Nat Commun. 2024 Jul 19;15(1):6076. doi: 10.1038/s41467-024-50063-z.

ABSTRACT

Current KRASG12C (OFF) inhibitors that target inactive GDP-bound KRASG12C cause responses in less than half of patients and these responses are not durable. A class of RASG12C (ON) inhibitors that targets active GTP-bound KRASG12C blocks ERK signaling more potently than the inactive-state inhibitors. Sensitivity to either class of agents is strongly correlated with inhibition of mTORC1 activity. We have previously shown that PI3K/mTOR and ERK-signaling pathways converge on key cellular processes and that inhibition of both pathways is required for inhibition of these processes and for significant antitumor activity. We find here that the combination of a KRASG12C inhibitor with a selective mTORC1 kinase inhibitor causes synergistic inhibition of Cyclin D1 expression and cap-dependent translation. Moreover, BIM upregulation by KRASG12C inhibition and inhibition of MCL-1 expression by the mTORC1 inhibitor are both required to induce significant cell death. In vivo, this combination causes deep, durable tumor regressions and is well tolerated. This study suggests that the ERK and PI3K/mTOR pathways each mitigate the effects of inhibition of the other and that combinatorial inhibition is a potential strategy for treating KRASG12C-dependent lung cancer.

PMID:39025835 | DOI:10.1038/s41467-024-50063-z

PLoS Comput Biol. 2024 Jul 18;20(7):e1012010. doi: 10.1371/journal.pcbi.1012010. Online ahead of print.

ABSTRACT

During an infectious disease outbreak, public health policy makers are tasked with strategically implementing interventions whilst balancing competing objectives. To provide a quantitative framework that can be used to guide these decisions, it is helpful to devise a clear and specific objective function that can be evaluated to determine the optimal outbreak response. In this study, we have developed a mathematical modelling framework representing outbreaks of a novel emerging pathogen for which non-pharmaceutical interventions (NPIs) are imposed or removed based on thresholds for hospital occupancy. These thresholds are set at different levels to define four unique strategies for disease control. We illustrate that the optimal intervention strategy is contingent on the choice of objective function. Specifically, the optimal strategy depends on the extent to which policy makers prioritise reducing health costs due to infection over the costs associated with maintaining interventions. Motivated by the scenario early in the COVID-19 pandemic, we incorporate the development of a vaccine into our modelling framework and demonstrate that a policy maker's belief about when a vaccine will become available in future, and its eventual coverage (and/or effectiveness), affects the optimal strategy to adopt early in the outbreak. Furthermore, we show how uncertainty in these quantities can be accounted for when deciding which interventions to introduce. This research highlights the benefits of policy makers being explicit about the precise objectives of introducing interventions.

PMID:39024382 | DOI:10.1371/journal.pcbi.1012010

Am J Physiol Renal Physiol. 2024 Jul 18. doi: 10.1152/ajprenal.00142.2024. Online ahead of print.

ABSTRACT

Vasopressin controls water permeability in the renal collecting duct by regulating the water channel protein, aquaporin-2 (AQP2). Phosphoproteomic studies have identified multiple proteins that undergo phosphorylation changes in response to vasopressin. The kinases responsible for phosphorylation of most of these sites have not been identified. Here, we use large-scale Bayesian data integration methods to predict the responsible kinases for 51 phospho-proteomically identified vasopressin-regulated phosphorylation sites in the renal collecting duct. To do this, we applied Bayes' Rule to rank the 515 known mammalian protein kinases for each site. Bayes' rule was applied recursively to integrate each of seven independent data sets, each time using the posterior probability vector of a given step as the prior probability vector of the next step. 30 of the 33 phosphorylation sites that increase with vasopressin were predicted to be phosphorylated by protein kinase A catalytic subunit-a (PKA), consistent with prior studies implicating PKA in vasopressin signaling. Eighteen of the vasopressin-regulated phosphorylation sites were decreased in response to vasopressin and all but three of these sites were predicted to be targets of extracellular signal-regulated kinases, ERK1 and ERK2. This result implies that ERK1 and ERK2 are inhibited in response to vasopressin V2 receptor occupation, secondary to PKA activation. The six phosphorylation sites not predicted to be phosphorylated by PKA or ERK1/2 are potential targets of other protein kinases previously implicated in aquaporin-2 regulation, including cyclin-dependent kinase 18 (CDK18), calmodulin-dependent kinase 2d (CAMK2D). AMP-activated kinase catalytic subunit a-1 (PRKAA1) and CDC42 binding protein kinase beta (CDC42BPB).

PMID:39024358 | DOI:10.1152/ajprenal.00142.2024

Mol Biol Cell. 2024 Jul 18:mbcE23120494. doi: 10.1091/mbc.E23-12-0494. Online ahead of print.

ABSTRACT

Hypertension affects one billion people worldwide and is the most common risk factor for cardiovascular disease, yet a comprehensive picture of its underlying genetic factors is incomplete. Amongst regulators of blood pressure is the renal outer medullary potassium (ROMK) channel. While select ROMK mutants are prone to premature degradation and lead to disease, heterozygous carriers of some of these same alleles are protected from hypertension. Therefore, we hypothesized that gain-of-function (GoF) ROMK variants which increase potassium flux may predispose people to hypertension. To begin to test this hypothesis, we employed genetic screens and a candidate-based approach to identify six GoF variants in yeast. Subsequent functional assays in higher cells revealed two variant classes. The first group exhibited greater stability in the endoplasmic reticulum, enhanced channel assembly, and/or increased protein at the cell surface. The second group of variants resided in the PIP2-binding pocket, and computational modeling coupled with patch-clamp studies demonstrated a lower free energy for channel opening and slowed current rundown, consistent with an acquired PIP2-activated state. Together, these findings advance our understanding of ROMK structure-function, suggest the existence of hyperactive ROMK alleles in humans, and establish a system to facilitate the development of ROMK-targeted antihypertensives.

PMID:39024255 | DOI:10.1091/mbc.E23-12-0494

Elife. 2024 Jul 18;12:RP88173. doi: 10.7554/eLife.88173.

ABSTRACT

How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a 'synergistic global workspace', comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain's default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.

PMID:39022924 | DOI:10.7554/eLife.88173

iScience. 2024 Jun 6;27(7):110203. doi: 10.1016/j.isci.2024.110203. eCollection 2024 Jul 19.

ABSTRACT

Deleted in liver cancer 3 (DLC3) is a Rho GTPase-activating protein (RhoGAP) that plays a crucial role in maintaining adherens junction integrity and coordinating polarized vesicle transport by modulating Rho activity at the plasma membrane and endomembranes. By employing bioinformatical sequence analysis, in vitro experiments, and in cellulo assays we here identified a polybasic region (PBR) in DLC3 that facilitates the association of the protein with cellular membranes. Within the PBR, we mapped two serines whose phosphorylation can alter the electrostatic character of the region. Consequently, phosphomimetic mutations of these sites impaired the membrane association of DLC3. Furthermore, we found a new PBR-dependent localization of DLC3 at the midbody region, where the protein locally controlled Rho activity. Here, the phosphorylation-dependent regulation of DLC3 appeared to be required for proper cytokinesis. Our work thus provides a novel mechanism for spatiotemporal termination of Rho signaling by the RhoGAP protein DLC3.

PMID:39021807 | PMC:PMC11253157 | DOI:10.1016/j.isci.2024.110203

iScience. 2024 Jun 12;27(7):110253. doi: 10.1016/j.isci.2024.110253. eCollection 2024 Jul 19.

ABSTRACT

T cell co-inhibitory immune checkpoints, such as PD-1 or BTLA, are bona fide targets in cancer therapy. We used a human T cell reporter line to measure transcriptomic changes mediated by PD-1- and BTLA-induced signaling. T cell receptor (TCR)-complex stimulation resulted in the upregulation of a large number of genes but also in repression of a similar number of genes. PD-1 and BTLA signals attenuated transcriptomic changes mediated by TCR-complex signaling: upregulated genes tended to be suppressed and the expression of a significant number of downregulated genes was higher during PD-1 or BTLA signaling. BTLA was a significantly stronger attenuator of TCR-complex-induced transcriptome changes than PD-1. A strong overlap between genes that were regulated indicated quantitative rather than qualitative differences between these receptors. In line with their function as attenuators of TCR-complex-mediated changes, we found strongly regulated genes to be prime targets of PD-1 and BTLA signaling.

PMID:39021788 | PMC:PMC11253514 | DOI:10.1016/j.isci.2024.110253

Front Genet. 2024 Jul 3;15:1394971. doi: 10.3389/fgene.2024.1394971. eCollection 2024.

ABSTRACT

This study investigated how gene expression is affected by dietary fatty acids (FA) by using pigs as a reliable model for studying human diseases that involve lipid metabolism. This includes changes in FA composition in the liver, blood serum parameters and overall metabolic pathways. RNA-Seq data from 32 pigs were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA). Our aim was to identify changes in blood serum parameters and gene expression between diets containing 3% soybean oil (SOY3.0) and a standard pig production diet containing 1.5% soybean oil (SOY1.5). Significantly, both the SOY1.5 and SOY3.0 groups showed significant modules, with a higher number of co-expressed modules identified in the SOY3.0 group. Correlated modules and specific features were identified, including enriched terms and pathways such as the histone acetyltransferase complex, type I diabetes mellitus pathway, cholesterol metabolism, and metabolic pathways in SOY1.5, and pathways related to neurodegeneration and Alzheimer's disease in SOY3.0. The variation in co-expression observed for HDL in the groups analyzed suggests different regulatory patterns in response to the higher concentration of soybean oil. Key genes co-expressed with metabolic processes indicative of diseases such as Alzheimer's was also identified, as well as genes related to lipid transport and energy metabolism, including CCL5, PNISR, DEGS1. These findings are important for understanding the genetic and metabolic responses to dietary variation and contribute to the development of more precise nutritional strategies.

PMID:39021677 | PMC:PMC11252010 | DOI:10.3389/fgene.2024.1394971

Biochem Biophys Rep. 2024 Jun 21;39:101759. doi: 10.1016/j.bbrep.2024.101759. eCollection 2024 Sep.

ABSTRACT

Systems biology is an interdisciplinary field that aims to understand complex biological processes at the system level. The data, driven by high-throughput omics technologies, can be used to study the underpinning mechanisms of metabolite production under different conditions to harness this knowledge for the construction of regulatory networks, protein networks, metabolic models, and engineering of strains with enhanced target metabolite production in microalgae. In the current study, we comprehensively reviewed the recent progress in the application of these technologies for the characterization of carotenoid biosynthesis pathways in microalgae. Moreover, harnessing integrated approaches such as network analysis, meta-analysis, and machine learning models for deciphering the complexity of carotenoid biosynthesis pathways were comprehensively discussed.

PMID:39021674 | PMC:PMC11252604 | DOI:10.1016/j.bbrep.2024.101759

Case Rep Womens Health. 2024 May 10;42:e00613. doi: 10.1016/j.crwh.2024.e00613. eCollection 2024 Jun.

NO ABSTRACT

PMID:39021445 | PMC:PMC11252517 | DOI:10.1016/j.crwh.2024.e00613

Clin Transl Med. 2024 Jul;14(7):e1769. doi: 10.1002/ctm2.1769.

ABSTRACT

Recently, there is a rise in studies that recognize the importance of targeting ubiquitin and related molecular machinery in various therapeutic contexts. Here we briefly discuss the history of ubiquitin, its biological roles in protein degradation and beyond, as well as the current state of ubiquitin-targeting therapeutics across diseases. We conclude that targeting ubiquitin machinery is approaching a renaissance, and tapping its full potential will require embracing a wholistic perspective of ubiquitin's multifaceted roles.

PMID:39021054 | DOI:10.1002/ctm2.1769

Phys Rev E. 2024 Jun;109(6-1):064305. doi: 10.1103/PhysRevE.109.064305.

ABSTRACT

Traditional linear stability analysis based on matrix diagonalization is a computationally intensive process for high-dimensional systems of differential equations, posing substantial limitations for the exploration of Turing systems of pattern formation where an additional wave-number parameter needs to be investigated. In this paper, we introduce an efficient and intuitive technique that leverages Gershgorin's theorem to determine upper limits on regions of parameter space and the wave number beyond which Turing instabilities cannot occur. This method offers a streamlined avenue for exploring the phase diagrams of other complex multi-parametric models, such as those found in gene regulatory networks in systems biology. Due to its suitability for the asymptotic limit of infinitely large systems, it predicts the existence of a sweet spot in network size for maximal Jacobian stability.

PMID:39020955 | DOI:10.1103/PhysRevE.109.064305

Mol Cells. 2024 Jul 15:100092. doi: 10.1016/j.mocell.2024.100092. Online ahead of print.

ABSTRACT

Reverse genetics offers precise functional insights into genes through the targeted manipulation of gene expression followed by phenotypic assessment. While these approaches have proven effective in model organisms such as Saccharomyces cerevisiae, large-scale genetic manipulations in human cells were historically unfeasible due to methodological limitations. However, recent advancements in functional genomics, particularly CRISPR-based screening technologies and next-generation sequencing platforms, have enabled pooled screening technologies that allow massively parallel, unbiased assessments of biological phenomena in human cells. This review provides a comprehensive overview of cutting-edge functional genomic screening technologies applicable to human cells, ranging from shRNA screens to modern CRISPR screens. Additionally, we explore the integration of CRISPR platforms with single-cell approaches to monitor gene expression, chromatin accessibility, epigenetic regulation, and chromatin architecture following genetic perturbations at the omics level. By offering an in-depth understanding of these genomic screening methods, this review aims to provide insights into more targeted and effective strategies for genomic research and personalized medicine.

PMID:39019219 | DOI:10.1016/j.mocell.2024.100092

Toxicol Appl Pharmacol. 2024 Jul 15:117039. doi: 10.1016/j.taap.2024.117039. Online ahead of print.

ABSTRACT

The present study aimed to investigate the role of antidiabetic drug metformin on the cytoplasmic organization of oocytes. Germinal vesicle (GV) stage oocytes were collected from adult female Swiss albino mice and subjected to in vitro maturation (IVM) in various experimental groups- control, vehicle control (0.3% ethanol), metformin (50 μg/mL), high glucose and high lipid (HGHL, 10 mM glucose; 150 μM palmitic acid; 75 μM stearic acid and 200 μM oleic acid in ethanol), and HGHL supplemented with metformin. The metaphase II (MII) oocytes were analyzed for lipid accumulation, mitochondrial and endoplasmic reticulum (ER) distribution pattern, oxidative and ER stress, actin filament organization, cortical granule distribution pattern, spindle organization and chromosome alignment. An early polar body extrusion was observed in the HGHL group. However, the maturation rate at 24 h did not differ significantly among the experimental groups compared to the control. The HGHL conditions exhibited significantly higher levels of oxidative stress, ER stress, poor actin filament organization, increased lipid accumulation, altered mitochondrial distribution, spindle abnormalities, and chromosome misalignment compared to the control. Except for spindle organization, supplementation of metformin to the HGHL conditions improved all the parameters (non-significant for ER and actin distribution pattern). These results show that metformin exposure in the culture media helped to improve the hyperglycemia and hyperlipidemia-induced cytoplasmic anomalies except for spindle organization. Given the crucial role of spindle organization in proper chromosome segregation during oocyte maturation and meiotic resumption, the implications of metformin's limitations in this aspect warrant careful evaluation and further investigation.

PMID:39019093 | DOI:10.1016/j.taap.2024.117039

Cell Rep Med. 2024 Jul 16;5(7):101646. doi: 10.1016/j.xcrm.2024.101646.

ABSTRACT

Bowel movement frequency (BMF) directly impacts the gut microbiota and is linked to diseases like chronic kidney disease or dementia. In particular, prior work has shown that constipation is associated with an ecosystem-wide switch from fiber fermentation and short-chain fatty acid production to more detrimental protein fermentation and toxin production. Here, we analyze multi-omic data from generally healthy adults to see how BMF affects their molecular phenotypes, in a pre-disease context. Results show differential abundances of gut microbial genera, blood metabolites, and variation in lifestyle factors across BMF categories. These differences relate to inflammation, heart health, liver function, and kidney function. Causal mediation analysis indicates that the association between lower BMF and reduced kidney function is partially mediated by the microbially derived toxin 3-indoxyl sulfate (3-IS). This result, in a generally healthy context, suggests that the accumulation of microbiota-derived toxins associated with abnormal BMF precede organ damage and may be drivers of chronic, aging-related diseases.

PMID:39019013 | DOI:10.1016/j.xcrm.2024.101646

Cell Rep Med. 2024 Jul 16;5(7):101645. doi: 10.1016/j.xcrm.2024.101645.

ABSTRACT

Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.

PMID:39019012 | DOI:10.1016/j.xcrm.2024.101645

Cell Rep Med. 2024 Jul 16;5(7):101647. doi: 10.1016/j.xcrm.2024.101647.

ABSTRACT

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

PMID:39019006 | DOI:10.1016/j.xcrm.2024.101647

Chem Biol Interact. 2024 Jul 16;399:111136. doi: 10.1016/j.cbi.2024.111136. Online ahead of print.

NO ABSTRACT

PMID:39018829 | DOI:10.1016/j.cbi.2024.111136

J Ayurveda Integr Med. 2024 Jul 15;15(4):101016. doi: 10.1016/j.jaim.2024.101016. Online ahead of print.

ABSTRACT

Precision in personalized medicine is a crucial subject that needs comprehensive discussion and scientific validation. Traditional healthcare approaches like the Ayurvedic Sciences are often contextually linked with personalized medicine. However, it is unfortunate that this knowledge concerning Ayurveda and personalized medicine is restricted to applying systems biology techniques to 'prakriti' the phenotypic expression and characterization detailed in the literature. There are other significant constructs besides prakruti that interest an Ayurvedic physician, which accounts for crafting precision in evidence-based medicinal practices. There is this influential model of Ayurvedic healthcare practice wherein the physician maps specific personalized characters in addition to prakruti to deduce the host responses to endogenous and exposome conditions. Subsequently, tailored protocols are administered that bring about holistic, personalized outcomes. The review aimed to determine the effective methods for integrating Systems Biology, Ayurvedic Sciences, and Personalized Medicine (precision medicinebased). Ayurveda adopts a holistic approach, considering multiple variables and their interconnections, while the modern reductionist approach focuses on understanding complex details of smaller parts through rigorous experimentation. Despite seeming extremes, ongoing research on lifestyle, gut health, and spiritual well-being highlights the evolving intersection between traditional Ayurvedic practices and modern science. The current focus is on developing the fundamental concept of Ayurveda Biology by incorporating Systems Biology techniques. Challenges in this integration include understanding diverse data types, bridging interdisciplinary knowledge gaps, and addressing technological limitations and ethical concerns. Overcoming these challenges will require interdisciplinary collaboration, innovative methodologies, substantial investment in technology, and cultural sensitivity to preserve Ayurveda's core principles while leveraging modern scientific advancements. The focus of discussions and debates on such collaborations should be breakthrough clinical models, such as chronic inflammation, which can be objectively related to specific stages of disease manifestations described in Ayurveda. Validating patient characteristics with systems biology approaches, particularly in shared pathologies like chronic inflammation, is crucial for bringing prediction and precision to personalized medicine.

PMID:39018639 | DOI:10.1016/j.jaim.2024.101016

Environ Microbiome. 2024 Jul 17;19(1):48. doi: 10.1186/s40793-024-00596-z.

ABSTRACT

Seasonal floodplains in the Amazon basin are important sources of methane (CH4), while upland forests are known for their sink capacity. Climate change effects, including shifts in rainfall patterns and rising temperatures, may alter the functionality of soil microbial communities, leading to uncertain changes in CH4 cycling dynamics. To investigate the microbial feedback under climate change scenarios, we performed a microcosm experiment using soils from two floodplains (i.e., Amazonas and Tapajós rivers) and one upland forest. We employed a two-factorial experimental design comprising flooding (with non-flooded control) and temperature (at 27 °C and 30 °C, representing a 3 °C increase) as variables. We assessed prokaryotic community dynamics over 30 days using 16S rRNA gene sequencing and qPCR. These data were integrated with chemical properties, CH4 fluxes, and isotopic values and signatures. In the floodplains, temperature changes did not significantly affect the overall microbial composition and CH4 fluxes. CH4 emissions and uptake in response to flooding and non-flooding conditions, respectively, were observed in the floodplain soils. By contrast, in the upland forest, the higher temperature caused a sink-to-source shift under flooding conditions and reduced CH4 sink capability under dry conditions. The upland soil microbial communities also changed in response to increased temperature, with a higher percentage of specialist microbes observed. Floodplains showed higher total and relative abundances of methanogenic and methanotrophic microbes compared to forest soils. Isotopic data from some flooded samples from the Amazonas river floodplain indicated CH4 oxidation metabolism. This floodplain also showed a high relative abundance of aerobic and anaerobic CH4 oxidizing Bacteria and Archaea. Taken together, our data indicate that CH4 cycle dynamics and microbial communities in Amazonian floodplain and upland forest soils may respond differently to climate change effects. We also highlight the potential role of CH4 oxidation pathways in mitigating CH4 emissions in Amazonian floodplains.

PMID:39020395 | DOI:10.1186/s40793-024-00596-z