An effective all-atom potential for proteins

We describe and test an implicit solvent all-atom potential for simulations of protein folding and aggregation. The potential is developed through studies of structural and thermodynamic properties of 17 peptides with diverse secondary structure. Results obtained using the final form of the potential are presented for all these peptides. The same model, with unchanged parameters, is furthermore applied to a heterodimeric coiled-coil system, a mixed alpha/beta protein and a three-helix-bundle protein, with very good results. The computational efficiency of the potential makes it possible to investigate the free-energy landscape of these 49--67-residue systems with high statistical accuracy, using only modest computational resources by today's standards

Outcomes of allogeneic stem cell transplantation among patients with acute myeloid leukemia presenting active disease: Experience of a single European Comprehensive Cancer Center

Introduction: Allogeneic hematopoietic stem cell transplantation (ASCT) represents a potentially curative approach for patients with relapsed or refractory acute myeloid leukemia (AML). We report the outcome of relapsed/refractory AML patients treated with ASCT.Method: A retrospective cohort from 1994 to 2013 that included 61 patients with diagnosis of relapsed/refractory AML. Outcomes of interest were transplant-related mortality (TRM), incidence of acute and chronic graft-versus-host disease (GVHD), relapse incidence, progression-free survival (PFS) and overall survival (OS). Statistical significance was set at p<0.05.Results: The median age was 61 years (range 1 to 65). The cumulative incidence of 90 days, 1 year, and 3 years TRM were 60%, 26.7%, and 13.3%, respectively (p< 0.001). The incidence of relapse was 21.7% at 1 year, 13% at 3 years, and 8.7% at 5 years. Median OS was estimated to be 8 months (95CI 3.266-12.734) and median PFS, 3 months (95CI 1.835-4.165).Conclusion: In our cohort, TRM in first years after ASCT remains considerable, but ASCT in this setting seems to be a good choice for AML patients with active disease. However, novel approaches are needed to reduce TRM and relapse in this set of patients

Regression of target organ damage in children and adolescents with primary hypertension

We assessed the effects of 12 months of non-pharmacological and pharmacological therapy on 24-h ambulatory blood pressure, regression of target organ damage (TOD) and metabolic abnormalities in 86 children (14.1 ± 2.4 years) with primary hypertension. Twenty-four hour systolic and diastolic blood pressure (BP) decreased (130 ± 8 vs 126 ± 8, 73 ± 7 vs 70 ± 7, p = 0.0001 and 0.004 respectively). Body mass index (BMI) did not change, but waist-to-hip (0.85 ± 0.07 vs 0.83 ± 0.05, p = 0.01) and waist-to-height ratio (WHtR; 0.49 ± 0.07 vs 0.48 ± 0.05, p = 0.008) decreased. Left ventricular mass index (LVMi; 38.5 ± 10.7 vs 35.2 ± 7.5 g/m2.7, p = 0.0001), prevalence of left ventricular hypertrophy (46.5% vs 31.4%; p = 0.0001), carotid intima-media thickness (cIMT; 0.44 ± 0.05 vs 0.42 ± 0.04 mm, p = 0.0001), wall cross sectional area (WCSA; 7.5 ± 1.3 vs 6.9 ± 1.2 mm2, p = 0.002), hsCRP (1.1 ± 1.0 vs 0.7 ± 0.7 mg/l, p = 0.002), and LDL-cholesterol (115 ± 33 vs 107 ± 26 mg/dl, p = 0.001) decreased. Patients who had lowered BP had a lower cIMT at the second examination (0.41 ± 0.04 vs 0.43 ± 0.04 mm, p = 0.04) and lower initial hsCRP values (0.9 ± 0.7 vs 1.5 ± 1.3 mg/l, p = 0.04) in comparison to non-responders. Regression analysis revealed that the main predictor of LVMi decrease was a decrease in abdominal fat expressed as a decrease in waist circumference (WC) (R2 = 0.280, β = 0.558, p = 0.005), for WCSA-SDS a decrease in WC (R2 = 0.332, β = 0.611, p = 0.009) and for a cIMT-SDS decrease the main predictor was a decrease in hsCRP concentrations (R2 = 0.137, β = 0.412, p = 0.03). Standard antihypertensive treatment lowered BP and led to regression of TOD in hypertensive children. Lean body mass increase and decrease in abdominal obesity correlated with TOD regression

Hypertension in children with chronic kidney disease: pathophysiology and management

Arterial hypertension is very common in children with all stages of chronic kidney disease (CKD). While fluid overload and activation of the renin–angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension. Moreover, several drugs commonly administered in CKD, such as erythropoietin, glucocorticoids and cyclosporine A, independently raise blood pressure in a dose-dependent fashion. Because of the deleterious consequences of hypertension on the progression of renal disease and cardiovascular outcomes, an active screening approach should be adapted in patients with all stages of CKD. Before one starts antihypertensive treatment, non-pharmacological options should be explored. In hemodialysis patients a low salt diet, low dialysate sodium and stricter dialysis towards dry weight can often achieve adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are first-line therapy for patients with proteinuria, due to their additional anti-proteinuric properties. Diuretics are a useful alternative for non-proteinuric patients or as an add-on to renin–angiotensin system blockade. Multiple drug therapy is often needed to maintain blood pressure below the 90th percentile target, but adequate blood pressure control is essential for better renal and cardiovascular long-term outcomes

Patterns of mitochondrial DNA instability in Brassica campestris cultured cells

We previously showed that the mitochondrial DNA (mtDNA) of a Brassica campestris callus culture had undergone extensive rearrangements (i.e. large inversions and a duplication) relative to DNA of the control plant [54]. In this study we observed that after continued growth, the mtDNA of this culture continues to change, with rearranged forms amplifying and diminishing to varying proportions. Strikingly similar changes were detected in the mtDNA profiles of a variety of other long- and short-term callus and cell suspension lines. However, the proportions of parental (‘unrearranged’) and novel (‘rearranged’) forms varied in different cultured cell mtDNAs. To address the source of this heterogeneity, we compared the mtDNA organization of 28 individual plants from the parental seed stock. With the exception of one plant containing high levels of a novel plasmid-like mtDNA molecule, no significant variation was detected among individual plants and therefore source plant variation is unlikely to have contributed to the diversity of mitochondrial genomes observed in cultured cells. The source of this culture-induced heterogeneity was also investigated in 16 clones derived from single protoplasts. A mixed population of unrearranged and rearranged mtDNA molecules was apprent in each protoclone, suggesting that the observed heterogeneity in various cultures might reflect the genomic composition of each individual cell; however, the induction of an intercellular heterogeneity subsequent to the protoplast isolation was not tested and therefore cannot be ruled out. The results of this study support our earlier model that the rapid structural alteration of B. campestris mtDNA in vitro results from preferential amplification and reassortment of minor pre-existing forms of the genome rather than de novo rearrangement. Infrequent recombination between short dispersed repeated elements is proposed as the underlying mechanism for the formation of these minor mtDNA molecules.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43428/1/11103_2004_Article_BF00017914.pd

The adhesion function of the sodium channel beta subunit (beta 1) contributes to cardiac action potential propagation

Computational modeling indicates that cardiac conduction may involve ephaptic coupling – intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) –mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with NaV1.5. Smart patch clamp (SPC) indicated greater sodium current density (INa) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, βadp1, potently and selectively inhibited β1-mediated adhesion, in electric cell-substrate impedance sensing studies. βadp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal INa, but not whole cell INa, in myocyte monolayers. In optical mapping studies, βadp1 precipitated arrhythmogenic conduction slowing. In summary, β1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies