Forward to the special issue on Hox/Tale transcription factors in development and disease

Introduction.Peer Reviewe

"Self-regulation," a new facet of Hox genes' function

PMCID: PMC4482672[Background]: Precise temporal and spatial expression of the clustered Hox genes is essential for patterning the developing embryo. Temporal activation of Hox genes was shown to be cluster-autonomous. However, gene clustering appears dispensable for spatial colinear expression. Generally, a set of Hox genes expressed in a group of cells instructs these cells about their fate such that the differential expression of Hox genes results in morphological diversity. The spatial colinearity is considered to rely both on local and long-range cis regulation. [Results]: Here, we report on the global deregulation of HoxA and HoxD expression patterns upon inactivation of a subset of HOXA and HOXD proteins. [Conclusions]: Our data suggest the existence of a >self-regulation> mechanism, a process by which HOX proteins establish and/or maintain the spatial domains of the Hox gene family and we propose that the functionally dominant HOX proteins could contribute to generating the spatial parameters of Hox expression in a given tissue, i.e., HOX controlling the establishment of the ultimate HOX code.Grant sponsor: the Spanish Government; Grant number: BFU2011-24972; Grant sponsor: the Canadian Institutes for Health Research; Grant number: MOP-82880; Grant number: 126110. This work was supported by the Spanish Government to M.R. and by the Canadian Institutes for Health Research as well as the Canada Research Chair program to M.K. R.S was supported by a Formación Profesorado Universitario fellowship from the Spanish Ministry of Science and Innovation and currently supported by the Angelo Pizzagalli postdoctoral fellowship.Peer Reviewe

Debromination and Reusable Glass Fiber Recovery from Large Waste Circuit Board Pieces in Subcritical Water Treatment

The great economic, social, and environmental interest that favors an effective management of the recycling of waste printed circuit boards (WCBs) encourages research on the improvement of processes capable of mitigating their harmful effects. In this work, the debromination of large WCBs was first performed through a hydrothermal process employing potassium carbonate as an additive. A total of 32 runs were carried out at 225 °C, various CO32–/Br– anionic ratios of 1:1, 2:1, 4:1, and 6:1, treatment times from 30 to 360 min, proportion of submerged WCBs in the liquid of 100, 50, and 25% that corresponded with the use of three WCB sizes of 20 mm × 16.5 mm, 20 mm × 33 mm, and 80 mm × 33 mm, respectively, and solid/liquid ratios of 1:2 and 1:1 g/mL without other metallic catalysts. A debromination efficiency of 50 wt % was reached at only 225 °C (limited by mechanical reasons) and 360 min, using a CO32–/Br– anionic ratio of 4:1 and a solid/liquid ratio of 1:2 for a large WCB with only 25% of its volume submerged in the liquid. This means conservation of water and energy compared to previous studies. A muffle furnace was used later to thermally treat a total of 101 debrominated samples, at constant temperature or following a temperature scaling program. An estimated decrease in resistance to rupture of glass fibers of only around 50% was accomplished by following a temperature scaling program up to 475 °C, obtaining clean glass fibers of large size. The simple techniques proposed to obtain reusable glass fibers from WCBs as large as the size of the reactor allows (as it might be in their original size) could significantly improve interest in the industry.Support for this work was granted by the PID2019-105359RB-I00 project and the scholarship BES-2017-080382 from the Ministry of Science and Innovation of Spain and project UAUSTI20-05 from the University of Alicante

Optimization of Efficient Neuron Models With Realistic Firing Dynamics. The Case of the Cerebellar Granule Cell

Biologically relevant large-scale computational models currently represent one of the main methods in neuroscience for studying information processing primitives of brain areas. However, biologically realistic neuron models tend to be computationally heavy and thus prevent these models from being part of brain-area models including thousands or even millions of neurons. The cerebellar input layer represents a canonical example of large scale networks. In particular, the cerebellar granule cells, the most numerous cells in the whole mammalian brain, have been proposed as playing a pivotal role in the creation of somato-sensorial information representations. Enhanced burst frequency (spiking resonance) in the granule cells has been proposed as facilitating the input signal transmission at the theta-frequency band (4–12 Hz), but the functional role of this cell feature in the operation of the granular layer remains largely unclear. This study aims to develop a methodological pipeline for creating neuron models that maintain biological realism and computational efficiency whilst capturing essential aspects of single-neuron processing. Therefore, we selected a light computational neuron model template (the adaptive-exponential integrate-and-fire model), whose parameters were progressively refined using an automatic parameter tuning with evolutionary algorithms (EAs). The resulting point-neuron models are suitable for reproducing the main firing properties of a realistic granule cell from electrophysiological measurements, including the spiking resonance at the theta-frequency band, repetitive firing according to a specified intensityfrequency (I-F) curve and delayed firing under current-pulse stimulation. Interestingly, the proposed model also reproduced some other emergent properties (namely, silent at rest, rheobase and negligible adaptation under depolarizing currents) even though these properties were not set in the EA as a target in the fitness function (FF), proving that these features are compatible even in computationally simple models. The proposed methodology represents a valuable tool for adjusting AdEx models according to a FF defined in the spiking regime and based on biological data. These models are appropriate for future research of the functional implication of bursting resonance at the theta band in large-scale granular layer network models.FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento under the EmbBrain project A-TIC-276-UGR18University of Granada under the Young Researchers FellowshipMinisterio de Economia y Competitividad (MINECO)-FEDER TIN2016-81041-REuropean Human Brain Project SGA2 ( H2020-RIA) 785907European Human Brain Project SGA3 (European Commission) ( H2020-RIA) 945539CEREBIO P18-FR-237

Improving efficiency and feasibility of subcritical water debromination of printed circuit boards E-waste via potassium carbonate adding

Waste printed circuit boards (WCBs) were debrominated under hydrothermal treatment, using potassium carbonate as an alkaline additive to improve debromination efficiency (DE). Two different high-pressure reactors were used: a 1-L stirred reactor, where the evolution of the DE was followed over time at a low CO32−/Br− ratio (1:25), and an elementary 0.1-L non-stirred reactor, used to find the optimal parameters and to simplify the hydrothermal debromination (HTD) process. Considering both reactors, experiments were conducted changing the temperature (200 °C, 225 °C, 250 °C, 275 °C), and also the CO32−/Br− anionic ratio (1:50, 1:25, 1:10, 1:5, 1:2.5, 1:1, 2:1, 4:1) and the solid/liquid ratio (1:10, 1:5, 1:2) in the case of the 0.1-L reactor. No metallic catalyst was required. A maximum DE of about 98.9 wt % was reached in the agitated vessel at 275 °C after 4 h, with an additive/bromine ratio of 1:25. Similar DE (99.6 wt %) was also achieved in the non-stirred reactor at only 225 °C and after 2 h, using an additive/bromine ratio of 4:1 and a solid/liquid ratio of only 1:2. Concerning the solid phase behaviour during debromination, only 5 % of the net calorific value (NCV) was lost after a complete HTD treatment of WCB.Support for this work was granted by CTQ2016-76608-R project and the scholarship BES-2017-080382 from the Ministry of Economy, Industry and Competitiveness (Spain)

Impact of region-of-interest delineation methods, reconstruction algorithms, and intra- and inter-operator variability on internal dosimetry estimates using PET

Purpose Human dosimetry studies play a central role in radioligand development for positron emission tomography (PET). Drawing regions of interest (ROIs) on the PET images is used to measure the dose in each organ. In the study aspects related to ROI delineation methods were evaluated for two radioligands of different biodistribution (intestinal vs urinary). Procedures PET images were simulated from a human voxel-based phantom. Several ROI delineation methods were tested: antero-posterior projections (AP), 3D sub-samples of the organs (S), and a 3D volume covering the whole-organ (W). Inter- and intra-operator variability ROI drawing was evaluated by using human data. Results The effective dose estimates using S and W methods were comparable to the true values. AP methods overestimated (49 %) the dose for the radioligand with intestinal biodistribution. Moreover, the AP method showed the highest inter-operator variability: 11 ± 1 %. Conclusions The sub-sampled organ method showed the best balance between quantitative accuracy and inter- and intra-operator variability.Postprint (author's final draft

CathepsinKCre mediated deletion of βcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells

It is well established that activation of Wnt/βcatenin signaling in the osteoblast lineage leads to an increase in bone mass through a dual mechanism: increased osteoblastogenesis and decreased osteoclastogenesis. However, the effect of this pathway on the osteoclast lineage has been less explored. Here, we aimed to examine the effects of Wnt/βcatenin signaling in mature osteoclasts by generating mice lacking βcatenin in CathepsinK-expressing cells (Ctnnb1;CtsKCre mice). These mice developed a severe low-bone-mass phenotype with onset in the second month and in correlation with an excessive number of osteoclasts, detected by TRAP staining and histomorphometric quantification. We found that WNT3A, through the canonical pathway, promoted osteoclast apoptosis and therefore attenuated the number of M-CSF and RANKL-derived osteoclasts in vitro. This reveals a cell-autonomous effect of Wnt/βcatenin signaling in controlling the life span of mature osteoclasts. Furthermore, bone Opg expression in Ctnnb1;CtsKCre mice was dramatically decreased pointing to an additional external activation of osteoclasts. Accordingly, expression of CathepsinK was detected in TRAP-negative cells of the inner periosteal layer also expressing Col1. Our results indicate that the bone phenotype of Ctnnb1;CtsKCre animals combines a cell-autonomous effect in the mature osteoclast with indirect effects due to the additional targeting of osteoblastic cells.This work was supported by grant ISCIII PI12/01405 to JGM and grant BFU2014-57216-P to MAR from the Spanish Government and R01AR056679 from NIAMS/NIH to MA.Peer Reviewe

A Win–Win Combination to Inhibit Persistent Organic Pollutant Formation via the Co-Incineration of Polyvinyl Chloride E-Waste and Sewage Sludge

Persistent organic pollutant inhibition in the combustion process of polyvinyl chloride (PVC) by prior addition of an inhibitor is currently being studied, reducing the emission of pollutants, and thus reducing the large amount of waste PVC destined for landfill. In this work, the use of sewage sludge (SS) as an alternative to chemical inhibitors to improve the quality emissions of the incineration of polyvinyl chloride waste (PVC e-waste) was studied and optimized. Different combustion runs were carried out at 850 °C in a laboratory tubular reactor, varying both the molar ratio Ri (0.25, 0.50, 0.75) between inhibitors (N + S) and chlorine (Cl) and the oxygen ratio λ (0.15, 0.50) between actual oxygen and stoichiometric oxygen. The emissions of several semivolatile compounds families such as polycyclic aromatic hydrocarbons (PAHs), polychlorobenzenes (ClBzs), and polychlorophenols (ClPhs), with special interest in the emissions of the most toxic compounds, i.e., polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs), were analyzed. A notable decrease in PCDD/F and dl-PCB formation was achieved in most of the experiments, especially for those runs performed under an oxygen-rich atmosphere (λ = 0.50), where the addition of sludge was beneficial with inhibition ratios Ri ≥ 0.25. An inhibition ratio of 0.75 showed the best results with almost a 100% reduction in PCDD/F formation and a 95% reduction in dl-PCB formation.Support for this work was granted by CTQ2016-76608-R project and the scholarship BES-2017-080382 from the Ministry of Economy, Industry and Competitiveness (Spain). GC-MS/QQQ used in the analysis was supported by Project IDIFEDER/2018/004 by the Generalitat Valenciana (Spain)

The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm

Sperm capacitation is required for fertilization. At the molecular level, this process is associated with fast activation of protein kinase A. Downstream of this event, capacitating conditions lead to an increase in tyrosine phosphorylation. The identity of the tyrosine kinase(s) mediating this process has not been conclusively demonstrated. Recent experiments using stallion and human sperm have suggested a role for PYK2 based on the use of small molecule inhibitors directed against this kinase. However, crucially, loss-of-function experiments have not been reported. Here, we used both pharmacological inhibitors and genetically modified mice models to investigate the identity of the tyrosine kinase(s) mediating the increase in tyrosine phosphorylation in mouse sperm. Similar to stallion and human, PF431396 blocks the capacitation-associated increase in tyrosine phosphorylation. Yet, sperm from Pyk2(-/-) mice displayed a normal increase in tyrosine phosphorylation, implying that PYK2 is not responsible for this phosphorylation process. Here, we show that PF431396 can also inhibit FER, a tyrosine kinase known to be present in sperm. Sperm from mice targeted with a kinase-inactivating mutation in Fer failed to undergo capacitation-associated increases in tyrosine phosphorylation. Although these mice are fertile, their sperm displayed a reduced ability to fertilize metaphase II-arrested eggs in vitro.Fil: Alvau, Antonio. University of Massachussets; Estados UnidosFil: Battistone, Maria Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gervasi, Maria Gracia. University of Massachussets; Estados UnidosFil: Navarrete, Felipe A.. University of Massachussets; Estados UnidosFil: Xu, Xinran. State University of Colorado - Fort Collins; Estados UnidosFil: Sánchez Cárdenas, Claudia. Universidad Nacional Autónoma de México. Instituto de Biotecnología; MéxicoFil: De la Vega Beltran, José Luis. Universidad Nacional Autónoma de México. Instituto de Biotecnología; MéxicoFil: Da Ros, Vanina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Greer, Peter. Queens University; CanadáFil: Darszon, Alberto. Universidad Nacional Autónoma de México. Instituto de Biotecnología; MéxicoFil: Krapf, Diego. State University of Colorado - Fort Collins; Estados UnidosFil: Salicioni, Ana María. University of Massachussets; Estados UnidosFil: Cuasnicu, Patricia Sara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Visconti, Pablo E.. University of Massachussets; Estados Unido

Impact of long-term hfd intake on the peripheral and central igf system in male and female mice

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex-and diet-dependent.This research was funded by grants from the Spanish Ministry of Science and Innovation (BFU2017-82565-C21-R2 to J.A.C. and L.M.F.), Spanish Ministry of Education, Culture and Sports (university training grant PU13/00909 to A.F.-R.), Fondo de Investigación Sanitaria (PI1900166 to J.A.) and Fondos FEDER. Centro de Investigación Biomédica en Red Fisiopatología de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (J.A.