Tectonic Implication of the 5th March 2005, Doublet Earthquake in Ilan, Taiwan

The 5th March 2005 earthquake doublet focal mechanism was determined as strike-slip faulting from Harvard and BATS moment tensor inversion. However, based on first motion polarities, the first shock has a normal focal mechanism (Wu et al. 2008a). This discrepancy has caused a debate over the focal mechanism solution because different focal mechanisms have different tectonic implications. Based on the dislocation determination from Global Position System (GPS) measurements, we find this event includes both tensile and strike-slip components. This finding illustrates the reason for the differences in the determined focal mechanisms using two different types of seismic data and analyzing methods. Field mapping and microstructure examination results indicate that the ductile deformation around the study area was characterized by the evolution from transpression to transtension with a predominant strike-slip component, but present-day active structures may be dominated by normal faulting. Thus, the active tensile slip result determined from dislocation modeling strongly suggests that the back arc extension of the Okinawa trough influences the stress state in this region, and changes the major transtension from strike-slip faulting to normal faulting

Nitric oxide activates ATP-sensitive potassium channels in mammalian sensory neurons: action by direct S-nitrosylation

<p>Abstract</p> <p>Background</p> <p>ATP-sensitive potassium (K_ATP) channels in neurons regulate excitability, neurotransmitter release and mediate protection from cell-death. Furthermore, activation of K_ATPchannels is suppressed in DRG neurons after painful-like nerve injury. NO-dependent mechanisms modulate both K_ATPchannels and participate in the pathophysiology and pharmacology of neuropathic pain. Therefore, we investigated NO modulation of K_ATPchannels in control and axotomized DRG neurons.</p> <p>Results</p> <p>Cell-attached and cell-free recordings of K_ATPcurrents in large DRG neurons from control rats (sham surgery, SS) revealed activation of K_ATPchannels by NO exogenously released by the NO donor SNAP, through decreased sensitivity to [ATP]i.</p> <p>This NO-induced K_ATPchannel activation was not altered in ganglia from animals that demonstrated sustained hyperalgesia-type response to nociceptive stimulation following spinal nerve ligation. However, baseline opening of K_ATPchannels and their activation induced by metabolic inhibition was suppressed by axotomy. Failure to block the NO-mediated amplification of K_ATPcurrents with specific inhibitors of sGC and PKG indicated that the classical sGC/cGMP/PKG signaling pathway was not involved in the activation by SNAP. NO-induced activation of K_ATPchannels remained intact in cell-free patches, was reversed by DTT, a thiol-reducing agent, and prevented by NEM, a thiol-alkylating agent. Other findings indicated that the mechanisms by which NO activates K_ATPchannels involve direct S-nitrosylation of cysteine residues in the SUR1 subunit. Specifically, current through recombinant wild-type SUR1/Kir6.2 channels expressed in COS7 cells was activated by NO, but channels formed only from truncated isoform Kir6.2 subunits without SUR1 subunits were insensitive to NO. Further, mutagenesis of SUR1 indicated that NO-induced K_ATPchannel activation involves interaction of NO with residues in the NBD1 of the SUR1 subunit.</p> <p>Conclusion</p> <p>NO activates K_ATPchannels in large DRG neurons via direct S-nitrosylation of cysteine residues in the SUR1 subunit. The capacity of NO to activate K_ATPchannels via this mechanism remains intact even after spinal nerve ligation, thus providing opportunities for selective pharmacological enhancement of K_ATPcurrent even after decrease of this current by painful-like nerve injury.</p

A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro

AbstractTAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

A simple method to assess freezing of gait in Parkinson's disease patients

Freezing of gait (FOG) can be assessed by clinical and instrumental methods. Clinical examination has the advantage of being available to most clinicians; however, it requires experience and may not reveal FOG even for cases confirmed by the medical history. Instrumental methods have an advantage in that they may be used for ambulatory monitoring. The aim of the present study was to describe and evaluate a new instrumental method based on a force sensitive resistor and Pearson's correlation coefficient (Pcc) for the assessment of FOG. Nine patients with Parkinson's disease in the "on" state walked through a corridor, passed through a doorway and made a U-turn. We analyzed 24 FOG episodes by computing the Pcc between one "regular/normal" step and the rest of the steps. The Pcc reached +/- 1 for "normal" locomotion, while correlation diminished due to the lack of periodicity during FOG episodes. Gait was assessed in parallel with video. FOG episodes determined from the video were all detected with the proposed method. The computed duration of the FOG episodes was compared with those estimated from the video. The method was sensitive to various types of freezing; although no differences due to different types of freezing were detected. The study showed that Pcc analysis permitted the computerized detection of FOG in a simple manner analogous to human visual judgment, and its automation may be useful in clinical practice to provide a record of the history of FOG