Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection.

Monocytes and T-cells are critical to the host response to acute bacterial infection but monocytes are primarily viewed as amplifying the inflammatory signal. The mechanisms of cell death regulating T-cell numbers at sites of infection are incompletely characterized. T-cell death in cultures of peripheral blood mononuclear cells (PBMC) showed 'classic' features of apoptosis following exposure to pneumococci. Conversely, purified CD3(+) T-cells cultured with pneumococci demonstrated necrosis with membrane permeabilization. The death of purified CD3(+) T-cells was not inhibited by necrostatin, but required the bacterial toxin pneumolysin. Apoptosis of CD3(+) T-cells in PBMC cultures required 'classical' CD14(+) monocytes, which enhanced T-cell activation. CD3(+) T-cell death was enhanced in HIV-seropositive individuals. Monocyte-mediated CD3(+) T-cell apoptotic death was Fas-dependent both in vitro and in vivo. In the early stages of the T-cell dependent host response to pneumococci reduced Fas ligand mediated T-cell apoptosis was associated with decreased bacterial clearance in the lung and increased bacteremia. In summary monocytes converted pathogen-associated necrosis into Fas-dependent apoptosis and regulated levels of activated T-cells at sites of acute bacterial infection. These changes were associated with enhanced bacterial clearance in the lung and reduced levels of invasive pneumococcal disease

Onto what planes should Coulomb stress perturbations be resolved?

[1] Coulomb stress maps are produced by computing the tensorial stress perturbation due to an earthquake rupture and resolving this tensor onto planes of a particular orientation. It is often assumed that aftershock fault planes are ‘‘optimally oriented’’; in other words, the regional stress and coseismic stress change are used to compute the orientation of planes most likely to fail and the coseismic stress is resolved onto these orientations. This practice assumes that faults capable of sustaining aftershocks exist at all orientations, an assumption contradicted by the observation that aftershock focal mechanisms have strong preferred orientations consistent with mapped structural trends. Here we systematically investigate the best planes onto which stress should be resolved for the Landers, Hector Mine, Loma Prieta, and Northridge earthquakes by quantitatively comparing observed aftershock distributions with stress maps based on optimally oriented planes (two- and three-dimensional), main shock orientation, and regional structural trend. We find that the best model differs between different tectonic regions but that in all cases, models that incorporate the regional stress field tend to produce stress maps that best fit the observed aftershock distributions, although not all such models do so equally well. Our results suggest that when the regional stress field is poorly defined, or in structurally complex areas, the best model may be to fix the strike of the planes upon which the stress is to be resolved to that of the main shock but allow the dip and rake to vary

An observational test of the origin of accelerating moment release before large earthquakes

International audience[1] A progressive increase of seismic activity distributed over a wide region around a future earthquake epicenter is termed accelerating moment release (AMR). This phenomenon has been observed in several studies over the last 15 years, although there is no consensus about the physical origin of the effect. In a recent hypothesis known as the stress accumulation (SA) model, the AMR is thought to result from the last stage of loading in the earthquake cycle. In this view, the increasing seismicity is due to minor stress release as the whole region becomes sufficiently stressed for the major event to occur. The stress accumulation model makes specific predictions about the distribution of events in an AMR sequence. Because the AMR is predicted to be a result of loading on the main fault, the precursory activity should be concentrated in the positive lobes of the far-field stresses calculated by a backslip dislocation model of the main shock. To test this model, AMR is first found in optimal circular regions around the epicenters of each of the M w ! 6.5 earthquakes in central and southern California since 1950. A backslip dislocation model is then used to determine which of the precursory events occur in the regions predicted by stress accumulation. AMR is shown to occur preferentially in the lobes of the backslip stress field predicted by the stress accumulation model

Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations

Background: Raine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features. Methods: The medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1. Results: Family 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified. Conclusions: The clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations

Vinculin Controls PTEN Protein Level by Maintaining the Interaction of the Adherens Junction Protein β-Catenin with the Scaffolding Protein MAGI-2

PTEN is a frequently mutated tumor suppressor in malignancies. Interestingly, some malignancies exhibit undetectable PTEN protein without mutations or loss of PTEN mRNA. The cause(s) for this reduction in PTEN is unknown. Cancer cells frequently exhibit loss of cadherin, beta-catenin, alpha-catenin and/or vinculin, key elements of adherens junctions. Here we show that F9 vinculin-null (vin(-/-)) cells lack PTEN protein despite normal PTEN mRNA levels. Their PTEN protein expression was restored by transfection with vinculin or by inhibition of PTEN degradation. F9 vin(-/-) cells express PTEN protein upon transfection with a vinculin fragment (amino acids 243-1066) that is capable of interacting with alpha-catenin but unable to target into focal adhesions. On the other hand, disruption of adherens junctions with an E-cadherin blocking antibody reduced PTEN protein to undetectable levels in wild-type F9 cells. PTEN protein levels were restored in F9 vin(-/-) cells upon transfection with an E-cadherin-alpha-catenin fusion protein, which targets into adherens junctions and interacts with beta-catenin in F9 vin(-/-) cells. beta-Catenin is known to interact with MAGI-2. MAGI-2 interaction with PTEN in the cell membrane is known to prevent PTEN protein degradation. Thus, MAGI-2 overexpression in F9 vin(-/-) cells restored PTEN protein levels. Moreover, expression of vinculin mutants that reinstated the disrupted interactions of beta-catenin with MAGI-2 in F9 vin(-/-) cells also restored PTEN protein levels. These studies indicate that PTEN protein levels are dependent on the maintenance of beta-catenin-MAGI-2 interaction, in which vinculin plays a critical role

An excitable Rho GTPase signaling network generates dynamic subcellular contraction patterns

Rho GTPase-based signaling networks control cellular dynamics by coordinating protrusions and retractions in space and time. Here, we reveal a signaling network that generates pulses and propagating waves of cell contractions. These dynamic patterns emerge via self organization from an activator-inhibitor network, in which the small GTPase Rho amplifies its activity by recruiting its activator, GEF-H1. Rho also inhibits itself by local recruitment of acto myosin and the associated RhoGAP Myo9b. This network structure enables spontaneous, self limiting patterns of subcellular contractility that can explore mechanical cues in the extracellular environment. Indeed, acto-myosin pulse frequency in cells is altered by matrix elasticity, showing that coupling of contractility pulses to environmental deformations modulates network dynamics. Thus, our study reveals a mechanism that integrates intracellular biochemical and extracellular mechanical signals into subcellular activity patterns to control cellular contractility dynamics

Существует ли связь между средним уровнем mIDkIne и прогнозом заболевания COVID-19?

   The objective was aimed to measure plasma midkine (MK)* levels in patients with COVID-19 and assess its clinical significance.   Materials and Methods. 88 patients observed in our hospital with a diagnosis of COVID-19 were included in the study. The patients’ demographic characteristics, clinical, and laboratory data were studied, and the relationship between MK levels, prognosis, and other parameters was investigated.   Results. Of the 88 patients included in the study, 43 (48.9 %) were female and 45 (51.1%) were male. 24 (27%) patients died. The mean age of non-survivors was 70 ± 12.3 years and the survivors were 61.9 ± 18.2 years. Mortality predictors such as D-dimer, ferritin, troponin, LDH, CRP, and procalcitonin were significantly higher in non-survivors than in survivors (p < 0.05). The median MK level (IR) was 152.5 ± 125 pg/ml in all patients, 143 ± 149 pg/ml in survivors, and 165.5 ± 76 pg/ml in non-survivors (p = 0.546). The difference between these two groups was not statistically significant. The area under the ROC curve was found to be 0.542 (95% CI 0.423–0.661, p = 0.546).   Conclusion. MK is not a biomarker that can replace or reinforce known predictors of mortality in COVID-19 patients.   Цель. Исследование направлено на измерение уровня Midkine (MK)* в плазме крови у пациентов с COVID-19 и оценку его клинической значимости.   Материалы и методы. В исследование включены 88 пациентов, наблюдавшихся в клинике с диагнозом COVID-19. Изучены демографические характеристики пациентов, клинические и лабораторные данные, а также исследована взаимосвязь между уровнями MK, прогнозом и другими параметрами.   Результаты. Из 88 пациентов, включенных в исследование, 43 (48,9 %) были женщинами и 45 (51,1 %) – мужчинами. 24 (27 %) пациента умерли. Средний возраст невыживших составил 70 ± 12,3 года, а выживших – 61,9 ± 18,2 года. Предикторы смертности, такие как D-димер, ферритин, тропонин, ЛДГ, СРБ и прокальцитонин, были значительно выше у умерших, чем у выживших (р < 0,05). Медиана уровня МК (IR) составила 152,5 ± 125 пг/мл у всех пациентов, 143 ± 149 пг/мл у выживших и 165,5 ± 76 пг/мл у умерших (р = 0,546). Разница между этими 2 группами была незначима. Было обнаружено, что площадь под кривой ROC составляет 0,542 (95 % ДИ 0,423–0,661, р = 0,546).   Вывод. МК не является биомаркером, который может заменить или усилить известные предикторы смертности у пациентов с COVID-19