Motor learning is an essential component of human behavior. Many different factors can influence the process of motor learning, such as the amount of practice and type of feedback. Changes in task ...difficulty during training can also considerably impact motor learning. Typical motor learning studies include a sequential variation of task difficulty, i.e., easy to challenging, irrespective of user performance. However, many studies have reported the importance of performance-based task difficulty variation for effective motor learning and skill transfer. A performance-based adaptive algorithm for task difficulty variation based on the challenge-point framework is proposed in this study. The algorithm is described for postural adaptation during simultaneous upper-limb training. Ten healthy participants (28 ± 2.44 years) were recruited to validate the algorithm. Participants adapted to a postural target of 20° in the anterior direction from the initial upright posture while performing a unimanual reaching task using a robotic device. Results suggest a significant decrease in postural error after training. The algorithm successfully adapted the task difficulty based on the performance of the user. The proposed algorithm could be modified for different motor skills and can be further evaluated for different applications in order to maximize the potential benefits of rehabilitation sessions.
The greatest challenge in environmental toxicology is to understand the effects of mixture toxicity as environmental pollutants co-exist and exhibit combined effects. Thus, it is necessary to ...evaluate the mixture toxicity associated with two or more co-existing compounds. Pesticides are widely used to control pest, they are ubiquitous in nature and present in all environmental components. Pesticide residue can be detected in almost all components of environment and food samples. Imidacloprid (IMD) (neonicotinoid), dichlorvos (DIC) (organophosphate) and atrazine (ATZ) are three widely used pesticides for commercial uses. Present work includes the assessment of effects of individual exposure of IMD (27.5 mg/L), DIC (15 mg/L), and ATZ (03 mg/L) and in combination of three (CMD) (13.75 + 7.5 + 1.5 mg/L IMD, DIC & ATZ, respectively) in terms of LPO, GSH content and antioxidant enzymes activities (superoxide dismutase, catalase and glutathione peroxidase) in zebrafish (
), exposed for 24 h. CMD group exhibits highest lipid peroxidation than other individually exposed groups. Similarly, the activities of antioxidant enzymes were highest in CMD group with reduced GSH content. Results indicate that exposure to mixture of pesticides develops synergistic effects which were more toxic in compare to individual exposure and also produce toxicity in all examined tissues rather than selective organ toxicity.
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•Risperidone Drug induced alteration in Caenorhabditis elegans.•Liquid Culture Assay requires lower drug concentration.•Feeding and Locomotion behavior are vital parameters for onset ...of toxicity.•Alteration in feeding and locomotion reflects time-dependent toxicity.•Higher duration of exposures show impregnated alteration in behavior.
Antipsychotic drugs (APDs) are prescribed for the treatment of psychiatric illness. However, these drugs can also contribute to several developmental and behavioral disorders. Contemporary studies to evaluate the toxic effects of numerous atypical antipsychotics are reported to cause behavioral alteration at variable doses in mammals and nematodes. Risperidone, the second most prescribed drug in India, requires more exploration of its adverse effects on humans. Here, we explore effects on feeding behavior and locomotion patterns due to risperidone exposure in C. elegans model. The study targets to work out the toxic effects of risperidone exposure on feeding and locomotion behavior in addition to the expected pharmacological effects.
N2 wild type strain was exposed in liquid culture assay for 2, 4, 6, 8, 10, and 12 hours with fixed 50 µM concentration. Feeding behavior was depleted due to inhibition in pharyngeal pumping varying from 11.05% - 45.67% in a time-dependent manner. Results of locomotion assay also show time-varying increase in reversals (4.9%–34.03%) and omega bends (26.23%–62.17%) with reduction in turn counts (29.07%- 42.2%) and peristaltic speed (31.38%–42.22%) amongst exposed groups as to control. The present work shows behavioral alterations due to risperidone exposure (50 µM) in C. elegans is in a time-dependent manner. The study concludes that risperidone exposure in C. elegans produces toxic effects with time, possibly caused by antagonizing other receptors apart from serotonin (5-H2T) and dopamine (D2) adding to its expected pharmacological effects.
Clostridium botulinum neurotoxins are the most potent toxins to humans. The recognition and cleavage of SNAREs are prime evente in exhibiting their toxicity. We report here the crystal structure of ...the catalytically active full-length botulinum serotype E catalytic domain (BoNT E) in complex with SNAP-25 (a SNARE protein) substrate peptide Arg180-Ile181-Met182-Glu183 (P1–P3′). It is remarkable that the peptide spanning the scissile bond binds to but bypasses cleavage by the enzyme and inhibits the catalysis fairly with Ki ∼69 μm. The inhibitory peptide occupies the active site of BoNT E and shows well defined electron density. The catalytic zinc and the conserved key residue Tyr350 of the enzyme facilitate the docking of Arg180 (P1) by interacting with its carbonyl oxygen that displaces the nucleophilic water. The general base Glu212 side chain interacts with the main chain amino group of P1 and P1′. Conserved Arg347 of BoNT E stabilizes the proper docking of the Ile181 (P1′) main chain, whereas the hydrophobic pockets stabilize the side chains of Ile181 (P1′) and Met182 (P2′), and the 250 loop stabilizes Glu183 (P3′). Structural and functional analysis revealed an important role for the P1′ residue and S1′ pocket in driving substrate recognition and docking at the active site. This study is the first of its kind and rationalizes the substrate cleavage strategy of BoNT E. Also, our complex structure opens up an excellent opportunity of structure-based drug design for this fast acting and extremely toxic high priority BoNT E.
The rate of protein evolution is determined by a combination of selective pressure on protein function and biophysical constraints on protein folding and structure. Determining the relative ...contributions of these properties is an unsolved problem in molecular evolution with broad implications for protein engineering and function prediction. As a case study, we examined the structural divergence of the rapidly evolving o -succinylbenzoate synthase (OSBS) family, which catalyzes a step in menaquinone synthesis in diverse microorganisms and plants. On average, the OSBS family is much more divergent than other protein families from the same set of species, with the most divergent family members sharing <15% sequence identity. Comparing 11 representative structures revealed that loss of quaternary structure and large deletions or insertions are associated with the family’s rapid evolution. Neither of these properties has been investigated in previous studies to identify factors that affect the rate of protein evolution. Intriguingly, one subfamily retained a multimeric quaternary structure and has small insertions and deletions compared with related enzymes that catalyze diverse reactions. Many proteins in this subfamily catalyze both OSBS and N -succinylamino acid racemization (NSAR). Retention of ancestral structural characteristics in the NSAR/OSBS subfamily suggests that the rate of protein evolution is not proportional to the capacity to evolve new protein functions. Instead, structural features that are conserved among proteins with diverse functions might contribute to the evolution of new functions.
Lucanthone and hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas hycanthone was pulled out of Phase II trials. ...Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC(50) values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and hycanthone were 5 µM and 80 nM, respectively. The K(D) values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage.
Studies were conducted to examine the effect of pre and post-treatment of selenium in mercury intoxication (20 μmole/ kg b.w. each given intraperitoneally) in mice in terms of lipid peroxidation ...(LPO), glutathione (GSH) content, activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and mercury concentration in liver, kidney and brain. No significant alteration was observed in all the organs examined after mercury or selenium treatment in LPO and GSH but administration of selenium (pre and post) resulted in an increase in the level of LPO and GSH. The activity of SOD was depleted in liver and kidney while that of GPx was lowered in liver of mercury exposed animals. Selenium administration resulted in restoration of the depletion of these enzymatic activities. The activity of CAT in liver and brain was enhanced both in mercury and selenium treated animals. Administration of selenium significantly arrested enhanced CAT activity. Kidney showed the highest mercury concentration among the organs examined. Administration of selenium resulted in further enhancement of mercury concentration in the tissues. An increase in selenium level in liver was observed after mercury treatment, which was also restored by mercury selenium co-administration. Our results indicate that the prooxidant effect of selenium was greater by its pretreatment.
Protein phosphorylation plays a crucial role in mitogenic signal transduction and regulation of cell growth and differentiation. Dual specificity protein phosphatase 23 (DUSP23) or VHZ mediates ...dephosphorylation of phospho-tyrosyl (pTyr) and phospho-seryl/threonyl (pSer/pThr) residues in specific proteins. In vitro, it can dephosphorylate p44ERK1 but not p54SAPK-β and enhance activation of c-Jun N-terminal kinase (JNK) and p38. Human VHZ, the smallest of the catalytically active protein-tyrosine phosphatases (PTP) reported to date (150 residues), is a class I Cys-based PTP and bears the distinctive active site signature motif HCXXGXXRS(T). We present the crystal structure of VHZ determined at 1.93Å resolution. The polypeptide chain adopts the typical αβα PTP fold, giving rise to a shallow active site cleft that supports dual phosphorylated substrate specificity. Within our crystals, the Thr-135–Tyr-136 from a symmetry-related molecule bind in the active site with a malate ion, where they mimic the phosphorylated TY motif of the MAPK activation loop in an enzyme-substrate/product complex. Analyses of intermolecular interactions between the enzyme and this pseudo substrate/product along with functional analysis of Phe-66, Leu-97, and Phe-99 residues provide insights into the mechanism of substrate binding and catalysis in VHZ.
Structural genomics of protein phosphatases Almo, Steven C; Bonanno, Jeffrey B; Sauder, J Michael ...
Journal of structural and functional genomics,
09/2007, Volume:
8, Issue:
2-3
Journal Article
Peer reviewed
Open access
The New York SGX Research Center for Structural Genomics (NYSGXRC) of the NIGMS Protein Structure Initiative (PSI) has applied its high-throughput X-ray crystallographic structure determination ...platform to systematic studies of all human protein phosphatases and protein phosphatases from biomedically-relevant pathogens. To date, the NYSGXRC has determined structures of 21 distinct protein phosphatases: 14 from human, 2 from mouse, 2 from the pathogen Toxoplasma gondii, 1 from Trypanosoma brucei, the parasite responsible for African sleeping sickness, and 2 from the principal mosquito vector of malaria in Africa, Anopheles gambiae. These structures provide insights into both normal and pathophysiologic processes, including transcriptional regulation, regulation of major signaling pathways, neural development, and type 1 diabetes. In conjunction with the contributions of other international structural genomics consortia, these efforts promise to provide an unprecedented database and materials repository for structure-guided experimental and computational discovery of inhibitors for all classes of protein phosphatases.
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