The forerunners and successful partnerships behind the BioNTech mRNA vaccine.

The discovery of nucleic acids stands as a paramount achievement in the history of scientific endeavors. By applying transformative advancements in the fields of chemistry and physics to biological systems, researchers unveiled the enigmatic nature of life. Notably, messenger RNA (mRNA) emerged as a crucial player in this profound revelation, serving as a transient intermediary for genetic information transfer between genes and proteins. Groundbreaking investigations carried out from 1944 to 1961 led to the initial identification of this pivotal molecule, captivating scientific interest for the past three decades. The field of mRNA research has witnessed a transformative shift owing to the development of cap analogs and nucleotide modifications. This revolutionary progress has fostered a new generation of potent therapeutics. Prior to the advent of the coronavirus pandemic, numerous scientists had already begun exploring the unique properties of mRNA. However, with the onset of the pandemic, mRNA catapulted into the limelight as a heroic agent, providing the foundation for highly effective vaccines that have played a crucial role in mitigating the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The successive generations of cap analogs have significantly enhanced the translation efficacy of mRNA, while the discovery of suitable purification, packaging, and delivery methods has paved the way for groundbreaking medical breakthroughs. Pioneers in the field such as Katalin Karikó, Drew Weissman, Edward Darzynkiewicz, Robert Rhodes, Ugur Sahin, and Ozlem Tureci have made significant contributions during the early stages of mRNA research, warranting acknowledgement for their visionary endeavors. The narrative of mRNA represents a remarkable journey marked by a succession of breakthroughs in a discipline that holds immense promise for the future of medicine. Thanks to the pioneering work of these exceptional scientists, we are well-positioned to unlock the full potential of this extraordinary molecule, ushering in a new era of medical advancements.

Lycopene ­ the impact of supplementation on the skin aging process / Likopen ­ wplyw suplementacji na proces starzenia sie skóry.

The skin aging process is affected by multiple different factors (including sun exposure, smoking, poor diet) and reactive oxygen species (ROS). Under their influence, the skin becomes weaker, mainly elastin and collagen fibers are damaged. The amount of lipids is also reduced, leading to the death of the skin cells. The presence of free radicals also blocks the natural ability of the epidermis to regenerate. Each of these factors determines the acceleration of the signs of aging. To some extent, our body is able to deal with the free radicals by producing antioxidants. Regular supplementation is also a beneficial solution. Lycopene is a red pigment naturally found in tomatoes and is a known antioxidant. Among the carotenoids, it is the strongest singlet oxygen quencher and scavenger of peroxygen radicals, making it an important defense mechanism in the human body. The aim of this paper is to present the biological properties of lycopene in relation to its beneficial effect on the aging process of the skin.

Identification of DNA Methylation Changes in European Beech Seeds during Desiccation and Storage.

Ageing and deterioration of seeds is a major problem for the maintenance of seed quality and viability during long-term storage. Prediction of early stages of seed deterioration in order to point out the plantlets' regeneration time is a major challenge of successful storage. In preserved seeds, damages accumulate within cells at the rate mainly related to their moisture content and temperature of storage. Current research reveals global alterations in DNA methylation in lipid-rich intermediate seeds during desiccation and storage at various regimes covering nonoptimal and optimal conditions. We show for the first time that monitoring of 5-methylcytosine (m5C) level in seeds can be used as a truly universal viability marker regardless of postharvest category of seeds and their composition. For seeds stored up to three years, in varied conditions, moisture content, temperature, and time of storage had significant influence on seedling emergence and DNA methylation (p < 0.05). Similarities among lipid-rich intermediate and orthodox seeds regarding different reactions of embryonic axes and cotyledons to desiccation are newly revealed. Along with previous studies on seeds dramatically different in desiccation tolerance (recalcitrant vs. orthodox), results regarding lipid-rich seeds positioned in-between (intermediate) prove that maintaining global DNA methylation status is crucial for maintaining seed viability.

Epigenetic on Earth and in Space / Epigenetyka na Ziemi i w kosmosie.

The year 1961 went down in history with exceptional scientific achievements. On May 13, the journal Nature published two articles on the first isolation of messenger ribonucleic acid (mRNA), which is an intermediate product between a gene and a protein. Just two weeks later, on May 27, the first letter of the genetic code, phenylalanine, was discovered. These discoveries made it possible to understand how genetic information is encoded and processed, thus causing the dynamic development of molecular biology. The breakthroughs of 1961 concerned not only nucleic acids. On April 12, the first human, Yuri Gagarin, entered space. Eight years later, in 1969, Neil Armstrong made his first walk on the moon, uttering the famous phrase: It is a small step for man, but a great leap for humanity. The era of conquering and learning about the cosmos has begun, mainly motivated by the natural curiosity of man and the desire to learn about the surrounding reality. The environmental factors in space are very different from terrestrial conditions, which raises questions about their effects on living organisms. In search of answers, a variety of scientific research has been carried out at the International Space Station (ISS) for over twenty years. As space travel is set to become more common in the near future, detailed studies of the effects of long-term space missions on the human body are required. These studies are currently carried out, among others using molecular biology techniques that enable detailed analysis of nucleic acids and proteins, but not only. The breakthrough achievements of 1961 initiated the development both in the field of molecular biology and the science of space, thanks to which today, 60 years after those events, we can combine knowledge and technological achievements from both fields to analyze and understand changes at the molecular level that occur as a result of being in organisms in outer space.

DNA Methylation as an Early Indicator of Aging in Stored Seeds of "Exceptional" Species Populus nigra L.

Ex situ preservation of genetic resources is an essential strategy for the conservation of plant biodiversity. In this regard, seed storage is the most convenient and efficient way of preserving germplasm for future plant breeding efforts. A better understanding of the molecular changes that occur during seed desiccation and aging is necessary to improve conservation protocols, as well as real-time methods for monitoring seed quality. In the present study, we assessed changes in the level of genomic 5-methylcytosine (5mC) in seeds of Populus nigra L. by 2D-TLC. Epigenetic changes were characterized in response to several seed storage regimes. Our results demonstrate that P. nigra seeds represent an intermediate type of post-harvest behavior, falling between recalcitrant and orthodox seeds. This was also true for the epigenetic response of P. nigra seeds to external factors. A crucial question is whether aging in seeds is initiated by a decline in the level of 5mC, or if epigenetic changes induce a process that leads to deterioration. In our study, we demonstrate for the first time that 5mC levels decrease during storage and that the decline can be detected before any changes in seed germination are evident. Once P. nigra seeds reached an 8-10% reduction in the level of 5mC, a substantial decrease in germination occurred. The decline in the level of 5mC appears to be a critical parameter underlying the rapid deterioration of intermediate seeds. Thus, the measurement of 5mC can be a fast, real-time method for assessing asymptomatic aging in stored seeds.

A new molecular mechanism of RNA circularization and the microRNA sponge formation.

A new mechanism of RNA circularization driven by specific binding of miRNAs is described. We identified the 71 CUUCC pentanucleotide motifs distributed regularly throughout the entire molecule of CDR1as RNA that bind to 71 miRNAs through their seed sequence GGAAG. The sequential binding of miR-7 RNAs (71 molecules) brings both ends of CDR1as RNA (1 molecule) together and stimulate phosphodiester bond formation between nucleotides C1 and A1299 at the 5' and 3' end, respectively. The binding of miRNAs to CDR1as RNA results in the unique complex formation, which shows three specific structural domains: (i) two short helixes with an internal loop, (ii) the hinge, and (iii) the triple-helix. The proposed mechanism explains specific RNA circularization and its function as a miRNAs sponge. Furthermore, the existing wet experimental data on the interaction of CDR1as RNA with miR-7 fully supports our observation. Although miR-671 shows the same seed sequence as miR-7, it forms an almost perfect double helix with CDR1as RNA and induces the cleavage of CDR1as, but does not stimulate circularization. To check how common is the proposed mechanism among circular RNAs, we analyzed the most recent circAtlas database counting almost 1.1 million sequences. It turned out that there are a huge number of circRNAs, which showed miRNAs seed binding sequences distributed through the whole circRNA sequences and prove that circularization of linear transcript is miRNA dependent.Communicated by Ramaswamy H. Sarma.

100 years of RNA. The Diamond Jubilee of Information RNA / 100 lat RNA. Diamentowy jubileusz informacyjnego RNA.

The year 2021 marks not only 60 years since the discovery of messenger RNA and the genetic code. Already 100 yaers passed since RNA was discovered. On the occasion of this special anniversary, we would like to recall the most important events in the history of nucleic acids that led to the above discoveries. We remind the beginning of a new era in science caused by the isolation of nuclein and then nucleic acid, whose components and properties were gradually learned, often by little-known researchers. The distinction of RNA and DNA and the analysis of their occurrence in cells made it possible to formulate the first conclusions about the functions of these compounds. Conclusions on the ratio of nitrogenous bases in DNA led to the knowledge of the structure of the double helix, triggering an avalanche of questions about the essence of transmission of genetic information. Answers began to emerge with the discovery of mRNA, and knowledge of the first three nucleotides encoding an amino acid caused a race to decipher the genetic code. The above discoveries are the foundation of molecular biology. The diamond jubilee coincided with the development of an mRNA-based vaccine against the SARS-CoV-2.

Reducing SARS-CoV-2 pathological protein activity with small molecules.

Coronaviruses are dangerous human and animal pathogens. The newly identified coronavirus SARS-CoV-2 is the causative agent of COVID-19 outbreak, which is a real threat to human health and life. The world has been struggling with this epidemic for about a year, yet there are still no targeted drugs and effective treatments are very limited. Due to the long process of developing new drugs, reposition of existing ones is one of the best ways to deal with an epidemic of emergency infectious diseases. Among the existing drugs, there are candidates potentially able to inhibit the SARS-CoV-2 replication, and thus inhibit the infection of the virus. Some therapeutics target several proteins, and many diseases share molecular paths. In such cases, the use of existing pharmaceuticals for more than one purpose can reduce the time needed to design new drugs. The aim of this review was to analyze the key targets of viral infection and potential drugs acting on them, as well as to discuss various strategies and therapeutic approaches, including the possible use of natural products. We highlighted the approach based on increasing the involvement of human deaminases, particularly APOBEC deaminases in editing of SARS-CoV-2 RNA. This can reduce the cytosine content in the viral genome, leading to the loss of its integrity. We also indicated the nucleic acid technologies as potential approaches for COVID-19 treatment. Among numerous promising natural products, we pointed out curcumin and cannabidiol as good candidates for being anti-SARS-CoV-2 agents.

The model structure of the hammerhead ribozyme formed by RNAs of reciprocal chirality.

RNA-based tools are frequently used to modulate gene expression in living cells. However, the stability and effectiveness of such RNA-based tools is limited by cellular nuclease activity. One way to increase RNA's resistance to nucleases is to replace its D-ribose backbone with L-ribose isomers. This modification changes chirality of an entire RNA molecule to L-form giving it more chance of survival when introduced into cells. Recently, we have described the activity of left-handed hammerhead ribozyme (L-Rz, L-HH) that can specifically hydrolyse RNA with the opposite chirality at a predetermined location. To understand the structural background of the RNA specific cleavage in a heterochiral complex, we used circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy as well as performed molecular modelling and dynamics simulations of homo- and heterochiral RNA complexes. The active ribozyme-target heterochiral complex showed a mixed chirality as well as low field imino proton NMR signals. We modelled the 3D structures of the oligoribonucleotides with their ribozyme counterparts of reciprocal chirality. L- or D-ribozyme formed a stable, homochiral helix 2, and two short double heterochiral helixes 1 and 3 of D- or L-RNA strand thorough irregular Watson-Crick base pairs. The formation of the heterochiral complexes is supported by the result of simulation molecular dynamics. These new observations suggest that L-catalytic nucleic acids can be used as tools in translational biology and diagnostics.

Reducing SARS-CoV-2 pathological protein activity with small molecules / 药物分析学报

Coronaviruses are dangerous human and animal pathogens.The newly identified coronavirus SARS-CoV-2 is the causative agent of COVID-19 outbreak,which is a real threat to human health and life.The world has been struggling with this epidemic for about a year,yet there are still no targeted drugs and effective treatments are very limited.Due to the long process of developing new drugs,reposition of existing ones is one of the best ways to deal with an epidemic of emergency infectious diseases.Among the existing drugs,there are candidates potentially able to inhibit the SARS-CoV-2 replication,and thus inhibit the infection of the virus.Some therapeutics target several proteins,and many diseases share molecular paths.In such cases,the use of existing pharmaceuticals for more than one purpose can reduce the time needed to design new drugs.The aim of this review was to analyze the key targets of viral infection and potential drugs acting on them,as well as to discuss various strategies and therapeutic approaches,including the possible use of natural products.We highlighted the approach based on increasing the involvement of human deaminases,particularly APOBEC deaminases in editing of SARS-CoV-2 RNA.This can reduce the cytosine content in the viral genome,leading to the loss of its integrity.We also indicated the nucleic acid technologies as potential approaches for COVID-19 treatment.Among numerous promising natural products,we pointed out curcumin and cannabidiol as good candidates for being anti-SARS-CoV-2 agents.

Cancer Stem Cell-Inducing Media Activates Senescence Reprogramming in Fibroblasts.

Cellular senescence is a tumor-suppressive mechanism blocking cell proliferation in response to stress. However, recent evidence suggests that senescent tumor cells can re-enter the cell cycle to become cancer stem cells, leading to relapse after cancer chemotherapy treatment. Understanding how the senescence reprogramming process is a precursor to cancer stem cell formation is of great medical importance. To study the interplay between senescence, stemness, and cancer, we applied a stem cell medium (SCM) to human embryonic fibroblasts (MRC5 and WI-38) and cancer cell lines (A549 and 293T). MRC5 and WI-38 cells treated with SCM showed symptoms of oxidative stress and became senescent. Transcriptome analysis over a time course of SCM-induced senescence, revealed a developmental process overlapping with the upregulation of genes for growth arrest and the senescence-associated secretory phenotype (SASP). We demonstrate that histone demethylases jumonji domain-containing protein D3 (Jmjd3) and ubiquitously transcribed tetratricopeptide repeat, X chromosome (Utx), which operate by remodeling chromatin structure, are implicated in the senescence reprogramming process to block stem cell formation in fibroblasts. In contrast, A549 and 293T cells cultured in SCM were converted to cancer stem cells that displayed the phenotype of senescence uncoupled from growth arrest. The direct overexpression of DNA methyltransferases (Dnmt1 and Dnmt3A), ten-eleven translocation methylcytosine dioxygenases (Tet1 and Tet3), Jmjd3, and Utx proteins could activate senescence-associated beta-galactosidase (SA-ß-gal) activity in 293T cells, suggesting that epigenetic alteration and chromatin remodeling factors trigger the senescence response. Overall, our study suggests that chromatin machinery controlling senescence reprogramming is significant in cancer stem cell formation.

T-psi-C: user friendly database of tRNA sequences and structures.

tRNAs have been widely studied for their role as genetic code decoders in the ribosome during translation, but have recently received new attention due to the discovery of novel roles beyond decoding, often in connection with human diseases. Yet, existing tRNA databases have not been updated for more than a decade, so they do not contain this new functional information and have not kept pace with the rate of discovery in this field. Therefore, a regularly updated database that contains information about newly discovered characteristics of tRNA molecules and can be regularly updated is strongly needed. Here, we report the creation of the T-psi-C database (http://tpsic.igcz.poznan.pl), an up-to-date collection of tRNA sequences that contains data obtained from high-throughput tRNA sequencing, e.g. all isoacceptors and isodecoders for human HEK293 cells. This database also contains 3D tRNA structures obtained from Protein Data Bank and generated using homology modeling. The T-psi-C database can be continuously updated by any member of the scientific community, and contains its own application programming interface (API), which allows users to retrieve or upload data in JSON format. Altogether, T-psi-C is user-friendly, easy to develop and an up-to-date source of knowledge about tRNAs.

Biological activity of N6-furfuryladenosine / Aktywnosc biologiczna N6-furfuryloadenozyny.

Cytokinins are a group of plant hormones which play an important role in plant growth and development. They produce various effects when applied to intact plants. They particularly stimulate protein synthesis and participate in cell cycle control. First discovered cytokinin was N6-furfuryladenine (kinetin). It is a strong inhibitor of proteins and nucleic acids oxidation in vitro and in vivo. Both kinetin and its ribosides (N6-furfuryladenosine, kinetin riboside) as natural compounds occur in the milk of coconuts on the nanomole level. Kinetin riboside selectively inhibits the proliferation of cancer cells and induce their apoptosis. This review focuses on the kinetin riboside occurrence, and primarily on its metabolism, and biological activity.

Mitochondrial Transcriptome Control and Intercompartment Cross-Talk During Plant Development.

We address here organellar genetic regulation and intercompartment genome coordination. We developed earlier a strategy relying on a tRNA-like shuttle to mediate import of nuclear transgene-encoded custom RNAs into mitochondria in plants. In the present work, we used this strategy to drive trans-cleaving hammerhead ribozymes into the organelles, to knock down specific mitochondrial RNAs and analyze the regulatory impact. In a similar approach, the tRNA mimic was used to import into mitochondria in Arabidopsis thaliana the orf77, an RNA associated with cytoplasmic male sterility in maize and possessing sequence identities with the atp9 mitochondrial RNA. In both cases, inducible expression of the transgenes allowed to characterise early regulation and signaling responses triggered by these respective manipulations of the organellar transcriptome. The results imply that the mitochondrial transcriptome is tightly controlled by a "buffering" mechanism at the early and intermediate stages of plant development, a control that is released at later stages. On the other hand, high throughput analyses showed that knocking down a specific mitochondrial mRNA triggered a retrograde signaling and an anterograde nuclear transcriptome response involving a series of transcription factor genes and small RNAs. Our results strongly support transcriptome coordination mechanisms within the organelles and between the organelles and the nucleus.

Interaction of small molecules with polynucleotide repeats and frameshift site RNA.

This mini-review describes the interaction between small molecules and RNA, in addition to its application either in treating RNA-associated diseases or detecting target molecules. In the case of RNA-associated disease treatment, the designed small molecules interact with RNA sites, forming adducts and providing successful therapeutic strategies over oligonucleotides. On the other hand, synthetically designed RNA moieties (aptamers) interact with target molecules like toxins, drugs, hormones; these interactions are useful in the detection, quantification or separation of these target moieties.

Let food be your medicine: nutraceutical properties of lycopene.

Currently, an increase in the awareness of a healthy lifestyle has been observed in society. People are seeking added health benefits from their dietary intake. Thus, functional foods with supplemented components that promote wellness are becoming popular. Lycopene is a carotenoid that gives vegetables and fruits their red color. Due to its chemical structure, lycopene acts as an antioxidant, which is the basis for its health-promoting properties. Oxidative stress is recognized as an important agent of many chronic diseases; thus, lycopene appears to be a universal medicine. Lycopene has the greatest antioxidant potential among carotenoids. Nutraceutical effects of lycopene have been reported for patients with cancer, infertility, metabolic syndrome and liver damage. Therefore, its supplementation can function as a proper causative treatment of disease. In this review, we highlight primary research and clinical trials involving lycopene and its impact on human health.

Nano-mediated delivery of double-stranded RNA for gene therapy of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common type of malignant gliomas, characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior. Disappointing results in the treatment of gliomas with surgery, radiation and chemotherapy have fueled a search for new therapeutic targets and treatment modalities. Here we report new approach towards RNA interference therapy of glioblastoma multiforme based on the magnetic nanoparticles delivery of the double-stranded RNA (dsRNA) with homological sequences to mRNA of tenascin-C (TN-C), named ATN-RNA. The obtained nanocomposite consisted of polyethyleneimine (PEI) coated magnetic nanoparticles conjugated to the dsRNA show high efficiency in ATN-RNA delivery, resulting not only in significant TN-C expression level suppressesion, but also impairing the tumor cells migration. Moreover, synthesized nanomaterials show high contrast properties in magnetic resonance imaging (MRI) and low cytotoxicity combining with lack of induction of interferon response. We believe that the present work is a successful combination of effective, functional, non-immunostimulatory dsRNA delivery system based on magnetic nanoparticles with high potential for further application in GBM therapy.

[Life as a way of the functioning of matter - Theory of organic being of Jedrzej Sniadecki]. / Zycie jako sposób istnienia materii ­ Teoria jestestw organicznych Jedrzeja Sniadeckiego.

In 2018 we celebrate the 250th anniversary of the Jedrzej Sniadecki's birth. This work aims to show the importance of his thoughts for the development of natural sciences. He studied at some of the largest universities in Europe, where he met great scientists of the enlightenment. The effects can be seen in his works. He was remembered as a founder of Polish biochemistry, anthropology and pathology, also as the author of chemical terminology and language. The essence of his thoughts is "Theory of Organic being", which is an attempt to answer the question: "what is life?". Jedrzej Sniadecki introduced a new definition of life based on the term "organic power". This work shows how import are the thoughts of Jedrzej Sniadecki in the context of the times in which he lived, as well as the following development of natural sciences, what makes him and his theories worth memory.

Novel insights and innovations in biotechnology towards improved quality of life.

Resolution of old problems with new tools seems to be a new way of challenging and finding the keys to innovation. A holistic view of different branches of science and industry, including services for society, is critically important for the development of modern science. The International Congress Eurobiotech 2017 was a special opportunity for such a universal view. In this paper, we discuss the application of different small RNAs, stem cells, epigenetics and sequencing, as well as art and bioeconomy. Our most significant message is not a new one but is very universal: biotechnology is vital for society.

Synthesis and biological assay of new 2'-deoxyuridine dimers containing a 1,2,3-triazole linker. Part I.

We describe a simple method for the synthesis of modified dinucleosides containing pyrimidine nucleoside analogues (2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine). Six different dimers with a 1,2,3-triazole linkage were obtained by azide-alkyne 1,3-dipolar cycloaddition (click reaction), starting from propargylated 2'-deoxyuridine and 5'-azido-nucleoside derivatives. Their cytotoxic activity was tested in five human cancer cell lines: cervical (HeLa), high grade gliomas (U-118 MG, U-87 MG, T98G), liver (HepG2), and normal human fibroblast cell line (MRC-5) using the sulforhodamine B (SRB) assay. The experiment showed that the obtained dimers with a 1,2,3-triazole moiety were very stable compounds, also in the physiological-like media, and had no anticancer activity.