Fundamental Molecules Research Articles

Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application.

Reprogramming energy metabolism is pivotal to tumor development. Ketone bodies (KBs), which are generated during lipid metabolism, are fundamental bioactive molecules that can be modulated to satisfy the escalating metabolic needs of cancer cells. At present, a burgeoning body of research is concentrating on the metabolism of KBs within tumors, investigating their roles as signaling mediators, drivers of post-translational modifications, and regulators of inflammation and oxidative stress. The ketogenic diet (KD) may enhance the sensitivity of various cancers to standard therapies, such as chemotherapy and radiotherapy, by exploiting the reprogrammed metabolism of cancer cells and shifting the metabolic state from glucose reliance to KB utilization, rendering it a promising candidate for adjunct cancer therapy. Nonetheless, numerous questions remain regarding the expression of key metabolic genes across different tumors, the regulation of their activities, and the impact of individual KBs on various tumor types. Further investigation is imperative to resolve the conflicting data concerning KB synthesis and functionality within tumors. This review aims to encapsulate the intricate roles of KBs in cancer metabolism, elucidating a comprehensive grasp of their mechanisms and highlighting emerging clinical applications, thereby setting the stage for future investigations into their therapeutic potential.

Behavior of Trapped Molecules in Lantern-Like Carcerand Superphanes.

Superphanes are a group of organic molecules from the cyclophane family. They are characterized by the presence of two parallel benzene rings joined together by six bridges. If these bridges are sufficiently long, the superphane cavity can be large enough to trap small molecules or ions. Using ab initio (time scale of 80 ps) and classical (up to 200 ns) molecular dynamics (MD) methods, we study the behavior of five fundamental molecules (M = H2O, NH3, HF, HCN, MeOH) encapsulated inside the experimentally reported lantern-like superphane and its two derivatives featuring slightly modified side bridges. The main focus is studying the dynamics of hydrogen bonds between the trapped M molecule and the imino nitrogen atoms of the side chains of the host superphane. The length of the N···H hydrogen bond increases in the following order: HF < HCN < H2O < MeOH < NH3. The mobility of the trapped molecule and its preferred position inside the superphane cage depend not only on the type of this molecule but also largely on the in/out conformational arrangement of the imino nitrogens in the side chains of the superphane. Their inward-pointing positions allow the formation of strong N···H hydrogen bonds. For this reason, these nitrogens are the preferred sites of interaction. The mobility of the molecules and their residence times on each side of the superphane have been explained by referring to the symmetry and conformation of the given superphane cage. All force field MD simulations have shown that the encapsulated molecule remained inside the superphane cage for 200 ns without any escape event to the outside. Moreover, our simulations based on some endohedral complexes in the water box also showed no exchange event. Thus, the superphanes we study are true carcerand molecules. We attribute this property to the hydrophobic side chains and their pinwheel arrangement, which makes the side walls of the studied superphanes fairly impenetrable to small molecules.

Mass Spectrometry Analysis of Nucleic Acid Modifications: From Beginning to Future.

Nucleic acids are fundamental biological molecules that encode and convey genetic information within living organisms. Over 150 modifications have been found in nucleic acids, which are involved in critical biological functions, including regulating gene expression, stabilizing nucleic acid structure, modulating protein translation, and so on. The dysregulation of nucleic acid modifications is correlated with many diseases such as cancers and neurological disorders. However, it is still challenging to simultaneously characterize and quantify diverse modifications using traditional genomic methods. Mass spectrometry (MS) has served as a crucial tool to solve this issue, and can directly identify the modified species through their distinct mass differences compared to the canonical ones and provide accurate quantitative information. This review surveys the history of nucleic acid modification discovery, advancements in MS-based methods, nucleic acid sample preparation, and applications in biological and medical research. We expect the high-throughput and valuable quantitative information from MS analysis will be more broadly applied to studying nucleic acid modification status in different pathological conditions, which is key to filling gaps in traditional genomics and transcriptomics research and enabling researchers to gain insights into epigenetics and epitranscriptomics.

Research Progress on Saccharide Molecule Detection Based on Nanopores.

Saccharides, being one of the fundamental molecules of life, play essential roles in the physiological and pathological functions of cells. However, their intricate structures pose challenges for detection. Nanopore technology, with its high sensitivity and capability for single-molecule-level analysis, has revolutionized the identification and structural analysis of saccharide molecules. This review focuses on recent advancements in nanopore technology for carbohydrate detection, presenting an array of methods that leverage the molecular complexity of saccharides. Biological nanopore techniques utilize specific protein binding or pore modifications to trigger typical resistive pulses, enabling the high-sensitivity detection of monosaccharides and oligosaccharides. In solid-state nanopore sensing, boronic acid modification and pH gating mechanisms are employed for the specific recognition and quantitative analysis of polysaccharides. The integration of artificial intelligence algorithms can further enhance the accuracy and reliability of analyses. Serving as a crucial tool in carbohydrate detection, we foresee significant potential in the application of nanopore technology for the detection of carbohydrate molecules in disease diagnosis, drug screening, and biosensing, fostering innovative progress in related research domains.

Comparative analysis of 43 distinct RNA modifications by nanopore tRNA sequencing.

Transfer RNAs are the fundamental adapter molecules of protein synthesis and the most abundant and heterogeneous class of noncoding RNA molecules in cells. The study of tRNA repertoires remains challenging, complicated by the presence of dozens of post transcriptional modifications. Nanopore sequencing is an emerging technology with promise for both tRNA sequencing and the detection of RNA modifications; however, such studies have been limited by the throughput and accuracy of direct RNA sequencing methods. Moreover, detection of the complete set of tRNA modifications by nanopore sequencing remains challenging. Here we show that recent updates to nanopore direct RNA sequencing chemistry (RNA004) combined with our own optimizations to tRNA sequencing protocols and analysis workflows enable high throughput coverage of tRNA molecules and characterization of nanopore signals produced by 43 distinct RNA modifications. We share best practices and protocols for nanopore sequencing of tRNA and further report successful detection of low abundance mitochondrial and viral tRNAs, providing proof of concept for use of nanopore sequencing to study tRNA populations in the context of infection and organelle biology. This work provides a roadmap to guide future efforts towards de novo detection of RNA modifications across multiple organisms using nanopore sequencing.

The Pigment World: Life's Origins as Photon-Dissipating Pigments.

Many of the fundamental molecules of life share extraordinary pigment-like optical properties in the long-wavelength UV-C spectral region. These include strong photon absorption and rapid (sub-pico-second) dissipation of the induced electronic excitation energy into heat through peaked conical intersections. These properties have been attributed to a "natural selection" of molecules resistant to the dangerous UV-C light incident on Earth's surface during the Archean. In contrast, the "thermodynamic dissipation theory for the origin of life" argues that, far from being detrimental, UV-C light was, in fact, the thermodynamic potential driving the dissipative structuring of life at its origin. The optical properties were thus the thermodynamic "design goals" of microscopic dissipative structuring of organic UV-C pigments, today known as the "fundamental molecules of life", from common precursors under this light. This "UV-C Pigment World" evolved towards greater solar photon dissipation through more complex dissipative structuring pathways, eventually producing visible pigments to dissipate less energetic, but higher intensity, visible photons up to wavelengths of the "red edge". The propagation and dispersal of organic pigments, catalyzed by animals, and their coupling with abiotic dissipative processes, such as the water cycle, culminated in the apex photon dissipative structure, today's biosphere.

Mechanisms of glycine formation in cold interstellar media: a theoretical study.

The possibility of the formation of glycine (Gly) from fundamental gas molecules in cold interstellar media was studied using quantum chemical methods, transition state theory and microcanonical molecular dynamics simulations with surface hopping dynamics (NVE-MDSH). This theoretical study emphasized five photochemical pathways in the lowest singlet-excited (S 1) state, thermochemical processes after non-radiative S 1→S 0 relaxations, and photo-to-thermal energy conversion in the NVE ensemble. The optimized reaction pathways suggested that to generate a reactive singlet dihydroxy carbene (HOCOH) intermediate, photochemical pathways involving the H2O…CO van der Waals and H2O-OC hydrogen bond precursors (Ch (1)_Step (1)) possess considerably lower energy barriers than the S 0 state pathways. The Gibbs free energy barriers (∆G ǂ ) calculated after the non-radiative S 1 →S 0 relaxations indicated higher spontaneous temperatures (T s) for the formation of the HOCOH intermediate (Ch (1)_Step (1)) than for Gly formation (Ch (1)_Step (2) and Ch (4)). Although the termolecular reaction in Ch (4) possesses a low energy barrier, and is thermodynamically favourable, the high exothermic S 1 →S 0 relaxation energy leads to the separation of the weakly associated H2O…CH2NH…CO complex into single molecules. The NVE-MDSH results also confirmed that the molecular processes after the S 1 →S 0 relaxations are thermally selective, and because the non-radiative S 1 →S 0 relaxation temperatures are exceedingly higher than T s, the formation of Gly on consecutive reaction pathways is non-synergistic with low yields and several side products. Based on the theoretical results, photo-to-thermal control strategies to promote desirable photochemical products are proposed. They could be used as guidelines for future theoretical and experimental research on photochemical reactions.

Cellular Metabolic Labeling of Nucleic Acids and Its Applications

AbstractNucleic acids are considered as fundamental molecules of living systems, which serve as universal genetic information messengers and repositories. To uncover the multifaceted aspects of nucleic acid function and metabolism within cells, labeling has become indispensable. This labeling technique enables the visualization, isolation, characterization, and even quantification of specific nucleic acid species. This review delves into cellular metabolic approaches for nucleic acid labeling, wherein enzymatic steps are employed to introduce nucleic acid modifications before conjugation with a label for detection or isolation. The discussion begins with metabolic labeling for DNA, RNA with various reactive groups and post‐transcriptional RNA labeling for RNA methylation and acetylation sites, emphasizing recent advancements in the field and then, we spotlighted pertinent applications for cellular imaging and sequencing. of labeling.

Reaction dynamics on amorphous solid water surfaces using interatomic machine-learned potentials

Context. Energy redistribution after a chemical reaction is one of the few mechanisms that can explain the diffusion and desorption of molecules which require more energy than the thermal energy available in quiescent molecular clouds (10 K). This energy distribution can be important in phosphorous hydrides, elusive yet fundamental molecules for interstellar prebiotic chemistry. Aims. Our goal with this study is to use state-of-the-art methods to determine the fate of the chemical energy in the simplest phosphorous hydride reaction. Methods. We studied the reaction dynamics of the P + H → PH reaction on amorphous solid water, a reaction of astrophysical interest, using ab initio molecular dynamics with atomic forces evaluated by a neural network interatomic potential. Results. We found that the exact nature of the initial phosphorous binding sites is less relevant for the energy dissipation process because the nascent PH molecule rapidly migrates to sites with higher binding energy after the reaction. Non-thermal diffusion and desorption after reaction were observed and occurred early in the dynamics, essentially decoupled from the dissipation of the chemical reaction energy. From an extensive sampling of on-site reactions, we constrained the average dissipated reaction energy within the simulation time (50 ps) to be between 50 and 70%. Most importantly, the fraction of translational energy acquired by the formed molecule was found to be mostly between 1 and 5%. Conclusions. Including these values, specifically for the test cases of 2% and 5% of translational energy conversion, in astrochemical models, reveals very low gas-phase abundances of PHx molecules and reflects that considering binding energy distributions is paramount to correctly merging microscopic and macroscopic modelling of non-thermal surface astrochemical processes. Finally, we found that PD molecules dissipate more of the reaction energy. This effect can be relevant for the deuterium fractionation and preferential distillation of molecules in the interstellar medium.

Fundamental Molecules in the Pathways and Regulation of Apoptosis

Fundamental Molecules in the Pathways and Regulation of Apoptosis

Fatty Acid Vesicles as Hard UV-C Shields for Early Life

Theories on life’s origin generally acknowledge the advantage of a semi-permeable vesicle (protocell) for enhancing the chemical reaction–diffusion processes involved in abiogenesis. However, more and more evidence indicates that the origin of life is concerned with the photo-chemical dissipative structuring of the fundamental molecules under soft UV-C light (245–275 nm). In this paper, we analyze the Mie UV scattering properties of such a vesicle created with long-chain fatty acids. We find that the vesicle could have provided early life with a shield from the faint but destructive hard UV-C ionizing light (180–210 nm) that probably bathed Earth’s surface from before the origin of life and at least until 1200 million years after, until the formation of a protective ozone layer as a result of the evolution of oxygenic photosynthesis.

André K. Eckhardt.

"In five years, I hope to be running a productive lab where my students are working on multiple projects, helping us get to a better understanding of fundamental molecules and chemistry … My favorite saying is 'The beauty of chemistry is its infinity.' " Find out more about André K. Eckhardt in his Introducing … Profile.

André K. Eckhardt

Graphical Abstract „In five years, I hope to be running a productive lab where my students are working on multiple projects, helping us get to a better understanding of fundamental molecules and chemistry … My favorite saying is ‘The beauty of chemistry is its infinity.’ “ Find out more about André K. Eckhardt in his Introducing … Profile.

Enhanced frequency-doubled pulse generation pumped by fundamental soliton molecules

To the best of our knowledge, this is the first experimental demonstration of enhanced pulse frequency doubling efficiency pumped by fundamental soliton molecules (SMs). A 1.0-µm polarization-maintaining (PM) ytterbium-doped oscillator-compressor system is first constructed to output various mode-locked pulse patterns, i.e., single-pulse-type dissipative solitons (DSs), noise-like pulses (NLPs) and soliton molecules (SMs), at a fundamental repetition rate of 62.7 MHz, respectively, by managing the intracavity dispersion parameters. Then, these pulse patterns are used as pump seeds for exciting frequency-doubled pulse generation at a wavelength of 515 nm based on second harmonic generation (SHG) in a commercial periodically polarized LiNbO3 (PPLN) crystal. Among the abovementioned pulse pump schemes, the SHG conversion efficiency is increased by up to 29 % when fundamental SMs are used as pump seeds for frequency-doubled pulse generation compared with the use of a conventional single-pulse-type DS pump scheme. Our work provides a promising technique for enhancing frequency-doubled pulse generation, which contributes to an in-depth understanding of frequency-doubled pulse generation with a coherent multipulse pump scheme.

Strategy for RNA-Seq Experimental Design and Data Analysis.

Ribonucleic acids (RNAs) are fundamental molecules that control regulation and expression of the genome and therefore the function of a cell. Robust analysis and quantification of RNA transcripts hold critical importance in understanding cell function, altered phenotypes in different biological context, for understanding and targeting diseases. The development of RNA-sequencing (RNA-Seq) now provides opportunities to analyze the expression and function of RNA molecules at an unprecedented scale. However, the strategy for RNA-Seq experimental design and data analysis can substantially differ depending on the biological application. The design choice could also have significant impact for downstream results and interpretation of data. Here we describe key critical considerations required for RNA-Seq experimental design and also describe a step-by-step bioinformatics workflow detailing the different steps required for RNA-Seq data analysis. We believe this article will be a valuable guide for designing and analyzing RNA-Seq data to address a wide range of different biological questions.

Bi2O2Te Nanosheets Saturable Absorber‐Based Passive Mode‐Locked Fiber Laser: From Soliton Molecules to Harmonic Soliton

AbstractAs a recent addition to the emerging 2D bismuth oxychalcogenides (Bi2O2X, where X = S, Se, and Te), atomically‐thin bismuth oxytellurium (Bi2O2Te) exhibits unique thermoelectric and photoelectric properties. In this study, high‐quality Bi2O2Te nanosheets (NSs)‐based saturable absorber (SA) with a modulation depth of 8.2% is developed using the liquid phase exfoliation (LPE) method and is successfully applied to a passively mode‐locked Er‐doped fiber laser (EDFL) for the first time (with reference to the available literature). Due to the excellent nonlinear saturable absorption property of Bi2O2Te NSs, various switchable and stable mode‐locking states can be realized in the same EDFL, including fundamental frequency conventional soliton (CS), soliton molecules, and harmonic mode‐locking (HML) states. Among them, the CS pulse at 7.48 MHz (fundamental frequency) with a high signal‐to‐noise ratio (SNR) of 67.25 dB is obtained. The 2nd, 3rd, and 4th‐order soliton molecules are observed with a soliton pulse separation of ≈6.2 ps. Moreover, for HML, a maximum repetition rate of 1.78 GHz (i.e., corresponding to the 238th‐order harmonic) is obtained. The results reveal that Bi2O2Te NSs demonstrate excellent nonlinear optical modulation properties and can serve as a fundamental basis for promotion of academic research and innovation of engineering applications involving ultrafast photonics.

Understanding the mechano and chemo response of retinoblastoma tumor cells

IntroductionCellular homeostasis with its environment is bidirectional and dynamic in nature. Extracellular matrix plays an important role in retinoblastoma tumor cell's response to chemotherapeutic drugs. The present study was designed to investigate the effect of mechanotransduction along with the chemotherapeutic effect on RB cells grown on three-dimensional matrices. MethodsMatrigels of varying stiffness (low and high) were prepared and characterized. Drug sensitivity of RB cells on various matrigel stiffness was measured using cytotoxicity (MTT) assay and IC50 value was found for carboplatin and etoposide. Further, the effect on the proliferation and migration of RB cells in various stiffness matrigels was investigated. FindingsThe results showed that drug sensitivity decreased with an increase in matrix stiffness when compared to RB cells grown in suspension. In higher stiffness, the drug sensitivity decreases with an increase in cell proliferation. Data from a gene expression study revealed that Vinculin was variably regulated between metastatic and non-metastatic tumor cells, and upregulated RhoA was altered in different stiffness gradient matrigel during drug treatment. InterpretationThese results enhance the understanding of the fundamental molecules responding to drug sensitivity in a stiffness-altering environment. Additionally, it provides a new avenue for understanding how RB cells respond to chemotherapeutic intervention.

Reply to Lars Olof Björn's comment on “Fundamental molecules of life are pigments which arose and co-evolved as a response to the thermodynamic imperative of dissipating the prevailing solar spectrum” by Michaelian and Simeonov (2015)

Abstract. Lars Björn doubts our assertion that the driving force behind the origin and evolution of life has been the thermodynamic imperative of increasing the entropy production of the biosphere through increasing global solar photon dissipation. Björn bases his critique on the fact that the albedo of non-biological material can sometimes be lower than that of biological material and concludes that such examples counter our assertion. Our reply to Björn, however, is that albedo (reflection) is only one factor involved in the entropy production through photon dissipation occurring in the interaction of light with material. The other contributions to entropy production, which were listed in our article, are (1) the shift towards the infrared of the emitted spectrum (including a wavelength-dependent emissivity), (2) the diffuse reflection and emission of light into a greater outgoing solid angle, and (3) the heat of photon dissipation inducing evapotranspiration in the pigmented leaf, thereby coupling to the abiotic dissipative processes of the water cycle, which, besides shifting the emitted spectrum even further towards the infrared, promotes pigment production over the entire Earth surface. His analysis, therefore, does not provide a legitimate reason for doubting our assertion that life and evolution are driven by photon dissipation. We remain emphatic in our assertion that the fundamental molecules of life were originally dissipatively structured UV-C pigments arising in response to the thermodynamic imperative of dissipating the prevailing Archean solar spectrum. In the following, we respond to Björn's comment using the same section headings.

Biosensors and machine learning for enhanced detection, stratification, and classification of cells: a review.

Biological cells, by definition, are the basic units which contain the fundamental molecules of life of which all living things are composed. Understanding how they function and differentiating cells from one another, therefore, is of paramount importance for disease diagnostics as well as therapeutics. Sensors focusing on the detection and stratification of cells have gained popularity as technological advancements have allowed for the miniaturization of various components inching us closer to Point-of-Care (POC) solutions with each passing day. Furthermore, Machine Learning has allowed for enhancement in the analytical capabilities of these various biosensing modalities, especially the challenging task of classification of cells into various categories using a data-driven approach rather than physics-driven. In this review, we provide an account of how Machine Learning has been applied explicitly to sensors that detect and classify cells. We also provide a comparison of how different sensing modalities and algorithms affect the classifier accuracy and the dataset size required.

Dissipative Photochemical Abiogenesis of the Purines.

We have proposed that the abiogenesis of life around the beginning of the Archean may have been an example of “spontaneous” microscopic dissipative structuring of UV-C pigments under the prevailing surface ultraviolet solar spectrum. The thermodynamic function of these Archean pigments (the “fundamental molecules of life”), as for the visible pigments of today, was to dissipate the incident solar light into heat. We have previously described the non-equilibrium thermodynamics and the photochemical mechanisms which may have been involved in the dissipative structuring of the purines adenine and hypoxanthine from the common precursor molecules of hydrogen cyanide and water under this UV light. In this article, we extend our analysis to include the production of the other two important purines, guanine and xanthine. The photochemical reactions are presumed to occur within a fatty acid vesicle floating on a hot (∼80 °C) neutral pH ocean surface exposed to the prevailing UV-C light. Reaction–diffusion equations are resolved under different environmental conditions. Significant amounts of adenine (∼ M) and guanine (∼ M) are obtained within 60 Archean days, starting from realistic concentrations of the precursors hydrogen cyanide and cyanogen (∼ M).