A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl

Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest

Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation

Synthesis of Oleoylethanolamide Using Lipase

An effective process for the enzymatic synthesis of oleoylethanolamide is described in this study. The process included purification of a commercial oleic acid product and then optimization of the reaction between the purified oleic acid and ethanolamine in the presence of hexane and a lipase. Under the optimal amidation reaction conditions identified, oleoylethanolamide was obtained with 96.6% purity. The synthesis was also conducted on a large scale (50 mmol of each of the reactants), and oleoylethanolamide purity and yield after crystallization purification were 96.1 and 73.5%, respectively. Compared to the previous studies, the current method of preparing high-purity oleoylethanolamide is more effective and economically feasible. The scalability and ease for such synthesis make it possible to study the biological and nutritional functions of the cannabinoid-like oleoylethanolamide in animal or human subjects

Bisphosphonates as antimyeloma drugs

In patients with symptomatic multiple myeloma (MM), bisphosphonate (BP) treatment has been widely used to prevent bone loss and preserve skeletal health because of its proven effects on inhibiting osteoclast-mediated bone resorption. In addition to their effects on osteoclasts, it is becoming increasingly evident that BPs may have additional effects on the bone microenvironment and cells other than osteoclasts that may potentially inhibit the development and progression of MM. This review focuses on the pathophysiology of MM with an emphasis on the events that drive MM progression within the bone and the mechanisms by which BPs may inhibit specific processes. The underlying molecular mechanisms that drive the modulation of cellular fate and function and consequent physiological outcomes are described. Direct effects on myeloma cell growth and survival and the interactions between myeloma cells and the bone microenvironment are discussed. Clinical evidence of the antimyeloma effects of BPs is emerging and is also reviewed

Discovery of novel herpes simplexviruses in wild gorillas, bonobos, and chimpanzees supports zoonotic origin of HSV-2

Viruses closely related to human pathogens can reveal the origins of human infectious diseases. Human herpes simplexvirus type 1 (HSV-1) and type 2 (HSV-2) are hypothesized to have arisen via host-virus codivergence and cross-species transmission. We report the discovery of novel herpes simplexviruses during a large-scale screening of fecal samples from wild gorillas, bonobos, and chimpanzees. Phylogenetic analysis indicates that, contrary to expectation, simplexviruses from these African apes are all more closely related to HSV-2 than to HSV-1. Molecular clock-based hypothesis testing suggests the divergence between HSV-1 and the African great ape simplexviruses likely represents a codivergence event between humans and gorillas. The simplexviruses infecting African great apes subsequently experienced multiple cross-species transmission events over the past 3 My, the most recent of which occurred between humans and bonobos around 1 Ma. These findings revise our understanding of the origins of human herpes simplexviruses and suggest that HSV-2 is one of the earliest zoonotic pathogens

Towards a multisensor station for automated biodiversity monitoring

Rapid changes of the biosphere observed in recent years are caused by both small and large scale drivers, like shifts in temperature, transformations in land-use, or changes in the energy budget of systems. While the latter processes are easily quantifiable, documentation of the loss of biodiversity and community structure is more difficult. Changes in organismal abundance and diversity are barely documented. Censuses of species are usually fragmentary and inferred by often spatially, temporally and ecologically unsatisfactory simple species lists for individual study sites. Thus, detrimental global processes and their drivers often remain unrevealed. A major impediment to monitoring species diversity is the lack of human taxonomic expertise that is implicitly required for large-scale and fine-grained assessments. Another is the large amount of personnel and associated costs needed to cover large scales, or the inaccessibility of remote but nonetheless affected areas. To overcome these limitations we propose a network of Automated Multisensor stations for Monitoring of species Diversity (AMMODs) to pave the way for a new generation of biodiversity assessment centers. This network combines cutting-edge technologies with biodiversity informatics and expert systems that conserve expert knowledge. Each AMMOD station combines autonomous samplers for insects, pollen and spores, audio recorders for vocalizing animals, sensors for volatile organic compounds emitted by plants (pVOCs) and camera traps for mammals and small invertebrates. AMMODs are largely self-containing and have the ability to pre-process data (e.g. for noise filtering) prior to transmission to receiver stations for storage, integration and analyses. Installation on sites that are difficult to access require a sophisticated and challenging system design with optimum balance between power requirements, bandwidth for data transmission, required service, and operation under all environmental conditions for years. An important prerequisite for automated species identification are databases of DNA barcodes, animal sounds, for pVOCs, and images used as training data for automated species identification. AMMOD stations thus become a key component to advance the field of biodiversity monitoring for research and policy by delivering biodiversity data at an unprecedented spatial and temporal resolution. (C) 2022 Published by Elsevier GmbH on behalf of Gesellschaft fur Okologie

Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?

<p>Abstract</p> <p>Background</p> <p>Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies.</p> <p>Methods</p> <p>Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients.</p> <p>Results</p> <p>We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). <it>CYP3A4*1B</it>, <it>CYP3A5*3 </it>and <it>CYP3A5*6 </it>alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. <it>CYP3A5*1/CYP3A5*1 </it>and <it>CYP3A5*1/CYP3A5*3 </it>genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin.</p> <p>Conclusion</p> <p>A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders.</p

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds

RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS

Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels