Cohesin-mediated loop anchors confine the locations of human replication origins.

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3-6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.

Effectiveness of the Rigo Chêneau versus Boston-style orthoses for adolescent idiopathic scoliosis: a retrospective study.

BACKGROUND: Bracing can effectively treat adolescent idiopathic scoliosis (AIS), but patient outcomes have not been compared by brace type. We compared outcomes of AIS patients treated with Rigo Chêneau orthoses (RCOs) or custom-molded Boston-style thoracolumbosacral orthoses (TLSOs). METHODS: We retrospectively reviewed patient records from one scoliosis center from 1999 through 2014. Patients were studied from initial treatment until skeletal maturity or surgery. Inclusion criteria were a diagnosis of AIS, initial major curve between 25° and 40°, use of an RCO or TLSO, and no previous scoliosis treatment. RESULTS: The study included 108 patients (93 girls) with a mean (±standard deviation) age at brace initiation of 12.5 ± 1.3 years. Thirteen patients wore an RCO, and 95 wore a TLSO. Mean pre-bracing major curves were 32.7° ± 4.8° in the RCO group and 31.4° ± 4.4° in the TLSO group (p = 0.387). Mean brace wear time was similar between groups. Mean differences in major curve from baseline to follow-up were -0.4° ± 9.9° in the RCO group and 6.9° ± 12.1° in the TLSO group (p = 0.028). Percent changes in major curve from baseline to follow-up were 0.0% ± 30.5% for the RCO group and 21.3% ± 38.8% for the TLSO group (p = 0.030). No RCO patients and 34% of TLSO patients progressed to spinal surgery (p = 0.019). At follow-up, major curves improved by 6° or more in 31% of the RCO group and 13% of the TLSO group (p = 0.100). CONCLUSIONS: Patients treated with RCOs compared with Boston-style TLSOs had similar baseline characteristics and brace wear time yet significantly lower rates of spinal surgery. Patients with RCOs also had lower mean and percent major curve progression versus those with TLSOs.