Machine Learning in Epigenomics: Insights into Cancer Biology and Medicine.

The recent deluge of genome-wide technologies for the mapping of the epigenome and resulting data in cancer samples has provided the opportunity for gaining insights into and understanding the roles of epigenetic processes in cancer. However, the complexity, high-dimensionality, sparsity, and noise associated with these data pose challenges for extensive integrative analyses. Machine Learning (ML) algorithms are particularly suited for epigenomic data analyses due to their flexibility and ability to learn underlying hidden structures. We will discuss four overlapping but distinct major categories under ML: dimensionality reduction, unsupervised methods, supervised methods, and deep learning (DL). We review the preferred use cases of these algorithms in analyses of cancer epigenomics data with the hope to provide an overview of how ML approaches can be used to explore fundamental questions on the roles of epigenome in cancer biology and medicine.

Redefining macrophage and neutrophil biology in the metastatic cascade.

Tumor cells metastasize to distant organs through a complex series of events that are driven by tumor intrinsic and extrinsic factors. In particular, non-malignant stromal cells, including immune cells, modify tumor metastatic behavior. Of these cells, tumor-associated innate immune cells, particularly macrophages and neutrophils, suppress the cytotoxic activity of innate and adaptive killer cells and interact with tumor cells to promote their growth and malignancy. These findings in mouse cancer models suggest that targeting these sub-populations of immune cells holds therapeutic promise in treating metastatic disease. In this review, we describe the origin and role of the macrophages, neutrophils, and their progenitors in the metastatic cascade and suggest strategies that might enhance cancer therapy.

Large-scale analysis of 2,152 Ig-seq datasets reveals key features of B cell biology and the antibody repertoire.

Antibody repertoire sequencing enables researchers to acquire millions of B cell receptors and investigate these molecules at the single-nucleotide level. This power and resolution in studying humoral responses have led to its wide applications. However, most of these studies were conducted with a limited number of samples. Given the extraordinary diversity, assessment of these key features with a large sample set is demanded. Thus, we collect and systematically analyze 2,152 high-quality heavy-chain antibody repertoires. Our study reveals that 52 core variable genes universally contribute to more than 99% of each individual's repertoire; a distal interspersed preferences characterize V gene recombination; the number of public clones between two repertoires follows a linear model, and the positive selection dominates at RGYW motif in somatic hypermutations. Thus, this population-level analysis resolves some critical features of the antibody repertoire and may have significant value to the large cadre of scientists.

La educación alimentaria y nutricional: un estudio descriptivo en la formación del docente de Biología / Food and nutritional education: descriptive study in the training of Biology teachers

RESUMEN Introducción: el docente de Biología debe contribuir a la educación para la salud, y dentro de ella a la educación alimentaria y nutricional de los estudiantes, mediante el proceso de enseñanza-aprendizaje de los contenidos relacionados con la Biología. Objetivo: describir los conocimientos y comportamientos sobre educación alimentaria y nutricional que poseen los estudiantes de la carrera de Licenciatura en Educación, especialidad Biología, en la Universidad de Matanzas. Materiales y métodos: se realizó un estudio descriptivo de los conocimientos y comportamientos sobre educación alimentaria y nutricional en 21 estudiantes de la carrera de Licenciatura en Educación, especialidad Biología, de la Universidad de Matanzas, en enero de 2020. Los métodos teóricos empleados fueron el histórico-lógico, el analítico-sintético y el inductivo-deductivo. Como método empírico se utilizó la encuesta. Resultados: los estudiantes presentan insuficientes conocimientos sobre los nutrientes que aportan diversos alimentos, y desconocimiento sobre las biomoléculas y su importancia para el correcto funcionamiento del organismo. Muestran interés por el consumo de la comida denominada chatarra, y obvian la necesidad del consumo de vegetales, frutas y viandas hervidas. Conclusiones: los estudiantes encuestados presentaron limitados conocimientos sobre alimentación y nutrición como procesos inherentes a la vida humana, que determinan la educación alimentaria y nutricional como un factor básico para evitar enfermedades que repercuten en su salud, e impiden que puedan realizar su labor educativa como docentes de Biología, líderes de la promoción de salud en la escuela y la comunidad (AU).

ABSTRACT Introduction: the teacher who teaches Biology must make good use of the different curricular contents to contribute to health education and within it to food and nutritional education of students. Objective: to describe the knowledge and behaviors on food and nutrition education that students of the degree course of Education in Biology of the University of Matanzas have. Materials and methods: a descriptive study of the knowledge and behavior on food and nutritional education in 21 students of the degree course of Education in Biology of the University of Matanzas, in January 2020. The theoretical methods used were the historic-logical, the analytical-synthetic, and the inductive-deductive one. The survey was used as empiric method. Results: the students showed not enough knowledge on the nutrients provided by different foods, not knowing about biomolecules and their importance for the proper functioning of the body. They evidenced their preference for the consumption of the so called junk food, obviating the need of green vegetables, fruits and boiled vegetables. Conclusions: the surveyed students presented limited knowledge on food and nutrition as processes inherent to human life, which determine food and nutritional education as a basic factor to avoid diseases that affect their health. It is a constraint for carrying out an adequate educative work as Biology teachers and future leaders of health promotion at school and in the community (AU).

Angiotensin II and Angiotensin Receptors 1 and 2-Multifunctional System in Cells Biology, What Do We Know?

For years, the renin-angiotensin system (RAS) has been perceived as a system whose role is to primarily modulate the functioning of the cardiovascular system. Years of research into the role of RAS have provided the necessary data to confirm that the role of RAS is very complex and not limited to the cardiovascular system. The presence of individual elements of the renin-angiotensin (RA) system allows to control many processes, ranging from the memorization to pro-cancer processes. Maintaining the proportions between the individual axes of the RA system allows for achieving a balance, often called homeostasis. Thus, any disturbance in the expression or activity of individual RAS elements leads to pathophysiological processes.

Recent applications of N-acyl imidazole chemistry in chemical biology.

N-Acyl imidazoles are unique electrophiles that exhibit moderate reactivity, relatively long-half life, and high solubility in water. Thanks to their tunable reactivity and chemical selectivity, the application of N-acyl imidazole derivatives has launched to a number of chemical biology researches, which include chemical synthesis of peptide/protein, chemical labeling of native proteins of interest (POIs), and structural analysis and functional manipulation of RNAs. Since proteins and RNAs play pivotal roles in numerous biological events in all living organisms, the methods that enable the chemical modification of endogenously existing POIs and RNAs in live cells may offer a variety of opportunities not only for fundamental scientific study but also for biotechnology and drug development. In this review, we discuss the recent progress of N-acyl imidazole chemistry that contributes to the chemical labeling and functional control of endogenous proteins and RNAs under multimolecularly crowded biological conditions of live cells.

A System Biology-Based Approach for Designing Combination Therapy in Cancer Precision Medicine.

In this paper, we have used an agent-based stochastic tumor growth model and presented a mathematical and theoretical perspective to cancer therapy. This perspective can be used to theoretical study of precision medicine and combination therapy in individuals. We have conducted a series of in silico combination therapy experiments. Based on cancer drugs and new findings of cancer biology, we hypothesize relationships between model parameters which in some cases represent individual genome characteristics and cancer drugs, i.e., in our approach, therapy players are delegated by biologically reasonable parameters. In silico experiments showed that combined therapies are more effective when players affect tumor via different mechanisms and have different physical dimensions. This research presents for the first time an algorithm as a theoretical viewpoint for the prediction of effectiveness and classification of therapy sets.

Human organoids: model systems for human biology and medicine.

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids - which are stem cell-derived 3D culture systems - it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.

A lower affinity to cytosolic proteins reveals VDAC3 isoform-specific role in mitochondrial biology.

Voltage-dependent anion channel (VDAC) is the major pathway for the transport of ions and metabolites across the mitochondrial outer membrane. Among the three known mammalian VDAC isoforms, VDAC3 is the least characterized, but unique functional roles have been proposed in cellular and animal models. Yet, a high-sequence similarity between VDAC1 and VDAC3 is indicative of a similar pore-forming structure. Here, we conclusively show that VDAC3 forms stable, highly conductive voltage-gated channels that, much like VDAC1, are weakly anion selective and facilitate metabolite exchange, but exhibit unique properties when interacting with the cytosolic proteins α-synuclein and tubulin. These two proteins are known to be potent regulators of VDAC1 and induce similar characteristic blockages (on the millisecond time scale) of VDAC3, but with 10- to 100-fold reduced on-rates and altered α-synuclein blocking times, indicative of an isoform-specific function. Through cysteine scanning mutagenesis, we found that VDAC3's cysteine residues regulate its interaction with α-synuclein, demonstrating VDAC3-unique functional properties and further highlighting a general molecular mechanism for VDAC isoform-specific regulation of mitochondrial bioenergetics.

In situ structural biology using in-cell NMR.

BACKGROUND: Accumulating evidence from the experimental and computational studies indicated that the functional properties of proteins are different between in vitro and living cells, raising the necessity to examine the protein structure under the native intracellular milieu. To gain structural information of the proteins inside the living cells at an atomic resolution, in-cell NMR method has been developed for the past two decades. SCOPE OF REVIEW: In this review, we will overview the recent progress in the methodological developments and the biological applications of in-cell NMR, and discuss the advances and challenges in this filed. MAJOR CONCLUSIONS: A number of methods were developed to enrich the isotope-labeled proteins inside the cells, enabling the in-cell NMR observation of bacterial cells as well as eukaryotic cells. In-cell NMR has been applied to various biological systems, including de novo structure determinations, protein/protein or protein/drug interactions, and monitoring of chemical reactions exerted by the endogenous enzymes. The bioreactor system, in which the cells in the NMR tube are perfused by fresh culture medium, enabled the long-term in-cell NMR measurements, and the real-time observations of intracellular responses upon external stimuli. GENERAL SIGNIFICANCE: In-cell NMR has become a unique technology for its ability to obtain the function-related structural information of the target proteins under the physiological or pathological cellular environments, which cannot be reconstituted in vitro.

CryoSTEM tomography in biology.

Electron cryo-tomography using the scanning transmission modality (STEM) enables 3D reconstruction of unstained, vitrified specimens as thick as 1µm or more. Contrast is related to mass/thickness and atomic number, providing quantifiable chemical characterization and mass mapping of intact prokaryotic and eukaryotic cells. Energy dispersive X-ray spectroscopy by STEM provides a simple, on-the-spot chemical identification of the elemental composition in sub-cellular organic bodies or mineral deposits. This chapter provides basic background and practical information for performing cryo-STEM tomography on vitrified biological cells.

Potential applications of engineered nanoparticles in medicine and biology: an update.

Nanotechnology advancements have led to the development of its allied fields, such as nanoparticle synthesis and their applications in the field of biomedicine. Nanotechnology driven innovations have given a hope to the patients as well as physicians in solving the complex medical problems. Nanoparticles with a size ranging from 0.2 to 100 nm are associated with an increased surface to volume ratio. Moreover, the physico-chemical and biological properties of nanoparticles can be modified depending on the applications. Different nanoparticles have been documented with a wide range of applications in various fields of medicine and biology including cancer therapy, drug delivery, tissue engineering, regenerative medicine, biomolecules detection, and also as antimicrobial agents. However, the development of stable and effective nanoparticles requires a profound knowledge on both physico-chemical features of nanomaterials and their intended applications. Further, the health risks associated with the use of engineered nanoparticles needs a serious attention.

Same Redox Evidence But Different Physiological "Stories": The Rashomon Effect in Biology.

The Rashomon effect - a phenomenon studied in the arts and social sciences - occurs when the same event is given contradictory interpretations by different individuals involved. The effect was named after Akira Kurosawa's 1950 film Rashomon, in which a murder is described in four contradictory ways by four witnesses. In the film, a samurai has been killed under mysterious circumstances. Four people give contradictory reports about the crime. In particular, the samurai's wife claims that she was sexually abused by a bandit, fainted, and then awoke to find her husband dead; the bandit claims that he seduced the wife and challenged the samurai in a battle to victory or at least to an honorable death; the woodcutter (who may have been an onlooker) claims that he witnessed the rape and murder but was not involved; and the dead samurai's spirit claims that he committed suicide. The Rashomon effect is not only about constructing different versions of the world based on differences in perspective; it occurs when such differences appear together with the absence of evidence to assess any version of the truth, plus "the social pressure for closure on the question." In this commentary, we describe the relevance of the Rashomon effect beyond the arts and social sciences, namely in the field of biology. We use examples from redox biology, which is full of contradictions, thus making it fertile ground on which to apply reasoning derived from the Rashomon effect.

Fluorescent Chemosensors as Future Tools for Cancer Biology.

It is well established that aberrant cellular biochemical activity is strongly linked to the formation and progression of various cancers. Assays that could aid in cancer diagnostics, assessing anticancer drug resistance, and in the discovery of new anticancer drugs are highly warranted. In recent years, a large number of small molecule-based fluorescent chemosensors have been developed for monitoring the activity of enzymes and small biomolecular constituents. These probes have shown several advantages over traditional methods, such as the ability to directly and selectively measure activity of their targets within complex cellular environments. This review will summarize recently developed fluorescent chemosensors that have potential applications in the field of cancer biology.

A molecular engineering toolbox for the structural biologist.

Exciting new technological developments have pushed the boundaries of structural biology, and have enabled studies of biological macromolecules and assemblies that would have been unthinkable not long ago. Yet, the enhanced capabilities of structural biologists to pry into the complex molecular world have also placed new demands on the abilities of protein engineers to reproduce this complexity into the test tube. With this challenge in mind, we review the contents of the modern molecular engineering toolbox that allow the manipulation of proteins in a site-specific and chemically well-defined fashion. Thus, we cover concepts related to the modification of cysteines and other natural amino acids, native chemical ligation, intein and sortase-based approaches, amber suppression, as well as chemical and enzymatic bio-conjugation strategies. We also describe how these tools can be used to aid methodology development in X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy and in the studies of dynamic interactions. It is our hope that this monograph will inspire structural biologists and protein engineers alike to apply these tools to novel systems, and to enhance and broaden their scope to meet the outstanding challenges in understanding the molecular basis of cellular processes and disease.

Tumor biology remains the main determinant of prognosis in retroperitoneal sarcomas: a 14-year single-center experience.

AIM: To review our experience in the management of retroperitoneal sarcomas (RPSs) in a single institution, with a predominantly Asian population, and identify associated prognostic factors for overall survival (OS), disease-free survival (DFS) and local recurrence. MATERIALS AND METHODS: All RPSs diagnosed and managed at our center between January 2000 and March 2014 were included. Exclusion criteria included patients whose medical records were untraceable and patients who underwent biopsy but did not undergo resection. The variables studied were age, gender, histological subtype, tumor size, tumor grade, surgical margins, type of presentation of tumor (primary or recurrent) and presence of contiguous organ resection. The primary outcome measured was OS. RESULTS: Eighty-five patients underwent resection of RPS with curative intent. Eight patients underwent adjuvant chemotherapy and 15 patients underwent radiotherapy. The median DFS was 21 months (range: 0-146) and median OS was 45 months (range: 1-233). On univariate analysis, resection margin (P = 0.04), tumor grade (P = 0.011) and type of presentation of tumor (P = 0.007) were found to significantly affect OS. Patients with tumor adherent to contiguous organs had a greater OS as compared to patients with tumor invasive into the contiguous organs (P = 0.02). CONCLUSION: An aggressive surgical approach in primary and recurrent RPS is associated with good OS. Complete resection, with contiguous organ resection if necessary should be performed to achieve microscopically negative surgical margins to allow for long-term survival. However, tumor biology remains the main determinant for OS.

Biological causal links on physiological and evolutionary time scales.

Correlation does not imply causation. If two variables, say A and B, are correlated, it could be because A causes B, or that B causes A, or because a third factor affects them both. We suggest that in many cases in biology, the causal link might be bi-directional: A causes B through a fast-acting physiological process, while B causes A through a slowly accumulating evolutionary process. Furthermore, many trained biologists tend to consistently focus at first on the fast-acting direction, and overlook the slower process in the opposite direction. We analyse several examples from modern biology that demonstrate this bias (codon usage optimality and gene expression, gene duplication and genetic dispensability, stem cell division and cancer risk, and the microbiome and host metabolism) and also discuss an example from linguistics. These examples demonstrate mutual effects between the fast physiological processes and the slow evolutionary ones. We believe that building awareness of inference biases among biologists who tend to prefer one causal direction over another could improve scientific reasoning.

Why magnetic and electromagnetic effects in biology are irreproducible and contradictory?

The main source of magnetic and electromagnetic effects in biological systems is now generally accepted and demonstrated in this paper to be radical pair mechanism which implies pairwise generation of radicals in biochemical reactions. This mechanism was convincingly established for enzymatic adenosine triphosphate (ATP) and desoxynucleic acid (DNA) synthesis by using catalyzing metal ions with magnetic nuclei ((25)Mg, (43)Ca, (67)Zn) and supported by magnetic field effects on these reactions. The mechanism, is shown to function in medicine as a medical remedy or technology (trans-cranial magnetic stimulation, nuclear magnetic control of the ATP synthesis in heart muscle, the killing of cancer cells by suppression of DNA synthesis). However, the majority of magnetic effects in biology remain to be irreproducible, contradictory, and enigmatic. Three sources of such a state are shown in this paper to be: the presence of paramagnetic metal ions as a component of enzymatic site or as an impurity in an uncontrollable amount; the property of the radical pair mechanism to function at a rather high concentration of catalyzing metal ions, when at least two ions enter into the catalytic site; and the kinetic restrictions, which imply compatibility of chemical and spin dynamics in radical pair. It is important to keep in mind these factors to properly understand and predict magnetic effects in magneto-biology and biology itself and deliberately use them in medicine.

A Compact "Water Window" Microscope with 60 nm Spatial Resolution for Applications in Biology and Nanotechnology.

Short illumination wavelength allows an extension of the diffraction limit toward nanometer scale; thus, improving spatial resolution in optical systems. Soft X-ray (SXR) radiation, from "water window" spectral range, λ=2.3-4.4 nm wavelength, which is particularly suitable for biological imaging due to natural optical contrast provides better spatial resolution than one obtained with visible light microscopes. The high contrast in the "water window" is obtained because of selective radiation absorption by carbon and water, which are constituents of the biological samples. The development of SXR microscopes permits the visualization of features on the nanometer scale, but often with a tradeoff, which can be seen between the exposure time and the size and complexity of the microscopes. Thus, herein, we present a desk-top system, which overcomes the already mentioned limitations and is capable of resolving 60 nm features with very short exposure time. Even though the system is in its initial stage of development, we present different applications of the system for biology and nanotechnology. Construction of the microscope with recently acquired images of various samples will be presented and discussed. Such a high resolution imaging system represents an interesting solution for biomedical, material science, and nanotechnology applications.