M6A2Target: a comprehensive database for targets of m6A writers, erasers and readers.

N6-methyladenosine (m6A) is the most abundant posttranscriptional modification in mammalian mRNA molecules and has a crucial function in the regulation of many fundamental biological processes. The m6A modification is a dynamic and reversible process regulated by a series of writers, erasers and readers (WERs). Different WERs might have different functions, and even the same WER might function differently in different conditions, which are mostly due to different downstream genes being targeted by the WERs. Therefore, identification of the targets of WERs is particularly important for elucidating this dynamic modification. However, there is still no public repository to host the known targets of WERs. Therefore, we developed the m6A WER target gene database (m6A2Target) to provide a comprehensive resource of the targets of m6A WERs. M6A2Target provides a user-friendly interface to present WER targets in two different modules: 'Validated Targets', referred to as WER targets identified from low-throughput studies, and 'Potential Targets', including WER targets analyzed from high-throughput studies. Compared to other existing m6A-associated databases, m6A2Target is the first specific resource for m6A WER target genes. M6A2Target is freely accessible at http://m6a2target.canceromics.org.

ALKBH8 as a potential N6 -methyladenosine (m6 A) eraser in insects.

The N6 -methyladenosine (m6 A) machinery functions through three groups of proteins in eukaryotic cells, including m6 A writers, erasers and readers. The m6 A cellular machinery has mostly been characterised in mammalian species, and the relevant literature on insects is currently scant. While homologues of m6 A writers and readers have been reported from insects, no erasers have been described so far. Here, using BLAST search, we searched for potential erasers in insects. While we found homologues of human m6 A eraser ALKBH5 in termites, beetles and true bugs, they could not be found in representative dipteran and lepidopteran species. However, a potential m6 A eraser, ALKBH8, was identified and experimentally investigated. Our results showed that ALKBH8 can reduce the m6 A levels of Aedes aegypti and Drosophila melanogaster RNAs, suggesting that AeALKBH8 could be a candidate m6 A eraser in insects.

Recent Advances in RNA m6A Modification in Solid Tumors and Tumor Immunity.

An analogous field to epigenetics is referred to as epitranscriptomics, which focuses on the study of post-transcriptional chemical modifications in RNA. RNA molecules, including mRNA, tRNA, rRNA, and other non-coding RNA molecules, can be edited with numerous modifications. The most prevalent modification in eukaryotic mRNA is N6-methyladenosine (m6A), which is a reversible modification found in over 7000 human genes. Recent technological advances have accelerated the characterization of these modifications, and they have been shown to play important roles in many biological processes, including pathogenic processes such as cancer. In this chapter, we discuss the role of m6A mRNA modification in cancer with a focus on solid tumor biology and immunity. m6A RNA methylation and its regulatory proteins can play context-dependent roles in solid tumor development and progression by modulating RNA metabolism to drive oncogenic or tumor-suppressive cellular pathways. m6A RNA methylation also plays dynamic roles within both immune cells and tumor cells to mediate the anti-tumor immune response. Finally, an emerging area of research within epitranscriptomics studies the role of m6A RNA methylation in promoting sensitivity or resistance to cancer therapies, including chemotherapy, targeted therapy, and immunotherapy. Overall, our understanding of m6A RNA methylation in solid tumors has advanced significantly, and continued research is needed both to fill gaps in knowledge and to identify potential areas of focus for therapeutic development.

Attosecond-Level Delay Sensing via Temporal Quantum Erasing.

Traditional Hong-Ou-Mandel (HOM) interferometry, insensitive to photons phase mismatch, proved to be a rugged single-photon interferometric technique. By introducing a post-beam splitter polarization-dependent delay, it is possible to recover phase-sensitive fringes, obtaining a temporal quantum eraser that maintains the ruggedness of the original HOM with enhanced sensitivity. This setup shows promising applications in biological sensing and optical metrology, where high sensitivity requirements are coupled with the necessity to keep light intensity as low as possible to avoid power-induced degradation. In this paper, we developed a highly sensitive single photon birefringence-induced delay sensor operating in the telecom range (1550 nm). By using a temporal quantum eraser based on common path Hongr-Ou-Mandel Interferometry, we were able to achieve a sensitivity of 4 as for an integration time of 2·104 s.

Thermodynamical versus Logical Irreversibility: A Concrete Objection to Landauer's Principle.

Landauer's principle states that the logical irreversibility of an operation, such as erasing one bit, whatever its physical implementation, necessarily implies its thermodynamical irreversibility. In this paper, a very simple counterexample of physical implementation (that uses a two-to-one relation between logic and thermodynamic states) is given that allows one bit to be erased in a thermodynamical quasistatic manner (i.e., one that may tend to be reversible if slowed down enough).

Interaction between m6A and ncRNAs and Its Association with Diseases.

Noncoding RNAs (ncRNA) are a kind of endogenous RNA that regulate many vital bioprocesses with limited ability to encode polypeptides. Most of them are involved in transcriptional and posttranscriptional regulations, thus showing some biological effects. N6-methyladenosine (m6A) RNA modification is a reversible modification that adjusts RNA's functions and stability. The enzymes that regulate m6A can be divided into "writers," "readers," and "erasers." Mechanically, m6A modification of microRNA is mainly identified by DGVR8, participating in the processing of primary micro-RNAs, while m6A modification on long noncoding RNA (lnc-RNA) can change its spatial structure and stability to regulate its RNA- or protein-binding ability. The m6A-modified lnc-RNA and circular RNA can act as competing endogenous RNAs, sponge downstream miRNA. Moreover, ncRNA can also regulate m6A level of downstream molecules. Here, we elaborate on recent advances about pathways and underlying molecular mechanisms of how the interaction between m6A and ncRNA is involved in the occurrence and development of various diseases, especially cancer.

Recent Advances on DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications.

The modification of DNA bases is a classic hallmark of epigenetics. Four forms of modified cytosine-5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine-have been discovered in eukaryotic DNA. In addition to cytosine carbon-5 modifications, cytosine and adenine methylated in the exocyclic amine-N4-methylcytosine and N6-methyladenine-are other modified DNA bases discovered even earlier. Each modified base can be considered a distinct epigenetic signal with broader biological implications beyond simple chemical changes. Since 1994, several crystal structures of proteins and enzymes involved in writing, reading, and erasing modified bases have become available. Here, we present a structural synopsis of writers, readers, and erasers of the modified bases from prokaryotes and eukaryotes. Despite significant differences in structures and functions, they are remarkably similar regarding their engagement in flipping a target base/nucleotide within DNA for specific recognitions and/or reactions. We thus highlight base flipping as a common structural framework broadly applied by distinct classes of proteins and enzymes across phyla for epigenetic regulations of DNA.

Can Quantum Correlations Lead to Violation of the Second Law of Thermodynamics?

Quantum entanglement can cause the efficiency of a heat engine to be greater than the efficiency of the Carnot cycle. However, this does not mean a violation of the second law of thermodynamics, since there is no local equilibrium for pure quantum states, and, in the absence of local equilibrium, thermodynamics cannot be formulated correctly. Von Neumann entropy is not a thermodynamic quantity, although it can characterize the ordering of a system. In the case of the entanglement of the particles of the system with the environment, the concept of an isolated system should be refined. In any case, quantum correlations cannot lead to a violation of the second law of thermodynamics in any of its formulations. This article is devoted to a technical discussion of the expected results on the role of quantum entanglement in thermodynamics.

Re-Thinking the World with Neutral Monism:Removing the Boundaries Between Mind, Matter, and Spacetime.

Herein we are not interested in merely using dynamical systems theory, graph theory, information theory, etc., to model the relationship between brain dynamics and networks, and various states and degrees of conscious processes. We are interested in the question of how phenomenal conscious experience and fundamental physics are most deeply related. Any attempt to mathematically and formally model conscious experience and its relationship to physics must begin with some metaphysical assumption in mind about the nature of conscious experience, the nature of matter and the nature of the relationship between them. These days the most prominent metaphysical fixed points are strong emergence or some variant of panpsychism. In this paper we will detail another distinct metaphysical starting point known as neutral monism. In particular, we will focus on a variant of the neutral monism of William James and Bertrand Russell. Rather than starting with physics as fundamental, as both strong emergence and panpsychism do in their own way, our goal is to suggest how one might derive fundamental physics from neutral monism. Thus, starting with two axioms grounded in our characterization of neutral monism, we will sketch out a derivation of and explanation for some key features of relativity and quantum mechanics that suggest a unity between those two theories that is generally unappreciated. Our mode of explanation throughout will be of the principle as opposed to constructive variety in something like Einstein's sense of those terms. We will argue throughout that a bias towards property dualism and a bias toward reductive dynamical and constructive explanation lead to the hard problem and the explanatory gap in consciousness studies, and lead to serious unresolved problems in fundamental physics, such as the measurement problem and the mystery of entanglement in quantum mechanics and lack of progress in producing an empirically well-grounded theory of quantum gravity. We hope to show that given our take on neutral monism and all that follows from it, the aforementioned problems can be satisfactorily resolved leaving us with a far more intuitive and commonsense model of the relationship between conscious experience and physics.

Functions of N6-methyladenosine and its role in cancer.

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity.

The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazoans. It contributes to physiology and pathogenesis of many human diseases through its downstream target genes. Emerging studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation. In this review, we will discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.

Aberrant Regulation of mRNA m6A Modification in Cancer Development.

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m6A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m6A writers and erasers, respectively. Selective recognition and binding by distinct m6A reader proteins lead mRNA to divergent destinies. m6A has been reported to influence almost every stage of mRNA metabolism and to regulate multiple biological processes. Accumulating evidence strongly supports the correlation between aberrant cellular m6A level and cancer. We summarize here that deregulation of m6A modification, resulting from aberrant expression or function of m6A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression. Understanding the regulation and functional mechanism of mRNA m6A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers.

Use of a plastic eraser for ear reconstruction training.

BACKGROUND: Microtia reconstruction is a challenging procedure, especially in developing nations. The most complex part is learning how to fabricate a framework from costal cartilage. We herein propose a training regimen for ear reconstruction with the use of a plastic eraser. MATERIALS AND METHODS: The texture of a plastic eraser made from polyvinyl chloride is similar to that of human costal cartilage. The first step of the training is carving out the sixth through eighth rib cartilages from a block of plastic eraser. The second step is a fabrication of the framework from plastic rib cartilages, referring to a template from the intact auricle. RESULTS: As plastic erasers are inexpensive and universally available, inexperienced surgeons can repeatedly perform this framework training. Following several of these training sessions in developing nations, the co-authors and local surgeons successfully performed their microtia reconstructions in a reasonable operative time. CONCLUSIONS: This realistic carving model allows surgeons to gain experience before performing an actual ear reconstruction, even in resource-constrained circumstances.

Hierarchical Patterning of Cells with a Microeraser and Electrospun Nanofibers.

For tissue engineering applications, it is important to develop fabrication strategies for building models with controlled cell distributions in defined structures. Here, a simple, flexible approach (named the µ-eraser strategy) is developed to construct multicell micropatterns. This approach involves pressing a poly(dimethylsiloxane) stamp to erase cells growing on substrates, and seeding other types of cells. The pressing/seeding process can be conducted in any designed pattern at desired time point. In a proof of concept, multicell micropatterns of human lung adenocarcinoma epithelial A549 cells, murine fibroblast (FB) cells and murine osteoblast (OB) cells are achieved on Petri dishes and electrospun sheets. Besides forming multicell micropatterns, the cell orientation can be regulated by microstripes and alignment of nanofibers. On Petri dishes and random fiber sheets, FB and OB cells align along microstripes, while A549 cells do not. However, when growing on aligned fiber sheets, no matter whether solo-cultured or co-cultured, all cells in micropatterns orient along the fibers. Based on this technique, a platform is built up to investigate rates of cell migration and interinvasion under solo-culture and co-culture systems. It is believed that this µ-eraser strategy has promise for biological, pharmaceutical, and biomedical applications.

A microdeletion encompassing PHF21A in an individual with global developmental delay and craniofacial anomalies.

In Potocki-Shaffer syndrome (PSS), the full phenotypic spectrum is manifested when deletions are at least 2.1 Mb in size at 11p11.2. The PSS-associated genes EXT2 and ALX4, together with PHF21A, all map to this region flanked by markers D11S1393 and D11S1319. Being proximal to EXT2 and ALX4, a 1.1 Mb region containing 12 annotated genes had been identified by deletion mapping to explain PSS phenotypes except multiple exostoses and parietal foramina. Here, we report a male patient with partial PSS phenotypes including global developmental delay, craniofacial anomalies, minor limb anomalies, and micropenis. Using microarray, qPCR, RT-qPCR, and Western blot analyses, we refined the candidate gene region, which harbors five genes, by excluding two genes, SLC35C1 and CRY2, which resulted in a corroborating role of PHF21A in developmental delay and craniofacial anomalies. This microdeletion contains the least number of genes at 11p11.2 reported to date. Additionally, we also discuss the phenotypes observed in our patient with respect to those of published cases of microdeletions across the Potocki-Shaffer interval.

N6-methyladenine RNA methylation epigenetic modification and diabetic microvascular complications.

N6-methyladensine (m6A) has been identified as the best-characterized and the most abundant mRNA modification in eukaryotes. It can be dynamically regulated, removed, and recognized by its specific cellular components (respectively called "writers," "erasers," "readers") and have become a hot research field in a variety of biological processes and diseases. Currently, the underlying molecular mechanisms of m6A epigenetic modification in diabetes mellitus (DM) and diabetic microvascular complications have not been extensively clarified. In this review, we focus on the effects and possible mechanisms of m6A as possible potential biomarkers and therapeutic targets in the treatment of DM and diabetic microvascular complications.

Clinician's Guide to Epitranscriptomics: An Example of N1-Methyladenosine (m1A) RNA Modification and Cancer.

Epitranscriptomics is the study of modifications of RNA molecules by small molecular residues, such as the methyl (-CH3) group. These modifications are inheritable and reversible. A specific group of enzymes called "writers" introduces the change to the RNA; "erasers" delete it, while "readers" stimulate a downstream effect. Epitranscriptomic changes are present in every type of organism from single-celled ones to plants and animals and are a key to normal development as well as pathologic processes. Oncology is a fast-paced field, where a better understanding of tumor biology and (epi)genetics is necessary to provide new therapeutic targets and better clinical outcomes. Recently, changes to the epitranscriptome have been shown to be drivers of tumorigenesis, biomarkers, and means of predicting outcomes, as well as potential therapeutic targets. In this review, we aimed to give a concise overview of epitranscriptomics in the context of neoplastic disease with a focus on N1-methyladenosine (m1A) modification, in layman's terms, to bring closer this omics to clinicians and their future clinical practice.

Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer's Disease.

Patients with Alzheimer's disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H2S. The repeat CAG expansion and m6A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut-brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H2S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H2S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H2S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting ß-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits ß-amyloid deposits by increasing the mitochondrial transsulfuration of H2S production.

N6-methyladenine RNA Methylation Epigenetic Modification and Kidney Diseases.

RNA methylation modification is a rapidly developing field in epigenetics. N6-methyladensine (m6A) is the most common internal modification in eukaryotic mRNA. m6A group regulates RNA splicing, stability, translocation, and translation. Enzymes catalyzing this process were termed as writers, erasers, and readers. Recent studies have focused on exploring the role of RNA methylation in human diseases. RNA methylation modifications, particularly m6A, play important roles in the pathogenesis of kidney diseases. In this review, we provide a brief description of m6A and summarize the impact of m6A on acute and chronic kidney disease (CKD) and possible future study directions for this research.

The role of regulators of RNA m6A methylation in lung cancer.

N6-methyladenosine (m6A) modification is found the most prevalent and abundant post-transcriptional mRNA modification in eukaryotic cells. It regulates almost all stages of RNA life cycle including splicing, translocation, stability, decay and translation. As a dynamic and reversible process, m6A modification is catalyzed by the RNA methyltransferases ('writers'), removed by the demethylases ('erasers'), and interacts with m6A-binding proteins ('readers'). Recent studies have revealed that these m6A modification regulators are frequently expressed aberrantly in various types of cancer, and involved in cell proliferation, differentiation, metabolism, particularly, in tumorigenesis and tumor progression through diverse mechanisms. In this review, the m6A modification process and its regulatory functions in lung cancer are summarized. Furthermore, the research progress in the inhibitor development of m6A modification, and the potential of targeting m6A modifying proteins for clinical application are discussed.