Although the biological activity of the insect moulting hormone ecdysone, is manifested through a hormonally regulated transcriptional cascade associated with chromosomal puffing, a direct association of the receptor with the puff has yet to be established. The cloned ecdysone receptor (EcR) is by itself incapable of high-affinity DNA binding or transcriptional activation. Rather, these activities are dependent on heterodimer formation with Ultraspiracle (USP) the insect homologue of vertebrate retinoid X receptor. Here we report that native EcR and USP are co-localized on ecdysone-responsive loci of polytene chromosomes. Moreover, we show that natural ecdysones selectively promote physical association between EcR and USP, and conversely, that high-affinity hormone binding requires both EcR and USP. Replacement of USP with retinoid X receptor produces heterodimers with distinct pharmacological and functional properties. These results redefine the ecdysone receptor as a dynamic complex whose activity may be altered by combinatorial interactions among subunits and ligand.

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A phytochrome-like protein called Ppr was discovered in the purple photosynthetic bacterium Rhodospirillum centenum. Ppr has a photoactive yellow protein (PYP) amino-terminal domain, a central domain with similarity to phytochrome, and a carboxyl-terminal histidine kinase domain. Reconstitution experiments demonstrate that Ppr covalently attaches the blue light-absorbing chromophore p-hydroxycinnamic acid and that it has a photocycle that is spectrally similar to, but kinetically slower than, that of PYP. Ppr also regulates chalcone synthase gene expression in response to blue light with autophosphorylation inhibited in vitro by blue light. Phylogenetic analysis demonstrates that R. centenum Ppr may be ancestral to cyanobacterial and plant phytochromes.

Aims Left bundle branch pacing (LBBP) recently emerges as a novel pacing modality. We aimed to evaluate the feasibility and cardiac synchrony of permanent LBBP in bradycardia patients. Methods and results Left bundle branch pacing was successfully performed in 56 pacemaker-indicated patients with normal cardiac function. Left bundle branch pacing was achieved by penetrating the interventricular septum (IVS) into the left side sub-endocardium with the pacing lead. His-bundle pacing (HBP) was successfully performed in another 29 patients, 19 of whom had right ventricular septal pacing (RVSP) for backup pacing. The QRS duration, left ventricular (LV) activation time (LVAT), and mechanical synchrony using phase analysis of gated SPECT myocardial perfusion imaging were evaluated. Paced QRS duration in LBBP group was significantly shorter than that in RVSP group (117.8 ± 11.0 ms vs. 158.1 ± 11.1 ms, P < 0.0001) and wider than that in HBP group (99.7 ± 15.6 ms, P < 0.0001). Left bundle branch potential was recorded during procedure in 37 patients (67.3%). Left bundle branch pacing patients with potential had shorter LVAT than those without potential (73.1 ± 11.3 ms vs. 83.2 ± 16.8 ms, P = 0.03). Left bundle branch pacing patients with potential had similar LV mechanical synchrony to those in HBP group. R-wave amplitude and capture threshold of LBBP were 17.0 ± 6.7 mV and 0.5 ± 0.1 V, respectively at implant and remained stable during a mean follow-up of 4.5 months without lead-related complications. Conclusion Permanent LBBP through IVS is safe and feasible in bradycardia patients. Left bundle branch pacing could achieve favourable cardiac electrical and LV mechanical synchrony.

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BackgroundLeft bundle branch area pacing (LBBAP) was reported to improve cardiac function by correcting complete left bundle branch block (CLBBB). Our study aimed to compare the efficacy of LBBAP and biventricular pacing (BIVP) in heart failure patients with CLBBB.MethodsTen patients prospectively underwent LBBAP (LBB‐CRT group) and 30 patients received BIVP (BIV‐CRT group) were matched using propensity score matching. LBBAP was achieved by the trans‐interventricular septum method. Echocardiography, electrocardiogram, NYHA classification, and blood B‐type natriuretic peptide concentration were evaluated at preimplantation and at 6‐month follow up. CRT response was defined as at least 15% decrease in left ventricular end‐systolic volume.ResultsIn the LBB‐CRT group, CLBBB were successfully corrected by LBBAP with no complications. QRS duration (QRSd) significantly decreased after implantation in both groups, and the decrease of QRSd in the LBB‐CRT group was significantly greater than that in the BIV‐CRT group (60.80 ± 20.09 vs. 33.00 ± 21.48 ms, p = .0009). The echocardiographic measurements including left ventricular end‐diastolic diameter, left ventricular end‐systolic diameter, and left ventricular ejection fraction significantly improved after 6 months in both groups. The response rate was significantly higher in LBB‐CRT group than BIV‐CRT group (100.00% vs. 63.33%, p = .038). The percentage of patients in New York Heart Association classification Grades I and II was significantly higher in the LBB‐CRT group compared with that in the BIV‐CRT group (median 1.5 vs. 2.0, p = .029) at 6‐month follow‐up.ConclusionsIt is effective and safe to correct CLBBB with LBBAP in heart failure patients. Compared with BIVP, LBBAP can better optimize electrical synchrony and improve cardiac function.

BACKGROUND.Current methods for the detection and surveillance of bladder cancer (BCa) are often invasive and/or possess suboptimal sensitivity and specificity, especially in early-stage, minimal, and residual tumors. METHODS.We developed an efficient method, termed utMeMA, for the detection of urine tumor DNA methylation at multiple genomic regions by MassARRAY. We identified the BCa-specific methylation markers by combined analyses of cohorts from Sun Yat-sen Memorial Hospital (SYSMH), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) database. The BCa diagnostic model was built in a retrospective cohort (n = 313) and validated in a multicenter, prospective cohort (n = 175). The performance of this diagnostic assay was analyzed and compared with urine cytology and FISH. RESULTS.We first discovered 26 significant methylation markers of BCa in combined analyses. We built and validated a 2-marker-based diagnostic model that discriminated among patients with BCa with high accuracy (86.7%), sensitivity (90.0%), and specificity (83.1%). Furthermore, the utMeMA-based assay achieved a great improvement in sensitivity over urine cytology and FISH, especially in the detection of early-stage (stage Ta and low-grade tumor, 64.5% vs. 11.8%, 15.8%), minimal (81.0% vs. 14.8%, 37.9%), residual (93.3% vs. 27.3%, 64.3%), and recurrent (89.5% vs. 31.4%, 52.8%) tumors. The urine diagnostic score from this assay was better associated with tumor malignancy and burden. CONCLUSION.Urine tumor DNA methylation assessment for early diagnosis, minimal, residual tumor detection and surveillance in BCa is a rapid, high-throughput, noninvasive, and promising approach, which may reduce the burden of cystoscopy and blind second surgery.