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.

Molecular mechanisms of precise timing in cell lysis.

Many biological systems exhibit precise timing of events, and one of the most known examples is cell lysis, which is a process of breaking bacterial host cells in the virus infection cycle. However, the underlying microscopic picture of precise timing remains not well understood. We present a novel theoretical approach to explain the molecular mechanisms of effectively deterministic dynamics in biological systems. Our hypothesis is based on the idea of stochastic coupling between relevant underlying biophysical and biochemical processes that lead to noise cancellation. To test this hypothesis, we introduced a minimal discrete-state stochastic model to investigate how holin proteins produced by bacteriophages break the inner membranes of gram-negative bacteria. By explicitly solving this model, the dynamic properties of cell lysis are fully evaluated, and theoretical predictions quantitatively agree with available experimental data for both wild-type and holin mutants. It is found that the observed threshold-like behavior is a result of the balance between holin proteins entering the membrane and leaving the membrane during the lysis. Theoretical analysis suggests that the cell lysis achieves precise timing for wild-type species by maximizing the number of holins in the membrane and narrowing their spatial distribution. In contrast, for mutated species, these conditions are not satisfied. Our theoretical approach presents a possible molecular picture of precise dynamic regulation in intrinsically random biological processes.

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.

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.

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.

Loss of endocytosis-associated RabGEF1 causes aberrant morphogenesis and altered autophagy in photoreceptors leading to retinal degeneration.

Rab-GTPases and associated effectors mediate cargo transport through the endomembrane system of eukaryotic cells, regulating key processes such as membrane turnover, signal transduction, protein recycling and degradation. Using developmental transcriptome data, we identified Rabgef1 (encoding the protein RabGEF1 or Rabex-5) as the only gene associated with Rab GTPases that exhibited strong concordance with retinal photoreceptor differentiation. Loss of Rabgef1 in mice (Rabgef1-/-) resulted in defects specifically of photoreceptor morphology and almost complete loss of both rod and cone function as early as eye opening; however, aberrant outer segment formation could only partly account for visual function deficits. RabGEF1 protein in retinal photoreceptors interacts with Rabaptin-5, and RabGEF1 absence leads to reduction of early endosomes consistent with studies in other mammalian cells and tissues. Electron microscopy analyses reveal abnormal accumulation of macromolecular aggregates in autophagosome-like vacuoles and enhanced immunostaining for LC3A/B and p62 in Rabgef1-/- photoreceptors, consistent with compromised autophagy. Transcriptome analysis of the developing Rabgef1-/- retina reveals altered expression of 2469 genes related to multiple pathways including phototransduction, mitochondria, oxidative stress and endocytosis, suggesting an early trajectory of photoreceptor cell death. Our results implicate an essential role of the RabGEF1-modulated endocytic and autophagic pathways in photoreceptor differentiation and homeostasis. We propose that RabGEF1 and associated components are potential candidates for syndromic traits that include a retinopathy phenotype.

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.

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.

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.

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.

Mechanism of Dynamic Binding of Replication Protein A to ssDNA.

Replication protein A (RPA) serves as a hub protein inside eukaryotic cells, where it coordinates crucial DNA metabolic processes and activates the DNA-damage response system. A characteristic feature of its action is to associate with single-stranded DNA (ssDNA) intermediates before handing them over to downstream proteins. The length of ssDNA intermediates differs for different pathways. This means that RPA must have mechanisms for selective processing of ssDNA intermediates based on their length, the knowledge of which is fundamental to elucidate when and how DNA repair and replication processes are symphonized. By employing extensive molecular dynamics simulations, we investigated the mechanism of binding of RPA to ssDNA of different lengths. We show that the binding involves dynamic equilibrium with a stable intermediate, the population of which increases with the length of ssDNA. The vital underlying factors are decoded through collective variable principal component analysis. It suggests a differently orchestrated set of interactions that define the action of RPA based on the length of ssDNA intermediates. We further estimated the association kinetics that matches excellently well with previous experimental studies and probed the diffusion mechanism of RPA to ssDNA. RPA diffuses on short ssDNA through progressive "bulge" formation. With long ssDNA, we observed a conformational change in ssDNA coupled with its binding to RPA in a cooperative fashion. This unanticipated binding mechanism successfully explains how the "short-lived", long ssDNA intermediates are processed quickly in vivo. This study thus reveals the molecular basis of several recent experimental observations related to RPA binding to ssDNA and provides novel insights into the RPA functioning in DNA repair and replication.

Adipocyte Model of Mycobacterium tuberculosis Infection Reveals Differential Availability of Iron to Bacilli in the Lipid-Rich Caseous Environment.

Mycobacterium tuberculosis, a successful human pathogen, utilizes multiple carbon sources from the host but adapts to a fatty-acid-rich environment in vivo We sought to delineate the physiologic response of M. tuberculosis to a lipid-rich environment by using differentiated adipocytes as a model system. Global transcriptome profiling based on RNA sequencing was performed for bacilli from infected adipocytes and preadipocytes. Genes involved in de novo fatty acid synthesis were downregulated, while those predicted to be involved in triglyceride biosynthesis were upregulated, in bacilli isolated from adipocytes, indicating reliance on host-derived fatty acids. Transcription factor network analysis indicated suppression of IdeR-regulated genes, suggesting decreased iron uptake by M. tuberculosis in the adipocyte model. This suppression of iron uptake coincided with higher ferritin and iron levels in adipocytes than in preadipocytes. In accord with the role of iron in mediating oxidative stress, we observed upregulation of genes involved in mitigating oxidative stress in M. tuberculosis isolated from adipocytes. We provide evidence that oleic acid, a major host-derived fatty acid, helps reduce the bacterial cytoplasm, thereby providing a safe haven for an M. tuberculosis mutant that is sensitive to iron-mediated oxidative stress. Via an independent mechanism, host ferritin is also able to rescue the growth of this mutant. Our work highlights the inherent synergy between macronutrients and micronutrients of the host environment that converge to provide resilience to the pathogen. This complex synergy afforded by the adipocyte model of infection will aid in the identification of genes required by M. tuberculosis in a caseous host environment.

Searching target sites on DNA by proteins: Role of DNA dynamics under confinement.

DNA-binding proteins (DBPs) rapidly search and specifically bind to their target sites on genomic DNA in order to trigger many cellular regulatory processes. It has been suggested that the facilitation of search dynamics is achieved by combining 3D diffusion with one-dimensional sliding and hopping dynamics of interacting proteins. Although, recent studies have advanced the knowledge of molecular determinants that affect one-dimensional search efficiency, the role of DNA molecule is poorly understood. In this study, by using coarse-grained simulations, we propose that dynamics of DNA molecule and its degree of confinement due to cellular crowding concertedly regulate its groove geometry and modulate the inter-communication with DBPs. Under weak confinement, DNA dynamics promotes many short, rotation-decoupled sliding events interspersed by hopping dynamics. While this results in faster 1D diffusion, associated probability of missing targets by jumping over them increases. In contrast, strong confinement favours rotation-coupled sliding to locate targets but lacks structural flexibility to achieve desired specificity. By testing under physiological crowding, our study provides a plausible mechanism on how DNA molecule may help in maintaining an optimal balance between fast hopping and rotation-coupled sliding dynamics, to locate target sites rapidly and form specific complexes precisely.

Proteogenomics of rare taxonomic phyla: A prospective treasure trove of protein coding genes.

Sustainable innovations in sequencing technologies have resulted in a torrent of microbial genome sequencing projects. However, the prokaryotic genomes sequenced so far are unequally distributed along their phylogenetic tree; few phyla contain the majority, the rest only a few representatives. Accurate genome annotation lags far behind genome sequencing. While automated computational prediction, aided by comparative genomics, remains a popular choice for genome annotation, substantial fraction of these annotations are erroneous. Proteogenomics utilizes protein level experimental observations to annotate protein coding genes on a genome wide scale. Benefits of proteogenomics include discovery and correction of gene annotations regardless of their phylogenetic conservation. This not only allows detection of common, conserved proteins but also the discovery of protein products of rare genes that may be horizontally transferred or taxonomy specific. Chances of encountering such genes are more in rare phyla that comprise a small number of complete genome sequences. We collated all bacterial and archaeal proteogenomic studies carried out to date and reviewed them in the context of genome sequencing projects. Here, we present a comprehensive list of microbial proteogenomic studies, their taxonomic distribution, and also urge for targeted proteogenomics of underexplored taxa to build an extensive reference of protein coding genes.

Role of single photon emission computerised tomography in evaluating osseointegration of indigenous DRDO implants: An in vivo study.

BACKGROUND: A study of first indigenous titanium dental implant developed by DRDO was undertaken at INMAS, Delhi. The aim was to establish the time taken for osseointegration, along with objectives to define the time of implant loading and compare the osseointegration of indigenous dental implants with already established dental implant systems. METHODS: 21 subjects rehabilitated using 39 indigenous dental implants were evaluated by bone SPECT before implantation and at regular intervals towards establishing the aim and objectives. RESULTS: The rise followed by fall in Osteoblastic activity indicates the postoperative physiologic changes, which peaked at 2 weeks (mean) post-implantation and falls off to pre-implantation levels in 12 weeks (mean) indicating completion of osseointegration, healing and time of loading. CONCLUSION: It can be summarized that the Osteoblastic activity of indigenous dental implants completes within three months, which can be taken as the time required for complete healing/osseointegration and loading the implants. On comparison with the available data of already established implants the figures appear similar, indicating indigenous implants to be similar in biologic behaviour.

Estimation of radiation dose to patients from (18) FDG whole body PET/CT investigations using dynamic PET scan protocol.

BACKGROUND & OBJECTIVES: There is a growing concern over the radiation exposure of patients from undergoing 18FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography/computed tomography) whole body investigations. The aim of the present study was to study the kinetics of 18FDG distributions and estimate the radiation dose received by patients undergoing 18FDG whole body PET/CT investigations. METHODS: Dynamic PET scans in different regions of the body were performed in 49 patients so as to measure percentage uptake of 18FDG in brain, liver, spleen, adrenals, kidneys and stomach. The residence time in these organs was calculated and radiation dose was estimated using OLINDA software. The radiation dose from the CT component was computed using the software CT-Expo and measured using computed tomography dose index (CTDI) phantom and ionization chamber. As per the clinical protocol, the patients were refrained from eating and drinking for a minimum period of 4 h prior to the study. RESULTS: The estimated residence time in males was 0.196 h (brain), 0.09 h (liver), 0.007 h (spleen), 0.0006 h (adrenals), 0.013 h (kidneys) and 0.005 h (stomach) whereas it was 0.189 h (brain), 0.11 h (liver), 0.01 h (spleen), 0.0007 h (adrenals), 0.02 h (kidneys) and 0.004 h (stomach) in females. The effective dose was found to be 0.020 mSv/MBq in males and 0.025 mSv/MBq in females from internally administered 18FDG and 6.8 mSv in males and 7.9 mSv in females from the CT component. For an administered activity of 370 MBq of 18FDG, the effective dose from PET/CT investigations was estimated to be 14.2 mSv in males and 17.2 mSv in females. INTERPRETATION & CONCLUSIONS: The present results did not demonstrate significant difference in the kinetics of 18FDG distribution in male and female patients. The estimated PET/CT doses were found to be higher than many other conventional diagnostic radiology examinations suggesting that all efforts should be made to clinically justify and carefully weigh the risk-benefit ratios prior to every 18FDG whole body PET/CT scan.

Discovery of rare protein-coding genes in model methylotroph Methylobacterium extorquens AM1.

Proteogenomics involves the use of MS to refine annotation of protein-coding genes and discover genes in a genome. We carried out comprehensive proteogenomic analysis of Methylobacterium extorquens AM1 (ME-AM1) from publicly available proteomics data with a motive to improve annotation for methylotrophs; organisms capable of surviving in reduced carbon compounds such as methanol. Besides identifying 2482(50%) proteins, 29 new genes were discovered and 66 annotated gene models were revised in ME-AM1 genome. One such novel gene is identified with 75 peptides, lacks homolog in other methylobacteria but has glycosyl transferase and lipopolysaccharide biosynthesis protein domains, indicating its potential role in outer membrane synthesis. Many novel genes are present only in ME-AM1 among methylobacteria. Distant homologs of these genes in unrelated taxonomic classes and low GC-content of few genes suggest lateral gene transfer as a potential mode of their origin. Annotations of methylotrophy related genes were also improved by the discovery of a short gene in methylotrophy gene island and redefining a gene important for pyrroquinoline quinone synthesis, essential for methylotrophy. The combined use of proteogenomics and rigorous bioinformatics analysis greatly enhanced the annotation of protein-coding genes in model methylotroph ME-AM1 genome.

How Transcription Factors Binding Stimulates Transcriptional Bursting.

Transcription is a fundamental biological process of transferring genetic information which often occurs in stochastic bursts when periods of intense activity alternate with quiescent phases. Recent experiments identified strong correlations between the association of transcription factors (TFs) to gene promoters on DNA and transcriptional activity. However, the underlying molecular mechanisms of this phenomenon remain not well understood. Here, we present a theoretical framework that allowed us to investigate how binding dynamics of TF influences transcriptional bursting. Our minimal theoretical model incorporates the most relevant physical-chemical features, including TF exchange among multiple binding sites at gene promoters and TF association/dissociation dynamics. Using analytical calculations supported by Monte Carlo computer simulations, it is demonstrated that transcriptional bursting dynamics depends on the strength of TF binding and the number of binding sites. Stronger TF binding affinity prolongs burst duration but reduces variability, while an optimal number of binding sites maximizes transcriptional noise, facilitating cellular adaptation. Our theoretical method explains available experimental observations quantitatively, confirming the model's predictive accuracy. This study provides important insights into molecular mechanisms of gene expression and regulation, offering a new theoretical tool for understanding complex biological processes.

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.

Elucidating Physicochemical Features of Holin Proteins Responsible for Bacterial Cell Lysis.

Bacterial resistance to conventional antibiotics stimulated the development of so-called "phage therapies" that rely on cell lysis, which is a process of destroying bacterial cells due to their infections by bacterial viruses. For λ bacteriophages, it is known that the critical role in this process is played by holin proteins that aggregate in cellular membranes before breaking them apart. While multiple experimental studies probed various aspects of cell lysis, the underlying molecular mechanisms remain not well understood. Here we investigate what physicochemical properties of holin proteins are the most relevant for these processes by employing statistical correlation analysis of cell lysis dynamics for different experimentally observed mutant species. Our findings reveal significant correlations between various physicochemical features and cell lysis dynamics. Notably, we uncover a strong inverse correlation between local hydrophobicity and cell lysis times, underscoring the crucial role of hydrophobic interactions in membrane disruption. Stimulated by these observations, a predictive model capable of explicitly estimating cell lysis times for any holin protein mutants based on their mean hydrophobicity values is developed. Our study not only provides important microscopic insights into cell lysis phenomena but also proposes specific routes to optimize medical and biotechnological applications of bacteriophages.