CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy.

Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

Yeast heterochromatin regulators Sir2 and Sir3 act directly at euchromatic DNA replication origins.

Most active DNA replication origins are found within euchromatin, while origins within heterochromatin are often inactive or inhibited. In yeast, origin activity within heterochromatin is negatively controlled by the histone H4K16 deacetylase, Sir2, and at some heterochromatic loci also by the nucleosome binding protein, Sir3. The prevailing view has been that direct functions of Sir2 and Sir3 are confined to heterochromatin. However, growth defects in yeast mutants compromised for loading the MCM helicase, such as cdc6-4, are suppressed by deletion of either SIR2 or SIR3. While these and other observations indicate that SIR2,3 can have a negative impact on at least some euchromatic origins, the genomic scale of this effect was unknown. It was also unknown whether this suppression resulted from direct functions of Sir2,3 within euchromatin, or was an indirect effect of their previously established roles within heterochromatin. Using MCM ChIP-Seq, we show that a SIR2 deletion rescued MCM complex loading at ~80% of euchromatic origins in cdc6-4 cells. Therefore, Sir2 exhibited a pervasive effect at the majority of euchromatic origins. Using MNase-H4K16ac ChIP-Seq, we show that origin-adjacent nucleosomes were depleted for H4K16 acetylation in a SIR2-dependent manner in wild type (i.e. CDC6) cells. In addition, we present evidence that both Sir2 and Sir3 bound to nucleosomes adjacent to euchromatic origins. The relative levels of each of these molecular hallmarks of yeast heterochromatin-SIR2-dependent H4K16 hypoacetylation, Sir2, and Sir3 -correlated with how strongly a SIR2 deletion suppressed the MCM loading defect in cdc6-4 cells. Finally, a screen for histone H3 and H4 mutants that could suppress the cdc6-4 growth defect identified amino acids that map to a surface of the nucleosome important for Sir3 binding. We conclude that heterochromatin proteins directly modify the local chromatin environment of euchromatic DNA replication origins.

How do social determinants affect human trafficking in Southeast Asia, and what can we do about it? A systematic review.

BACKGROUND: The sale of women and children accounts for the greatest proportion of human trafficking globally, with Southeast Asia acting as the illegal industry's largest international hub. At least 225,000 women and children are trafficked from the region every year, accounting for approximately one-third of the global human trade. The health ramifications of trafficking are severe: many survivors contract infectious diseases including sexually transmitted infections and develop mental health conditions, including anxiety, panic disorder, and major depression. The complications associated with studying a highly secretive illegal trade have severely limited research on effective prevention measures. Because this presents a challenge for organizations that hope to develop prevention strategies, we asked the following question: How do social determinants facilitate or mitigate trafficking of women and children in Southeast Asia, and what recommendations does the literature provide for combating trafficking via these social determinants? METHODS: Using a Cochrane-based systematic search methodology, five independent researchers reviewed 1,148 articles from the past ten years (2001­2011). After three phases of independent review, they selected and analyzed 61 articles to identify the determinants that impact trafficking of women and children in Southeast Asia. RESULTS: Key social determinants that facilitate trafficking include poverty, female gender, lack of policy and enforcement, age, migration, displacement and conflict, ethnicity, culture, ignorance of trafficking methods, and caste status. Conversely, protective determinants that mitigate trafficking include formal education, citizenship, maternal education, higher caste status, and birth order. Recommendations relating to a variety of the determinants are identified and discussed in detail. CONCLUSIONS: Social determinants are central to the processes that mitigate and facilitate the sale and exploitation of women and children in Southeast Asia. Specifically, the facilitation of education and empowerment, along with the creation and enforcement of effective policies, could lessen the vulnerability of women and children to modern-day slavery.