Department of Bioscience & Bioengineering

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The tumor suppressor protein Pdcd4 is thought to suppress translation of mRNAs containing structured 5′-UTRs by interacting with translation initiation factor eIF4A and inhibiting its helicase activity. However, natural target mRNAs regulated by Pdcd4 so far are mostly unknown. Here, we identified p53 mRNA as a translational target of Pdcd4. We found that Pdcd4 is associated with p53 mRNA and suppresses its translation. The inhibitory effect of Pdcd4 on the translation of p53 mRNA depends on the ability of Pdcd4 to interact with eIF4A and is mediated by the 5′-UTR of p53 mRNA, which is able to form a stable stem-loop structure. We show that treatment of cells with DNA-damaging agents decreases the expression of Pdcd4. This suggests that translational suppression by Pdcd4 plays a role in maintaining a low level of p53 in unstressed cells and that this suppression is abrogated due to low levels of Pdcd4 after DNA damage. Overall, our work demonstrates for the first time that Pdcd4 is directly involved in translational suppression of a natural mRNA with a 5′-structured UTR and provides novel insight into the translational control of p53 expression. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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Journal of Biological Chemistry

Tumor suppressor protein Pdcd4 inhibits translation of p53 mRNA

Natively unfolded or intrinsically disordered proteins (IDPs) are under intense scrutiny due to their involvement in both normal biological functions and abnormal protein misfolding disorders. Polypeptide chain collapse of amyloidogenic IDPs is believed to play a key role in protein misfolding, oligomerization, and aggregation leading to amyloid fibril formation, which is implicated in a number of human diseases. In this work, we used bovine κ-casein, which serves as an archetypal model protein for amyloidogenic IDPs. Using a variety of biophysical tools involving both prediction and spectroscopic techniques, we first established that monomeric κ-casein adopts a collapsed premolten-globule-like conformational ensemble under physiological conditions. Our time-resolved fluorescence and light-scattering data indicate a change in the mean hydrodynamic radius from ∼4.6 nm to ∼1.9 nm upon chain collapse. We then took the advantage of two cysteines separated by 77 amino-acid residues and covalently labeled them using thiol-reactive pyrene maleimide. This dual-labeled protein demonstrated a strong excimer formation upon renaturation from urea- and acid-denatured states under both equilibrium and kinetic conditions, providing compelling evidence of polypeptide chain collapse under physiological conditions. The implication of the IDP chain collapse in protein aggregation and amyloid formation is also discussed. © 2011 Biophysical Society.

Biophysical Journal

Chain collapse of an amyloidogenic intrinsically disordered protein

Serum albumins are multi-domain all α-helical proteins that are present in the circulatory system and aid in the transport of a variety of metabolites, endogenous ligands, drugs etc. Earlier observations have indicated that serum albumins adopt a range of reversible conformational isomers depending on the pH of the solution. Herein, we report the concurrent changes in the protein conformation and size that are inherent to the pH-induced conformational isomers of bovine serum albumin (BSA). We have investigated the fluorescence properties of both intrinsic (tryptophan) and extrinsic (ANS, pyrene) fluorophores to shed light into the structural features of the pH-dependent conformers. We have been able to identify a number of conformational isomers using multiple fluorescence observables as a function of pH titration. Our results indicate that at pH 3, a partially-folded, 'molten-globule-like' state is populated. Moreover, equilibrium unfolding studies indicated that the 'molten-globule-like' state unfolds in a non-cooperative fashion and is thermodynamically less stable than the native state. The fluorescence-based approach described in the present work has implications in the study of pH-induced conformational plasticity of other physiologically relevant proteins. © Springer Science+Business Media, LLC 2011.

Journal of Fluorescence

pH-Induced conformational isomerization of bovine serum albumin studied by extrinsic and intrinsic protein fluorescence

Energy extraction from one source and perhaps in tandem from multiple natural sources such as wind, ocean waves and perhaps geothermal resources with devices that are not susceptible to wear and tear remains an outstanding challenge. Here we propose a simple, strongly non-linear system which is potentially capable of being tuned to just about any driving frequency and amplitude. The system consists of an alignment of N elastic spheres that are barely in contact and are of fixed or variable radius and held between two ends. When a persistent driving force is imparted at an edge grain, the system can end up in an oversqueezed state. Since a mechanical system must respond to unbalanced forces, such an oversqueezed system must eventually dilate. Persistent presence of the driving force can then end up forcing the system to vacillate between the oversqueezed and dilated states. The frequencies associated with such breathing processes are non-universal, depending on the system parameters and the details of the driving force itself This is why confined driven granular alignments can be made to respond to a wide range of frequencies and hence can turn out to be potentially useful tools for energy extraction. Here we briefly summarize our earlier work where we showed how these systems respond to a fixed driving force and then provide new results on the system response when time-dependent driving forces are involved. Needless to say, these systems may, in due course, be realized as both mechanical systems and as electrical circuits. © Authors 2011.

Proceedings of the Institution of Mechanical Engineers. Part I: Journal of Systems and Control Engineering

Non-linear resonance-like processes in confined driven granular alignments and energy harvesting

The study of the dynamics of 1D chains with both harmonic and nonlinear interactions, as in the Fermi-Pasta-Ulam (FPU) and related problems, has played a central role in efforts to identify the broad consequences of nonlinearity in these systems. Here we study the dynamics of highly localized excitations, or discrete breathers, which are known to be initiated by the quasistatic stretching of bonds between adjacent particles. We show via dynamical simulations that acoustic waves introduced by the harmonic term stabilize the discrete breather by suppressing the breather's tendency to delocalize and disperse. We conclude that the harmonic term, and hence acoustic waves, are essential for the existence of localized breathers in these systems. © Indian Academy of Sciences.

Pramana - Journal of Physics

Linearity stabilizes discrete breathers

Sustained ability to absorb impulses at varied temperatures using light, hard materials and at length scales of few centimeters has been a challenge. The tapered chains while effective have been difficult to construct for applications. Here we build on Hong's granular protector concept to show that strong inertial mismatches due to alternate sets of few massive and light grains in elastically matched monosized granular alignments seem promising in absorbing impulses across millisecond time scales within a few centimeters. We propose a system which could find applications in the context of the construction and automobile industries, in combat, and elsewhere. © 2011 American Institute of Physics.

Applied Physics Letters

Impulse absorption using small, hard panels of embedded cylinders with granular alignments

Objective-: To investigate the role of recombinant human interleukin-11 (rhIL-11) on in vivo mobilization of CD34/vascular endothelial growth factor receptor (VEGFR) 2 mononuclear cells and collateral vessel remodeling in a mouse model of hindlimb ischemia. Methods and results-: We observed that treatment of Sv129 mice with continuous infusion of 200-μg/kg rhIL-11 per day led to in vivo mobilization of CD34/VEGFR2 cells that peaked at 72 hours. Sv129 mice pretreated with rhIL-11 for 72 hours before femoral artery ligation showed a 3-fold increase in plantar vessel perfusion, leading to faster blood flow recovery; and a 20-fold increase in circulating CD34/VEGFR2 cells after 8 days of rhIL-11 treatment. Histologically, experimental mice had a 3-fold increase in collateral vessel luminal diameter after 21 days of rhIL-11 treatment and a 4.4-fold influx of perivascular CD34/VEGFR2 cells after 8 days of therapy. Functionally, rhIL-11-treated mice showed better hindlimb appearance and use scores when compared with syngeneic mice treated with PBS under the same experimental conditions. Conclusion-: These novel findings show that rhIL-11 promotes in vivo mobilization of CD34/VEGFR2 mononuclear cells, enhances collateral vessel growth, and increases recovery of perfusion after femoral artery ligation. Thus, rhIL-11 has a promising role for development as an adjunctive treatment of patients with peripheral vascular disease. © 2011 American Heart Association, Inc.

Arteriosclerosis, Thrombosis, and Vascular Biology

Recombinant human interleukin-11 treatment enhances collateral vessel growth after femoral artery ligation

Journal of Biosciences

Brain-muscle interface: The next-generation BMI

Brains of adult mammals retain remarkable ability to undergo plastic reorganization. Deafferentations due to peripheral nerve or spinal cord injuries, result in parts of the somatosensory cortex which loose their peripheral inputs, acquiring novel inputs originating in the intact parts of the system. For example, after injuries to the dorsal columns of the spinal cord at cervical levels, intact inputs from the face expand to reactivate neurons in the deafferented hand cortex. The reorganization results in changes in the topographic organization of the brain, which takes place at multiple levels of the system - the cortex, the thalamic nuclei and the brain stem nuclei. The ability of the brain to reorganize has the potential to be utilized for facilitating functional recoveries by potentiation of remaining neuronal circuits after injuries. Brain reorganization can also have undesirable perceptual consequences such as phantom sensations. Experiments from many laboratories have lead to our current understanding of the nature of reorganization, and have given tantalizing clues about the possible mechanisms of adult brain plasticity. © 2012 by Nova Science Publishers, Inc. All rights reserved.

Expanding Horizons of the Mind Science(s)

Plasticity of the somatosensory system following spinal and peripheral injuries

Selection of reliable genes from a huge gene expression data containing high intergene correlation is essential to carry out a diagnostic test and successful treatment. In this regard, a rough set based gene selection algorithm is reported, which selects a set of genes by maximizing the relevance and significance of the selected genes. A gene ontology-based similarity measure is proposed to analyze the functional diversity of the selected genes. It also helps to analyze the effectiveness of different gene selection methods. The performance of the rough set based gene selection algorithm, along with a comparison with other gene selection methods, is studied using the predictive accuracy of K-nearest neighbor rule and support vector machine on two cancer and one arthritis microarray data sets. An important finding is that the rough set based gene selection algorithm selects more functionally diverse set of genes than the existing algorithms. © 2011 Springer-Verlag.