Fgf Signaling Controls the Number of Phalanges and Tip Formation in Developing Digits

AbstractTetrapods have two pairs of limbs, each typically with five digits, each of which has a defined number of phalanges derived from an archetypal formula [1]. Much progress has been made in understanding vertebrate limb initiation and the patterning processes that determine digit number in developing limb buds, but little is known about how phalange number is controlled. We and others previously showed that an additional phalange can be induced in a chick toe if sonic hedgehog protein is applied in between developing digit primordia [2, 3]. Here we show that formation of an additional phalange is associated with prolonged Fgf8 expression in the overlying apical ridge and that an Fgf Receptor inhibitor blocks its formation. The additional phalange is produced by elongation and segmentation of the penultimate phalange, suggesting that the digit tip forms when Fgf signaling ceases by a special mechanism, possibly involving Wnt signaling. Consistent with this, Fgfs inhibit tip formation whereas attenuation of Fgf signaling induces tip formation prematurely. We propose that duration of Fgf signaling from the ridge, responsible for elongation of digit primordia, coupled with a characteristic periodicity of joint formation, generates the appropriate number of phalanges in each digit. We also propose that the process that generates the digit tips is independent of that which generates more proximal phalanges. This has implications for understanding human limb congenital malformations and evolution of digit diversity

Machine Learning Algorithm to Predict Acidemia Using Electronic Fetal Monitoring Recording Parameters

Background: Electronic fetal monitoring (EFM) is the universal method for the surveillance of fetal well-being in intrapartum. Our objective was to predict acidemia from fetal heart signal features using machine learning algorithms. Methods: A case–control 1:2 study was carried out compromising 378 infants, born in the Miguel Servet University Hospital, Spain. Neonatal acidemia was defined as pH < 7.10. Using EFM recording logistic regression, random forest and neural networks models were built to predict acidemia. Validation of models was performed by means of discrimination, calibration, and clinical utility. Results: Best performance was attained using a random forest model built with 100 trees. The discrimination ability was good, with an area under the Receiver Operating Characteristic curve (AUC) of 0.865. The calibration showed a slight overestimation of acidemia occurrence for probabilities above 0.4. The clinical utility showed that for 33% cutoff point, missing 5% of acidotic cases, 46% of unnecessary cesarean sections could be prevented. Logistic regression and neural networks showed similar discrimination ability but with worse calibration and clinical utility. Conclusions: The combination of the variables extracted from EFM recording provided a predictive model of acidemia that showed good accuracy and provides a practical tool to prevent unnecessary cesarean sections

Sox9 Expression in Amniotes: Species-Specific Differences in the Formation of Digits

In tetrapods the digit pattern has evolved to adapt to distinct locomotive strategies. The number of digits varies between species or even between hindlimb and forelimb within the same species. These facts illustrate the plasticity of embryonic limb autopods. Sox9 is a precocious marker of skeletal differentiation of limb mesenchymal cells. Its pattern of expression in the developing limb has been widely studied and reflects the activity of signaling cascades responsible for skeletogenesis. In this assay we stress previously overlooked differences in the pattern of expression of Sox9 in limbs of avian, mouse and turtle embryos which may reflect signaling differences associated with distinct limb skeletal morphologies observed in these species. Furthermore, we show that Sox9 gene expression is higher and maintained in the interdigital region in species with webbed digits in comparison with free digit animals

Machine learning algorithms combining slope deceleration and fetal heart rate features to predict acidemia

Electronic fetal monitoring (EFM) is widely used in intrapartum care as the standard method for monitoring fetal well-being. Our objective was to employ machine learning algorithms to predict acidemia by analyzing specific features extracted from the fetal heart signal within a 30 min window, with a focus on the last deceleration occurring closest to delivery. To achieve this, we conducted a case–control study involving 502 infants born at Miguel Servet University Hospital in Spain, maintaining a 1:1 ratio between cases and controls. Neonatal acidemia was defined as a pH level below 7.10 in the umbilical arterial blood. We constructed logistic regression, classification trees, random forest, and neural network models by combining EFM features to predict acidemia. Model validation included assessments of discrimination, calibration, and clinical utility. Our findings revealed that the random forest model achieved the highest area under the receiver characteristic curve (AUC) of 0.971, but logistic regression had the best specificity, 0.879, for a sensitivity of 0.95. In terms of clinical utility, implementing a cutoff point of 31% in the logistic regression model would prevent unnecessary cesarean sections in 51% of cases while missing only 5% of acidotic cases. By combining the extracted variables from EFM recordings, we provide a practical tool to assist in avoiding unnecessary cesarean sections

Role of FGFs in the control of programmed cell death during limb development

10 páginas, 8 figuras.We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways. As previously demonstrated, cell death is inhibited for short intervals (12 hours) after administration of FGFs. However, this initial inhibition is followed (24 hours) by a dramatic increase in cell death, which can be abolished by treatments with a BMP antagonist (Noggin or Gremlin). Conversely, blockage of FGF signaling by applying a specific FGF-inhibitor (SU5402) into the interdigital regions inhibits both physiological cell death and that mediated by exogenous BMPs. Furthermore, FGF receptors 1, 2 and 3 are expressed in the autopodial mesoderm during the regression of the interdigital tissue, and the expression of FGFR3 in the interdigital regions is regulated by FGFs and BMPs in the same fashion as apopotosis. Together our findings indicate that, in the absence of FGF signaling BMPs are not sufficient to trigger apoptosis in the developing limb. Although we provide evidence for a positive influence of FGFs on BMP gene expression, the physiological implication of FGFs in apoptosis appears to result from their requirement for the expression of genes of the apoptotic cascade. We have identified MSX2 and Snail as candidate genes associated with apoptosis the expression of which requires the combined action of FGFs and BMPs.This work was supported by grants to J. M. H. (DGESIC/PM98-0061 and Fundación Valdecilla) to M. A. N. (DGESIC/PM98-0125) and to D. Macias (Junta de Extremadura; IPR99C035). J. J. S.-E. was supported by an MRC programme grant to Cheryll Tickle; J. C.-M. was supported by DGAPA (UNAM) and J. A. M. by a grant from the Junta de Extremadura (Consejeria de Educación y Juventud/Fondo Social Europeo).Peer reviewe

p38γ and p38δ modulate innate immune response by regulating MEF2D activation

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using Mapk12/Mapk13 deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a Mapk12D171A/D171A/Mapk13-/- (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and Candida albicans infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of Nos2 and Il1b mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity

p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases

descripción no proporcionada por scopusThis research was funded by the MCIN/AEI/10.13039/501100011033 (PID2019-108349RB100 and SAF2016-79792R) to AC and JJSE; Villum Foundation, grant no. 13152 to KA; by Agencia Estatal de Investigación (PID2019-104867RBI00/AEI/10.13039/501100011033) and the Instituto de Salud Carlos III- Fondo Europeo de Desarrollo Regional (CIBERONC/CB16/12/00273 and ICI20/00057) to AM and AB. PF received MCIN FPI fellowship (BES-2017-080139)