Technological advances in transmission electron microscopes and detectors have turned cryogenic electron microscopy (cryo-EM) into an essential tool for structural biology. A commonly used cryo-EM data analysis method, single particle analysis, averages hundreds of thousands of low-dose images of individual macromolecular complexes to determine a density map of the complex. The presence of symmetry

Myocardial function is tuned by dynamic changes in length and load via mechano-calcium feedback. This regulation may be significantly affected by heart rhythm. We evaluated the mechano-induced modulation of contractility and Ca-transient (CaT) in the rat myocardium subjected to twitch-by-twitch shortening–re-lengthening (↓–↑) trains of different lengths (N = 1 … 720 cycles) at low (1 Hz) and near-physiological

OBJECTIVES Variability of ion currents is major issue when used for significance testing. One of the simplest approach to reduce variability is normalization to cell membrane size. However, efficacy of Ca2+ currents (ICa) normalization is unknown. Beside absolute variability, the type of distribution since non-Gaussian distribution makes application of nonparametric test necessary. METHODS We retrospectively

A variety of techniques of cell capacitance measurement have been proposed and applied in cellular electrophysiology. They are mostly based on the evaluation of membrane current responses to small changes in the membrane voltage. One of the currently used approaches applies the least-squares fit of an exponential current decay in response to voltage clamped rectangular pulses. In this study, we propose

The function of ion channels to mediate the flux of ions through membranes of living cells depends on their number, conductance, and open probability. The open probability, PO, characterizes gating of channels that is sensitive to experimental conditions and that can be determined in single-channel experiments. Individual experimental records and even whole series of single-channel activity measurements

Schizophrenia (SZ) is a mental disorder characterized by neurocognitive dysfunctions and a reduction in occupational and social functioning. Several studies have provided evidence for mitochondrial dysfunction in the pathophysiology of SZ. In this sense, it is known that the addition of genetic variations in mitochondrial DNA (mtDNA) impairs oxidative phosphorylation of enzymatic complexes in mitochondria

Well over a century ago, Otto Frank, working at Carl Ludwig's Institute of Physiology in Munich, studying the isolated, blood-perfused, frog heart preparation, demonstrated that there are two distinct pressure-volume relations in the heart: one for isovolumic twitches and a second (located inferiorly) for afterloaded twitches. Whereas Starling, working at UCL two decades later, referenced Frank's publication

In December 2019, an atypical pneumonia invaded the city of Wuhan, China, and the causative agent of this disease turned out to be a new coronavirus. In January 2020, the World Health Organization named the new coronavirus 2019-nCoV and subsequently it is referred to as SARS-CoV2 and the related disease as CoViD-19 (Lai et al., 2020). Very quickly, the epidemic led to a pandemic and it is now a worldwide

Cell survival or death is one critical issue in inflammatory responses. Ferroptosis, which is characterized by iron-dependent lethal lipid peroxidation, has been found to participate in the development of cancers, degenerative brain diseases and ischemia-reperfusion injuries. Incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes represents a vulnerability to invasion of microbials

Causal relationships lie at the very core of scientific description of biophysical phenomena. Nevertheless, observable facts involving changes in system shape, dimension and symmetry may elude simple cause and effect inductive explanations. Here we argue that numerous physical and biological phenomena such as chaotic dynamics, symmetry breaking, long-range collisionless neural interactions, zero-valued

Bioinformatics refers to an ever evolving huge field of research based on millions of algorithms, designated to several data banks. Such algorithms are either supervised or unsupervised. In this article, a detailed overview of the supervised and unsupervised techniques is presented with the aid of examples. The aim of this article is to provide the readers with the basic understanding of the state

Although theories regarding the role of sequence-specific DNA resonance in biology have abounded for over 40 years, the published evidence for it is lacking. Here, the authors reasoned that for sustained resonance signaling, the number of oscillating DNA sequences per genome should be exceptionally high and that, therefore, genomic repeats of various sizes are good candidates for serving as resonators

Autophagy is a tightly-regulated multi-step process involving the lysosomal degradation of proteins and cytoplasmic organelles. Central to this process is the formation of the autophagosome, a double membrane-bound vesicle, which is fuse with lysosomes or endosomes, and then deliver its cytoplasmic cargo to the lysosomes. Here, we summarize the recent process of autophagy, focusing on protein molecules

Breast cancer (BC) is a serious worldwide disease that threatens women's health. Particularly, the morbidity of triple-negative breast cancer (TNBC) is higher than that of other BC types due to its high molecular heterogeneity, metastatic potential and poor prognosis. TNBC lacks of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), so there are still

Gap junctions mediate cellular communication and homeostasis by controlling the intercellular exchange of small and hydrophilic molecules and ions. Gap junction channels are formed by the docking of 2 hemichannels of adjacent cells, which in turn are composed of 6 connexin subunits. Connexin proteins as such can also control the cellular life cycle independent of their channel activities. This has

Electrophysiologists routinely use simple voltage steps to evaluate cell membrane capacitance derived from corresponding current responses. Frequently, the resting membrane voltage Vrest is employed as holding potential for the subsequent command voltage step and more or less accurate methods are utilised to analyse the transient current. Another choice as holding potential is the peak of the “quasi

Calcium (Ca2+) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca2+ levels are regulated by a variety of Ca2+-handling proteins. In turn, Ca2+ modulates numerous electrophysiological processes. Accordingly, Ca2+-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including

Herein, we review recent works on the role that the tRNA molecule played in the early origins of biological systems. tRNAs gave origin to the first genes (mRNA), the peptidyl transferase center (PTC), the 16S ribosomal molecule, proto-tRNAs were at the core of a proto-translation system, and the anticodon and operational codes appeared in tRNAs molecules. Metabolic pathways emerged from evolutionary

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), kills more people than any other bacterium. TB control is threatened by the continued spread of drug resistance; multi-drug and extensively drug resistant Mtb require longer, more costly, treatment with multiple drugs causing worse side effects and have a lower likelihood of treatment success. The urgent need for better treatment

Mycobacterium tuberculosis strictly depends on oxygen to multiply, and the terminal oxidases are a vital part of the oxidative phosphorylation pathway. The bacterium possesses two aerobic respiratory branches: a cytochrome bcc-aa3 and a bacteria-specific cytochrome bd oxidase. The identification of small-molecule inhibitors of the cytochrome bcc-aa3 under numerous experimental conditions reflects the

Many theorists in recent years have been calling for evolutionary biology to move beyond the Modern Synthesis - the paradigm that has long provided the theoretical backbone for the discipline. Terms like "postmodern synthesis," "integrative synthesis," and "extended evolutionary synthesis" have been invoked by various critics in connection with the many recent developments that pose deep challenges

Atrial fibrillation (AF) is the most common cardiac arrhythmia, associated with an increased risk of stroke and heart failure. Acute AF occurs in response to sudden increases of atrial hemodynamic load, leading to atrial stretch. The mechanisms of stretch-induced AF were investigated in large mammals with controversial results. We optimized an approach to monitor rat atrial electrical activity using

T-cell based immunity is mediated through specific T cell receptor (TCR) recognition of a small antigenic peptide in complex with a host immune molecule, major histocompatibility complex (pMHC). The interaction of a TCR and its pMHC ligand is generally quite weak, degenerate and biophysically unfavorable. Yet, the resulting immune response is extremely effective, being both sensitive and specific.

DNA methylation is an epigenetic factor, which plays important roles in embryo and many other diseases development. This factor determines gene expression, and when half of them have CpG islands, DNA methylation and its enzyme effectors have been under the vast studies. Whole genome DNA demethylation is a crucial step of embryogenesis and also cell fate determination in embryos. Therefore, demethylation

Background Cardiac optical mapping enables direct and high spatio-temporal resolution recording of action potential (AP) morphology. Temporal alterations in AP morphology are both predictive and consequent of arrhythmia. Here we sought to test if methods that quantify regularity of recorded waveforms could be applied to detect and quantify periods of temporal instability in optical mapping datasets

Protein synthesis in all the living cells is mediated by a large protein-RNA complex called the ribosome. These macromolecular complexes can range from 2.5 (prokaryotes) to 4.2 MDa. (eukaryotes) in size and undergo various conformational transitions during protein synthesis to translate the genetic code into the nascent polypeptide chains. Recent advances in cryo-electron microscopy (cryo-EM) and image

The current density (J) is a parameter routinely used to characterize individual ionic membrane currents. Its evaluation is based on the presumption that the magnitude of whole-cell ionic membrane current (I) is directly proportional to the cell membrane capacitance (C), i.e. I positively and strongly correlates with C and the regression line describing I–C relation intersects the y-axis close to the

Tuberculosis (TB) remains the foremost cause of death by infectious disease and is propagated by the pathogen Mycobacterium tuberculosis (Mtb). The virulence associated with Mtb is mediated by proteins secreted into host cells by the type VII secretion system (T7SS), making this system a candidate for future drug and vaccine development. However, while many of the components involved in the T7SS have

Optogenetics enables cell-type specific monitoring and actuation via light-activated proteins. In cardiac research, expressing light-activated depolarising ion channels in cardiomyocytes allows optical pacing and defibrillation. Previous studies largely relied on epicardial illumination. Light penetration through the myocardium is however problematic when moving to larger animals and humans. To overcome

The causative agent of Tuberculosis (TB) Mycobacterium tuberculosis (Mtb) encounters unfavourable environmental conditions in the lungs, including nutrient limitation, low oxygen tensions and/or low/high pH values. These harsh conditions in the host triggers Mtb to enter a dormant state in which the pathogen does not replicate and uses host-derived fatty acids instead of carbohydrates as an energy

Drug induced degradation of a target protein is a novel concept in drug discovery. Traditionally drugs modulate activity, as opposed to abundance, of their targets. Degradation inducing ligands act catalytically. Thus, one advantage of target degradation over the classical on-target mechanism is that lower drug concentration may be sufficient to cause the desired cellular effects. The first promoters

The branched respiratory chain of Mycobacterium tuberculosis has attracted attention as a highly promising target for next-generation antibacterials. This system includes two terminal oxidases of which the exclusively bacterial cytochrome bd represents the less energy-efficient one. Albeit dispensable for growth under standard laboratory conditions, cytochrome bd is important during environmental stress

Cellular bioenergetics is an area showing promise for the development of new antimicrobials, antimalarials and cancer therapy. Enzymes involved in central carbon metabolism and energy generation are essential mediators of bacterial physiology, persistence and pathogenicity, lending themselves natural interest for drug discovery. In particular, succinate and malate are two major focal points in both

It has long been known that the electrophysiological effects of many cardioactive drugs strongly depend on the rate dependent frequency. This was recognized first for class I antiarrhythmic agents: their Vmax suppressive effect was attenuated at long cycle lengths. Later many Ca2+ channel blockers were also found to follow such kinetics. The explanation was provided by the modulated and the guarded

Non-equilibrium-statistical models of intracellular transport are built. The most significant features of these models are microscopic reversibility and the explicit considerations of the driving forces of the process - the ATP-ADP chemical potential difference. In this paper, water transport using contractile vacuoles, the transport and assembly of microtubules and microfilaments, the protein distribution

Biomolecules can be synthesized in interstellar ice grains subject to UV radiation and cosmic rays. I show that on time scales of ≳106 years, these processes lead to the formation of large percolation clusters of organic molecules. Some of these clusters would have ended up on proto-planets where large, loosely bound aggregates of clusters (superclusters) would have formed. The interior regions of

X-ray crystallography and electron microscopy maps resolved to 3-8 Å are generally sufficient for tracing the path of the polypeptide chain in space, while often insufficient for unambiguously registering the sequence on the path (i.e., threading). Frequently, however, additional information is available from other biophysical experiments, physical principles, statistical analyses, and other prior

Proteomics is the extensive investigation of proteins which has empowered the recognizable proof of consistently expanding quantities of protein. Proteins are necessary part of living life form, with numerous capacities. The proteome is the complete arrangement of proteins that are created or altered by a life form or framework of the organism. Proteome fluctuates with time and unambiguous prerequisites

Virtually all single-particle cryo-EM experiments currently suffer from specimen adherence to the air-water interface, leading to a non-uniform distribution in the set of projection views. Whereas it is well accepted that uniform projection distributions can lead to high-resolution reconstructions, non-uniform (anisotropic) distributions can negatively affect map quality, elongate structural features

Dewetting transition - a concept borrowed from fluid mechanics - is a physiological process that takes place inside the hydrophobic pores of ion channels. This transient phenomenon causes a metastable state that forbids water molecules to cross microscopic receptor cavities. This leads to a decreased conductance, a closure of the pore and, subsequently, severe impairment of cellular performance. We

One of the important physicochemical features of the proteins specifically multi-subunit types is their stability at high temperatures. The kinetics of the dissociation and denaturation of proteins possessing at least two subunits has certain challenges because the overall mechanism of dissociation can include hidden reversible and/or irreversible steps (conformational lock). There are numerous proteins

We review the main lines of evidence (molecular, cellular and whole organism) published since the 1970s demonstrating Lamarckian Inheritance in animals, plants and microorganisms viz. the transgenerational inheritance of environmentally-induced acquired characteristics. The studies in animals demonstrate the genetic permeability of the soma-germline Weismann Barrier. The widespread nature of environmentally-directed

Experimental information from small angle X-ray scattering (SAXS) is conjugated with nuclear magnetic resonance (NMR) spectroscopy data for the improvement of protein structure determination, particularly for flexible, multidomain or intrinsically disordered proteins. Individually, each of these techniques presents capabilities and limitations: NMR excels in local information, providing atomic resolution

Self-referential cellular homeostasis is maintained by the measured assessment of both internal status and external conditions based within an integrated cellular information field. This cellular field attachment to biologic information space-time coordinates environmental inputs by connecting the cellular senome, as the sum of the sensory experiences of the cell, with its genome and epigenome. In

I argue here that polygenic scores are a public health hazard because the underlying methodology, genome wide association, from which they are derived, incorrectly assumes that the information encoded in the genomic DNA sequence is causal in terms of the cellular phenotype. This is not so when the cell is viewed from the perspective of a) fundamental physics, b) the protein chemistry that characterises

The novel cancer theory named 'the tissue organization field theory' (TOFT) suggests that carcinogenesis is a process analogous to embryonic development, whereby organs are formed through interactions among different cell types. The suggested 'morphological remodelling' of the epithelium under hypoxia in gut breathing fish (GBF) has many common features with carcinogenesis. It appears that research

BACKGROUND The genetic control strategies of vector borne diseases includes the replacement of a vector population by "disease-refractory" mosquitoes and the release of mosquitoes with a gene to control the vector's reproduction rates. Wolbachia are common intracellular bacteria that are found in arthropods and nematodes. Wolbachia infected male mosquitos have been used in different experimental trials

Effect of environment coupling on the quantum-biological phenomenon of proton tunneling in the hydrogen bonds of the adenine-thymine base pair in DNA was modeled within the framework of quantum statistics and perturbation theory. A number of important thermodynamic indicators including partition function, free energy, and entropy were then calculated and examined. The proton was then assumed to be

ATM, ATR and DNA-PKCs are key effectors of DNA Damage response and have been extensively linked to tumourigenesis and survival of cancer cells after radio/chemotherapy. Despite numerous efforts, the structures of these proteins remained elusive until very recently. The resolution revolution in Cryo-EM allowed for molecular details of these proteins to be seen for the first time. Here we provide a comprehensive

Endogenous bioelectric patterns within tissues are an important driver of morphogenesis and a tractable component of a number of disease states. Developing system-level understanding of the dynamics by which non-neural bioelectric circuits regulate complex downstream cascades is a key step towards both, an evolutionary understanding of ion channel genes, and novel strategies in regenerative medicine