The molecular chaperone Hsp70 family members function by a bidirectional heterotrophic allosteric mechanism

The Hsp70 family is one of the most important and conserved molecular chaperone families. It is well documented that Hsp70 family members assist many cellular processes involving protein quality control, as follows: protein folding, transport through membranes, protein degradation, escape from aggregation, intracellular signaling, among several others. The Hsp70 proteins act as a cellular pivot capable of receiving and distributing substrates among the other molecular chaperone families. Despite the high identity of the Hsp70 proteins, there are several homologue Hsp70 members that do not have the same role in the cell, which allow them to develop and participate in such large number of activities. The Hsp70 proteins are composed of two main domains: one that binds ATP and hydrolyses it to ADP and another which directly interacts with substrates. These domains present bidirectional heterotrophic allosteric regulation allowing a fine regulated cycle of substrate binding and release. The general mechanism of the Hsp70s cycle is under the control of ATP hydrolysis that modulates the low (ATP-bound state) and high (ADP-bound state) affinity states of Hsp70 for substrates. An important feature of the Hsp70s cycle is that they have several co-chaperones that modulate their cycle and that can also interact and select substrates. Here, we review some known details of the bidirectional heterotrophic allosteric mechanism and other important features for Hsp70s regulating cycle and function.     

A shift in the current: new applications and concepts for microbe-electrode electron exchange

Perceived applications of microbe-electrode interactions are shifting from production of electric power to other technologies, some of which even consume current. Electrodes can serve as stable, long-term electron acceptors for contaminant-degrading microbes to promote rapid degradation of organic pollutants in anaerobic subsurface environments. Solar and other forms of renewable electrical energy can be used to provide electrons extracted from water to microorganisms on electrodes at suitably low potentials for a number of groundwater bioremediation applications as well as for the production of fuels and other organic compounds from carbon dioxide. The understanding of how microorganisms exchange electrons with electrodes has improved substantially and is expected to be helpful in optimizing practical applications of microbe-electrode interactions, as well as yielding insights into related natural environmental phenomena.     

Can cognitive training improve episodic memory?

Neuroscience-inspired approaches to train cognitive abilities are bringing about a paradigm shift in the way scientists view the treatment of memory dysfunction, but it can be challenging to prove whether such approaches have significant effects.     

Functional network organization of the human brain

Real-world complex systems may be mathematically modeled as graphs, revealing properties of the system. Here we study graphs of functional brain organization in healthy adults using resting state functional connectivity MRI. We propose two novel brain-wide graphs, one of 264 putative functional areas, the other a modification of voxelwise networks that eliminates potentially artificial short-distance relationships. These graphs contain many subgraphs in good agreement with known functional brain systems. Other subgraphs lack established functional identities; we suggest possible functional characteristics for these subgraphs. Further, graph measures of the areal network indicate that the default mode subgraph shares network properties with sensory and motor subgraphs: it is internally integrated but isolated from other subgraphs, much like a "processing" system. The modified voxelwise graph also reveals spatial motifs in the patterning of systems across the cortex.     

Damping capacity is evolutionarily conserved in the radial silk of orb-weaving spiders

Orb-weaving spiders depend upon their two-dimensional silk traps to stop insects in mid flight. While the silks used to construct orb webs must be extremely tough to absorb the tremendous kinetic energy of insect prey, webs must also minimize the return of that energy to prey to prevent insects from bouncing out of oscillating webs. We therefore predict that the damping capacity of major ampullate spider silk, which forms the supporting frames and radial threads of orb webs, should be evolutionarily conserved among orb-weaving spiders. We test this prediction by comparing silk from six diverse species of orb spiders. Silk was taken directly from the radii of orb webs and a Nano Bionix test system was used either to sequentially extend the silk to 25% strain in 5% increments while relaxing it fully between each cycle, or to pull virgin silk samples to 15% strain. Damping capacity was then calculated as the percent difference in loading and unloading energies. Damping capacity increased after yield for all species and typically ranged from 40 to 50% within each cycle for sequentially pulled silk and from 50 to 70% for virgin samples. Lower damping at smaller strains may allow orb webs to withstand minor perturbations from wind and small prey while still retaining the ability to capture large insects. The similarity in damping capacity of silk from the radii spun by diverse spiders highlights the importance of energy absorption by silk for orb-weaving spiders.     

Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.     

Discovery of a novel series of selective HCN1 blockers

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.     

2,3-Substituted quinoxalin-6-amine analogs as antiproliferatives: a structure-activity relationship study

The quinoxaline core is considered a privileged scaffold as it is found in a variety of biologically relevant molecules. Here we report the synthesis of a quinoxalin-6-amine library, screening against a panel of cancer cell lines and a structure-activity relationship (SAR). This resulted in the identification of a bisfuranylquinoxalineurea analog (7c) that has low micromolar potency against the panel of cancer cell lines. We also show that cells treated with quinoxalineurea 7c results in caspase 3/7 activation, PARP cleavage and Mcl-1 dependent apoptosis.     

Antiplasmodial and cytotoxicity evaluation of 3-functionalized 2-azetidinone derivatives

3-Azido-, 3-amino- and 3-(1,2,3-triazol-1-yl)-β-lactams were synthesized and evaluated for their antiplasmodial activity against four strains of Plasmodium falciparum and KB cells for their cytotoxicity profiles. The presence of a cyclohexyl substituent at N-1 and a phenyl group on the triazole ring markedly improved the activity profiles of triazole-tethered β-lactam exhibiting IC₅₀ values of 1.13, 1.21 and 1.00 μM against 3D7, K1 and W2 strains respectively.