BackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms.Methodology/Principal FindingsWe performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5′) exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls.Conclusions/SignificanceThe consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

Post-translational sulfation of tyrosines affects the affinity and binding of at least some chemokine receptors to their ligand(s) and has been hypothesized to be a feature in all chemokine receptors. This binding initiates downstream signaling cascades. By this mechanism, tyrosine sulfation can influence the cells involved in acute and chronic events of cellular immunity. These events include leukocyte trafficking and airway inflammation important in asthma and chronic obstructive pulmonary disease (COPD). We are using computational methods to convert the poorly defined hypothesis of more widespread sulfation of chemokine receptors to more specific assessments of how closely the sequence environment of each tyrosine residue resembles the sequence environment of tyrosine residues proven to be sulfated. Thus, we provide specific and readily tested hypotheses about the tyrosine residues in all of the chemokine receptors. Tyrosine sulfation was predicted with high scores in the N-terminus domain of 13 out of 18 human chemokine receptor proteins using a position-specific scoring matrix, which was determined to be 94.2% accurate based on Receiver Operating Characteristic analysis. The remaining chemokine receptors have sites exhibiting features of tyrosine sulfation. These putative sites demonstrate clustering in a manner consistent with known tyrosine sulfation sites and conservation both within the chemokine receptor family and across mammalian species. Human chemokine receptors important in asthma and COPD, such as CXCR1, CXCR2, CXCR3, CXCR4, CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, contain at least one known or predicted tyrosine sulfation site. Recognition that tyrosine sulfation is found in most clinically relevant chemokine receptors could help the development of specific receptor-ligand antagonists to modulate events important in airway diseases.

There are few studies on the role of phonation cues in the perception of lexical tones in tonal languages where pitch is the primary dimension of contrast. This study shows that listeners are sensitive to creaky phonation in native tonal perception in Cantonese, a language in which the low falling tone, Tone 4, has anecdotally been reported to be sometimes creaky. First, in a multi-speaker corpus of lab speech, it is documented that creak occurs systematically more often on Tone 4 than other tones. Second, for stimuli drawn from this corpus, listeners identified Tone 4 with 20% higher accuracy when it was realized with creak than when it was not. Third, in a two-alternative forced choice task of identifying stimuli as Tone 4 or Tone 6 (the low level tone) isolating creak from any concomitant pitch cues, listeners had a higher proportion of Tone 4 responses for creaky stimuli. Finally, listeners had more Tone 4 responses for creaky stimuli with longer durations of nonmodal phonation. These results underscore that differences in voice quality contribute to human perception of tone alongside f0. Automatic tonal recognition and clinical applications for tone would benefit from attention to voice quality beyond f0 and pitch.

Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

While it has long been clear that prosody should be part of the grammar influencing the action of the syntactic parser, how to bring prosody into computational models of syntactic parsing has remained unclear. The challenge is that prosodic information in the speech signal is the result of the interaction of a multitude of conditioning factors. From this output, how can we factor out the contribution of syntax to conditioning prosodic events? And if we are able to do that factorization and define a production model from the syntactic grammar to a prosodified utterance, how can we then define a comprehension model based on that production model? In this case study of the Samoan morphosyntax-prosody interface, we show how to factor out the influence of syntax on prosody in empirical work and confirm there is invariable morphosyntactic conditioning of high edge tones. Then, we show how this invariability can be precisely characterized and used by a parsing model that factors the various influences of morphosyntax on tonal events. We expect that models of these kinds can be extended to more comprehensive perspectives on Samoan and to languages where the syntax/prosody coupling is more complex.