The 5-HT1A receptor antagonist WAY-100635 maleate reprograms metabolism to promote RGC differentiation and regeneration in retino-visual centers.

Metabolic collapse of retinal ganglion cells (RGCs) onsets glaucoma, yet no approved drug directly protects these neurons. Through a live-cell mitochondrial screen in human stem-cell-derived hRGCs we uncovered WAY-100635 (WAY), a clinically tested 5-HT1A antagonist, as a systemic neuroprotectant. WAY triggers a reversible cyclic-AMP surge that activates PGC-1α-driven reversible mitochondrial biogenesis and suppresses apoptosis.

Chemically induced partial unfolding of the multifunctional apurinic/apyrimidinic endonuclease 1.

Apurinic/apyrimidinic endonuclease I (APE1) acts as both an endonuclease and a redox factor to ensure cell survival. The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded.

Thermal Hazard Analysis of Two Non-Ideal Explosives Based on Ammonium Perchlorate/Ammonium Nitrate and Aluminium Powder.

In recent years, various kinds of civil explosive detonation accidents have occurred frequently around the world, resulting in substantial human casualties and significant property losses. It is generally believed that thermal stimulation plays a critical role in triggering the detonation of explosives; consequently, the study of the thermal hazards of explosives is of great significance to many aspects of safety emergency management practices in the production, transportation, storage, and use of explosives. It is known that the thermal stability of the ammonium perchlorate-aluminium system and the ammonium nitrate-aluminium system has been extensively investigated previously in the literature.

Backbone Isomerization to Enhance Thermal Stability and Decrease Mechanical Sensitivities of 10 Nitro-Substituted Bipyrazoles.

The development of novel, environmentally friendly, and high-energy oxidizers remains interesting and challenging for replacing halogen-containing ammonium perchloride (). The trinitromethyl moiety is one of the most promising substituents for designing high-energy density oxidizers. In this study, a backbone isomerization strategy was utilized to manipulate the properties of 10 nitro group-substituted bipyrazoles containing the largest number of nitro groups among the bis-azole backbones so far.

Chemically induced partial unfolding of the multifunctional Apurinic/apyrimidinic endonuclease 1.

Apurinic/apyrimidinic endonuclease I (APE1) acts as both an endonuclease and a redox factor to ensure cell survival. The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded.

Molecular Dynamics Simulations of the Thermal Decomposition of 3,4-Bis(3-nitrofurazan-4-yl)furoxan.

When stimulated, for example, by a high temperature, the physical and chemical properties of energetic materials (EMs) may change, and, in turn, their overall performance is affected. Therefore, thermal stability is crucial for EMs, especially the thermal dynamic behavior. In the past decade, significant efforts have been made to study the thermal dynamic behavior of 3,4-bis(3-nitrofurazan-4-yl)furoxan (DNTF), one of the new high-energy-density materials (HEDMs).

Enzyme catalysis prior to aromatic residues: Reverse engineering of a dephospho-CoA kinase.

The wide variety of protein structures and functions results from the diverse properties of the 20 canonical amino acids. The generally accepted hypothesis is that early protein evolution was associated with enrichment of a primordial alphabet, thereby enabling increased protein catalytic efficiencies and functional diversification. Aromatic amino acids were likely among the last additions to genetic code.

--A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS.

Aberrant expression of the transcription factor ERG is a key driving event in approximately one-half of all of prostate cancers. Lacking an enzymatic pocket and mainly disordered, the structure of ERG is difficult to exploit for therapeutic design. We recently identified EWS as a specific interacting partner of ERG that is required for oncogenic function.

The thermal decomposition process of Composition B by ReaxFF/lg force field.

Composition B is a melt-cast explosive consisting of mixtures of TNT and RDX. It has many excellent properties, but there are still multiple safety problems when it is used. Therefore, it is of importance to understand the thermal decomposition mechanism of Composition B.

Many-to-one binding by intrinsically disordered protein regions.

Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping.

Association between interleukin-2, interleukin-10, secretory immunoglobulin A and immunoglobulin G expression in vaginal fluid and human papilloma virus outcome in patients with cervical lesions.

The present study was designed to investigate the association between a change in vaginal local immunity and human papilloma virus (HPV) infection outcome in patients with cervical lesions, through the study of the expression of vaginal local immune factors, interleukin (IL)-2, IL-10, secretory immunoglobulin A (sIgA) and IgG, in patients with different grades of cervical lesions and different degrees of cervical lesions caused by HPV infection prior to and following treatment. The experimental group comprised 136 patients with low-grade squamous intraepithelial lesions, 236 patients with high-grade squamous intraepithelial lesions and 133 patients with cervical squamous cell carcinoma, while the control group comprised 100 time- and location-matched healthy women. The concentrations of sIgA, IgG, IL-2 and IL-10 in the vaginal lavage fluid, were detected using ELISA prior to treatment and at 3, 6 and 12 months after treatment.

Difference in vaginal microecology, local immunity and HPV infection among childbearing-age women with different degrees of cervical lesions in Inner Mongolia.

Background: This study aims to investigate the difference in vaginal microecology, local immunity and HPV infection among childbearing-age women with different degrees of cervical lesions.

Methods: A total of 432 patients were included in this study. Among these patients, 136 patients had LSIL, 263 patients had HSIL and 33 patients had CSCC.

Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation.

Cardiac voltage-gated sodium channels (Nav1.5) play an essential role in regulating cardiac electric activity by initiating and propagating action potentials in the heart. Altered Nav1.

Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons.

Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin.

CaMKII Controls Whether Touch Is Painful.

Unlabelled: The sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Aβ-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history.

Improving protein order-disorder classification using charge-hydropathy plots.

Background: The earliest whole protein order/disorder predictor (Uversky et al., Proteins, 41: 415-427 (2000)), herein called the charge-hydropathy (C-H) plot, was originally developed using the Kyte-Doolittle (1982) hydropathy scale (Kyte & Doolittle., J.

Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding.

Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity.

High-throughput characterization of intrinsic disorder in proteins from the Protein Structure Initiative.

The identification of intrinsically disordered proteins (IDPs) among the targets that fail to form satisfactory crystal structures in the Protein Structure Initiative represents a key to reducing the costs and time for determining three-dimensional structures of proteins. To help in this endeavor, several Protein Structure Initiative Centers were asked to send samples of both crystallizable proteins and proteins that failed to crystallize. The abundance of intrinsic disorder in these proteins was evaluated via computational analysis using predictors of natural disordered regions (PONDR®) and the potential cleavage sites and corresponding fragments were determined.

Subclassifying disordered proteins by the CH-CDF plot method.

Intrinsically disordered proteins (IDPs) are associated with a wide range of functions. We suggest that sequence-based subtypes, which we call flavors, may provide the basis for different biological functions. The problem is to find a method that separates IDPs into different flavor / function groups.

Intrinsic protein disorder and protein-protein interactions.

Intrinsically disordered proteins often bind to more than one partner. In this study, we focused on 11 sets of complexes in which the same disordered segment becomes bound to two or more distinct partners. For this collection of protein complexes, two or more partners of each disordered segment were selected to have less than 25% amino acid identity at structurally aligned positions.

TOP-IDP-scale: a new amino acid scale measuring propensity for intrinsic disorder.

Intrinsically disordered proteins carry out various biological functions while lacking ordered secondary and/or tertiary structure. In order to find general intrinsic properties of amino acid residues that are responsible for the absence of ordered structure in intrinsically disordered proteins we surveyed 517 amino acid scales. Each of these scales was taken as an independent attribute for the subsequent analysis.

The unfoldomics decade: an update on intrinsically disordered proteins.

Background: Our first predictor of protein disorder was published just over a decade ago in the Proceedings of the IEEE International Conference on Neural Networks (Romero P, Obradovic Z, Kissinger C, Villafranca JE, Dunker AK (1997) Identifying disordered regions in proteins from amino acid sequence. Proceedings of the IEEE International Conference on Neural Networks, 1: 90-95). By now more than twenty other laboratory groups have joined the efforts to improve the prediction of protein disorder.

Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners.

Background: Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks.

Mining alpha-helix-forming molecular recognition features with cross species sequence alignments.

Previously described algorithms for mining alpha-helix-forming molecular recognition elements (MoREs), described by Oldfield et al. (Oldfield, C. J.