S-Palmitoylation is a widespread post-translational modification of integral and/or peripheral proteins occurring in all eukaryotic cells. The family of S-palmitoylated proteins is large and diverse ...and recently, estrogen receptor isoforms (ERalpha and ERbeta) belonging to the nuclear receptor superfamily have been added to the palmitoylproteoma. S-Palmitoylation allows ERalpha and ERbeta localization at the plasma membrane, where they associate with caveolin-1. Upon 17beta-estradiol (E2) stimulation, ERalpha dissociates from caveolin-1 allowing the activation of rapid signals relevant for cell proliferation. In contrast to ERalpha, E2 increases ERbeta association with caveolin-1 and activates p38 kinase and the downstream pro-apoptotic cascade (i.e., caspase-3 activation and PARP cleavage). These data highlight the physiological role of palmitoylation in modulating the ERalpha and ERbeta localization at the plasma membrane and the regulation of different E2-induced non-genomic functions relevant for controlling cell proliferation.
Racial disparities in pain management have been previously reported for children receiving emergency care.
To determine whether patient race or ethnicity is associated with the broader goal of pain ...management and sedation among pediatric patients mechanically ventilated for acute respiratory failure.
Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white,
= 1,233), non-Hispanic Black (Black,
= 502), or Hispanic of any race (Hispanic,
= 536).
Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%).
Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out.Clinical trial registered with clinicaltrials.gov (NCT00814099).
Abstract The mechanical behavior of bone tissue's ultra- and micro- structure is fundamental to assessment of macroscopic bone mechanics. This paper explores the ultra-structural characteristics of ...human femoral tissue responsible for energy absorption of secondary osteons under mechanical loading. A novel mathematical interpretation of single osteon mechanics elucidates the behavior of the collagen–apatite interface. Fully calcified single osteon specimens were mechanically tested quasi-statically under cyclic torsional loading about their longitudinal axis. On each hysteretic diagram, all cycles after the initial monotonic cycle appear pinched and share two points. Stiffness degradation and pinching degradation were investigated on the torque versus deflection-angle-per-unit-length diagrams as the number of cycles increases, in relation to the appearance of osteons in cross-section under circularly polarized light microscopy. Material science's Bauschinger effect, originally defined for metals and later extended to structures reinforced with metal bars, is adapted to describe pinching. Material science's prying effect, defined as amplification of eccentric tensile load through lever action, is employed to explain pinching. The presence of the two points shared by all complete cycles is analyzed in terms of the mathematical fixed point theorem. The results allow formulation of the following conjectures: (1) the prying of carbonated apatite crystallites at the interface with the 40 nm long bands of non-calcified collagen fibrils causes pinching; (2) the prying effect increases with the increasing percentage of collagen–apatite elements that form a larger angle with the osteon axis; and (3) micro-cracks increase more in number than in length as the number of cycles increases.
During infection,
Mycobacterium leprae is faced with the host macrophagic environment limiting the growth of the bacilli. However, (pseudo-)enzymatic detoxification systems, including truncated ...hemoglobin O (
Ml-trHbO), could allow this mycobacterium to persist in vivo. Here, kinetics of peroxynitrite (ONOOH/ONOO
−) detoxification by ferryl
Ml-trHbO (
Ml-trHbO
Fe(IV)
O), obtained by treatment with H
2O
2, is reported. Values of the second-order rate constant for peroxynitrite detoxification by
Ml-trHbO
Fe(IV)
O (
i.e., of
Ml-trHbO
Fe(III) formation;
k
on), at pH 7.2 and 22.0
°C, are 1.5
×
10
4
M
−1
s
−1, and 2.2
×
10
4
M
−1
s
−1, in the absence of and presence of physiological levels of CO
2 (∼1.2
×
10
−3
M), respectively. Values of
k
on increase on decreasing pH with a p
K
a value of 6.7, this suggests that ONOOH reacts preferentially with
Ml-trHbO
Fe(IV)
O. In turn, peroxynitrite acts as an antioxidant of
Ml-trHbO
Fe(IV)
O, which could be responsible for the oxidative damage of the mycobacterium. As a whole,
Ml-trHbO can undertake within the same cycle H
2O
2 and peroxynitrite detoxification.
Abstract RV function is an important component of overall heart function with prognostic value in predicting symptomatic limitation and outcome in different cardiovascular pathologies. RV ...longitudinal contraction accounts for the majority of total RV function, up to 80%, as compared to transverse shortening. Calculation of RV volume and RV ejection fraction (RVEF) remains hampered by the complex RV geometry and we lack of good geometric model allowing the calculation of right ventricular ejection fraction; secondly, the large apical trabeculations of the right ventricle make the endocardial delineation more difficult to obtain than for the left ventricle. To notice, the gold standard method for the assessment of the chamber (MRI) is resource intensive and cannot be employed in many settings. Considering these problems, multiple parameters have been developed for the evaluation of RV systolic function: tricuspid annular plane systolic excursion (TAPSE), systolic excursion velocity (S'), longitudinal strain by speckle tracking.
Among several mechanisms underlying the well-known trophic and protective effects of 17beta-estradiol (E2) in the brain, we recently reported that E2 induces the up-regulation of two anti-apoptotic ...and neuroprotectant proteins: huntingtin (HTT) and neuroglobin (NGB). Here, we investigate the role of this up-regulation. The obtained results indicate that E2 promotes NGB-HTT association, induces the localization of the complex at the mitochondria, and protects SK-N-BE neuroblastoma cells and murine striatal cells, which express wild-type HTT (i.e., polyQ7), against H2O2-induced apoptosis. All E2 effects were completely abolished in HTT-knocked out SK-N-BE cells and in striatal neurons expressing the mutated form of HTT (mHTT; i.e., polyQ111) typical of Huntington's disease (HD). As a whole, these data provide a new function of wild-type HTT which drives E2-induced NGB in mitochondria modulating NGB anti-apoptotic activity. This new function is lost by HTT polyQ pathological expansion. These data evidence the existence of a novel E2/HTT/NGB neuroprotective axis that may play a relevant role in the development of HD therapeutics.
Background: Polyamines are essential for cell growth and differentiation; compounds interfering with their metabolism are potential anticancer agents. Polyamine oxidase (PAO) plays a central role in ...polyamine homeostasis. The enzyme utilises an FAD cofactor to catalyse the oxidation of the secondary amino groups of spermine and spermidine.
Results: The first crystal structure of a polyamine oxidase has been determined to a resolution of 1.9 Å. PAO from
Zea mays contains two domains, which define a remarkable 30 Ålong U-shaped catalytic tunnel at their interface. The structure of PAO in complex with the inhibitor MDL72527 reveals the residues forming the catalytic machinery and unusual enzyme-inhibitor CH···O H bonds. A ring of glutamate and aspartate residues surrounding one of the two tunnel openings contributes to the steering of the substrate towards the inside of the tunnel.
Conclusions: PAO specifically oxidises substrates that have both primary and secondary amino groups. The complex with MDL72527 shows that the primary amino groups are essential for the proper alignment of the substrate with respect to the flavin. Conservation of an N-terminal sequence motif indicates that PAO is member of a novel family of flavoenzymes. Among these, monoamine oxidase displays significant sequence homology with PAO, suggesting a similar overall folding topology.
The pancreatic Kunitz inhibitor, also known as aprotinin, bovine basic pancreatic trypsin inhibitor (BPTI), and trypsin-kallikrein inhibitor, is one of the most extensively studied globular proteins. ...It has proved to be a particularly attractive and powerful tool for studying protein conformation as well as molecular bases of protein/protein interaction(s) and (macro)molecular recognition. BPTI has a relatively broad specificity, inhibiting trypsin- as well as chymotrypsin- and elastase-like serine (pro)enzymes endowed with very different primary specificity. BPTI reacts rapidly with serine proteases to form stable complexes, but the enzyme: inhibitor complex formation may involve several intermediates corresponding to discrete reaction steps. Moreover, BPTI inhibits the nitric oxide synthase type-I and -II action and impairs K+ transport by Ca2+-activated K+ channels. Clinically, the use of BPTI in selected surgical interventions, such as cardiopulmonary surgery and orthotopic liver transplantation, is advised, as it significantly reduces hemorrhagic complications and thus blood-transfusion requirements. Here, the structural, inhibition, and bio-medical aspects of BPTI are reported.
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