catena-Poly[[[diaqua­iron(II)]-μ-pyrazine-2,3-dicarboxyl­ato] dihydrate]

The crystal structure of the title compound, {[Fe(C6H2N2O4)(H2O)2]·2H2O}n, was synthesized by a diffusion method. It has a one-dimensional polymeric chain structure and the chains are further connected into a three-dimensional structure by hydrogen bonds. The FeII ion has a distorted octa­hedral coordination environment, with two N and two O atoms from the pyrazine-2,3-dicarboxyl­ate ligands in the equatorial plane and with two water mol­ecules in axial positions. The Fe atom lies on a crystallographic centre of symmetry and a twofold rotation axis passes through the pyrazine ring

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

Funder: Howard Hughes Medical Institute (HHMI); doi: https://doi.org/10.13039/100000011Abstract: The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Comparison of the effect of acetylated polyamines and N⁸-acetylspermidine deacetylase inhibitor, APAH, on LS180 and multidrug resistant cells

Multidrug resistance (MDR) is a major obstacle of current chemotherapy. In this study, we investigated the effects ofpolyamines, acetylated polyamines and APAH, a polyamine deacetylase inhibitor, on LS180 cells and the derived MDR LS180 Ad-50 cells. L.ethal concentrations for 20% of the cells (LC20) for N8 -acetylspermidine (N8 - AcSPD) and SPD were 12.5 and 7 times greater for LS180 Ad-50 cells than for LS180 cells, respectively. However, there was no difference in LC20 levels for N1-AcSPD in LS180 and LS180 Ad-50 cells. Addition of 100 nM APAH to N8-AcSPD increased its LC20 to 17 foldgreater in MDR compared to non:·MDR cells. and resulted in increased cell growth at 5 μM N8-AcSPD. Furthermore, exposure to the LC20 concentrations of N8 -AcSPD for 48 hrs caused no significant change of intracellular Rhodamine (Rh) 123 concentrations. Adding 100 nM APAH to this N8 -AcSPD experiment led to a decrease of intracellular Rh123 concentration of 15-20% in both LS 180 and LS 180 Ad-50 cells. These Rh 123 concentrations further decreased in the presence of higher concentrations of APAH. Pretreatment of the cells with APAH did not affect these results. Kinetic studies suggest that APAH may be a non-competitive transport inhibitor of Rh123 transporter

Comparison of the effect of acetylated polyamines and N⁸-acetylspermidine deacetylase inhibitor, APAH, on LS180 and multidrug resistant cells

Multidrug resistance (MDR) is a major obstacle of current chemotherapy. In this study, we investigated the effects ofpolyamines, acetylated polyamines and APAH, a polyamine deacetylase inhibitor, on LS180 cells and the derived MDR LS180 Ad-50 cells. L.ethal concentrations for 20% of the cells (LC20) for N8 -acetylspermidine (N8 - AcSPD) and SPD were 12.5 and 7 times greater for LS180 Ad-50 cells than for LS180 cells, respectively. However, there was no difference in LC20 levels for N1-AcSPD in LS180 and LS180 Ad-50 cells. Addition of 100 nM APAH to N8-AcSPD increased its LC20 to 17 foldgreater in MDR compared to non:·MDR cells. and resulted in increased cell growth at 5 μM N8-AcSPD. Furthermore, exposure to the LC20 concentrations of N8 -AcSPD for 48 hrs caused no significant change of intracellular Rhodamine (Rh) 123 concentrations. Adding 100 nM APAH to this N8 -AcSPD experiment led to a decrease of intracellular Rh123 concentration of 15-20% in both LS 180 and LS 180 Ad-50 cells. These Rh 123 concentrations further decreased in the presence of higher concentrations of APAH. Pretreatment of the cells with APAH did not affect these results. Kinetic studies suggest that APAH may be a non-competitive transport inhibitor of Rh123 transporter

Cutting edge: Natalizumab blocks adhesion but not initial contact of human T cells to the blood-brain barrier in vivo in an animal model of multiple sclerosis

The humanized anti-alpha(4) integrin Ab Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. Natalizumab is thought to exert its therapeutic efficacy by blocking the alpha(4) integrin-mediated binding of circulating immune cells to the blood-brain barrier (BBB). As alpha(4) integrins control other immunological processes, natalizumab may, however, execute its beneficial effects elsewhere. By means of intravital microscopy we demonstrate that natalizumab specifically inhibits the firm adhesion but not the rolling or capture of human T cells on the inflamed BBB in mice with acute experimental autoimmune encephalomyelitis (EAE). The efficiency of natalizumab to block T cell adhesion to the inflamed BBB was found to be more effective in EAE than in acute systemic TNF-alpha-induced inflammation. Our data demonstrate that alpha(4) integrin-mediated adhesion of human T cells to the inflamed BBB during EAE is efficiently blocked by natalizumab and thus provide the first direct in vivo proof of concept of this therapy in multiple sclerosis

Genome-Wide Identification of the Q-type C2H2 Transcription Factor Family in Alfalfa (Medicago sativa) and Expression Analysis under Different Abiotic Stresses

Q-type C2H2 zinc-finger protein (C2H2-ZFP) transcription factors are associated with many plant growth development and environmental stress responses. To date, there have been few analyses of the Q-type C2H2-ZFP gene family in alfalfa (Medicago sativa subsp. sativa). In this study, we identified 58 Q-type C2H2-ZFPs across the entire alfalfa genome, and the gene structure, motif composition, chromosomal mapping, and cis-regulatory elements were explored, as well as the expression profiles of specific tissues and the response under different abiotic stresses. According to their phylogenetic features, these 58 MsZFPs were divided into 12 subgroups. Synteny analysis showed that duplication events play a vital role in the expansion of the MsZFP gene family. The collinearity results showed that a total of 26 and 42 of the 58 MsZFP genes were homologous with Arabidopsis and M. truncatula, respectively. The expression profiles showed that C2H2-ZFP genes played various roles in different tissues and abiotic stresses. The results of subsequent quantitative real-time polymerase chain reaction (qRT-PCR) showed that the nine selected MsZFP genes were rapidly induced under different abiotic stresses, indicating that C2H2-ZFP genes are closely related to abiotic stress. This study provides results on MsZFP genes, their response to various abiotic stresses, and new information on the C2H2 family in alfalfa

Adaptive Multi-Channel Residual Shrinkage Networks for the Diagnosis of Multi-Fault Gearbox

Intelligent fault diagnosis is a hot research topic in machinery and equipment health monitoring. However, most intelligent fault diagnosis models have good performance in single fault mode, but poor performance in multiple fault modes. In real industrial scenarios, the interference of noise also makes it difficult for intelligent diagnostic models to extract fault features. To solve these problems, an adaptive multi-channel residual shrinkage network (AMC-RSN) is proposed in this paper. First, a channel attention mechanism module is constructed in the residual block and a soft thresholding function is introduced for noise reduction. Then, an adaptive multi-channel network is constructed to fuse the feature information of each channel in order to extract as many features as possible. Finally, the Meta-ACON activation function is used before the fully connected layer to decide whether to activate the neurons by the model outputs. The method was implemented in gearbox fault diagnosis, and the experimental results show that AMC-RSN has better diagnostic results than other networks under various faults and strong noises