Several research programmes have demonstrated how Transcranial Ultrasound Stimulation (TUS) can non-invasively and reversibly mechanically perturb neuronal functions. However, the mechanisms through which such reversible and a priori non-damaging behaviour can be observed remain largely unknown. While several TUS protocols have demonstrated motor and behavioural alterations in in vivo models, in vitro

Genomic stability is critical for cell survival and its effective repair when damaged is a vital process for preserving genetic information. Failure to correctly repair the genome can lead to the accumulation of mutations that ultimately drives carcinogenesis. Life has evolved sophisticated surveillance, repair pathways, and mechanisms to recognize and mend genomic lesions to preserve its integrity

Neural stimulation with infrared radiation has been explored for brain tissue, peripheral nerves, and cranial nerves including the auditory nerve. Initial experiments were conducted at wavelengths between λ = 1,850 and λ = 2,140 nm and the radiant energy was delivered with square pulses. Water absorption of the infrared radiation at λ = 1,860 nm is similar to absorption at wavelengths between λ = 1

It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its structural homolog, butyrylcholinesterase, it is widely distributed both within and outside the nervous system, and, in many cases, the role of both enzymes remains obscure. The transient appearance of the cholinesterases in embryonic tissues

Non-homologous end joining (NHEJ) is the preferred pathway for the repair of DNA double-strand breaks in humans. Here we describe three structural aspect aspects of the repair pathway: stages, scaffolds and strings. We discuss their orchestration of DNA repair to guarantee robust and efficient NHEJ. We focus on structural studies over the past two decades not only using X-ray diffraction, but also

In this manuscript, we interpret the implications of a discovery we made in 1993 for the understanding of the spread of excitation waves in axon, central gray matter (isolated retina) and heart. We propose that the initial burst of energy dissipation in these waves measured as potentials drops, ionic activities marked changes or optical properties being mostly the effect of dissociated water becoming

The maintenance of genome integrity is critical for the faithful replication of the genome during cell division and for protecting cells from accumulation of DNA damage, which if left unrepaired leads to a loss of genetic information, a breakdown in cell function and ultimately cell death and cancer. ATM and ATR are master kinases that are integral to homologous recombination-mediated repair of double

Cancer is one of the healthcare problems that affect many communities around the world. Many factors contribute to cancer development. Besides, these factors are counted as the main impediment in cancer immunotherapy. Myeloid-derived suppressor cells (MDSCs) are one of these impediments. MDSCs inhibit the immune responses through various mechanisms such as inhibitory cytokine release and nitric oxide

One of the most striking phenomena in biology is the action potential (AP), a nonlinear pulse with threshold and amplitude saturation (all-or-none-behavior) that propagates along neurons and other cells. In the classical interpretation the AP is considered to be an electrical phenomenon – a regenerating current flowing in a “biological cable”. In contrast, the thermodynamic interpretation has emphasized

The DNA damage response (DDR) is orchestrated by three apical signalling kinases: ATM, ATR and DNA-PKcs. Despite their central roles, structural and biochemical understanding has remained limited, mainly due to their large size. Recent advances in cryo-electron microscopy allowed for the structural analysis of these kinases, revealing their overall architecture and providing high resolution structures

Proliferating cell nuclear antigen (PCNA) is an essential protein that regulates the systematic recruitment and activity of proteins in a multitude of biochemical processes. Very few proteins, if any, bear similar responsibilities to those of PCNA, and its list of roles only continues to expand. However, even as one of the most well-studied proteins in research, many questions still remain about the

A variety of coronaviruses (CoVs) have infected humans and caused mild to severe respiratory diseases that could result in mortality. The human CoVs (HCoVs) belong to the genera of α- and β-CoVs that originate in rodents and bats and are transmitted to humans via zoonotic contacts. The binding of viral spike proteins to the host cell receptors is essential for mediating fusion of viral and host cell

Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer

The Mre11-Rad50-Nbs1/Xrs2 protein complex plays a pivotal role in the detection and repair of DNA double strand breaks. Through traditional and emerging structural biology techniques, various functional structural states of this complex have been visualized; however, relatively little is known about the transitions between these states. Indeed, it is these structural transitions that are important

This article attempts to review our work in the field since 2008, attempts to put it in a coherent framework and takes a courageous look vis-à-vis the bigger picture. It summarizes our approach, successes and open questions to start from physical principles when approaching living systems. It stresses the importance of conservation laws versus material and/or structural approaches to living systems

Mammalian cells contain an elaborate network of organelles and molecular machines that orchestrate essential cellular processes. Visualization of this network at a molecular level is vital for understanding these cellular processes. Here we present a model system based on nerve growth factor (NGF)-differentiated PC12 cells (PC12+) and suitable for high resolution imaging of organelles and molecular

The thermodynamic (TD) properties of biological membranes play a central role for living systems. It has been suggested, for instance, that nonlinear pulses such as action potentials (APs) can only exist if the membrane state is in vicinity of a TD transition. Herein, two membrane properties in living systems – excitability and velocity – are analyzed for a broad spectrum of conditions (temperature

The Fanconi Anemia (FA) pathway maintains genome stability by preventing DNA damage from occurring when replication is blocked. Central to the FA pathway is the monoubiquitination of FANCI-FANCD2 mediated by a ubiquitin RING-E3 ligase complex called the FA core complex. Genetic mutation in any component of the FA core complex results in defective FANCI-FANCD2 monoubiquitination and phenotypes of DNA

Mechano-electric coupling (MEC) in atrial tissue has received sparse investigation to date, despite the well-known association between chronic atrial dilation and atrial fibrillation (AF). Of note, no fewer than six different mechanisms pertaining to stretch-activated channels, cellular capacitance and geometric effects have been identified in the literature as potential players. In this mini review

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific

Linking complex, multigenic traits to protein activity is an important challenge in current biology, including applications in the medical sciences, agriculture, or forestry. Two simple algorithms are presented here to establish that link. The first one describes synergistic interactions of n proteins in shaping a complex trait (‘weak emergence’) as opposed to a simply additive ‘modular’ contribution

The transient receptor potential Melastatin 4 (TRPM4) channel is a calcium-activated non-selective cation channel expressed widely. In the heart, using a knock-out mouse model, the TRPM4 channel has been shown to be involved in multiple processes, including β-adrenergic regulation, cardiac conduction, action potential duration and hypertrophic adaptations. This channel was recently shown to be involved

Stochastic processes at molecular, cellular and higher levels in organisms are not simply noise. Organisms also use stochasticity at all levels to generate new DNA sequences, as in the immune system, and new forms of behaviour, as in the nervous system. The harnessing of stochasticity therefore endows organisms with the means to actively influence the direction of their development and evolution.

Atrial fibrillation (AF) is a multifactorial disease, which often occurs in the presence of underlying cardiac abnormalities and is supported by electrophysiological and structural alterations, generally referred to as atrial remodeling. Abnormal substrates are commonly encountered in various conditions that predispose to AF, such as hypertension, heart failure, obesity, and sleep apnea, in which atrial

Cryo-electron microscopy (cryoEM) has become one of the most important approach for structural biology. However, barriers are still there for an increased successful rate, a better resolution and improved efficiency from sample preparation, data collection to image processing. CryoEM sample preparation is one of the bottlenecks with many efforts made recently, including the optimization of supporting

The theory of the morphogenic field suggests that chemical signaling is supplemented by electromagnetic signaling governing the structure and shape of tissues, organs and the body. The theory of DNA resonance suggests that the morphogenic field is created by the genomic DNA which sends and receives electromagnetic signals in a sequence-specific manner. Previously, the authors have proposed the existence

All living entities are cognitive and dependent on ambiguous information. Any assessment of that imprecision is necessarily a measuring function. Individual cells measure information to sustain self-referential homeostatic equipoise (self-identity) in juxtaposition to the external environment. The validity of that information is improved by its collective assessment. The reception of cellular information

The term “thermoeconomics” denotes a paradigm shift in our understanding of the role of energy in living systems, and in evolution. It is based on the proposition that energy in biological evolution can best be defined and understood, not in terms of the Second Law of Thermodynamics but in terms of such economic criteria as productivity, efficiency, and especially the costs and benefits (or “profitability”)

Assembly of KU and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at DNA double strand breaks (DSBs) forms DNA-PK holoenzyme as a critical initiating step for non-homologous end joining (NHEJ) repair of DSBs produced by radiation and chemotherapies. Advanced cryo-electron microscopy (cryo-EM) imaging together with breakthrough macromolecular X-ray crystal (MX) structures of KU and DNA-PKcs

Ultrasound (US) can modify the plant growth and development. Previous assessments of the transcriptome of in vitro potato (Solanum tuberosum L.) exposed to US transmitted through air (AB-US) or liquid (PE-US) revealed the up- or down-regulation of several stress-related differentially expressed genes (DEGs) related to abiotic stress. In a bid to better characterize stress-related elements over a four-week

DNA inter-strand crosslinks (ICLs) are dangerous lesions that can be caused by a variety of endogenous and exogenous bifunctional compounds. Because covalently linking both strands of the double helix locally disrupts DNA replication and transcription, failure to remove even a single ICL can be fatal to the cell. Thus, multiple ICL repair pathways have evolved, with the best studied being the canonical

The eukaryotic chaperonin TRiC/CCT plays a major role in assisting the folding of many proteins through an ATP-driven allosteric cycle. Recent structures elucidated by cryo-electron microscopy provide a broad view of the conformations visited at various stages of the chaperonin cycle, including a sequential activation of its subunits in response to nucleotide binding. But we lack a thorough mechanistic

Experimental observations in lipid monolayers at the air-water interface have demonstrated that solitary sound pulses can be excited. These pulses propagate electrical, chemical, and thermal variations in addition to the mechanical changes in lateral pressure and lipid density, and can interact with nearby ions, polymers, and water. In addition, it was demonstrated that sound pulses that reversibly

40 years ago a single experiment upset a decade of painstaking research on the mechanisms of rhythm generation in the heart. It did so by turning a theory of pacemaker activity upside down. Instead of attributing rhythm to decaying potassium current carrying outward current, it attributed the pacemaker depolarization to the slow activation of a channel conducting sodium ions into cardiac cells. But

This article reviews work over the past three decades that is related to the contribution of the pacemaker current, If, to basal and autonomically regulated spontaneous rate in the sinoatrial node. It also addresses how the actions of the pacemaker current relate to those of Ca homeostasis with respect to basal and autonomically regulated rhythm. In this regard, it explores the relative contributions

Single-stranded RNA bacteriophages (ssRNA phages) are small spherical RNA viruses that infect bacteria with retractile pili. The single positive-sense genomic RNA of ssRNA phages, which is protected by a capsid shell, is delivered into the host via the retraction of the host pili. Structures involved in ssRNA phage infection cycle are essential for understanding the underlying mechanisms that can be

Cardiac fibroblasts are interspersed within mammalian cardiac tissue. Fibroblasts are mechanically passive; however, they may communicate electrically with cardiomyocytes via gap junctions and thus affect the electrical and mechanical activity of myocytes. Several in-silico studies at both cellular (0D) and ventricular (3D) levels analysed the effects of fibroblasts on the myocardial electrical function

The brain is composed of electrically excitable neuronal networks regulated by the activity of voltage-gated ion channels. Further portraying the molecular composition of the brain, however, will not reveal anything remotely reminiscent of a feeling, a sensation or a conscious experience. In classical physics, addressing the mind–brain problem is a formidable task because no physical mechanism is able

It has long been known that there is no measurable heat production associated with the nerve pulse. Rather, one finds that heat production is biphasic, and a heat release during the first phase of the action potential is followed by the reabsorption of a similar amount of heat during the second phase. We review the long history the measurement of heat production in nerves and provide a new analysis

Despite the long and broad acceptance of the Goldman - Hodgkin - Katz equation (GHK eq.) and the Hodgkin - Huxley equation (HH eq.) as strong tools for the quantitative analysis of the membrane potential behavior, for a long time they have been utilized as separate concepts. That is the GHK eq. and the HH eq. have not been associated with each other mathematically. In this paper, an attempt to associate

In-silico models of cardiac myocytes allow simulating experiments in numbers on series of myocytes as well as on large populations of myocytes assembled in 3D structures. The simulated myocyte populations should have realistic values and statistical dispersions of biophysical parameters such as myocyte dimensions and volume and areas of the peripheral membrane and transverse-axial tubular system (TATS)

The transformation of electrical signals into mechanical action of the heart underlying blood circulation results in mechanical stimuli during active contraction or passive filling distention, which conversely modulate electrical signals. This feedback mechanism is known as cardiac mechano-electric coupling (MEC). The cardiac MEC involves complex activation of mechanical biosensors initiating short-term

Aims After summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling. Methods and results Mn2+-quench analysis in cardiomyocytes from several Trpc-deficient

Dimethylformamidase (DMFase) catalyzes the hydrolysis of dimethylformamide, an industrial solvent, introduced into the environment by humans. Recently, we determined the structures of dimethylformamidase by electron cryo microscopy and X-ray crystallography revealing a tetrameric enzyme with a mononuclear iron at the active site. DMFase from Paracoccus sp. isolated from a waste water treatment plant

Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular

Cardiac hypertrophy, defined as an increase in mass of the heart, is a complex process driven by simultaneous changes in hemodynamics, mechanical stimuli, and hormonal inputs. It occurs not only during pre- and post-natal development but also in adults in response to exercise, pregnancy, and a range of cardiovascular diseases. One of the most exciting recent developments in the field of cardiac biomechanics

A complete understanding of how an orientation distribution contributes to a cryo-EM reconstruction remains lacking. It is necessary to begin critically assessing the set of views to gain an understanding of its effect on experimental reconstructions. Toward that end, we recently suggested that the type of orientation distribution may alter resolution measures in a systematic manner. We introduced

JSPR is a single particle cryo-EM image processing and 3D reconstruction software developed in the Jiang laboratory at Purdue University. It began as a few refinement scripts for symmetric and asymmetric reconstructions of icosahedral viruses, but has grown into a comprehensive suite of tools for building ab initio reconstructions, high resolution refinements of viruses, protein complexes of arbitrary

Intrinsic disorder in proteins resulting in considerable variation in structure can lead to multiple functions including multi-specificity and diverse pathologies. Protein interfaces can involve disordered regions that assemble through a concerted-fold-and-bind mechanism. The binding involves both enthalpic and entropic gains by exploiting ‘hot spots’ on the partner and displacing water molecules placed

The origin of the incessant rhythmical heartbeat and the mechanism of muscle contraction have fascinated scientists over centuries. This short review outlines physiological explanations that were discussed in the 19th century starting with Albrecht von Haller (1708–1777), an 18th century physiologist who proposed that the heart has an intrinsic irritability. He argued that under normal conditions the

The distribution of data presented in many electrophysiological studies is presumed to be normal without any convincing evidence. To test this presumption, the cell membrane capacitance and magnitude of inward rectifier potassium currents were recorded by the whole-cell patch clamp technique in rat atrial myocytes. Statistical analysis of the data showed that these variables were not distributed normally

Electron cryotomography is a rapidly evolving method for imaging macromolecules directly within the native environment of cells and tissues. Combined with sub-tomogram averaging, it allows structural and cell biologists to obtain sub-nanometre resolution structures in situ. However, low throughput in cryo-ET sample preparation and data acquisition, as well as difficulties in target localisation and

Important concepts from colloidal physical chemistry such as coacervation, phase transitions, emergent properties and ionic association, are currently emerging in the lexicon of cellular biology, prompted mostly by recent experimental observations of liquid phase coexistence in the cell cytosol. Nevertheless, from an historical point of view, the application of these concepts in cell biology is not

The transient receptor potential (TRP) ion channel family is composed of twenty-seven channel proteins that are ubiquitously expressed in the human body. The TRPV (vanilloid) subfamily has been a recent target of investigation within the cardiovascular field. TRPV1, which is sensitive to heat as well as vanilloids, is the best characterized TRPV channel and is the namesake for the subfamily that includes

TWIK-related K+ channel (TREK-1) two-pore-domain potassium (K2P) channels mediate background potassium currents and regulate cellular excitability in many different types of cells. Their functional activity is controlled by a broad variety of different physiological stimuli, such as temperature, extracellular or intracellular pH, lipids and mechanical stress. By linking cellular excitability to mechanical

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