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"Albert, K"
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Analysis of ancestry heterozygosity suggests that hybrid incompatibilities in threespine stickleback are environment dependent
Hybrid incompatibilities occur when interactions between opposite ancestry alleles at different loci reduce the fitness of hybrids. Most work on incompatibilities has focused on those that are “intrinsic,” meaning they affect viability and sterility in the laboratory. Theory predicts that ecological selection can also underlie hybrid incompatibilities, but tests of this hypothesis using sequence data are scarce. In this article, we compiled genetic data for F 2 hybrid crosses between divergent populations of threespine stickleback fish ( Gasterosteus aculeatus L.) that were born and raised in either the field (seminatural experimental ponds) or the laboratory (aquaria). Because selection against incompatibilities results in elevated ancestry heterozygosity, we tested the prediction that ancestry heterozygosity will be higher in pond-raised fish compared to those raised in aquaria. We found that ancestry heterozygosity was elevated by approximately 3% in crosses raised in ponds compared to those raised in aquaria. Additional analyses support a phenotypic basis for incompatibility and suggest that environment-specific single-locus heterozygote advantage is not the cause of selection on ancestry heterozygosity. Our study provides evidence that, in stickleback, a coarse—albeit indirect—signal of environment-dependent hybrid incompatibility is reliably detectable and suggests that extrinsic incompatibilities can evolve before intrinsic incompatibilities.
Journal Article
Network medicine : complex systems in human disease and therapeutics
\"Network medicine, a new field which developed from the application of systems biology approaches to human disease, embraces the complexity of multifactorial influences on disease, which can be driven by non-linear effects and molecular and statistical interactions.The development of comprehensive and affordable Omics platforms provides the data types for network medicine, and graph theory and statistical physics provide the theoretical framework to analyze networks. While network medicine provides a fundamentally different approach to understanding disease etiology, it will also lead to key differences in how diseases are treated--with multiple molecular targets that may require manipulation in a coordinated, dynamic fashion. Much remains to be learned regarding the optimal approaches to integrate different Omics data types and to perform network analyses; this book provides an overview of the progress that has been made and the challenges that remain.\"-- Provided by publisher
Book
Hippocampal spatial representations exhibit a hyperbolic geometry that expands with experience
Daily experience suggests that we perceive distances near us linearly. However, the actual geometry of spatial representation in the brain is unknown. Here we report that neurons in the CA1 region of rat hippocampus that mediate spatial perception represent space according to a non-linear hyperbolic geometry. This geometry uses an exponential scale and yields greater positional information than a linear scale. We found that the size of the representation matches the optimal predictions for the number of CA1 neurons. The representations also dynamically expanded proportional to the logarithm of time that the animal spent exploring the environment, in correspondence with the maximal mutual information that can be received. The dynamic changes tracked even small variations due to changes in the running speed of the animal. These results demonstrate how neural circuits achieve efficient representations using dynamic hyperbolic geometry.
Most spatial navigation studies assume a linear map of space. This study reports that neural representations of space follow non-linear hyperbolic coordinates. These representations also expand with experience along a maximally informative limit.
Journal Article
The path to the clinic: a comprehensive review on direct KRASG12C inhibitors
The
RAS
oncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in the
KRAS
gene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring the
KRAS
G12C
mutation. Adagrasib (MRTX849) and other direct KRAS
G12C
inhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRAS
G12C
mutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRAS
G12C
inhibitors and summarize the ongoing clinical trials of all direct KRAS
G12C
inhibitors.
Journal Article
Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit
ObjectiveButyrate exerts metabolic benefits in mice and humans, the underlying mechanisms being still unclear. We aimed to investigate the effect of butyrate on appetite and energy expenditure, and to what extent these two components contribute to the beneficial metabolic effects of butyrate.DesignAcute effects of butyrate on appetite and its method of action were investigated in mice following an intragastric gavage or intravenous injection of butyrate. To study the contribution of satiety to the metabolic benefits of butyrate, mice were fed a high-fat diet with butyrate, and an additional pair-fed group was included. Mechanistic involvement of the gut-brain neural circuit was investigated in vagotomised mice.ResultsAcute oral, but not intravenous, butyrate administration decreased food intake, suppressed the activity of orexigenic neurons that express neuropeptide Y in the hypothalamus, and decreased neuronal activity within the nucleus tractus solitarius and dorsal vagal complex in the brainstem. Chronic butyrate supplementation prevented diet-induced obesity, hyperinsulinaemia, hypertriglyceridaemia and hepatic steatosis, largely attributed to a reduction in food intake. Butyrate also modestly promoted fat oxidation and activated brown adipose tissue (BAT), evident from increased utilisation of plasma triglyceride-derived fatty acids. This effect was not due to the reduced food intake, but explained by an increased sympathetic outflow to BAT. Subdiaphragmatic vagotomy abolished the effects of butyrate on food intake as well as the stimulation of metabolic activity in BAT.ConclusionButyrate acts on the gut-brain neural circuit to improve energy metabolism via reducing energy intake and enhancing fat oxidation by activating BAT.
Journal Article
Batman and the Outsiders
\"In these tales from the 1980s, Batman splits off from the Justice League of America to form his own super-team known as the Outsiders. Including established heroes Black Lightning and Metamorpho as well as dynamic new heroes Katana, Geo-Force, and Halo, the team fought for justice on an international stage. Combining superhero action with espionage, the Outsiders brought their own brand of justice to Geo-Force's nation of Markovia, Katana's homeland of Japan, and across the globe.\"-- Provided by publisher.
BOOK
Prone position in ARDS patients: why, when, how and for whom
In ARDS patients, the change from supine to prone position generates a more even distribution of the gas–tissue ratios along the dependent–nondependent axis and a more homogeneous distribution of lung stress and strain. The change to prone position is generally accompanied by a marked improvement in arterial blood gases, which is mainly due to a better overall ventilation/perfusion matching. Improvement in oxygenation and reduction in mortality are the main reasons to implement prone position in patients with ARDS. The main reason explaining a decreased mortality is less overdistension in non-dependent lung regions and less cyclical opening and closing in dependent lung regions. The only absolute contraindication for implementing prone position is an unstable spinal fracture. The maneuver to change from supine to prone and vice versa requires a skilled team of 4–5 caregivers. The most frequent adverse events are pressure sores and facial edema. Recently, the use of prone position has been extended to non-intubated spontaneously breathing patients affected with COVID-19 ARDS. The effects of this intervention on outcomes are still uncertain.
Journal Article