Epigenome-metabolism nexus in the retina: implications for aging and disease.

Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome-metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function.

Selective transcriptomic dysregulation of metabolic pathways in liver and retina by short- and long-term dietary hyperglycemia.

A high glycemic index (HGI) diet induces hyperglycemia, a risk factor for diseases affecting multiple organ systems. Here, we evaluated tissue-specific adaptations in the liver and retina after feeding HGI diet to mice for 1 or 12 month. In the liver, genes associated with inflammation and fatty acid metabolism were altered within 1 month of HGI diet, whereas 12-month HGI diet-fed group showed dysregulated expression of cytochrome P450 genes and overexpression of lipogenic factors including Srebf1 and Elovl5. In contrast, retinal transcriptome exhibited HGI-related notable alterations in energy metabolism genes only after 12 months. Liver fatty acid profiles in HGI group revealed higher levels of monounsaturated and lower levels of saturated and polyunsaturated fatty acids. Additionally, HGI diet increased blood low-density lipoprotein, and diet-aging interactions affected expression of mitochondrial oxidative phosphorylation genes in the liver and disease-associated genes in retina. Thus, our findings provide new insights into retinal and hepatic adaptive mechanisms to dietary hyperglycemia.

Why Are Nucleosome Breathing Dynamics Asymmetric?

In eukaryotic cells, DNA is bound to nucleosomes, but DNA segments occasionally unbind in the process known as nucleosome breathing. Although DNA can unwrap simultaneously from both ends of the nucleosome (symmetric breathing), experiments indicate that DNA prefers to dissociate from only one end (asymmetric breathing). However, the molecular origin of the asymmetry is not understood. We developed a new theoretical approach that gives microscopic explanations of asymmetric breathing. It is based on a stochastic description that leads to a comprehensive evaluation of dynamics by using effective free-energy landscapes. It is shown that asymmetric breathing follows the kinetically preferred pathways. In addition, it is also found that asymmetric breathing leads to a faster target search by transcription factors. Theoretical predictions, supported by computer simulations, agree with experiments. It is proposed that nature utilizes the symmetry of nucleosome breathing to achieve a better dynamic accessibility of chromatin for more efficient genetic regulation.

Antibacterial, antibiofilm and larvicidal activity of silver nanoparticles synthesized from spider silk protein.

Green synthesis of silver nanoparticles has gained attention due to its simple process of synthesis and varied applications. Scientists have tried its synthesis from a wide range of materials, but there is lack of reports that can use the metabolites of insects. Here in this study, we have used the spider silk protein which is considered as complete waste collected from household and field sources and processed to synthesize silver nanoparticles which were subsequently analyzed using different analytical tools like SEM, TEM, FTIR, and XRD. The spider silk protein-mediated synthesized nanoparticle (SP-AgNPs) showed a sharp peak at 420 nm when analyzed spectrophotometrically giving an indication of successful synthesis of AgNP. The synthesized nanoparticle ranges from 10 to 40 nm and were of varied shapes. The synthesized SP-AgNPs showed remarkable antibacterial activity. The MIC values against B. subtilis and E. coli were recorded 45 and 40 µg/mL respectively. Further to know the mechanisms of antibacterial activity protein leakage and conductivity measurement were conducted. The synthesized nanoparticle also showed excellent antibiofilm activity with inhibition percentages of 74 % and 68 % for E. coli and B. subtilis respectively at MIC concentration of the treatment. Finally, the synthesized nanoparticles was applied as mosquito larvicidal agent against Culex sp. and the difference between LC50 and LD90 value was recorded as statistically significant (p < 0.0267) during 24 h of incubation. Therefore, it can be said that spider-web could be an excellent biological reducing and capping agent for heavy metal nanoparticle synthesis that can minimize the ailments caused by mosquitoes and pathogenic microorganisms.

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function.

Very-long-chain polyunsaturated fatty acids (VLCPUFAs; C24-38) constitute a unique class of PUFA that have important biological roles, but the lack of a suitable dietary source has limited research in this field. We produced an n-3 C24-28-rich VLCPUFA-oil concentrated from fish oil to study its bioavailability and physiological functions in C57BL/6J mice. The serum and retinal C24:5 levels increased significantly compared to control after a single-dose gavage, and VLCPUFAs were incorporated into the liver, brain, and eyes after 8-week supplementation. Dietary VLCPUFAs resulted in favorable cardiometabolic changes, and improved electroretinography responses and visual performance. VLCPUFA supplementation changed the expression of genes involved in PPAR signaling pathways. Further in vitro studies demonstrated that the VLCPUFA-oil and chemically synthesized C24:5 are potent agonists for PPARs. The multiple potential beneficial effects of fish oil-derived VLCPUFAs on cardiometabolic risk and eye health in mice support future efforts to develop VLCPUFA-oil into a supplemental therapy.

Characterization of a biofilm-forming, amylase-producing, and heavy-metal-bioremediating strain Micrococcus sp. BirBP01 isolated from oligotrophic subsurface lateritic soil.

Lateritic soil is the reddish to brown-colored soil composed mainly of iron or aluminium oxides, hydroxides, or oxyhydroxides. Information on bacteria that inhabit this soil type, their ecological role, and metabolic potential are scarce. We have isolated and partially characterized a bacterial strain BirBP01 from a lead, calcium, and magnesium-rich, oligotrophic subsurface lateritic soil-sample collected from 12-feet deep horizon of a laterite mining pit in Birbhum district, India. The isolate is a biofilm-forming, Gram-positive bacterium having a sarcinae arrangement, mesophilic, slightly alkaliphilic, able to produce amylase, and resistant against multiple heavy-metals. BirBP01 has the ability to bioremediate 51% of Pb, 30% of Zn, and 22% of Cu through biosorption, possibly into the biofilm matrix. The bioremediating ability of the bacterium alleviated the inhibitory effect of heavy-metals on the germination of chickpea (Cicer arietinum L.) seeds. 16S rRNA gene-based phylogenetic analysis revealed that BirBP01 is a member of the genus Micrococcus. It showed more than 99% identity of the 16S rRNA gene sequence, and clustered within the same branch of the phylogenetic tree, with strains of M. yunnanensis, M. endophyticus, and M. luteus. The ability to produce amylase, and bioremediate heavy-metals signify that Micrococcus sp. BirBP01 could be potentially a good candidate for industrial applications, and to clean up heavy-metal contaminated sites.

Role of Nucleosome Sliding in the Protein Target Search for Covered DNA Sites.

Associations of transcription factors (TFs) with specific sites on DNA initiate major cellular processes. But DNA in eukaryotic cells is covered by nucleosomes which prevent TFs from binding. However, nucleosome structures on DNA are not static and exhibit breathing and sliding. We develop a theoretical framework to investigate the effect of nucleosome sliding on a protein target search. By analysis of a discrete-state stochastic model of nucleosome sliding, search dynamics are explicitly evaluated. It is found that for long sliding lengths the target search dynamics are faster for normal TFs that cannot enter the nucleosomal DNA. But for more realistic short sliding lengths, the so-called pioneer TFs, which can invade nucleosomal DNA, locate specific sites faster. It is also suggested that nucleosome breathing, which is a faster process, has a stronger effect on protein search dynamics than that of nucleosome sliding. Theoretical arguments to explain these observations are presented.

Network Biology and Medicine to Rescue: Applications for Retinal Disease Mechanisms and Therapy.

Inherited retinal degenerations (IRDs) are clinically and genetically heterogenous blinding diseases that manifest through dysfunction of target cells, photoreceptors, and retinal pigment epithelium (RPE) in the retina. Despite knowledge of numerous underlying genetic defects, current therapeutic approaches, including gene centric applications, have had limited success, thereby asserting the need of new directions for basic and translational research. Human diseases have commonalities that can be represented in a network form, called diseasome, which captures relationships among disease genes, proteins, metabolites, and patient meta-data. Clinical and genetic information of IRDs suggest shared relationships among pathobiological factors, making these a model case for network medicine. Characterization of the diseasome would considerably improve our understanding of retinal pathologies and permit better design of targeted therapies for disrupted regions within the integrated disease network. Network medicine in synergy with the ongoing artificial intelligence revolution can boost therapeutic developments, especially gene agnostic treatment opportunities.

Nucleosome Breathing Facilitates the Search for Hidden DNA Sites by Pioneer Transcription Factors.

Transfer of genetic information starts with transcription factors (TFs) binding to specific sites on DNA. But in living cells, DNA is mostly covered by nucleosomes. There are proteins, known as pioneer TFs, that can efficiently reach the DNA sites hidden by nucleosomes, although the underlying mechanisms are not understood. Using the recently proposed idea of interaction-compensation mechanism, we develop a stochastic model for the target search on DNA with nucleosome breathing. It is found that nucleosome breathing can significantly accelerate the search by pioneer TFs in comparison to situations without breathing. We argue that this is the result of the interaction-compensation mechanism that allows proteins to enter the inner nucleosome region through the outer DNA segment. It is suggested that nature optimized pioneer TFs to take advantage of nucleosome breathing. The presented theoretical picture provides a possible microscopic explanation for the successful invasion of nucleosome-buried genes.

Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects.

Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene CEP290. We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in rd16 organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.

Leber congenital amaurosis (LCA) is an inherited disease that affects the eyes and causes sight loss in early childhood, which generally gets worse over time. Individuals with this condition have genetic mutations that result in the death of light-sensitive cells, known as photoreceptors, in a region called the retina at the back of the eye. Patients carrying a genetic change in the gene CEP290 account for 20-25% of all LCA. At present, treatment options are only available for a limited number of patients with LCA. One option is to use small molecules as drugs that may target or bypass the faulty processes within the eye to help the photoreceptors survive in many different forms of LCA and other retinal diseases. However, over 90% of new drug candidates fail the first phase of clinical trials for human diseases. This in part due to the candidates having been developed using cell cultures or animal models that do not faithfully reflect how the human body works. Recent advances in cell and developmental biology are now enabling researchers to use stem cells derived from humans to grow retina tissues in a dish in the laboratory. These tissues, known as retinal organoids, behave in a more similar way to retinas in human eyes than those of traditional animal models. However, the methods for making and maintaining human retinal organoids are time-consuming and labor-intensive, which has so far limited their use in the search for new therapies. To address this challenge, Chen et al. developed a large-scale approach to grow retinal organoids from rd16 mutant mice stem cells (which are a good model for LCA caused by mutations to CEP290) and used the photoreceptors from these organoids to screen over 6,000 existing drugs for their ability to promote the survival of photoreceptors. The experiments found that the drug reserpine, which was previously approved to treat high blood pressure, also helped photoreceptors to survive in the diseased organoids. Reserpine also had a similar effect in retinal organoids derived from human patients with LCA and in the rd16 mice themselves. Further experiments suggest that reserpine may help patients with LCA by partially restoring a process by which the body destroys and recycles old and damaged proteins in the cells. The next steps following on from this work will be to perform further tests to demonstrate that this use of reserpine is safe to enter clinical trials as a treatment for LCA and other similar eye diseases.

Synthesis, characterization and optimization of chicken bile-mediated silver nanoparticles: a mechanistic insight into antibacterial and antibiofilm activity.

The fast-growing urbanization and slow progress in the field of waste management have led to the accumulation of large quantities of animal wastes. The present work focused on the synthesis of low-cost and eco-friendly chicken bile juice-mediated silver nanoparticles (BJ-AgNP). Results reveal that bile juices have enough potentiality towards the synthesis of almost uniform sizes (average size < 50 nm) of BJ-AgNPs which remains stable for more than 6 months. Response surface methodology (RSM) successfully demonstrated the optimised condition of BJ-AgNP synthesis. Factors like concentration of salt and bile extract and temperature are significantly responsible for nanoparticle synthesis. The synthesis of nanoparticle was further characterized using UV-Vis, TEM, FESEM, XRD, FTIR, TGA, and EDS. The synthesised nanoparticle showed excellent bactericidal activity against both Gram positive and Gram negative bacteria with MIC and MBC of 40 and 50 µg/mL for Bacillus subtilis (MTCC-441) and 60 and 60 µg/mL for Eschecheria coli (MTCC-1687) respectively. The synthesised nanoparticle also exhibited as an antibiofilm activity against B. subtilis, with ~89% biofilm inhibition efficacy at 4 X MIC, having optimal bacterial concentration of 106 CFU/mL. Therefore, the present findings clearly demonstrated that an absolute animal waste could be a valuable ingredient in the field of therapeutic nanoscience.

Understanding protein diffusion on force-induced stretched DNA conformation.

DNA morphology is subjected to environmental conditions and is closely coupled with its function. For example, DNA experiences stretching forces during several biological processes, including transcription and genome transactions, that significantly alter its conformation from that of B-DNA. Indeed, a well-defined 1.5 times extended conformation of dsDNA, known as Σ-DNA, has been reported in DNA complexes with proteins such as Rad51 and RecA. A striking feature in Σ-DNA is that the nucleobases are partitioned into triplets of three locally stacked bases separated by an empty rise gap of ∼ 5 Å. The functional role of such a DNA base triplet was hypothesized to be coupled with the ease of recognition of DNA bases by DNA-binding proteins (DBPs) and the physical origin of three letters (codon/anti-codon) in the genetic code. However, the underlying mechanism of base-triplet formation and the ease of DNA base-pair recognition by DBPs remain elusive. To investigate, here, we study the diffusion of a protein on a force-induced stretched DNA using coarse-grained molecular dynamics simulations. Upon pulling at the 3' end of DNA by constant forces, DNA exhibits a conformational transition from B-DNA to a ladder-like S-DNA conformation via Σ-DNA intermediate. The resulting stretched DNA conformations exhibit non-uniform base-pair clusters such as doublets, triplets, and quadruplets, of which triplets are energetically more stable than others. We find that protein favors the triplet formation compared to its unbound form while interacting non-specifically along DNA, and the relative population of it governs the ruggedness of the protein-DNA binding energy landscape and enhances the efficiency of DNA base recognition. Furthermore, we analyze the translocation mechanism of a DBP under different force regimes and underscore the significance of triplet formation in regulating the facilitated diffusion of protein on DNA. Our study, thus, provides a plausible framework for understanding the structure-function relationship between triplet formation and base recognition by a DBP and helps to understand gene regulation in complex regulatory processes.

Nucleosome breathing facilitates cooperative binding of pluripotency factors Sox2 and Oct4 to DNA.

Critical lineage commitment events are staged by multiple transcription factors (TFs) binding to their cognate motifs, often positioned at nucleosome-enriched regions of chromatin. The underlying mechanism remains elusive due to difficulty in disentangling the heterogeneity in chromatin states. Using a novel coarse-grained model and molecular dynamics simulations, here we probe the association of Sox2 and Oct4 proteins that show clustered binding at the entry-exit region of a nucleosome. The model captures the conformational heterogeneity of nucleosome breathing dynamics that features repeated wrap-unwrap transitions of a DNA segment from one end of the nucleosome. During the dynamics, DNA forms bulges that diffuse stochastically and may regulate the target search dynamics of a protein by nonspecifically interacting with it. The overall search kinetics of the TF pair follows a "dissociation-compensated-association" mechanism, where Oct4 binding is facilitated by the association of Sox2. The cooperativity stems from a change in entropy caused by an alteration in the nucleosome dynamics upon TF binding. The binding pattern is consistent with a live-cell single-particle tracking experiment, suggesting the mechanism observed for clustered binding of a TF pair, which is a hallmark of cis-regulatory elements, has broader implications in understanding gene regulation in a complex chromatin environment.

Virtual screening and docking analysis of novel ligands for selective enhancement of tea (Camellia sinensis) flavonoids.

Flavour of tea is mainly contributed by a group of polyphenols - flavonoids. However, the content of flavonoid fluctuates seasonally and is found to be higher in the first flush of tea, when compared to the second flush. This disparity in the flavonoid content, and hence taste, incurs heavy economic losses to the tea plantation industry each harvest season. For our present study, four key product-specific enzymes (PAL, FNS, FLS and ANS) of the tea-specific flavonoid pathway were selected to perform molecular docking studies with specific virtually screened allosteric modulators. Results of docking analyses showed Naringenin, 2-Morpholin-4-ium-4-ylethanesulfonate, 6-C-Glucosylquercetin, 2-Oxoglutaric acid, 3,5,7,3',4'-pentahydroxyflavone to be capable of improving the spontaneity of the enzyme-substrate reactions in terms of docking score, RMSD values, and non-covalent interactions (H-bond,hydrophobic interaction, Π-stacking, salt bridge, etc.). Further, the evolutionary relationship of tea flavonoid pathway enzymes was constructed and compared with related taxa. The codon usage-based of tea flavonoid biosynthetic genes indicated the non-biasness of their nucleotide composition. Overall this study will provide a direction towards putative ligand-dependent enhancement of flavonoid content, irrespective of seasonal variation.

Bio-fabricated silver nanoparticles for controlling dengue and filaria vectors and their characterization, as well as toxicological risk assessment in aquatic mesocosms.

The present study is focused on synthesis of silver nanoparticles from weeds and an assessment of their mosquito larvicidal efficacy. This study also presented the toxicological effects as well as the stability of these nanoparticles in aquatic mesocosms. The weed Digiteria sanguinallis was first time used for the synthesis of silver nanoparticles. The synthesized nanoparticles were characterized by various analytical techniques, such as UV-VIS, TEM, FESEM, EDX, XRD, FTIR, and zeta potential study. The result revealed that the nanoparticles are crystalline, spherical shape with band gap 2.44 eV, and average size 18 nm. The LC50 value of synthesized AgNPs were recorded as 7.47 and 6.31 mg/L at 24 h against Cx. quinquefasciatus and A. albopictus respectively. In contrast, larvicidal activity of weed extract was insignificant against two target species. In aquatic mesocosm study, AgNPs (LC50 dose) does not alter the nature of water parameters within experimental period. However only EC % and ORP were changes because of silver ion oxidation. In biochemical parameters, only stress enzymes for animal and plant species were moderately altered under long term exposure. But glycogen, protein, and AchE of two mosquito species were significantly changed under same mesocosm setup within short exposure. Comparatively, in control mesocosm, synthesized AgNPs are naturally change their nano form within 20 days with the presence of all non-target species and pond sediment. Therefore, it can be concluded that biosynthesized AgNPs could be used as a larvicidal agent in near future with negligible effects on aquatic organisms.

Flavonoid mediated selective cross-talk between plants and beneficial soil microbiome.

Plants generate a wide variety of organic components during their different growth phases. The majority of those compounds have been classified as primary and secondary metabolites. Secondary metabolites are essential in plants' adaptation to new changing environments and in managing several biotic and abiotic stress. It also invests some of its photosynthesized carbon as secondary metabolites to establish a mutual relationship with soil microorganisms in that specific niche. As soil harbors both pathogenic and beneficial microorganisms, it is essential to identify some specific metabolites that can discriminate beneficial and pathogenic ones. Thus, a detailed understanding of metabolite's architectures that interact with beneficial microorganisms could open a new horizon of ecology and agricultural research. Flavonoids are used as classic examples of secondary metabolites in this study to demonstrate recent developments in understanding and realizing how these valuable metabolites can be controlled at different levels. Most of the research was focused on plant flavonoids, which shield the host plant against competitors or predators, as well as having other ecological implications. Thus, in the present review, our goal is to cover a wide range of functional and signalling activities of secondary metabolites especially, flavonoids mediated selective cross-talk between plant and its beneficial soil microbiome. Here, we have summarized recent advances in understanding the interactions between plant species and their rhizosphere microbiomes through root exudates (flavonoids), with a focus on how these exudates facilitate rhizospheric associations. Supplementary Information: The online version contains supplementary material available at 10.1007/s11101-022-09806-3.

Multiomics analyses reveal early metabolic imbalance and mitochondrial stress in neonatal photoreceptors leading to cell death in Pde6brd1/rd1 mouse model of retinal degeneration.

Retinal diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset and severity. Mutations in over 200 genes can lead to photoreceptor dysfunction and/or cell death in retinal neurodegeneration. To deduce molecular pathways that initiate and/or drive cell death, we adopted a temporal multiomics approach and examined molecular and cellular events in newborn and developing photoreceptors before the onset of degeneration in a widely-used Pde6brd1/rd1 (rd1) mouse, a model of autosomal recessive retinitis pigmentosa caused by PDE6B mutations. Transcriptome profiling of neonatal and developing rods from the rd1 retina revealed early downregulation of genes associated with anabolic pathways and energy metabolism. Quantitative proteomics of rd1 retina showed early changes in calcium signaling and oxidative phosphorylation, with specific partial bypass of complex I electron transfer, which precede the onset of cell death. Concurrently, we detected alterations in central carbon metabolism, including dysregulation of components associated with glycolysis, pentose phosphate and purine biosynthesis. Ex vivo assays of oxygen consumption and transmission electron microscopy validated early and progressive mitochondrial stress and abnormalities in mitochondrial structure and function of rd1 rods. These data uncover mitochondrial overactivation and related metabolic alterations as determinants of early pathology and implicate aberrant calcium signaling as an initiator of higher mitochondrial stress. Our studies thus provide a mechanistic framework with mitochondrial damage and metabolic disruptions as early drivers of photoreceptor cell death in retinal degeneration.

Tea and its phytochemicals: Hidden health benefits & modulation of signaling cascade by phytochemicals.

Tea, one of the most widely consumed beverages, is prepared from the leaves of the Camellia sinensis. The promising health recompenses of tea have been linked to its different phenolic components, which have diverse biological characteristics. Tea also contains several flavonoids, alkaloids, phenolic, theanine, etc., which are associated with anti-oxidant characteristics and a variety of health benefits. It can also lower the pervasiveness of neurological disorders as well as prevent different types of cancer, metabolic syndromes, cardiovascular diseases, urinary stone, obesity, type 2 diabetes. Keeping in mind that tea helps to improve health and prevents many diseases, its consumption has been regarded as a "health-promoting habit" and current medical investigators have established the scientific basis for this concept over time. The current review provides new updated information and perspectives on the tea phytochemicals and their overall health benefits based on molecular processes, experimental studies, and clinical trials.

Exploring tea (Camellia sinensis) microbiome: Insights into the functional characteristics and their impact on tea growth promotion.

Tea (Camellia sinensis) is perhaps the most popular and economic beverage in the globe due to its distinctive fragrance and flavour generated by the leaves of commercially farmed tea plants. The tea microbiome has now become a prominent topic of attention for microbiologists in recent years as it can help the plant for soil nutrient acquisition as well as stress management. Tea roots are well known to be colonized by Arbuscular Mycorrhizal Fungi (AMF) and many other beneficial microorganisms that boost the growth of the tea which increases leaf amino acids, protein, caffeine, and polyphenols content. One of the primary goals of rhizosphere microbial biology is to aid in the establishment of agricultural systems that provide high quantities of the food supply while minimizing environmental effects and anthropogenic activities. The present review is aimed to highlight the importance of microbes (along with their phylogeny) derived from cultivated and natural tea rhizospheres to understand the role of AMF and rhizospheric bacterial population to improve plant growth, enhancement of tea quality, and protecting tea plants from pathogens. This review also summarizes recent advances in our understanding of the diversity and profile of tea-associated bacteria. The utilization of the tea microbiome as a "natural resource" could provide holistic development in tea cultivation to ensure sustainability, highlighting knowledge gaps and future microbiome research.

Kinetic origin of nucleosome invasion by pioneer transcription factors.

Recently, a cryo-electron microscopy study has captured different stages of nucleosome breathing dynamics that show partial unwrapping of DNA from histone core to permit transient access to the DNA sites by transcription factors. In practice, however, only a subset of transcription factors named pioneer factors can invade nucleosomes and bind to specific DNA sites to trigger essential DNA metabolic processes. We propose a discrete-state stochastic model that considers the interplay of nucleosome breathing and protein dynamics explicitly and estimate the mean time to search the target DNA sites. It is found that the molecular principle governing the search process on nucleosome is very different compared to that on naked DNA. The pioneer factors minimize their search times on nucleosomal DNA by compensating their nucleosome association rates by dissociation rates. A fine balance between the two presents a tradeoff between their nuclear mobility and error associated with the search process.