The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Effectiveness and tolerability of transdermal buprenorphine patches: a multicenter, prospective, open-label study in Asian patients with moderate to severe chronic musculoskeletal pain

Abstract Background We examined the effectiveness and tolerability of transdermal buprenorphine (TDB) treatment in real-world setting in Asian patients with musculoskeletal pain. Methods This was an open-label study conducted in Hong Kong, Korea, and the Philippines between June 2013 and April 2015. Eligible patients fulfilled the following criteria: 18 to 80 years of age; clinical diagnosis of osteoarthritis, rheumatoid arthritis, low back pain, or joint/muscle pain; chronic non-malignant pain of moderate to severe intensity (Box-Scale-11 [BS-11] pain score ≥ 4), not adequately controlled with non-opioid analgesics and requiring an opioid for adequate analgesia; and no prior history of opioid treatment. Patients started with a 5 μg/h buprenorphine patch and were titrated as necessary to a maximum of 40 μg/h over a 6-week period to achieve optimal pain control. Patients continued treatment with the titrated dose for 11 weeks. The primary efficacy endpoint was the change in BS-11 pain scores. Other endpoints included patients’ sleep quality and quality of life as assessed by the 8-item Global Sleep Quality Assessment Scale (GSQA) questionnaire and the EuroQol Group 5-Dimension Self-Report Questionnaire-3 Level version (EQ-5D-3 L), respectively. Tolerability was assessed by collecting adverse events. Results A total of 114 eligible patients were included in the analysis. The mean BS-11 score at baseline was 6.2 (SD 1.6). Following initiation of TDB, there was a statistically significant improvement in BS-11 score from baseline to visit 3 (least squares [LS] mean change: -2.27 [95% CI -2.66 to −1.87]), which was maintained till the end of the study (visit 7) (LS mean change: −2.64 [95% -3.05 to −2.23]) (p < 0.0001 for both). The proportion of patients who rated sleep quality as ‘good’ increased from 14.0% at baseline to 26.9% at visit 6. By visit 6, the mean EQ VAS score increased by 7.7 units (SD 17.9). There were also significant improvements in patients’ levels of functioning for all EQ-5D-3 L dimensions from baseline at visit 6 (p < 0.05 for all). Seventy-eight percent of patients reported TEAEs and 22.8% of patients discontinued due to TEAEs. TEAEs were generally mild to moderate in intensity (96.5%). Conclusions TDB provides effective pain relief with an acceptable tolerability profile over the 11-week treatment period in Asian patients with chronic musculoskeletal pain. More studies are needed to examine the long-term efficacy and safety of TBD treatment in this patient population. Trial registration ClinicalTrials.gov NCT01961271 . Registered 7 October 2013 (retrospectively registered; first patient was enrolled on 28 June 2013 and last patient last visit date was 26 Apr 2015)

‘Preaching Disaffection’ in the Presbyterian Atlantic: Jotham Blanchard and the Reform Crisis in Scotland and Nova Scotia, c. 1827–37

In the 1820s and '30s Jotham Blanchard (1800-38), assemblyman for Pictou, Nova Scotia, launched a reform campaign against the Nova Scotian government. With the help of his mentor, the Rev. Thomas McCulloch, a Presbyterian missionary from Scotland, Blanchard attacked the colonial establishment for its failure to support the Pictou Academy, a college of higher learning for religious dissenters. Connected to a transatlantic denominational information web, Blanchard and McCulloch were inspired by the radical ecclesiology of the Scottish United Secession Church, with which McCulloch was affiliated. In 1831 Blanchard travelled to Britain to lobby the Colonial Office. There he was aided by the ministers of the United Secession, currently embroiled in their own local campaign in support of the Reform Bill. Blanchard's visit impacted on the domestic scene and the two campaigns became closely interwoven. Unfortunately for Blanchard his mission failed and he was written out of Nova Scotian history. Colonial historiography, concerned with celebrating the role of local heroes in the struggle for national self-determination, has focused overwhelmingly on the legacy of Joseph Howe, the triumphant champion of responsible government. Situating the Nova Scotian campaign within a transatlantic context, this article resurrects Blanchard's career and underlines its importance.</p