Towards fully covariant machine learning

Any representation of data involves arbitrary investigator choices. Because those choices are external to the data-generating process, each choice leads to an exact symmetry, corresponding to the group of transformations that takes one possible representation to another. These are the passive symmetries; they include coordinate freedom, gauge symmetry, and units covariance, all of which have led to important results in physics. In machine learning, the most visible passive symmetry is the relabeling or permutation symmetry of graphs. Our goal is to understand the implications for machine learning of the many passive symmetries in play. We discuss dos and don'ts for machine learning practice if passive symmetries are to be respected. We discuss links to causal modeling, and argue that the implementation of passive symmetries is particularly valuable when the goal of the learning problem is to generalize out of sample. This paper is conceptual: It translates among the languages of physics, mathematics, and machine-learning. We believe that consideration and implementation of passive symmetries might help machine learning in the same ways that it transformed physics in the twentieth century.Comment: substantial revision from v1; submitted to TML

Retos en el diagnóstico y control del virus de la enfermedad de Marek en Colombia

Aunque la industria avícola colombiana ha crecido casi el doble en producción durante la última década, el diagnóstico de agentes infecciosos y caracterización de estos aún es escasa, y es poca la información acerca de las cepas virales circulantes en el país. Dentro de estos agentes se encuentra el Virus de la Enfermedad de Marek (VEM), el cual es un patógeno inmunosupresor que puede causar mortalidad elevada y graves pérdidas en la producción. Aunque es poco probable que ocurran casos clínicos de la enfermedad causada por el VEM, debido a los programas de vacunación generalizada con GaHV-2 (serotipo I) y HVT (serotipo III), la inmunosupresión que causan las infecciones subclínicas puede estar causando pérdidas considerables en la producción avícola nacional. El objetivo de esta revisión es describir brevemente la enfermedad de Marek y el estado actual del estudio de la infección en Colombia

p-SMAD2/3 and DICER promote pre-miR-21 processing during pressure overload-associated myocardial remodeling

AbstractTransforming growth factor-β (TGF-β) induces miR-21 expression which contributes to fibrotic events in the left ventricle (LV) under pressure overload. SMAD effectors of TGF-β signaling interact with DROSHA to promote primary miR-21 processing into precursor miR-21 (pre-miR-21). We hypothesize that p-SMAD-2 and -3 also interact with DICER1 to regulate the processing of pre-miR-21 to mature miR-21 in cardiac fibroblasts under experimental and clinical pressure overload. The subjects of the study were mice undergoing transverse aortic constriction (TAC) and patients with aortic stenosis (AS). In vitro, NIH-3T3 fibroblasts transfected with pre-miR-21 responded to TGF-β1 stimulation by overexpressing miR-21. Overexpression and silencing of SMAD2/3 resulted in higher and lower production of mature miR-21, respectively. DICER1 co-precipitated along with SMAD2/3 and both proteins were up-regulated in the LV from TAC-mice. Pre-miR-21 was isolated bound to the DICER1 maturation complex. Immunofluorescence analysis revealed co-localization of p-SMAD2/3 and DICER1 in NIH-3T3 and mouse cardiac fibroblasts. DICER1-p-SMAD2/3 protein–protein interaction was confirmed by in situ proximity ligation assay. Myocardial up-regulation of DICER1 constituted a response to pressure overload in TAC-mice. DICER mRNA levels correlated directly with those of TGF-β1, SMAD2 and SMAD3. In the LV from AS patients, DICER mRNA was up-regulated and its transcript levels correlated directly with TGF-β1, SMAD2, and SMAD3. Our results support that p-SMAD2/3 interacts with DICER1 to promote pre-miR-21 processing to mature miR-21. This new TGFβ-dependent regulatory mechanism is involved in miR-21 overexpression in cultured fibroblasts, and in the pressure overloaded LV of mice and human patients

BMP-7 attenuates left ventricular remodelling under pressure overload and facilitates reverse remodelling and functional recovery

Aims TGF-ß regulates tissue fibrosis: TGF-ß promotes fibrosis, whereas bone morphogenetic protein (BMP)-7 is antifibrotic. To demonstrate that (i) left ventricular (LV) remodelling after pressure overload is associated with disequilibrium in the signalling mediated by these cytokines, and (ii) BMP-7 exerts beneficial effects on LV remodelling and reverse remodelling. Methods and results We studied patients with aortic stenosis (AS) and mice subjected to transverse aortic constriction (TAC) and TAC release (de-TAC). LV morphology and function were assessed by echocardiography. LV biopsies were analysed by qPCR, immunoblotting, and histology. Pressure overload reduced BMP-7 and pSmad1/5/8 and increased TGF-ß and pSmad2/3 in AS patients and TAC mice. BMP-7 correlated inversely with collagen, fibronectin, and ß-MHC expressions, and with hypertrophy and diastolic dysfunction, and directly with the systolic function. Multiple linear regression disclosed BMP-7 and TGF-ß as hypertrophy predictors, negative and positive, respectively. BMP-7 prevented TGF-ß-elicited hypertrophic program in cardiomyocytes, and Col1A1 promoter activity in NIH-3T3 fibroblasts. The treatment of TAC mice with rBMP-7 attenuated the development of structural damage and dysfunction, and halted ongoing remodelling. The reverse remodelling after pressure overload release was facilitated by rBMP-7, and hampered by disrupting BMP-7 function using a neutralizing antibody or genetic deletion. Conclusion The disequilibrium between BMP-7 and TGF-ß signals plays a relevant role in the LV remodelling response to haemodynamic stress in TAC mice and AS patients. Our observations may provide new important insights aimed at developing novel therapies designed to prevent, halt, or reverse LV pathological remodelling in pressure overload cardiomyopathy

Correlative 3D cryo X-ray imaging reveals intracellular location and effect of designed antifibrotic protein-nanomaterial hybrids

Revealing the intracellular location of novel therapeutic agents is paramount for the understanding of their effect at the cell ultrastructure level. Here, we apply a novel correlative cryo 3D imaging approach to determine the intracellular fate of a designed protein-nanomaterial hybrid with antifibrotic properties that shows great promise in mitigating myocardial fibrosis. Cryo 3D structured illumination microscopy (cryo-3D-SIM) pinpoints the location and cryo soft X-ray tomography (cryo-SXT) reveals the ultrastructural environment and subcellular localization of this nanomaterial with spatial correlation accuracy down to 70 nm in whole cells. This novel high resolution 3D cryo correlative approach unambiguously locates the nanomaterial after overnight treatment within multivesicular bodies which have been associated with endosomal trafficking events by confocal microscopy. Moreover, this approach allows assessing the cellular response towards the treatment by evaluating the morphological changes induced. This is especially relevant for the future usage of nanoformulations in clinical practices. This correlative super-resolution and X-ray imaging strategy joins high specificity, by the use of fluorescence, with high spatial resolution at 30 nm (half pitch) provided by cryo-SXT in whole cells, without the need of staining or fixation, and can be of particular benefit to locate specific molecules in the native cellular environment in bio-nanomedicine

Flow cytometry multiplexed method for the detection of neutralizing human antibodies to the native SARS-CoV-2 spike protein

A correct identification of seropositive individuals for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is of paramount relevance to assess the degree of protection of a human population to present and future outbreaks of the COVID-19 pandemic. We describe here a sensitive and quantitative flow cytometry method using the cytometer-friendly non-adherent Jurkat T-cell line that stably expresses the full-length native spike “S” protein of SARS-CoV-2 and a truncated form of the human EGFR that serves a normalizing role. S protein and huEGFRt coding sequences are separated by a T2A self-cleaving sequence, allowing to accurately quantify the presence of anti-S immunoglobulins by calculating a score based on the ratio of fluorescence intensities obtained by double-staining with the test sera and anti-EGFR. The method allows to detect immune individuals regardless of the result of other serological tests or even repeated PCR monitoring. As examples of its use, we show that as much as 28% of the personnel working at the CBMSO in Madrid is already immune. Additionally, we show that anti-S antibodies with protective neutralizing activity are long-lasting and can be detected in sera 8 months after infectionThis work was funded by intramural grant CSIC-COVID19-004: 202020E081 (to B.A.) and CSIC-COVID19-004: 202020E165 (to MF). L.H has been supported by an FPI fellowship from the Spanish Ministry of Science and Innovation. I.B. has been supported by an H2020-MSCA-ITN-2016 training network grant of the European Union (GA 721358

Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients

Background: Various human cardiovascular pathophysiological conditions associate aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as promising biomarkers. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. This study was designed to determine the role of myocardial and plasmatic miR-21 in the maladaptive remodeling of the extracellular matrix induced by pressure overload in aortic stenosis (AS) patients and the clinical value of miR-21 as a biomarker for pathological myocardial fibrosis. Methods: In left ventricular biopsies from 75 AS patients and 32 surgical controls, we quantified the myocardial transcript levels of miR-21, miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma levels were determined in 25 healthy volunteers and in AS patients. In situ hybridization of miR-21 wasperformed in myocardial sections. Results: The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with controls and correlated directly with the echocardiographic mean transvalvular gradients. miR-21 overexpression was confined to interstitial cells and absent in cardiomyocytes. Using bootstrap validated multiple linear regression, the variance in myocardial collagen expression was predicted by myocardial miR-21 (70% of collagen variance) or plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK and PDCD4, and effectors of TGF-β signaling. Conclusions: Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis

Quaternary fossil horses within the Prados-Guatén Depression (Pantoja de La Sagra, Toledo)

Durante la primera reunión de campo del Grupo Madrileño de Cuaternario (GQM-AEQUA) se localizaron restos fragmentarios de dentición de caballos fósiles en los antiguos areneros de Pantoja de La Sagra (Toledo), actualmente en proceso de desmantelamiento y relleno. Ante la posibilidad de deterioro y pérdida los restos fueron recolectados y trasladados al Museo Nacional de Ciencias Naturales (CSIC, Madrid) donde se ha procedido a su análisis. Las piezas fósiles analizadas responden a un maxilar izquierdo con tres piezas dentales in situ (molares y premolares), y otras siete más aisladas. Todos los dientes aislados, junto con el fragmento de maxilar existente, corresponden a un adulto joven. Los restos fósiles se encontraban asociados a un nivel de arenas fluviales situado unos cuatro metros por debajo de la superficie de la Terraza de +15 m de la Depresión Prados-Guatén definida como un nivel perteneciente al tránsito Pleistoceno inferior-medio, del antiguo Sistema fluvial Manzanares-Guatén por Silva (1988). En concreto los niveles superiores de esta terraza han sido interpretados como resultado de la superposición de los últimos depósitos del antiguo sistema fluvial y los primeros asociados al relleno de la Depresión por tributarios de área fuente más local tras su abandono como consecuencia del proceso de captura del valle inferior del Manzanares por parte del Río Jarama al SW de la Ciudad de Madrid (Silva et al., 1988). Los caracteres morfológicos y morfométricos de las piezas dentarias permiten identificarlos como Equus ferus cf. mosbachensis cuya distribución bioestratigráfica abarca la parte final del Pleistoceno Medio (c.a. 500-200 ka B.P.). Junto a los restos fósiles aparecieron también escasos fragmentos líticos correspondientes a productos de lascado en sílex de difícil atribución tecnológica. Los restos fósiles analizados, indican que el depósito extensivo de arenas fluviales en el eje de la Depresión, culminó durante el final del Pleistoceno medio, y que la dinámica fluvial de la Depresión tras su proceso de abandono fue de hecho más activa de lo que se pensaba con la instalación de sistemas de arroyos relevantes alimentados por cabeceras locales antes del encajamiento definitivo actual de los arroyos Prados y Guatén.During the first field-meeting of the Madrid Quaternary Research Group (GQM-AEQUA) several fossil teeth remnants of horses were localised at the ancient sand-quarries of Pantoja de La Sagra (Toledo), which presently are abandoned and refilling in progress. The possibility of deterioration and loss of the localised fossils remnants induced by the quarry works, they were collected and taken away to the Museo Nacional de Ciencias Naturales (CSIC, Madrid) for their preservation and analysis. Fossil remains correspond to a left maxilla with two in situ molars, another one inset on its alveolar cavity, fragments of premolar cavities, as well as other seven more isolated teeth. These fossils were outcropping in a sandy level at four meters below the +15 m fluvial terrace surface of the axial sector of de Prados-Guatén Depression, which is considered the last fluvial level belonging to the ancient Manzanares-Guatén fluvial system during the Lower-Middle Pleistocene transit (Silva, 1988). In detail, the upper fluvial sediments of this particular terrace level were interpreted as the result of the overlapping between the last materials deposited by the ancient Manzanares-Guatén fluvial system and the first ones resulting from the readjustment of former tributaries after the abandonment of the Depression caused by fluvial capture of the Lower Manzanares Valley SW Madrid City. The morphological features of the oclusal surface of the horse teeth and morphometric comparative analyses indicate that they belong to the specie Equus ferus, and probably to the subspecie mosbachensis. However due to the bad definition of this group in Europe and the few individuals analysed the better classification is Equus ferus cf. mosbachensis. The bioestratigraphic distribution of this fossil horse group in Europe extends on the upper part of the Middle Pleistocene (c.a. 500-200 ka B.P.). Few lithic artefacts outcropped also associated to the fossil remains, constituted by laminar flakes of hard technological classification. Fossil remains analysed in this work joint to the unique previous quaternary fossil mammal described for the Prados-Guatén Depression constituted by Mammuthus meridionalis NESTI of the former quarry of Esquivias adjacent to the AVE railway line (Silva et al., 1988b; 1999). The chronostratigraphic attribution of the fossil horses (Upper Middle Pleistocene) described here indicate that fluvial sedimentary activity within the Depression was relevant after its abandonment. Ancient tributaries of the former Manzanares-Guatén fluvial system, feed by local-intrabasinal headwaters, reworked the previous sandy sediments triggering multiepisodic deposition during the upper part of the Middle Pleistocene, before the more recent eventual incision of present streams dissecting the Depression

Evolution of star formation in the UKIDSS ultra deep survey field-I. Luminosity functions and cosmic star formation rate out to z = 1.6

We present new results on the cosmic star formation history in the Subaru/XMM-Newton Deep Survey (SXDS)-Ultra Deep Survey (UDS) field out to z = 1.6. We compile narrowband data from the Subaru Telescope and the Visible and Infrared Survey Telescope forAstronomy (VISTA) in conjunction with broad-band data from the SXDS and UDS, to makea selection of 5725 emission-line galaxies in 12 redshift slices, spanning 10 Gyr of cosmictime. We determine photometric redshifts for the sample using 11-band photometry, and usea spectroscopically confirmed subset to fine tune the resultant redshift distribution. We usethe maximum-likelihood technique to determine luminosity functions in each redshift slice and model the selection effects inherent in any narrow-band selection statistically, to obviatethe retrospective corrections ordinarily required. The deep narrow-band data are sensitive tovery low star formation rates (SFRs), and allow an accurate evaluation of the faint end slopeof the Schechter function, α We find that a is particularly sensitive to the assumed faintest broad-band magnitude of a galaxy capable of hosting an emission line, and propose thatthis limit should be empirically motivated. For this analysis, we base our threshold on thelimiting observed equivalent widths of emission lines in the local Universe. We compute thecharacteristic SFR of galaxies in each redshift slice, and the integrated SFR density,ρ SFR. Wefind our results to be in good agreement with the literature and parametrize the evolution of the SFR density as ρ SFR α(1 + z)4.58 confirming a steep decline in star formation activity since z ~ 1.6.Peer reviewe

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission