(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

Electrospinning is a simple versatile method to generate nanofibres. Remarkable progress has been made in the development of electrospinning process. The production of nanofibers is affected by many parameters, which influence the final material properties. Electrospun fibers have a wide range of applications such as energy storage and biomedical scaffolds. Polyacrylonitrile (PAN) has been widely used in the production of carbon nanofibers. PAN has received increasing interest in recent years, due to its excellent characteristics, such as spinnability, biocompatibility, and commercial viability, opening new applications in the biotechnological field. This paper provides an overview of the electrospinning process, its main parameters, and operation modes that affect nanofibers fabrication. A review of their biological applications is proposed. A focus is made on PAN fibers formation, functionalization, and application as scaffolds to allow cell growth. Overall, nanofibre scaffolds, made of stabilized PAN, appear as a powerful tool in medical applications needing controlled cell culture.

We report the isolation of two novel degrading bacterial strains active against the potential environmental pollutant acetamino-phen/paracetamol. Streptomyces Chrestomyceticus (RS2) and Streptomyces Flavofuscus (M33) collected from El-Natrun Valley, Egypt, water, sediment, and sand samples were taxonomically characterized via conidiophores morphologic characterization under Trans-mission Electron Microscope (TEM). Genotypic identification, done based on their 16S rRNA gene sequence analysis followed by BLAST alignment and deposited on the NCBI as 2 novel strains. The phylogenetic tree was constructed using an appropriate software. Acetaminophen degradation-products chemical structure was identified by GC/LC MS. The biological antimicrobial activity of some selected acetaminophen degradation-products extracts and derived compounds was examined against panel of test micro-organisms and found to be have high anti-microbial effect. In addition, in silico cheminformatics Swiss ADMET evaluation of these selected deg-radation extract for gastric absorption, distribution, hepatic metabolism, renal excretion as well as distribution to CNS and finally not mutagenic/teratogenic or genotoxic virtually. In vitro cytotoxic activity of these selected bio-degradation products was performed against HepG2 and MCF7 cancer cell lines, revealing that M33 and RS2 extract effect on acetaminophen/paracetamol bio-degradation products are potentially safe with higher IC50 on HepG2 and MCF7, in comparison to acetaminophen/paracetamol with IC50 of 108.5 μg/ml. Moreover, the in vivo acute oral single dose toxicity experiment was conducted, being compared with acetamino-phen/paracetamol to confirm that the bio-degradation products have lower toxicity than acetaminophen in vivo and in silico.

The persistence of diseases that affect construction workforce as a result of activities on construction sites poses a danger to the sustainable development of the industry. This resulted to a huge loss of skilled labour and economic development of the industry and the entire country. The arrival of the fourth industrial revolution (4IR) technologies urges an urgent need to assess the effect of the technology’s biological driver on the construction occupation related diseases. Therefore, this study is aimed at assessing the effect of 4IR on the construction occupation related diseases in Gauteng, South Africa. The study is quantitative in design and questionnaire survey were administered to project and Health and Safety (H&S) managers in Gauteng, South African construction sector using a proportionate simple random sampling technique. For data analysis, the Warp PLS-SEM 8.0 software algorithm was used for the analysis of the collated data. The study found that the effects of the 4IR’s biological driver variables ranges between moderate to high effects for genome sequencing (GENSE) and Neurotechnology (NEURO) respectively. The combined predictive relevance of the two (2) variables predicts 64% of the construction occupation related diseases. This implies that the adoption of the driver would help reduce the causes of construction-related diseases. Hence, implies that continuous deployment of 4IR technologies would ensure that construction occupation related diseases are easily identified and put on alert.

Despite identical genetic constitution, a cancer cell population can exhibit phenotypic variations termed as non-genetic/non-mutational heterogeneity. Such heterogeneity – a ubiquitous nature of biological systems – has been implicated in metastasis, therapy resistance and tumour relapse. Here, we review the evidence for existence, sources and implications of non-genetic heterogeneity in multiple cancer types. Stochasticity/ noise in transcription, protein conformation and/or external microenvironment can underlie such heterogeneity. Moreover, the existence of multiple possible cell states (phenotypes) as a consequence of the emergent dynamics of gene regulatory networks may enable reversible cell-state transitions (phenotypic plasticity) that can facilitate adaptive drug resistance and higher metastatic fitness. Finally, we highlight how computational and mathematical models can drive a better understanding of non-genetic heterogeneity and how a systems-level approach integrating mathematical modelling and in vitro/in vivo experiments can map the diverse phenotypic repertoire, and identify therapeutic vulnerabilities of an otherwise clonal cell population.

The strong couplings among ecological, economic, social and technological processes explains the complexification of human-made systems, and phenomena such as globalization, climate change, the increased urbanization and inequality of human societies, the power of information, and the COVID-19 syndemics. Among complexification’s essential features are non-decomposability, asynchronous behavior, components with many degrees of freedom, increased likelihood of catastrophic events, irreversibility, nonlinear phase spaces with immense combinatorial sizes, and the impossibility of long-term, detailed prediction. Sustainability for complex systems implies enough efficiency to explore and exploit their dynamic phase spaces and enough flexibility to coevolve with their environments. This in turn means solving intractable nonlinear semi-structured dynamic multi-objective optimization problems, with conflicting, incommensurable, non-cooperative objectives and purposes, under dynamic uncertainty, restricted access to materials, energy and information, and a given time horizon, aiming at enhancing the co-evolutionary power of the Biosphere and its human subsystems. Giving the high-stakes, the need for effective, efficient, diverse solutions, their local-global, present-future effects, and their unforeseen short, medium and long-term impacts, achieving sustainable complex systems implies the need for Sustainability-designed Universal Intelligent Agents, harnessing the strong functional coupling between human, artificial and nonhuman biological intelligence in a no-zero-sum game to achieve sustainability.

Drylands are arid and semiarid ecosystems, where the lack of rains imposes harsh conditions for the survival of organisms. These ecosystems are also susceptible to degradation and desertification, and their conservation depends on the understanding of the ecological functioning of vegetation and soil. In drylands, the vegetation is spatially structured as a mosaic of patches (vegetation) and interpatches (bare soil), a consequence of plant-plant interactions (facilitation and competition). Empirical data and modeling approaches reinforce the role of ecological facilitation for the maintenance of all organisms in drylands. However, the actual range of facilitation is still poorly known. Here, we explored data of meso- and micro-arthropods found in soil as bioindicators to infer the range of facilitation provided by plants to soil. We regarded data of abundances and species densities (independent samples) collected in random patches and bare soil places as dependent variables. Data of patch size and distances between bare soil and patches were arranged in a single shuffle, producing a 1-d coordinate system centered at the border of the patch. Discrete portions of this system are taken to calculate averages and variances of abundance and species density, and we investigated how soil communities variate across the patch border. We employ techniques of signal analysis to reduce the data noise and obtain a smooth and continuous behavior, which allowed us to fit a logistic function. Our findings indicate that soil communities suddenly change from simple patterns to numerous and diverse communities in bare soil regions, meaning that the influence of vegetation on soil goes beyond the patch border. We interpreted the variations in fauna as a consequence of the positive influence provided by plants (or its lack) on surrounding bare soil. We observe a fast decaying of fauna quantities at 0.35 m outside the patch border, a threshold that reveals the mean range of facilitation provided by plants. However, the changes in soil communities outside the patches seem not necessarily related to the efficiency of soil processes mediated by arthropods, which seem to be more active inside large patches. Concluding, we found a minimum patch-size (radius ~ 0.5 m) able to maintain high diverse communities in soil, and an average distance of vegetation influence along the patch border (halo between 0.35 and 0.50 m). This information can be interpreted in terms of facilitation provided by plants to soil conditions, which seems to differ from the quantitative functionality of soil processes. Our findings contribute to the general understanding of the ecological functioning of drylands, as well as to better plan conservation actions.

The key objective of the present paper is to propose a numerical scheme based on the homotopy analysis transform technique to analyze the time-fractional nonlinear predator-prey population model. The population model is coupled fractional order nonlinear partial differential equations often employed to narrate the dynamics of biological systems in which two species interact, first is a predator and the second is a prey. The proposed scheme provides the series solution with great freedom and flexibility by choosing appropriate parameters. The convergence of results is free from small or large parameters. Three examples are discussed to demonstrate the correctness and efficiency of the used computational approach.

Malaria is a prevalent disease in several tropical and subtropical regions, including Brazil, where remains a significant public health concern. Despite control efforts, reintroduction of endemics in areas without cases for decades poses a challenge. To assess factors influencing ma-laria risk, regional outbreak cluster analysis and a spatio-temporal models were developed for the Brazilian Amazon, incorporating climate, land use/cover interactions, endemic bird, and amphibian richness. Results showed that amphibian, bird richness and endemism correlated with a reduction in malaria risk. Presence of forest had a positive effect on risk, but it depended on its juxtaposition with anthropic land uses. Biodiversity and landscape composition, rather than forest formation presence alone, modulated malaria risk in the period. Areas with low en-demic species diversity and high human activity, predominantly anthropogenic landscapes posed high malaria risk. This study underscores the importance of considering the broader eco-logical context in malaria control efforts.

e Magnetic Ion Modulation (MIM) Theory presents a unified and groundbreaking mathematical framework for controlling and predicting ion behavior in both biological and non-biological systems using external magnetic fields. Central to the theory is the **Ion Modulation Constant** (Tn), a context-specific scaling factor that quantifies the number of ions modulated under specific conditions. This constant, although not universal, allows for accurate modeling of ion modulation in systems ranging from neuronal ion channels to plasma physics and quantum computing. The MIM equation incorporates ion properties such as magnetic moment and permeability, providing insights into neuromodulation for treating chronic pain and epilepsy, plasma confinement in fusion research, and stabilization of ion qubits in quantum computing. This paper includes detailed derivations of the Ion Modulation Constant, examples of its application to specific ions, and a comprehensive exploration of potential experimental validations.

Background Compliance with research ethics legislation is crucial for protecting people's rights in clinical trials. Researchers can alert publishers when they have concerns about possible non-compliance with this legislation by other authors, and this opportunity for independent scrutiny is important. Nevertheless, some alerts may turn out to be unfounded due to a misunderstanding of the legislation. Methods We present the analysis of the article by F. Franck et al., « Raising concerns on questionable ethics approvals - a case study of 456 trials from the Institut Hospitalo-Universitaire Méditerranée Infection», in which the authors explain having sent numerous emails to different publishers to express their concerns about potential ethical breaches in publications from a single French institution. We analyzed in detail the 248 studies that the authors present as suspects. We have also studied the texts of French law. Results Our detailed analysis of these 248 studies discovered that only 8 of them report research involving humans. All the others are secondary research on existing biological samples. In France, as in many other countries, secondary research on biological samples does not involve human subjects. Conclusions Assessing the ethical conformity of scientific publications must be based on a precise knowledge of the legislation and a rigorous analysis of these publications. When researchers who alert publishers confuse research involving the human person with research not involving the human person, the publishers are in danger of being misled by these unfounded alerts. This can have deleterious consequences.

Tadpole shrimp (Triops longicaudatus) has become a major pest for California rice farmers. Currently, management relies solely on the insecticide lambda-cyhalothrin. However, resistance to this pyrethroid was confirmed in 2016, thus identifying an effective and practical biological control method for TPS is a priority. Field trials were conducted from 2017 to 2018 to: (1) evaluate the efficacy of the predatory fish Gambusia affinis and the predatory beetles, Laccophilus maculosus (Say) and Tropisternus lateralis (Fabricius), in controlling TPS, (2) test the efficacy of several inoculation rates of Gambusia affinis at controlling TPS and (3) to explore early indicators of TPS activity and damage as monitoring tools. Both Gambusia affinis and the predatory beetle treatments were not significantly different from the commercial standard (lambda-cyhalothrin). Both four and five Gambusia per 1 m2 controlled TPS as well as lambda-cyhalothrin, and we observed that Gambusia affinis was able to reproduce in the field. Water turbidity was significantly correlated with TPS counts (R = 0.85, N = 20, P < 0.0001 (2017); R = 0.58, N = 30, P = 0.0007 (2018)). The number of dislodged seedlings was less reliably correlated with TPS count; in 2017 correlations were significant (R = 0.84, N = 20, P < 0.0001), however, in 2018 correlations were not significant (R = 0.18, N = 30, P = 0.35). With further refinement water turbidity could play a valuable role in monitoring TPS populations.

In the realm of modern drug discovery, the integration of chemoinformatics and quantitative structure-activity relationship (QSAR) modeling has emerged as a formidable alliance, enabling researchers to harness the vast potential of machine learning (ML) techniques for predictive molecular design and analysis. This review delves into the fundamental aspects of chemoinformatics, elucidating the intricate nature of chemical data and the crucial role of molecular descriptors in unveiling the underlying molecular properties. Molecular descriptors, including 2D fingerprints and topological indices, in conjunction with the structural-activity relationships (SARs), play a pivotal role in unlocking the pathway to small-molecule drug discovery. Technical intricacies of developing robust ML-QSAR models, including feature selection, model validation, and performance evaluation, are discussed herewith. Various ML algorithms, such as regression analysis and support vector machines, are showcased in the text for their ability to predict and comprehend the relationships between molecular structures and biological activities. This review serves as a comprehensive guide for researchers, providing an understanding of the synergy between chemoinformatics, QSAR, and ML. By embracing these cutting-edge technologies, predictive molecular analysis holds promise for expediting the discovery of novel therapeutic agents in the pharmaceutical sciences.

Biological systematics, exploring the structure of taxonomic diversity (TD), needs a proper conceptualization that would (a) make it complying with certain universal criteria of scientificity and (b) take into account specificity of its studied object. This article outlines a possible conceptual framework for this natural science discipline based on the ideas of contemporary conceptualism. One of the most fundamental of them includes a concept of cognitive situation shaped by three interrelated basic components—ontic, epistemic, and subjective. Its core position is taken by a taxonomic theory (TT) being a conceptual construct resulted from a “summative” effect of all three components and designed for studying TD. The general TT is shown to be composed by a hierarchically arranged array of partial TTs of various levels of generality, and this construct serves as a conceptual justification of taxonomic pluralism. Several kinds of partial TTs are suggested to recognise, viz., ontology- and epistemology-oriented, aspect- and object-based, etc. The aspect-based TTs are of special importance as the conceptual foundations of particular research programs in systematics. The object-based partial TTs are shown to be implemented by concepts of species and homology. A large-scale relation between taxonomic theory and nomenclature is briefly considered.

Equipped with an early social predisposition immediately post-birth, humans typically form associations with mothers and other family members through exposure learning, canalized by a spontaneous predisposition to biological motion, face configuration, and other cues of animacy. If impaired, reduced social preferences can lead to social interaction impairments such as autism spectrum disorder (ASD) via misguided canalization. Despite being taxonomically distant, domestic chicks also follow a homologous developmental trajectory toward adaptive socialization through imprinting, which is guided via predisposed preferences that are homologous to those of humans, thereby suggesting that chicks are valid animal models of ASD. In addition to the convergent similarities in predisposition with human newborns, accumulating evidence suggests the construct validity of the chick model. Considering the recent progress in the evolutionary neurobiology of vertebrates, we reviewed the advantages and limitations of the chick model of developmental mental diseases in humans.

To investigate the mass mortality of asari clams triggered by upwelling-driven hypoxia, we conducted biological and oceanographic observations of the Rokujo tidal flat in Mikawa Bay, central Japan. In addition, a simple laboratory experiment was conducted using sediments on a tidal flat containing macrobenthos to examine the possibility of hydrogen sulfide formation in tidal flats. The results of field observations showed that the number and biomass of asari clams decreased from September to October in the tidal flat when hypoxia was intermittent. In particular, hypoxia persisted for approximately one week from September 21, which was associated with the calm weather and stagnation of tidal currents owing to the neap tide. The hydrogen sulfide concentration in the water directly above the sediment exceeded 30 mg L-1 after 3 days of incubation. Our results suggest that the mass mortality of asari clams may be caused by the high concentration of hydrogen sulfide produced by sulfate reduction, which is attributed to the chain of biological die-off caused by the upwelling of hypoxic water mass accompanied by meteorological events, and calm conditions such as the neap tide period.

Lemon oils are amongst the highest volume and most frequently traded of the flavour and fragrance essential oils. Citronellal and citral are considered the key components responsible for the lemon note with citral (neral + geranial) preferred. Of the myriad of sources of citral, the Australian myrtaceous tree, Backhousia citriodora, is considered superior. This review examines the history, natural occurrence, the cultivation, the taxonomy, the chemistry, the biological activity, the toxicology, standardisation and the commercialisation of Backhousia citriodora especially in relation to its essential oil.

GIGANTEA (GI) is a gene involved in multiple biological functions, which were analysed and are partially conserved in a series of mono- and dicotyledonous plant species. The identified biological functions include control over the circadian rhythm, light signalling, cold tolerance, hormone signalling and photoperiodic flowering. The latter function is a central role of GI, as it involves a multitude of pathways, both dependent and independent of the gene CONSTANS(CO) as well as on the basis of interaction with miRNA. The complexity of gene function of GI increases due to the existence of paralogs showing changes in genome structure as well as incidences of sub- and neofunctionalization. We present an updated report of the biological function of GI, integrating late insights into its role in floral initiation, flower development and flower volatile production.

Xyleborus beetles, a diverse group of ambrosia beetles, present significant challenges to forestry and agriculture due to their damaging burrowing behavior and symbiotic relationships with fungi. This review synthesizes current knowledge on the biology, ecology, and management of Xyleborus. We explore the beetles' life cycle, reproductive strategies, habitat preferences, and feeding habits, emphasizing their ecological and economic impacts. Control and management strategies, including preventive measures, chemical and biological control, and integrated pest management (IPM), are critically evaluated. Recent advances in molecular genetics and behavioral studies offer insights into genetic diversity, population structure, and host selection mechanisms. Despite progress, managing Xyleborus effectively remains challenging. This review identifies future research needs and highlights innovative control methods, such as biopesticides and pheromone-based trapping systems.

The biological function of rapid eye movement (or REM) sleep—one of the great mysteries of neuroscience—remains unknown. Here, I demonstrate that the biological function of REM sleep is to heighten brain alertness, significantly reducing the high vulnerability of deep sleep. Every organism with a nervous system must undergo deep sleep: a necessity that comes with substantial vulnerability. Deep sleep, by lowering alertness, compromises the organism's safety, putting its survival at risk. Therefore, REM sleep is a necessary adaptation for any organism that must sleep. My primary goal here is to present a comprehensive conceptual framework—supported by extensive empirical evidence—to connect numerous disparate empirical findings under a unified theory of the biological function of REM sleep. Additionally, I also provide a historical narrative to explain its origin and subsequent evolution. The theory I developed to explain the function of REM sleep is not only widely corroborated but has also resisted numerous attempts at refutation. This allows me to claim that I solved this great enigma of neuroscience.

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Over 80% of hospitalizations are of those over 65 years of age with a 23-fold greater risk of death. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea. Particularly in those over 65, it can progress to pneumonia, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes, obesity and hypertension increase the chances of fatal disease, but they alone do not explain the variability in COVID-19 symptoms. Here, we present the molecular differences between the young, middle-aged and elderly that may determine whether COVID-19 is a mild or life-threatening illness. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase survival in the elderly, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection.

An adequate number of waste management facilities is the key element to meet circular economy goals. Using empirical data taken from official sources the research framework bases on an econometric model to compare the elasticity of cost on quantity of different alternatives such as waste-to-energy facilities, mechanical biological facilities and landfills impact on waste management cost. Results suggest that both waste-to-energy facilities (-0.278%) and landfills (-0.38%) concur to lower the cost while the higher the percentage of waste sent to mechanical biological treatment facilities, the higher the cost (0.788%). This figure deserves to be examined in more details as such facilities represent an intermediary step in the chain which efficiency depends on the industrial organization of the chain.

In humans, age-associated degrading changes are observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psy-chological abilities, and memory. Cross talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, ge-nome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirali-ty, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging re-lated to irreversible PTMs SP has been associated with the nontrivial interplay between poor so-matic and mental health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet un-der-appreciated hallmark of aging.

This paper presents a concise exploration of the synthetic biology currently to artificially 1 create life, juxtaposed against natural life’s emergence over Earth’s 4.5-billion-year history. It explores 2 the complexities of life’s origins, sustaining factors, and the consequences of synthetic life creation, 3 addressing key scientific milestones such as the Urey-Miller experiment and Jacques Monod’s pro- 4 posals. The narrative navigates through the roles of energy, Maxwell’s demons, bifurcations, and 5 genetic information in the emergence and evolution of complex biological systems. Despite significant 6 strides in genetic engineering, the challenge of creating life from scratch persists, necessitating a deep 7 understanding of diverse scientific disciplines. While synthetic biology holds promise for medicine 8 and biotechnology, the creation of truly autonomous synthetic life forms raises ethical concerns. The 9 paper also stresses the imperative for careful ethical evaluation of the societal and environmental 10 implications arising from these advancements.

Pomegranate (Punica granatum L.) is well known for its high content in bioactives including polyphenols, flavonoids and tannins, which have been shown to exhibit a wide range of biological activity such as antioxidant, antimicrobial and anticancer effects. It is worth noting that the majority of these molecules are found in the peels (PP), which are usually disposed of after processing, causing a significant amount of waste, amounting to more than 3.6 million t/y. This work investigates MW-assisted extraction (MAE) in water for the recovery of antioxidants from PP, including the optimization of temperature and extraction times. The total phenolics, anthocyanin, flavonoid and tannin contents of the recovered extracts have been determined, as have their antioxidant activities, which were found to be 356.35 mgGAE/gextr., 303.97 µgCy3G/gextr., 37.28 mgQE/gextr., 56.48 mgGAE/gextr. and 1.43 µmolTE/gextr., respectively (according to the adopted reference). All results have been compared with those obtained using a conventional protocol. In addition, the potential for water recycling by means of nanofiltration downstream in optimized MAE has been investigated, leading to overall water reuse of approx. 75%. Energy consumption (20.92W/mgGAE) and the common green metrics, RME, E-Factor and PMI (PME), have been considered in evaluating the proposed PP valorization strategy. Finally, the biological activity of the main products has been assessed. The antimicrobial properties of the PP extracts against three Gram-positive and three Gram-negative bacteria, and their antiproliferative activity towards human cancer cells have been tested. The S. aureus bacteria was the most susceptible to the PP extracts. All tested products displayed antiproliferative activity in HeLa cells when higher concentrations were tested, with D-PP/NF being the most effective. This result was also confirmed in a clonogenic analysis, which generally indicated the possible anti-cancer activity of pomegranate peel extracts obtained using this green approach.

Thai basil is a renowned medicinal plant and a rich source of bioactive antioxidant compounds having several health benefits, with actions to prevent of cancer, diabetes and cardiovascular disease. Plant cell and tissue culture technologies can be routinely established as an important, sustainable and low-cost biomass source for the production of high-value phytochemicals. The current study aimed at developing an effective protocol for the production of Thai basil leaf derived callus cultures with sustainable and high production of biomass and antioxidants as an alternative of leaves production. MS basal medium with various concentrations of plant growth regulators (PGRs) compatible with nutraceutical applications (i.e., gibberellic acid (GA3) and 6-benzylaminopurine (BAP) either alone or in combination with naphthalene acetic acid (NAA)) were evaluated. Among all tested PGRs, the combination BAP:NAA (5 mg/L:1 mg/L) yield maximum biomass accumulation (fresh weight (FW): 190 g/L and dry weight (DW): 13.05 g/L) as well as enhanced phenolic (346.08 mg/L) production. HPLC quantification analysis indicated high productions of chicoric acid (35.77 mg/g DW) and rosmarinic acid (7.35 mg/g DW) under optimized callus culture conditions. Antioxidant potential was assessed using both in vitro cell free and in vivo cellular antioxidant assays. Maximum in vitro antioxidant activity DPPH (93.2 % of radical scavenging activity) and ABTS (1322 µM Trolox equivalent antioxidant capacity) was also observed for the extracts from callus cultures grown on optimal conditions. In vivo cellular antioxidant activity assay confirmed the effective protection against oxidative stress of the corresponding extract by the maximum inhibition of ROS and RNS production. Compared to commercial leaves, callus extracts showed higher production of chicoric acid and rosmarinic acid associated with higher antioxidant capacity. In addition, this biological system also has a large capacity for continuous biomass production, thus demonstrating its high potential for possible nutraceutical applications.

One of the most prevalent and deadly types of cancer is breast cancer. The value and effectiveness of the current pharmacological therapy are, however, constrained. Using computational methods and publicly available data, the current study set out to identify the genes and molecular pathways linked to breast cancer. It also looked into potential treatments for the disease that would target these molecular processes. In this study, we mined genes that were strongly associated with breast cancer using text mining and GeneCodis. Using STRING and Cytoscape, protein-protein interaction (PPI) study was carried out. Candidate medications were then derived based on the drug-gene interaction study of the final genes. 2,658 genes linked to breast cancer were found by our investigation using text mining searches. Out of which 166 genes have been taken which are relevant to breast cancer. Ten genes representing ten pathways—which a total of ten proteins could target—were found by gene enrichment analysis. We have taken Holy Basil as our lead as it contains various bioactive compounds such as flavonoids, terpenoids, and phenolics, which have shown antioxidant, anti-inflammatory, and anticancer properties. For this analysis we choose the molecular docking technique to check the effects of different chemical constituents of Holy Tulsi on breast cancer targeted protein and compare their results. We’ve performed the molecular docking in between chemical constituents of Holy Basil and the targeted proteins and determined the binding affinity with the help of PyRx and BIOVIA Discovery studio software. Anti-mitotic activity of Pisum sativum using tulsi extract to check the cytotoxicity effect was done. To determine the toxicity level of the extract on rat liver was performed in the end. In conclusion, investigating candidate medications that target the genes/pathways relevant to breast cancer in order to uncover possible treatments may be accomplished through drug discovery employing in silico text mining and pathway analysis technologies along with the wet lab experimentation with plants and preclinicals.

Plant waste biomass is the most abundant renewable energy resource on Earth. The main problem of utilising this biomass in anaerobic digestion is the long and costly stage of degrading its complex structure into simple compounds. A promising solution to this problem are fungi of the Trichoderma genus, which show a high capacity to produce hydrolytic enzymes capable of degrading lignocellulosic biomass. This article discusses the structure of plant waste biomass and the problems resulting from its structure in the digestion process. It presents the methods of pre-treatment of lignocellulose with a particular focus on biological solutions. Based on the latest research findings, key parameters related to the application of Trichoderma sp. as a pre-treatment method are discussed. In addition, the possibility of using the digestate from agricultural biogas plants as a carrier for the multiplication of the Trichoderma sp. fungi, which are widely used in many industries, was discussed.

In 2010, Parties to the Convention on Biological Diversity (CBD) adopted the Strategic Plan for Biodiversity 2011–2020 to address the loss and degradation of nature. Subsequently, most biodiversity indicators continued to decline. Nevertheless, conservation actions can make a positive difference for biodiversity. The emerging Post-2020 Global Biodiversity Framework has potential to catalyze efforts to ‘bend the curve’ of biodiversity loss. Thus, the inclusion of a goal on species, articulated as Goal B in the Zero Draft of the Post-2020 Framework, is essential. However, as currently formulated, this goal is inadequate for preventing extinctions, and reversing population declines; both of which are required to achieve the CBD’s 2030 mission. We contend it is unacceptable that Goal B could be met while most threatened species deteriorated in status and many avoidable species extinctions occurred. We examine the limitations of the current wording and propose an articulation with robust scientific basis. A goal for species that strives to end extinctions and recover populations of all species that have experienced population declines, and especially those at risk of extinction, would help to align actors towards the transformative actions and interventions needed for humans to live in harmony with nature.

WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stem- ness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2^nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1, we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2^nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline’s efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (ra- dial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3^rd order biological hypotheses emerge some of which are con- firmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest.

The antimicrobial properties of the new strains of microorganisms isolated from natural sources of various ecological niches in the Moscow Region and the Republic of Tatarstan were studied. An antifungal activity of isolates was established in a test culture of toxin-producing microscopic fungi that cause various plant diseases: Fusarium oxysporum, Aspergillus flavus, Penicillium spp. and Candida albicans. Of the 46 studied microorganisms, 4 isolates (Bacillus subtilis, Propionibacterium freudenreichii, Lactobacillus plantarum and Streptomyces spp.) showed an ability to produce biologically active metabolites with a pronounced antimicrobial potential. This is promising in the growth and protection of the Scots pine, pedunculate oak and small-leaved linden forest crops from diseases caused by fungi Lophodermium pinastri Chev. and Microsphaera alphitoides stimulation. Based on selected isolates, a Bacterial product LRV composition has been developed. A Scots pine, pedunculate oak and small-leaved linden seedlings single and double foliar treatment with Bacterial product LRV at a concentration of 10 ml/l led to an increase in the growth of an above-ground part by 31.8, 51.9 and 25.4 %, respectively, and an underground part – by 25.0, 37.2 and 25.7 %, respectively, compared with the control. The weight of seedling at the end of the study exceeded the control variant by an average of 26.0, 44.0 and 78.0 %, respectively. A use of a plant protection Bacterial product LRV did not have a significant effect on a powdery mildew and Schütte disease damage to forest crops. A Biogeosystem Technique methodology has been developed to improve a long-term forest growing.

Non-ulcerated cutaneous leishmaniasis (NUCL) is an atypical and peculiar clinical form of the disease that was first described by Ponce et al. (1988) in Honduras (Central America), where iso-lated or disseminated popular and/or nodular skin lesions are commonly seen in adolescents and young adults. Leishmania (L.) chagasi was then incriminated as the causal agent of the disease, as well as of American visceral leishmaniasis (AVL), although NUCL has been shown to be more prevalent than AVL in the region. Considering, however, the dubious taxonomic character of the causal agent of NUCL, as there is no evidence of this form of disease associated with L. (L.) cha-gasi in South America, this study aimed to carry out a retrospective taxonomic analysis on a se-ries of studies on the diagnostic approach to the Honduran parasite in loco (El Tigre island, Amapala municipality, west coast of Honduras), where taxonomic characters of a biological (in vitro and in vivo), epidemiological (vector and canine reservoir), clinical-immunological (im-munopathological features of in situ skin lesion and systemic infection) and molecular (ge-nomic/phylogenetic analyses) nature were considered. The findings, particularly those of mo-lecular nature, such as: the Honduran parasite showed to be more ancestral (molecular clock analysis of the DNA polymerase alpha subunit gene) than all viscerotropic ones [L. (L.) chagasi, L. (L.) donovani and L. (L.) infantum], as well as presenting an absolutely unprecedented structural variation on chromosome 17 and the highest frequency of genomic SNPs (more than twice the number seen in the Brazilian parasite), in addition to representing a different phylogenetic lin-eage (mainly in the NJ - RNA Pol II tree) from those viscerotropic ones, have pointed to the characterization of a new leishmanine parasite, Leishmania (Leishmania) poncei n. sp. (Kinetoplas-tea: Trypanosomatidae), in honor of Professor Ponce, who was the first researcher to describe NUCL in Honduras.

This article delves into the historical development and ramifications of divergent theories that have emerged since the publication of Darwin's seminal work, "On the Origin of Species" in 1856. It traces the evolution of thought from Darwin's revolutionary ideas through the controversial era of eugenics, the groundbreaking discovery of DNA, the elucidation of Mendelian genetics, and the subsequent development of modern genetic theories. The article also explores the critical role of mathematical models, statistics, and data science in advancing genomics research over the last decade. This comprehensive exploration highlights how these theories and methods have fundamentally shaped our understanding of biology, evolution, human genetics, and complex biological systems.

Nerve agents have recently been used in battlefield operations, espionage wars and terrorist attacks. These compounds, like some pesticides, cause organophosphate poisoning. The rapid, non-contact detection of a sarin simulant has been demonstrated at the Diagnostics and Metrology Laboratory of the Italian National Agency for New Technologies, Energy and Sustainable Economic Development using laser photoacoustic spectroscopy, an infrared absorption technology. The first measurements, carried out with an experimental system based on a quantum cascade laser and developed for the assessment of food authenticity in the “fingerprint region”, show that a detection limit of 1 nanolitre is within the reach of the instrument when chemometric analysis is applied.

There were designed and synthesized two new sulfone 2-aminobenzimidazole derivatives. Coordination compounds were obtained with nickel(II), copper(II), zinc(II), cadmium(II) and mercury(II) and these novel ligands. There were fully characterized by spectroscopic and analytical techniques. Single crystal X-ray structural analysis was performed on order to study the relevant intra and inter non-covalent interactions, mainly H...π, lone pair·...π, π...π, highlighting the difference between the ethyl and phenyl groups in such interactions. Dimeric and trimeric supramolecular syntons were found for some of these compounds. Their biological activity was investigated, being the copper(II) compounds with the sulfone phenyl derivative the most active.

Since its first isolation in 1934, hyaluronic acid (HA) has been studied across a variety of research areas. This unbranched glycosaminoglycan consisting of repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronic acid is almost ubiquitary in humans and in other vertebrates. HA is involved in many key processes -including cell signaling, wound reparation, tissue regeneration, morphogenesis, matrix organization and pathobiology-, and has unique physico-chemical properties -such as biocompatibility, biodegradability, mucoadhesivity, hygroscopicity and viscoelasticity. For these reasons, exogenous HA has been investigated as drug delivery system and treatment in cancer, ophthalmology, arthrology, pneumology, rhinology, urology, aesthetic medicine and cosmetic. To improve and customize its properties and applications, HA can be subjected to chemical modifications: conjugation and crosslinking. The present review gives an overview regarding HA, describing its history, physico-chemical, structural and hydrodynamic properties, and biology –occurrence, biosynthesis (by hyaluronan synthases), degradation (by hyaluronidases and oxidative stress), roles, mechanisms of action and receptors. Furthermore, both conventional and recently emerging methods developed for the industrial production of HA and its chemical derivatization are presented. Finally, the medical, pharmaceutical and cosmetic applications of HA and its derivatives are reviewed, reporting examples of HA-based products which currently are on the market or are undergoing further investigations.

Three-dimensional convolutional neural networks (3D CNN) as a type of artificial intelligence (AI) are powerful in image processing and recognition using deep learning to perform generative and descriptive tasks. The advantage of CNN compared to its predecessors is that it automatically detects the important features without any human supervision. 3D CNN are used to extract features in three dimensions where input is a 3D volume or a sequence of 2D pictures e.g., slices in a cone-beam computer tomography scan (CBCT). The main aim of this article was to bridge interdisciplinary cooperation between forensic medical experts and deep learning engineers. With emphasis activating clinical forensic experts in the field with possibly basic knowledge of advanced artificial intelligence techniques with interest in its implementation in their efforts to advance the forensic research further. This paper introduces a novel workflow of 3D CNN analysis of full-head CBCT scans. Authors explore and present 3D CNN method for forensic research design concept in five perspectives: (1) sex determination, (2) biological age estimation, (3) 3D cephalometric landmark annotation, (4) growth vectors prediction, (5) facial soft-tissue estimation from the skull and vice versa. In conclusion, 3D CNN application can be a watershed moment in forensic medicine, leading to unprecedented improvement of forensic analysis workflows based on 3D neural networks.

Biological control, a well-established plant protection method, has garnered substantial attention in recent decades. Various approaches, including biological control agents (BCA), catch crops, biofumigation, sticky traps, and pheromones, have been extensively explored. While the effectiveness of these methods varies depending on specific circumstances, their collective significance has grown amid mounting pressures to curtail or eliminate conventional synthetic plant protection products. Previous review articles have highlighted the synergistic benefits of using two or more BCAs simultaneously, yet limited information exists regarding the concurrent use of diverse biological control methods. This comprehensive review incorporates a thorough literature search to assess the synergistic potential of concurrently employing two or more of these methods, followed by a discussion on perspectives of holistic management and mimicking of complex natural systems, shedding light on the vast potential and need for further research in this domain.

Microbiocontrol of Mycogone perniciosa is focused on casing soil antagonists use. Since no industrial producer strains of polyfunctional biologics were used in previous studies, research goal was to characterize Bacillus subtilis B-10 and M-22 effect on mycopathogen and reveal its control possibilities. Interactions between producer strains and M. perniciosa were evaluated using well method and spraying. Mycoparasite colony area and its lysis zone were determined. Biological efficacy was characterized by lysis zone proportion in total area occupied by the micromycete mycelium. Statistical processing included W-test, ANOVA, means (M) and standard errors (±SEM) calculation. The significance was assessed by t-test. M. perniciosa development suppressing by producer strains was established, indicates a prolonged B-10 and M-22 effect on mycopathogen. High biological efficacy of both strains at the early stages of mycopathogen development by introducing into the wells and spraying was shown: B-10 – 50.9–99.6 % and M-22 – 57.5–99.2 % respectively (p ≤ 0.05). Significant differences between producer strains were not revealed, although during the first exposure day to developed M. perniciosa colonies M-22 has shown greater activity. Preventive treatment high efficiency when producer strains completely suppressed mycoparasite development, permit recommending them both to introduce when preparing casing for M. perniciosa control.

The phenomenon of pathogens co-infection detected in the half fed on humans I. persulcatus tick in the south of the Far East was studied. Researchs were carried out on PEK, Vero, Vero-E6 cell lines, outbred mice, chicken embryos, using ELISA, PCR, IMFA, plaque formation, and electron microscopy. The tick contained an antigen and a genetic marker of the tick-borne encephalitis virus (TBEV). The patient had post-vaccination antibodies in a titer of 1:200, as a result of which, obviously, an antibody-dependent elimination of TBEV occurred. The tick-borne co-isolate also contained an unknown pathogen (Kiparisovo-144 virus), which, in our opinion, was a trigger for the activation of chronic infection in suckling white mice. In the laboratory coisolate, ectromelia virus was present, as evidenced by paw edema during intradermal infection of mice, characteristic rashes on the chorion-allantoic envilope of chicken embryos, and typical plaques on Vero-E6. The Kiparisovo-144 virus was not pathogenic for white mice and chicken embryos, but successfully multiplied in the PEK, Vero, and Vero-E6 lines. Viral co-infection was confirmed by electron microscopy. Passaging on mice contributed to an increase in the virulence of the co-isolate, whose titer increased by 10,000 times by the 5th passage, which poses a serious epidemiological danger.

DNA repair helps in maintaining the proper and healthy functioning for the cells in the human body. Failure in DNA repair process can lead to aberrations as well as tumorous stages. There are various types of damages that a DNA can go through, one of which is the DNA double strand breaks (DSB) that can be repaired via homologous recombination (HR). RAD51 plays a central role in HR and has been implicated as a negative/poor prognostic marker for colorectal adenocarcinoma, with high expression in colorectal cancer. Mechanistically, RAD51AP1 facilitates RAD51 during the repairing process by binding with RAD51 via two DNA binding sites, thus helping in the D-loop formation in the HR process. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, RAD51AP1-XRCC2 is one such 2^nd order combination whose relation needs to be tested under the influence recently developed Porcupine-WNT inhibitor ETC-1922159. The x-ray repair cross complementing XRCC family is known to work as a mediator or stabilizer for RAD51 during the HR process. The inhibitor is known to suppress Porcupine and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2^nd order level after the drug was administered. The in silico observations showed that the combination of RAD51AP1-XRCC2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both RAD51AP1 and XRCC2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3^rd order combinations of RAD51-X-X & RAD51AP1-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hibert Schmidth Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested RAD51/RAD51AP1 related 3^rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested.

Information is the currency of life, but the origin of prebiotic information remains a mystery. We propose transitional pathways from the cosmic building blocks of life to the complex prebiotic organic chemistry that led to the origin of information systems. The prebiotic information system, specifically the genetic code, is segregated, linear, and digital and probably appeared during biogenesis four billion years ago. In the peptide/RNA world, lipid membranes randomly encapsulated amino acids, RNA, and protein molecules, drawn from the prebiotic soup, to initiate a molecular symbiosis inside the protocells. This endosymbiosis led to the hierarchical emergence of several requisite components of the translation machine: tRNAs, aaRS, mRNAs, and ribosomes. When assembled in the right order, the translation machine created biosynthetic polypeptides, a process that transferred information from mRNAs to proteins. This was the beginning of the prebiotic information age. The molecular attraction between tRNA and amino acids led to different stages of the translation machines and the genetic code. tRNA is an ancient molecule that designed and built mRNA for storing the information of its cognate amino acid. Each mRNA strand became the storage device for the genetic information that encoded the amino acid sequences in triplet nucleotides. As information appeared in the digital languages of the codon within mRNA, and the genetic code for protein synthesis evolved, the prebiotic chemistry then became more organized and directional. The origin of the genetic code is enigmatic; herein we propose an evolutionary explanation: the demand for a wide range of specific enzymes in the peptide/RNA world was the main selective pressure for the origin of information-directed protein synthesis. We review three main concepts on the origin and evolution of the genetic code: the stereochemical theory, the coevolution theory, and the adaptive theory. These three theories are compatible with our coevolution model of the translation machines and the genetic code. We suggest biosynthetic pathways as the origin of the specific translation machines which provided the framework for the origin of the genetic code. During translation, the genetic code developed in three stages coincident with the refinement of the translation machines: GNC code developed by the pre-tRNA/pre-aaRS /pre-mRNA machine, SNS code by the tRNA/aaRS/mRNA machine, and finally the universal genetic code by the tRNA/aaRS/mRNA/ribosome machine. Our hypothesis provides the logical and incremental steps for the origin of the programmed protein synthesis. In order to understand the prebiotic information system better, we converted letter codons into numerical codons in the Universal Genetic Code Table. We have developed a software called CATI (Codon-Amino Acid-Translator-Imitator) to translate randomly chosen numerical codons into corresponding amino acids and vice versa. This conversion has granted us insight into how the translation might have worked in the peptide/RNA world. There is great potential in the application of numerical codons to bioinformatics such as barcoding, DNA mining, or DNA fingerprinting. We constructed the likely biochemical pathways for the origin of translation and the genetic code using the Model-View-Controller (MVC) software framework, and the translation machinery step-by-step. Using AnyLogic software we were able to simulate and visualize the entire evolution of the translation machines and the genetic code. The results indicate that the emergence of the information age from the peptide/RNA world was a watershed event in the origin of life about four billion years ago.

Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, Brancati et al.1 observe that mutations in poliovirus receptor related protein 4 (PVRL4), encoding cell adhesion molecule nectin-4, causes Ectodermal dysplasia-syndactyly syndrome. Interaction with cad- herins also implies an influence of nectin-4 on Wnt signaling, which plays a relevant role in limb development (Brancati et al.1). However, not much work has been done to explore the relation of Wnts and PVR family. In CRC cells treated with ETC-1922159, both were found up regulated. In a recent unpublished work in Open Science Framework, Sinha2, we had the opportunity to rank these unknown biological hypotheses for both up and down regulated genes at 2nd order level after drug administration. The search engine alloted high nu- merical valued rankings to some combinations of PVR-WNT, thus indicating a possibility of high combinatorial synergy also. The in-silico derived influences can be represented graphically as - PVR w.r.t WNT with PVR <- WNT9A; and WNT w.r.t PVR with WNT-7B/9A <- PVR and WNT4 <- PVRL2; In the light of the recent findings of PVR with IFN (interferon) and the known interactions between IFN and Wnts, there might be a possibilty to explore the bridge of PVR, IFN and WNTs. The 3 fold (PVR - IFN; IFN - WNT; WNT - PVR), 2 way cross family analysis might shed light on the possible combinations that might be of import. Here, we present a 2-way cross family analysis of multiple, such in-silico ranked 2nd order synergistic combinations, after ETC-1922159 treatment of CRC cells. Via this 2-way cross family analysis, we are able to discover through majority voting, the combinations that might of interest to biologists and also derive plausible influences of components of combinations among themselves. Note that these form biological hypotheses which indicate whether a particular combination and the direction of influence within the combination, exist synergistically in CRC cells. Wet lab tests will indicate the veracity of these combinations and if proven true, will lead to further study of mechanism between the components.

Gigantism in theropods represents one of the most intriguing phenomena in dinosaur evolution, showcasing extreme adaptations in body size and ecological roles. This literature review focuses on Giganotosaurus carolinii, one of the largest known theropods to have ever existed, to explore its unique aspects of gigantism and the subsequent ecological impacts. By analyzing features such as its skeletal morphology, comparative anatomy, and paleoenvironmental data, we assess the evolutionary pressures and biological constraints that shaped the gigantism observed in Giganotosaurus. We discover that the species exhibited a combination of physiological and ecological adaptations that allowed it to thrive as an apex predator in its Cretaceous environment. We will also further examine the implications of its size on prey dynamics, competition with other large theropods, and the overall ecosystem structure. Through a thorough, multidisciplinary approach, this research enhances our understanding of how gigantism influenced theropod behavior, interspecies interactions, and the broader paleoecological landscape.

This article challenges the notion of the randomness of mutations in eukaryotic cells by unveiling stress-induced human non-random genome editing mechanisms. To account for the existence of such mechanisms, I have developed molecular concepts of the cell environment and cell environmental stressors and, making use of a large quantity of published data, hypothesized the origin of some crucial biological leaps along the evolutionary path of life on Earth under the pressure of natural selection, in particular, 1) virus-cell mating as a primordial form of sexual recombination and symbiosis; 2) Lamarckian CRISPR-Cas systems; 3) eukaryotic gene development; 4) antiviral activity of retrotransposon-guided mutagenic enzymes and finally; 5) the exaptation of antiviral mutagenic mechanisms to stress-induced genome editing mechanisms directed at “hypertranscribed” endogenous genes. Genes transcribed at their maximum rate (hypertranscribed), yet still unable to meet new chronic environmental demands generated by “pollution”, are inadequate and generate more and more intronic retrotransposon transcripts. In this scenario, RNA-guided mutagenic enzymes (e.g. AID/APOBECs), which have been shown to bind to retrotransposon RNA-repetitive sequences, would be surgically targeted by intronic retrotransposons on opened chromatin regions of the same “hypertranscribed” genes. RNA-guided mutagenic enzymes may therefore “Lamarkianly” generate single nucleotide polymorphisms (SNP) and copy number variations (CNV), as well as transposon transposition and chromosomal translocations in the restricted areas of hyperfunctional and inadequate genes, leaving intact the rest of the genome. CNV and SNP of hypertranscribed genes may allow cells to surgically explore a new fitness scenario, which increases their adaptability to stressful environmental conditions. Like the mechanisms of immunoglobulin somatic hypermutation, non-random genome editing mechanisms may generate several cell mutants, and those codifying for the most environmentally-adequate proteins would have a survival advantage and would therefore be Darwinianly selected. Non-random genome editing mechanisms represent a link between environmental changes and biological novelty and plasticity, and provide a molecular basis to reconcile gene-centered and “ecological” views of evolution.

\textsc{Background} Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. Currently, a major problem in biology is to cherry pick the combinations based on expert advice, literature survey or guesses for investigation. The search and wet lab testing of these combinations costs a lot in terms of time, investment and energy. In a recent development of the PORCN-WNT inhibitor ETC-1922159 for colorectal cancer, a list of down-regulated genes were recorded in a time buffer after the administration of the drug. The regulation of the genes were recorded individually but for a majority, it is still not known which higher ($\geq 2$) order combinations might be playing a greater role in the pathway. \textsc{Results} The pipeline provides a prioritised list of important $2^{nd}$ order combinations of a range of family of genes involved in the Wnt pathway. More specifically, it reveals the various unexplored FZD-WNT combinations that have been untested till now in the pathway. In relation to ETC-1922159 affected combinations, the down-regulation of LGR-RNF family after the drug treatment is evident in these rankings as it takes bottom priorities for LGR5-RNF43 combination. The LGR6-RNF43 takes higher ranking than LGR5-RNF43, indicating that it might not be playing a greater role as LGR5 during the Wnt enhancing signals. These rankings confirm the efficacy of the proposed search engine design. \textsc{Conclusion} A pipeline has been developed to prioritise an $n^{th}$ order combination of factors that affect a signaling pathway. It takes into account the sensitivity indices computed from variance based (SOBOL) and density-kernel based (HSIC) methods to estimate the influence of each factor or combination of factors. These are then fed as feature vectors into a powerful support vector ranking algorithm that produces a ranked list of the interactions/combinations.