Two-stimuli manipulation of a biological motor

F1-ATPase is an enzyme acting as a rotary nano-motor. During catalysis subunits of this enzyme complex rotate relative to other parts of the enzyme. Here we demonstrate that the combination of two input stimuli causes stop of motor rotation. Application of either individual stimulus did not significantly influence motor motion. These findings may contribute to the development of logic gates using single biological motor molecules

Adjunctive dabigatran therapy improves outcome of experimental left-sided <i>Staphylococcus aureus</i> endocarditis

<div><p>Background</p><p><i>Staphylococcus aureus</i> is the most frequent and fatal cause of left-sided infective endocarditis (IE). New treatment strategies are needed to improve the outcome. <i>S</i>. <i>aureus</i> coagulase promotes clot and fibrin formation. We hypothesized that dabigatran, could reduce valve vegetations and inflammation in <i>S</i>. <i>aureus</i> IE.</p><p>Methods</p><p>We used a rat model of severe aortic valve <i>S</i>. <i>aureus</i> IE. All infected animals were randomized to receive adjunctive dabigatran (10 mg/kg b.i.d., <i>n</i> = 12) or saline (controls, <i>n</i> = 11) in combination with gentamicin. Valve vegetation size, bacterial load, cytokine, cell integrins expression and peripheral platelets and neutrophils were assessed 3 days post-infection.</p><p>Results</p><p>Adjunctive dabigatran treatment significantly reduced valve vegetation size compared to controls (p< 0.0001). A significant reduction of the bacterial load in aortic valves was seen in dabigatran group compared to controls (p = 0.02), as well as expression of key pro-inflammatory markers keratinocyte-derived chemokine, IL-6, ICAM-1, TIMP-1, L-selectin (p< 0.04). Moreover, the dabigatran group had a 2.5-fold increase of circulating platelets compared to controls and a higher expression of functional and activated platelets (CD62p⁺) unbound to neutrophils.</p><p>Conclusion</p><p>Adjunctive dabigatran reduced the vegetation size, bacterial load, and inflammation in experimental <i>S</i>. <i>aureus</i> IE.</p></div

Speckle-Tracking Echocardiography for Predicting Outcome in Chronic Aortic Regurgitation During Conservative Management and After Surgery

ObjectivesThe aim of this study was to test myocardial deformation imaging using speckle-tracking echocardiography for predicting outcomes in chronic aortic regurgitation.BackgroundIn chronic aortic regurgitation, left ventricular (LV) dysfunction must be detected early to allow timely surgery. Speckle-tracking echocardiography has been proposed for this purpose, but the clinical value of this method in aortic regurgitation has not been established.MethodsA longitudinal study was performed in 64 patients with moderate to severe aortic regurgitation. Thirty-five patients were managed conservatively with frequent clinical visits and sequential echocardiography and followed for an average of 19 ± 8 months, while 29 patients underwent surgery for the valve lesion and were followed for 6 months post-operatively. Baseline LV function by speckle-tracking and conventional echocardiography was compared with impaired outcome after surgery (defined as persisting symptoms or persisting LV dilation [LV end-diastolic volume index ≥87 ml/m2] or dysfunction [LV ejection fraction <50%]) and with disease progression during conservative management (defined as development of symptoms, increase in LV volume >15%, or decrease in LV ejection fraction >10%).ResultsReduced myocardial systolic strain, systolic strain rate, and early diastolic strain rate by speckle-tracking echocardiography was associated with disease progression during conservative management (−16.3% vs. −19.0%, p = 0.02; −1.04 vs. −1.19 s−1, p = 0.02; and 1.20 vs. 1.60 s−1, p = 0.002, respectively) and with impaired outcome after surgery (−11.5% vs. −15.6%, p = 0.01; −0.88 vs. −1.01 s−1, p = 0.04; and 0.98 vs. 1.33 s−1, p = 0.01, respectively). Conventional parameters of LV function and size (LV ejection fraction and LV end-diastolic volume index) were associated with outcome after surgery (p = 0.04 and p = 0.01, respectively) but not with outcome during conservative management (p = 0.57 and p = 0.39, respectively).ConclusionsSpeckle-tracking echocardiography is useful for the early detection of LV systolic and diastolic dysfunction in chronic aortic regurgitation

Cardiac dysfunction in a porcine model of pediatric malnutrition

Half a million children die annually of severe acute malnutrition and cardiac dysfunction may contribute to the mortality. However, cardiac function remains poorly examined in cases of severe acute malnutrition.To determine malnutrition-induced echocardiographic disturbances and longitudinal changes in plasma pro-atrial natriuretic peptide and cardiac troponin-T in a pediatric porcine model.Five-week old piglets (Duroc-x-Danish Landrace-x-Yorkshire) were fed a nutritionally inadequate maize-flour diet to induce malnutrition (MAIZE, n = 12) or a reference diet (AGE-REF, n = 12) for 7 weeks. Outcomes were compared to a weight-matched reference group (WEIGHT-REF, n = 8). Pro-atrial natriuretic peptide and cardiac troponin-T were measured weekly. Plasma pro-atrial natriuretic peptide decreased in both MAIZE and AGE-REF during the first 3 weeks but increased markedly in MAIZE relative to AGE-REF during week 5-7 (p ≤ 0.001). There was overall no difference in plasma cardiac troponin-T between groups. However, further analysis revealed that release of cardiac troponin-T in plasma was more frequent in AGE-REF compared with MAIZE (OR: 4.8; 95%CI: 1.2-19.7; p = 0.03). However, when release occurred, cardiac troponin-T concentration was 6.9-fold higher (95%CI: 3.0-15.9; p < 0.001) in MAIZE compared to AGE-REF. At week 7, the mean body weight in MAIZE was lower than AGE-REF (8.3 vs 32.4 kg, p < 0.001), whereas heart-weight relative to body-weight was similar across the three groups. The myocardial performance index was 86% higher in MAIZE vs AGE-REF (p < 0.001) and 27% higher in MAIZE vs WEIGHT-REF (p = 0.025).Malnutrition associates with cardiac dysfunction in a pediatric porcine model by increased myocardial performance index and pro-atrial natriuretic peptide and it associates with cardiac injury by elevated cardiac troponin-T. Clinical studies are needed to see if the same applies for children suffering from malnutrition

Identification and Functional Characterization of N-Terminally Acetylated Proteins in Drosophila melanogaster

A new study reveals a functional rule for N-terminal acetylation in higher eukaryotes called the (X)PX rule and describes a generic method that prevents this modification to allow the study of N-terminal acetylation in any given protein

Angiogenesis PET Tracer Uptake (⁶⁸Ga-NODAGA-E[(cRGDyK)]₂) in Induced Myocardial Infarction and Stromal Cell Treatment in Minipigs

Angiogenesis is considered integral to the reparative process after ischemic injury. The αvβ3 integrin is a critical modulator of angiogenesis and highly expressed in activated endothelial cells. 68Ga-NODAGA-E[(cRGDyK)]2 (RGD) is a positron-emission-tomography (PET) ligand targeted towards αvβ3 integrin. The aim was to present data for the uptake of RGD and correlate it with histology and to further illustrate the differences in angiogenesis due to porcine adipose-derived mesenchymal stromal cell (pASC) or saline treatment in minipigs after induction of myocardial infarction (MI). Three minipigs were treated with direct intra-myocardial injection of pASCs and two minipigs with saline. MI was confirmed by 82Rubidium (82Rb) dipyridamole stress PET. Mean Standardized Uptake Values (SUVmean) of RGD were higher in the infarct compared to non-infarct area one week and one month after MI in both pASC-treated (SUVmean: 1.23 vs. 0.88 and 1.02 vs. 0.86, p &lt; 0.05 for both) and non-pASC-treated minipigs (SUVmean: 1.44 vs. 1.07 and 1.26 vs. 1.04, p &lt; 0.05 for both). However, there was no difference in RGD uptake, ejection fractions, coronary flow reserves or capillary density in histology between the two groups. In summary, indications of angiogenesis were present in the infarcted myocardium. However, no differences between pASC-treated and non-pASC-treated minipigs could be demonstrated

Transient cardiac dysfunction but elevated cardiac and kidney biomarkers 24 h following an ultra-distance running event in Mexican Tarahumara.

BACKGROUND: The Mexican Tarahumara are accustomed to running ultra-distance races. No data exist on the acute physiological changes following ultra-distance running and physiological-biomarker associations in this population. Thus, we aimed to investigate the acute impact (≤ 24 h) on functional and biochemical changes of the cardiac muscle and biochemical changes associated with kidney function following a 63-km ultra-distance race with an altitude difference of 1800 m in Mexican Tarahumara athletes. METHODS: Ten Tarahumara male athletes (mean ± SD age = 29.9 ± 6.6 years) volunteered to participate in the study. VO2max was assessed by a sub-maximal step test individually calibrated combining heart rate and accelerometry. Standard transthoracic echocardiography methodology and venipuncture blood tests were carried out at four time points: pre-race, immediately post-race, 6 h, and 24 h post-race. RESULTS: Estimated mean VO2max was 54.5 (± 8.8) mL O2 min-1 kg-1 and average physiological activity intensity was 746 (± 143) J min-1 kg -1 (~ 11.5 METs). When compared to pre-race values, significant changes in left ventricular ejection fraction (LVEF) and LV end-diastolic volume (- 15%, p < 0.001 for both parameters), cardiac output (39%, p < 0.001), and maximal longitudinal velocity (- 13%, p < 0.009) were seen post-race with LVEF also being decreased at < 6 h post-race (- 8%, p < 0.014). Plasma biomarkers mid-regional pro-atrial natriuretic peptide, copeptin-ultra sensitive, and high-sensitivity cardiac troponin T remained significantly elevated at 24 h post-race, and the two latter were inversely associated with LVEF (p < 0.04). Kidney dysfunction was indicated by increased post-race copeptin-ultra sensitive. CONCLUSIONS: The athletes participating in this study had acute transient cardiac dysfunction as assessed by echocardiography but elevated cardiac and kidney biomarkers at 24 h following a 63-km race with extreme altitude variation

Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites.

BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC