Hyperdimensional computing with holographic and adaptive encoder.

Introduction: Brain-inspired computing has become an emerging field, where a growing number of works focus on developing algorithms that bring machine learning closer to human brains at the functional level. As one of the promising directions, Hyperdimensional Computing (HDC) is centered around the idea of having holographic and high-dimensional representation as the neural activities in our brains. Such representation is the fundamental enabler for the efficiency and robustness of HDC. However, existing HDC-based algorithms suffer from limitations within the encoder. To some extent, they all rely on manually selected encoders, meaning that the resulting representation is never adapted to the tasks at hand. Methods: In this paper, we propose FLASH, a novel hyperdimensional learning method that incorporates an adaptive and learnable encoder design, aiming at better overall learning performance while maintaining good properties of HDC representation. Current HDC encoders leverage Random Fourier Features (RFF) for kernel correspondence and enable locality-preserving encoding. We propose to learn the encoder matrix distribution via gradient descent and effectively adapt the kernel for a more suitable HDC encoding. Results: Our experiments on various regression datasets show that tuning the HDC encoder can significantly boost the accuracy, surpassing the current HDC-based algorithm and providing faster inference than other baselines, including RFF-based kernel ridge regression. Discussion: The results indicate the importance of an adaptive encoder and customized high-dimensional representation in HDC.

Pathological Character of Modifications to Coincident General Relativity: Cosmological Strong Coupling and Ghosts in f(Q) Theories.

The intrinsic presence of ghosts in the symmetric teleparallel framework is elucidated. We illustrate our general arguments in f(Q) theories by studying perturbations in the three inequivalent spatially flat cosmologies. Two of these branches exhibit reduced linear spectra, signalling they are infinitely strongly coupled. For the remaining branch we unveil the presence of seven gravitational degrees of freedom and show that at least one of them is a ghost. Our results rule out f(Q) cosmologies and clarify the number of propagating degrees of freedom in these theories.

Mutation and Selection Induce Correlations between Selection Coefficients and Mutation Rates.

AbstractThe joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different distributions are of immediate interest: (1) the "nominal" distribution of possible changes, prior to mutation or selection; (2) the "de novo" distribution of realized mutations; and (3) the "fixed" distribution of selectively established mutations. Here, we formally characterize the relationships between these joint distributions under the strong-selection/weak-mutation (SSWM) regime. The de novo distribution is enriched relative to the nominal distribution for the highest rate mutations, and the fixed distribution is further enriched for the most highly beneficial mutations. Whereas mutation rates and selection coefficients are often assumed to be uncorrelated, we show that even with no correlation in the nominal distribution, the resulting de novo and fixed distributions can have correlations with any combination of signs. Nonetheless, we suggest that natural systems with a finite number of beneficial mutations will frequently have the kind of nominal distribution that induces negative correlations in the fixed distribution. We apply our mathematical framework, along with population simulations, to explore joint distributions of selection coefficients and mutation rates from deep mutational scanning and cancer informatics. Finally, we consider the evolutionary implications of these joint distributions together with two additional joint distributions relevant to parallelism and the rate of adaptation.

Mutation bias and the predictability of evolution.

Predicting evolutionary outcomes is an important research goal in a diversity of contexts. The focus of evolutionary forecasting is usually on adaptive processes, and efforts to improve prediction typically focus on selection. However, adaptive processes often rely on new mutations, which can be strongly influenced by predictable biases in mutation. Here, we provide an overview of existing theory and evidence for such mutation-biased adaptation and consider the implications of these results for the problem of prediction, in regard to topics such as the evolution of infectious diseases, resistance to biochemical agents, as well as cancer and other kinds of somatic evolution. We argue that empirical knowledge of mutational biases is likely to improve in the near future, and that this knowledge is readily applicable to the challenges of short-term prediction. This article is part of the theme issue 'Interdisciplinary approaches to predicting evolutionary biology'.

Modifications in the piperazine ring of nucleozin affect anti-influenza activity.

The infection caused by the influenza virus is a latent tret. The limited access to vaccines and approved drugs highlights the need for additional antiviral agents. Nucleozin and its analogs have gain attention for their promising anti-influenza activity. To contribute to the advancement of the discovery and design of nucleozin analogs, we analyzed piperazine-modified nucleozin analogs to increase conformational freedom. Also, we describe a new synthetic strategy to obtain nucleozin and its analogues, three molecules were synthesized and two of them were biologically evaluated in vitro. Although the analogues were less active than nucleozin, the loss of activity highlights the need for the piperazine ring to maintain the activity of nucleozin analogs. Interestingly, this result agrees with the prediction of anti-influenza activity made with a QSAR model presented in this work. The proposed model and the synthetic route will be useful for the further development of nucleozin analogs with antiviral activity.

Mutation bias shapes the spectrum of adaptive substitutions.

Evolutionary adaptation often occurs by the fixation of beneficial mutations. This mode of adaptation can be characterized quantitatively by a spectrum of adaptive substitutions, i.e., a distribution for types of changes fixed in adaptation. Recent work establishes that the changes involved in adaptation reflect common types of mutations, raising the question of how strongly the mutation spectrum shapes the spectrum of adaptive substitutions. We address this question with a codon-based model for the spectrum of adaptive amino acid substitutions, applied to three large datasets covering thousands of amino acid changes identified in natural and experimental adaptation in Saccharomyces cerevisiae, Escherichia coli, and Mycobacterium tuberculosis Using species-specific mutation spectra based on prior knowledge, we find that the mutation spectrum has a proportional influence on the spectrum of adaptive substitutions in all three species. Indeed, we find that by inferring the mutation rates that best explain the spectrum of adaptive substitutions, we can accurately recover the species-specific mutation spectra. However, we also find that the predictive power of the model differs substantially between the three species. To better understand these differences, we use population simulations to explore the factors that influence how closely the spectrum of adaptive substitutions mirrors the mutation spectrum. The results show that the influence of the mutation spectrum decreases with increasing mutational supply ([Formula: see text]) and that predictive power is strongly affected by the number and diversity of beneficial mutations.

From genotypes to organisms: State-of-the-art and perspectives of a cornerstone in evolutionary dynamics.

Understanding how genotypes map onto phenotypes, fitness, and eventually organisms is arguably the next major missing piece in a fully predictive theory of evolution. We refer to this generally as the problem of the genotype-phenotype map. Though we are still far from achieving a complete picture of these relationships, our current understanding of simpler questions, such as the structure induced in the space of genotypes by sequences mapped to molecular structures, has revealed important facts that deeply affect the dynamical description of evolutionary processes. Empirical evidence supporting the fundamental relevance of features such as phenotypic bias is mounting as well, while the synthesis of conceptual and experimental progress leads to questioning current assumptions on the nature of evolutionary dynamics-cancer progression models or synthetic biology approaches being notable examples. This work delves with a critical and constructive attitude into our current knowledge of how genotypes map onto molecular phenotypes and organismal functions, and discusses theoretical and empirical avenues to broaden and improve this comprehension. As a final goal, this community should aim at deriving an updated picture of evolutionary processes soundly relying on the structural properties of genotype spaces, as revealed by modern techniques of molecular and functional analysis.

Mutation bias interacts with composition bias to influence adaptive evolution.

Mutation is a biased stochastic process, with some types of mutations occurring more frequently than others. Previous work has used synthetic genotype-phenotype landscapes to study how such mutation bias affects adaptive evolution. Here, we consider 746 empirical genotype-phenotype landscapes, each of which describes the binding affinity of target DNA sequences to a transcription factor, to study the influence of mutation bias on adaptive evolution of increased binding affinity. By using empirical genotype-phenotype landscapes, we need to make only few assumptions about landscape topography and about the DNA sequences that each landscape contains. The latter is particularly important because the set of sequences that a landscape contains determines the types of mutations that can occur along a mutational path to an adaptive peak. That is, landscapes can exhibit a composition bias-a statistical enrichment of a particular type of mutation relative to a null expectation, throughout an entire landscape or along particular mutational paths-that is independent of any bias in the mutation process. Our results reveal the way in which composition bias interacts with biases in the mutation process under different population genetic conditions, and how such interaction impacts fundamental properties of adaptive evolution, such as its predictability, as well as the evolution of genetic diversity and mutational robustness.

Targeting quorum sensing by designing azoline derivatives to inhibit the N-hexanoyl homoserine lactone-receptor CviR: Synthesis as well as biological and theoretical evaluations.

To counteract bacterial resistance, we investigated the interruption of quorum sensing mediated by non-classical bioisosteres of the N-hexanoyl homoserine lactone with an azoline core. For this purpose, a set of selected 2-substituted azolines was synthesized, establishing the basis for a new protocol to synthesize 2-amino imidazolines. The synthesized compounds were evaluated as inhibitors of violacein production in Chromobacterium violaceum. Theoretical studies on bioisostere-protein interactions were performed using CviR. The results show that some azolines decreased violacein production, suggesting an antiquorum sensing profile against Gram-negative bacteria. Docking and molecular dynamic simulations together with binding free energy calculations revealed the exact binding and inhibitory profiles. These theoretical results show relationship with the in vitro activity of the azoline series.

Relevancia clínica de las interacciones medicamentosas entre antiinflamatorios no esteroideos y antihipertensivos / Clinical relevance of drug interactions between nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensives

OBJETIVO: Establecer la relevancia clínica de las interacciones medicamentosas reportadas entre antiinflamatorios no esteroideos (AINE) y antihipertensivos basándose en la gravedad y la probabilidad de ocurrencia de la interacción. DISEÑO: Revisión sistemática. Fuentes de datos: Se realizó una búsqueda en PubMed/Medline utilizando los términos Mesh: NSAIDs, Antihypertensive drugs y Drug interactions. Extracción de datos Se incluyeron publicaciones entre 2002 y 2012 de estudios en humanos, en español e inglés y con acceso a texto completo. Fueron incluidos los artículos que la búsqueda arrojó y algunas de las referencias usadas en dichos trabajos. Fueron excluidos los trabajos con métodos in vitro, con efectos sobre la hipertensión ocular y aquellos que no consideraran la interacción AINE-antihipertensivos. Para la selección de los trabajos incluidos participaron 3 revisores independientes. Se usó una herramienta especialmente diseñada para la extracción de datos y análisis de la relevancia clínica de la interacción. RESULTADOS: Se incluyeron 19 artículos de los 50 encontrados. Allí se identificaron 21 interacciones de mecanismo farmacodinámico, clasificadas por su relevancia clínica en nivel 2 (riesgo alto; 76,2%) y nivel 3 (riesgo medio; 23,8%). Adicionalmente se encontró evidencia de 16 combinaciones que no presentaron interacción. CONCLUSIONES: Algunos AINE pueden disminuir la efectividad del tratamiento antihipertensivo cuando se utilizan simultáneamente con antihipertensivos, en especial con inhibidores de la enzima conversora de angiotensina, diuréticos, bloqueadores beta y antagonistas de los receptores de angiotensina. No se encontró evidencia de la modificación del efecto de los antagonistas de los canales de calcio, especialmente dihidropiridínicos, por el uso simultáneo con AINE

OBJECTIVE: To establish the clinical relevance of drug interactions between nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensives, based on the interaction severity and probability of occurrence. DESIGN: Systematic review. Data sources: A PubMed/Medline search was made using the MeSH terms: NSAIDs, Antihypertensive drugs, and Drug interactions. Data extraction: Articles between 2002 and 2012, human studies, in Spanish and English and full text access were included. Found articles were included and some of the references used in this works. Studies with in vitro methods, effects on ocular hypertension and those who do not consider the interaction NSAIDs, antihypertensives were excluded. For the selection of the papers included three independent reviewers were involved. We used a tool for data extraction and for assess of the interaction clinical relevance. RESULTS: Nineteen of 50 papers found were included. There were identified 21 interactions with pharmacodynamic mechanism, classified by their clinical relevance in level-2 high risk (76.2%) and level-3 medium risk (23.8%). In addition, evidence of 16 combinations of no interaction were found. CONCLUSIONS: Some NSAIDs may attenuate the effectiveness of antihypertensive drugs when used concurrently, especially with angiotensin converting enzyme inhibitors, diuretics, beta blockers and angiotensin receptors II blockers. There was no evidence of effect modification of calcium channel antagonists, especially dihydropyridine, by concurrent use of NSAID

[Systemic loxoscelism presented in a pregnant patient]. / Loxoscelismo sistémico en una mujer embarazada.

BACKGROUND: Loxoscelism is a condition caused by the inoculation of a series of proteolytic enzymes through the loxosceles spider bite (violinist). Morbidity and mortality is unknown in our country. The loxoscelism toxi-syndrome of local expression may have a good prognosis; however, viscera-cutaneus or systemic form has a serious and often fatal evolution. We report a case of a systemic variant developed in a pregnant patient. CLINICAL CASE: We present the first reported case of systemic loxoscelism in a pregnant patient, highlighting the survival of the mother-son, in the presence of viscera-cutaneus behavior. We describe the natural history of clinical expression, highlighting the benefit of current therapeutic antivenom fourth generation and immunoregulation role in supporting the therapeutic approach and the guideline of the surgical approach. CONCLUSIONS: The appropriate multidisciplinary management coupled with an early use of antivenom limits the severity and the potential development of complications. Clinical suspicion is the cornerstone of therapeutic management of these patients.

INTRODUCCIÓN: el loxoscelismo se debe a la inoculación de un conjunto de enzimas proteolíticas por la mordedura de la araña Loxosceles. Puede tener una expresión local, sin embargo, la forma viscerocutánea o sistémica tiene una evolución grave. Se presenta el primer caso de la variante sistémica en una mujer embarazada. CASO CLÍNICO: mujer con embarazo normoevolutivo de 28 semanas. Después de estar expuesta a un ambiente semirrural, presentó placa plana eritematosa en el glúteo derecho, con aumento de la temperatura e hiperestesia local. Fue hospitalizada para administrarle antibióticos parenterales, por considerarse que se trataba de la picadura de un insecto. A las cuatro horas se incrementó el dolor y la paciente desarrolló deshidratación e hipotensión severas hasta llegar al choque, por lo que se inició tratamiento con cristaloides, aminas vasopresoras y protección de la vía aérea. Se realizó operación cesárea, de la que se obtuvo un niño, y se efectuó desbridación en el glúteo derecho. El diagnóstico fue loxoscelismo sistémico, por lo que se administró el antiveneno específico. La paciente fue egresada a los dos meses. CONCLUSIONES: el manejo multidisciplinario oportuno, aunado al empleo del antiveneno, limitó la severidad y el desarrollo potencial de complicaciones. La sospecha clínica es la piedra angular del tratamiento en estos pacientes.

Comparison between two methods of scorpion venom milking in Morocco.

BACKGROUND: The present study compared two methods used successfully in a large-scale program for the collection of scorpion venoms, namely the milking of adult scorpions via manual and electrical stimulation. RESULTS: Our immunobiochemical characterizations clearly demonstrate that regularly applied electrical stimulation obtains scorpion venom more easily and, most importantly, in greater quantity. Qualitatively, the electrically collected venom showed lack of hemolymph contaminants such as hemocyanin. In contrast, manual obtainment of venom subjects scorpions to maximal trauma, leading to hemocyanin secretion. Our study highlighted the importance of reducing scorpion trauma during venom milking. CONCLUSIONS: In conclusion, to produce high quality antivenom with specific antibodies, it is necessary to collect venom by the gentler electrical stimulation method.

Comparison between two methods of scorpion venom milking in Morocco

Background The present study compared two methods used successfully in a large-scale program for the collection of scorpion venoms, namely the milking of adult scorpions via manual and electrical stimulation. Results Our immunobiochemical characterizations clearly demonstrate that regularly applied electrical stimulation obtains scorpion venom more easily and, most importantly, in greater quantity. Qualitatively, the electrically collected venom showed lack of hemolymph contaminants such as hemocyanin. In contrast, manual obtainment of venom subjects scorpions to maximal trauma, leading to hemocyanin secretion. Our study highlighted the importance of reducing scorpion trauma during venom milking. Conclusions In conclusion, to produce high quality antivenom with specific antibodies, it is necessary to collect venom by the gentler electrical stimulation method.

Comparison between two methods of scorpion venom milking in Morocco

Background The present study compared two methods used successfully in a large-scale program for the collection of scorpion venoms, namely the milking of adult scorpions via manual and electrical stimulation. Results Our immunobiochemical characterizations clearly demonstrate that regularly applied electrical stimulation obtains scorpion venom more easily and, most importantly, in greater quantity. Qualitatively, the electrically collected venom showed lack of hemolymph contaminants such as hemocyanin. In contrast, manual obtainment of venom subjects scorpions to maximal trauma, leading to hemocyanin secretion. Our study highlighted the importance of reducing scorpion trauma during venom milking. Conclusions In conclusion, to produce high quality antivenom with specific antibodies, it is necessary to collect venom by the gentler electrical stimulation method.(AU)

Imidazolines as non-classical bioisosteres of N-acyl homoserine lactones and quorum sensing inhibitors.

A series of selected 2-substituted imidazolines were synthesized in moderate to excellent yields by a modification of protocols reported in the literature. They were evaluated as potential non-classical bioisosteres of AHL with the aim of counteracting bacterial pathogenicity. Imidazolines 18a, 18e and 18f at various concentrations reduced the violacein production by Chromobacterium violaceum, suggesting an anti-quorum sensing profile against Gram-negative bacteria. Imidazoline 18b did not affect the production of violacein, but had a bacteriostatic effect at 100 µM and a bactericidal effect at 1 mM. Imidazoline 18a bearing a hexyl phenoxy moiety was the most active compound of the series, rendering a 72% inhibitory effect of quorum sensing at 100 µM. Imidazoline 18f bearing a phenyl nonamide substituent presented an inhibitory effect on quorum sensing at a very low concentration (1 nM), with a reduction percentage of 28%. This compound showed an irregular performance, decreasing inhibition at concentrations higher than 10 µM, until reaching 100 µM, at which concentration it increased the inhibitory effect with a 49% reduction percentage. When evaluated on Serratia marcescens, compound 18f inhibited the production of prodigiosin by 40% at 100 µM.

Displasia cleidocraneal / Cleidocranial dysplasia

RESUMEN Las displasias esqueléticas son enfermedades genéticas poco frecuentes, de evolución crónica y sin tratamiento curativo. Presentamos el caso clínicode un niño de 8 años atendido en el CESAC Nº 5de la Ciudad Autónoma de Buenos Aires, que consultópor un cuadro de rinosinusitis aguda y en elque se observó un fenotipo peculiar; se completóuna historia clínica detallada y se realizó el diagnósticopresuntivo de displasia cleidocraneal.Palabras clave: displasia esquelética, característicasfenotípicas

Displasia cleidocraneal / Cleidocranial dysplasia

RESUMEN Las displasias esqueléticas son enfermedades genéticas poco frecuentes, de evolución crónica y sin tratamiento curativo. Presentamos el caso clínicode un niño de 8 años atendido en el CESAC Nº 5de la Ciudad Autónoma de Buenos Aires, que consultópor un cuadro de rinosinusitis aguda y en elque se observó un fenotipo peculiar; se completóuna historia clínica detallada y se realizó el diagnósticopresuntivo de displasia cleidocraneal.Palabras clave: displasia esquelética, característicasfenotípicas

Laparoscopic management as the initial treatment of acute small bowel obstruction.

OBJECTIVES: We prospectively evaluated our experience with laparoscopic management of acute small bowel obstruction (SBO). METHODS: The study group included all patients requiring surgical intervention based on complete mechanical SBO by clinical assessment or who had failed conservative management. Patients with malignant causes were excluded. Experienced laparoscopic surgeons performed all operations. RESULTS: Between January 1998 to January 2003, 61 patients required operative intervention for acute SBO. Causes included adhesions, internal hernia, incarcerated incisional hernia, and inflammatory bowel disease. Laparoscopic techniques (LAP) alone were successfully used to complete 41 cases (67%). Twenty patients (33%) were converted (CONV) to either mini-laparotomy [7 patients (35%)] or standard midline laparotomy [13 patients (65%)]. A single band was identified in 25 patients (41%). Complications occurred in both groups. CONCLUSIONS: We believe all patients requiring surgery in the setting of acute small bowel obstruction should undergo a laparoscopic approach initially. By specifically identifying those patients with a single band as the cause of obstruction, a significant number of patients will be spared a large laparotomy incision. Conversion should not be viewed as failure, but rather, a sometimes necessary step in the optimal management of these patients.