Non-reversible Gaussian processes for identifying latent dynamical structure in neural data

A common goal in the analysis of neural data is to compress large population recordings into sets of interpretable, low-dimensional latent trajectories. This problem can be approached using Gaussian process (GP)-based methods which provide uncertainty quantification and principled model selection. However, standard GP priors do not distinguish between underlying dynamical processes and other forms of temporal autocorrelation. Here, we propose a new family of “dynamical” priors over trajectories, in the form of GP covariance functions that express a property shared by most dynamical systems: temporal non-reversibility. Non-reversibility is a universal signature of autonomous dynamical systems whose state trajectories follow consistent flow fields, such that any observed trajectory could not occur in reverse. Our new multi-output GP kernels can be used as drop-in replacements for standard kernels in multivariate regression, but also in latent variable models such as Gaussian process factor analysis (GPFA). We therefore introduce GPFADS (Gaussian Process Factor Analysis with Dynamical Structure), which models single-trial neural population activity using low-dimensional, non-reversible latent processes. Unlike previously proposed non-reversible multi-output kernels, ours admits a Kronecker factorization enabling fast and memory-efficient learning and inference. We apply GPFADS to synthetic data and show that it correctly recovers ground truth phase portraits. GPFADS also provides a probabilistic generalization of jPCA, a method originally developed for identifying latent rotational dynamics in neural data. When applied to monkey M1 neural recordings, GPFADS discovers latent trajectories with strong dynamical structure in the form of rotations

Delayed feedback in kernel bandits

Black box optimisation of an unknown function from expensive and noisy evaluations is a ubiquitous problem in machine learning, academic research and industrial production. An abstraction of the problem can be formulated as a kernel based bandit problem (also known as Bayesian optimisation), where a learner aims at optimising a kernelized function through sequential noisy observations. The existing work predominantly assumes feedback is immediately available; an assumption which fails in many real world situations, including recommendation systems, clinical trials and hyperparameter tuning. We consider a kernel bandit problem under stochastically delayed feedback, and propose an algorithm with O~(Γk(T)T−−−−−−√+E[τ]) regret, where T is the number of time steps, Γk(T) is the maximum information gain of the kernel with T observations, and τ is the delay random variable. This represents a significant improvement over the state of the art regret bound of O~(Γk(T)T−−√+E[τ]Γk(T)) reported in (Verma et al., 2022). In particular, for very non-smooth kernels, the information gain grows almost linearly in time, trivializing the existing results. We also validate our theoretical results with simulations

Culture media, DMSO and efflux affect the antibacterial activity of cisplatin and oxaliplatin

Cisplatin was originally discovered through its antibacterial action and subsequently has found use as a potent broad-spectrum anticancer agent. This study determines the effect of growth media and solvent on the antibacterial activity of cisplatin and its analogue, oxaliplatin. Escherichia coli MG1655 or MG1655 ΔtolC was treated with the platinum compounds under different conditions and susceptibility was determined. Our results showed that DMSO reduced the activity of cisplatin by fourfold (MIC 12·5 mg l-1 ) compared with 0·9% NaCl-solubilized cisplatin (MIC 3·12 mg l-1 ) when tested in MOPS. Surprisingly, complete loss of activity was observed in Mueller-Hinton Broth II (MHB II). By supplementing MOPS with individual components of MHB II such as the sulphur-containing amino acids, l-cysteine and l-methionine, individually or in combination reduced activity by ≥8-fold (MIC ≥25 mg l-1 ). Oxaliplatin was less active against E. coli (MIC 100 mg l-1 ) but exhibited similar inactivation in the presence of DMSO, MHBII or MOPS spiked with l-cysteine and l-methionine (MIC ≥400 mg l-1 ). Our data suggest that the antibacterial activity of cisplatin and oxaliplatin is modulated by both choice of solvent and composition of growth media. We demonstrate that this is primarily due to sulphur-containing amino acids cysteine and methionine, an essential component of the recommended media for testing antimicrobial susceptibility, MHBII

Reconstruction of Acinetobacter johnsonii ICE_NC genome using hybrid de novo genome assemblies and identification of the 12α-hydroxysteroid dehydrogenase gene

Aims: The role of a Acinetobacter johnsonii strain, isolated from a soil sample, in the biotransformation of bile acids (BAs) was already described but the enzymes responsible for these transformations were only partially purified and molecularly characterized. Methods and Results: This study describes the use of hybrid de novo assemblies, that combine long-read Oxford Nanopore and short-read Illumina sequencing strategies, to reconstruct the entire genome of A. johnsonii ICE_NC strain and to identify the coding region for a 12α-hydroxysteroid dehydrogenase (12α-HSDH), involved in BAs metabolism. The de novo assembly of the A. johnsonii ICE_NC genome was generated using Canu and Unicycler, both strategies yielded a circular chromosome of about 3.6 Mb and one 117 kb long plasmid. Gene annotation was performed on the final assemblies and the gene for 12α-HSDH was detected on the plasmid. Conclusions: Our findings illustrate the added value of long read sequencing in addressing the challenges of whole genome characterization and plasmid reconstruction in bacteria. These approaches also allowed the identification of the A. johnsonii ICE_NC gene for the 12α-HSDH enzyme, whose activity was confirmed at the biochemical level. Significance and impact or the study: At present, this is the first report on the characterization of a 12α-HSDH gene in an A. johnsonii strain able to biotransform cholic acid into ursodeoxycholic acid, a promising therapeutic agent for several diseases. © 2022 The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology

Spatial expression of DNA topoisomerase I genes during cell proliferation in Daucus carota

The spatial expression of carrot (Daucus carota L.) top1 genes encoding the two isoforms of the enzyme DNA topoisomerase I (EC 5.99.1.2) was investigated. In situ hybridization analysis performed with a probe recognizing both top1 transcripts provided evidence that in explanted hypocotyls induced to proliferate in vitro by the addition of the growth regulator 2,4-dichlorophenoxyacetic acid (2,4-D), the mRNA accumulation parallels the proliferation of provascular cells of the stelar cylinder. During somatic embryogenesis, the histological distribution of top1 transcripts was strongly evident at the stage of torpedo-shaped embryos, but gene expression was not only restricted to meristematic regions. When the spatial localization was extended to carrot vegetative apices and the investigation was carried out with specific probes for top1a and top1b, both transcripts preferentially accumulated in tissues having mitotic activity

Identification of the target and mode of action for the prokaryotic nucleotide excision repair inhibitor ATBC

In bacteria, nucleotide excision repair (NER) plays a major role in repairing DNA damage from a wide variety of sources. Therefore, its inhibition offers potential to develop a new antibacterial in combination with adjuvants, such as UV light. To date, only one known chemical inhibitor of NER is 2-(5-amino-1,3,4-thiadiazol-2-yl)benzo(f)chromen-3-one (ATBC) exists and targets Mycobacterium tuberculosis NER. To enable the design of future drugs, we need to understand its mechanism of action. To determine the mechanism of action, we used in silico structure-based prediction, which identified the ATP-binding pocket of Escherichia coli UvrA as a probable target. Growth studies in E. coli showed it was nontoxic alone, but able to impair growth when combined with DNA-damaging agents, and as we predicted, it reduced by an approximately 70% UvrA's ATPase rate. Since UvrA's ATPase activity is necessary for effective DNA binding, we used single-molecule microscopy to directly observe DNA association. We measured an approximately sevenfold reduction in UvrA molecules binding to a single molecule of dsDNA suspended between optically trapped beads. These data provide a clear mechanism of action for ATBC, and show that targeting UvrA's ATPase pocket is effective and ATBC provides an excellent framework for the derivation of more soluble inhibitors that can be tested for activity

Developing novel antimicrobials by combining cancer chemotherapeutics with bacterial DNA repair inhibitors

Cancer chemotherapeutics kill rapidly dividing cells, which includes cells of the immune system. The resulting neutropenia predisposes patients to infection, which delays treatment and is a major cause of morbidity and mortality. To tackle this problem, we have isolated several compounds that inhibit bacterial DNA repair, alone they are non-toxic, however in combination with DNA damaging anti-cancer drugs, they prevent bacterial growth. These compounds were identified through screening of an FDA-approved drug library in the presence of the anti-cancer compound cisplatin. Using a series of triage tests, the screen was reduced to a handful of drugs that were tested for specific activity against bacterial nucleotide excision DNA repair (NER). Five compounds emerged, of which three possess promising antimicrobial properties including cell penetrance, and the ability to block replication in a multi-drug resistant clinically relevant E. coli strain. This study suggests that targeting NER could offer a new therapeutic approach tailor-made for infections in cancer patients, by combining cancer chemotherapy with an adjuvant that targets DNA repair

Mediciones higrotérmicas efectuadas en una vivienda construida con bloques de hormigón celular curado en autoclave

Se presentan las mediciones efectuadas en un prototipo de vivienda social emplazada en el INTI, asimismo se realiza una evaluación higrotérmica y energética utilizando el programa de simulación ENERGY PLUS. Esta presentación corresponde a la segunda etapa del trabajo original “Vivienda de Interés Social INTI” en el cual se evalúan diferentes sistemas constructivos mediante ensayos y cálculos teóricos con el objeto de construir un prototipo que cumpla con los niveles de confort y características constructivas que establecen las Normas IRAM. El año 2003 se expuso dicha etapa en ASADES Formosa bajo el nombre “Evaluación integral del comportamiento higrotérmico y energético de variantes para la construcción de viviendas en tiempos cortos”. Los registros recogidos de la vivienda construida manifiestan un buen comportamiento térmico del sistema. La amplitud de las curvas de humedad y temperatura interna son notablemente menores que la externa a lo largo del año.This work presents measurements made in a social-interest house located in INTI. An energetic evaluation was also run with Energy Plus Software. This presentation belongs to a second part of the original work called “INTI´s social-interest house” where three types of constructions are evaluated by theoretical and experimental tests in order to build a model that checks the comfort levels that are specified in IRAM Standards. The first part of the project, “Integral evaluation of variants in higrothermal and energetic behavior for buildings in short periods” was exposed in 2003 in ASADES. The registries of the house built demonstrate an excellent thermal behavior of the system; the humidity curves and temperatures do not follow the outdoor measurements. Otherwise, they keep constant throughout the year with gradual oscillations.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

Mediciones higrotérmicas efectuadas en una vivienda construida con bloques de hormigón celular curado en autoclave

Se presentan las mediciones efectuadas en un prototipo de vivienda social emplazada en el INTI, asimismo se realiza una evaluación higrotérmica y energética utilizando el programa de simulación ENERGY PLUS. Esta presentación corresponde a la segunda etapa del trabajo original “Vivienda de Interés Social INTI” en el cual se evalúan diferentes sistemas constructivos mediante ensayos y cálculos teóricos con el objeto de construir un prototipo que cumpla con los niveles de confort y características constructivas que establecen las Normas IRAM. El año 2003 se expuso dicha etapa en ASADES Formosa bajo el nombre “Evaluación integral del comportamiento higrotérmico y energético de variantes para la construcción de viviendas en tiempos cortos”. Los registros recogidos de la vivienda construida manifiestan un buen comportamiento térmico del sistema. La amplitud de las curvas de humedad y temperatura interna son notablemente menores que la externa a lo largo del año.This work presents measurements made in a social-interest house located in INTI. An energetic evaluation was also run with Energy Plus Software. This presentation belongs to a second part of the original work called “INTI´s social-interest house” where three types of constructions are evaluated by theoretical and experimental tests in order to build a model that checks the comfort levels that are specified in IRAM Standards. The first part of the project, “Integral evaluation of variants in higrothermal and energetic behavior for buildings in short periods” was exposed in 2003 in ASADES. The registries of the house built demonstrate an excellent thermal behavior of the system; the humidity curves and temperatures do not follow the outdoor measurements. Otherwise, they keep constant throughout the year with gradual oscillations.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

Mediciones higrotérmicas efectuadas en una vivienda construida con bloques de hormigón celular curado en autoclave

Se presentan las mediciones efectuadas en un prototipo de vivienda social emplazada en el INTI, asimismo se realiza una evaluación higrotérmica y energética utilizando el programa de simulación ENERGY PLUS. Esta presentación corresponde a la segunda etapa del trabajo original “Vivienda de Interés Social INTI” en el cual se evalúan diferentes sistemas constructivos mediante ensayos y cálculos teóricos con el objeto de construir un prototipo que cumpla con los niveles de confort y características constructivas que establecen las Normas IRAM. El año 2003 se expuso dicha etapa en ASADES Formosa bajo el nombre “Evaluación integral del comportamiento higrotérmico y energético de variantes para la construcción de viviendas en tiempos cortos”. Los registros recogidos de la vivienda construida manifiestan un buen comportamiento térmico del sistema. La amplitud de las curvas de humedad y temperatura interna son notablemente menores que la externa a lo largo del año.This work presents measurements made in a social-interest house located in INTI. An energetic evaluation was also run with Energy Plus Software. This presentation belongs to a second part of the original work called “INTI´s social-interest house” where three types of constructions are evaluated by theoretical and experimental tests in order to build a model that checks the comfort levels that are specified in IRAM Standards. The first part of the project, “Integral evaluation of variants in higrothermal and energetic behavior for buildings in short periods” was exposed in 2003 in ASADES. The registries of the house built demonstrate an excellent thermal behavior of the system; the humidity curves and temperatures do not follow the outdoor measurements. Otherwise, they keep constant throughout the year with gradual oscillations.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES