreading its tentacles across the world due to lack of drugs at present. Being associated with cough, fever, and respiratory distress, this disease caused more than 15 % mortality worldwide. Due to its vital role in virus replication, Mpro/3CLpro has recently been regarded as a suitable target for drug design. The current study focused on the inhibitory activity of Calotropin, a component from milk of Calotropis gigantean, against Mpro protein from SARS-CoV-2. Till date there is no work is undertaken on in-silico analysis of this compound against Mpro of COVID-19 protein. In the present study, molecular docking studies were conducted by using Patchdock tool. Protein Interactions tool was used for protein interactions. The calculated parameters such as docking score indicated effective binding of Calotropin to Mpro protein. Interactions results indicated that, Mpro/ Calotropin complexes forms hydrophobic interactions. Therefore, Calotropin may represent potential herbal treatment to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.
Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies
Authors: Sakshi Piplani, Puneet Singh, David A. Winkler, Nikolai Petrovsky
Date: 2020-11-29 00:00:00

For fast development of COVID-19, it is only feasible to use drugs (off label use) or approved natural products that are already registered or been assessed for safety in previous human trials. These agents can be quickly assessed in COVID-19 patients, as their safety and pharmacokinetics should already be well understood. Computational methods offer promise for rapidly screening such products for potential SARS-CoV-2 activity by predicting and ranking the affinities of these compounds for specific virus protein targets. The RNA-dependent RNA polymerase (RdRP) is a promising target for SARS-CoV-2 drug development given it has no human homologs making RdRP inhibitors potentially safer, with fewer off-target effects that drugs targeting other viral proteins. We combined robust Vina docking on RdRP with molecular dynamic (MD) simulation of the top 80 identified drug candidates to yield a list of the most promising RdRP inhibitors. Literature reviews revealed that many of the predicted inhibitors had been shown to have activity in in vitro assays or had been predicted by other groups to have activity. The novel hits revealed by our screen can now be conveniently tested for activity in RdRP inhibition assays and if conformed testing for antiviral activity invitro before being tested in human trials
GPU accelerated enumeration and exploration of HP model genotype-phenotype maps for protein folding
Authors: S. Owen
Date: 2020-08-01 00:00:00
Tasks: CPU, GPU, Protein Folding

Evolution can be broadly described in terms of mutations of the genotype and the subsequent selection of the phenotype. The full enumeration of a given genotype-phenotype (GP) map is therefore a powerful technique in examining evolutionary landscapes. However, because the number of genotypes typically grows exponentially with genome length, such calculations rapidly become intractable. Here I apply graphics processing unit(GPU) techniques to the hydrophobic-polar (HP)model for protein folding. This GP map is a simple and well-studied model for the complex process of protein folding. Prior studies on relatively small 2D and 3D lattices have been exclusively carried out using conventional central processing unit (CPU) approaches. By using GPU techniques, I was able to reproduce the pioneering calculations of Li et al.[1] with a speed up of 580-700 fold over a CPU. I was also able to perform the largest enumeration to date of the 6x6 lattice. These novel calculations provide evidence that a popular "plum-pudding" metaphor that suggests that phenotypes are disconnected in genotype space does not describe the data. Instead a "spaghetti" metaphor of connected genotype networks may be more suitable. Furthermore, the data allows the relationships between designability and complexity within GP space to be explored. GPU approaches appear extremely well suited toGP mapping and the success of this work provides a promising introduction for its wider application in this field.
Glassy Carbon Microelectrode Arrays Enable Voltage-Peak Separated Simultaneous Detection of Dopamine and Serotonin Using Fast Scan Cyclic Voltammetry
Authors: Elisa Castagnola, Sanitta Thongpang, Mieko Hirabayashi, Giorgio Nava, Surabhi Nimbalkar, Tri Nguyen, Sandra Lara, Alexis Oyawale, James Bunnell, Chet Moritz, Sam Kassegne
Date: 2020-11-25 00:00:00

Progress in real-time, simultaneous in vivo detection of multiple neurotransmitters will help accelerate advances in neuroscience research. The need for development of probes capable of stable electrochemical detection of rapid neurotransmitter fluctuations with high sensitivity and selectivity and sub-second temporal resolution has, therefore, become compelling. Additionally, a higher spatial resolution multi-channel capability is required to capture the complex neurotransmission dynamics across different brain regions. These research needs have inspired the introduction of glassy carbon (GC) microelectrode arrays on flexible polymer substrates through carbon MEMS (C-MEMS) microfabrication process followed by a novel pattern transfer technique. These implantable GC microelectrodes offer unique advantages in electrochemical detection of electroactive neurotransmitters through the presence of active carboxyl, carbonyl, and hydroxyl functional groups. In addition, they offer fast electron transfer kinetics, capacitive electrochemical behavior, and wide electrochemical window. Here, we combine the use of these GC microelectrodes with the fast scan cyclic voltammetry (FSCV) technique to optimize the co-detection of dopamine and serotonin in vitro and in vivo. We demonstrate that using optimized FSCV triangular waveform at scan rates lower than 700 V/s and holding and switching at potentials of 0.4 and 1V respectively, it is possible to discriminate voltage reduction and oxidation peaks of serotonin and dopamine, with serotonin contributing distinct multiple oxidation peaks. Taken together, our results present a compelling case for a carbon-based MEA platform rich with active functional groups that allows for repeatable and stable detection of electroactive multiple neurotransmitters at concentrations as low as 10 nM