Biology subjects

Baker, J.

Publications and source records attributed to Baker, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

The coevolution of encephalization and manual dexterity in hominins and other primates

The human hand is one of our most remarkable features. We have long, opposable thumbs and a suite of other features argued to be adaptations for interacting with and manipulating our environment, literally extending the reach of our cognitive powers. Consequently, enhanced manipulative dexterity, tool use and increased brain size are considered key features of how our ancestors evolved. This hypothesis predicts that anatomical dexterity and brain size co-evolved, and that this should be evident in the morphology of the hand. To test this hypothesis and to understand how hominin evolution may have deviated from any general primate trend, we collected a dataset of finger length, thumb length, and brain size across 94 extinct and extant species of primates. Using phylogenetic comparative methods, we reveal a strong primate-wide association between brain size and relative thumb length. We further demonstrate that this general association accurately predicts the co-evolution of these traits in hominins. Whilst hominins have significantly long thumbs compared to other primates, we infer that they have arisen from the same underlying evolutionary process acting across the whole primate order: increasing manipulative ability associated with specialized neural control processes. The relationships we recover are consistent with positive feedback between manipulation, tool use and cognition and therefore may go some way towards explaining evolutionary trends towards larger brain sizes among primates, and particularly in hominins. Our results emphasize the role of manipulative abilities in cognitive evolution and emphasize how neural and bodily adaptations are interconnected.

evolutionary biology↗

bioRxiv2024

Climatic-environmental influences on hominin brain size over the last 5 million years

A large brain relative to body mass is considered a distinguishing hominin trait. It has frequently been related to a suite of social, behavioral, technological, and other cognitive adaptations that differentiate humans from other species. The processes underlying large brain size evolution have therefore been a subject of rigorous scientific debate. Many hypotheses have been proposed to explain how climate and environment drive the selection of larger brain sizes, but monotonic influences of climate-environmental selective pressures are often assumed and rarely have between- and within-species effects been considered. Here, we apply Bayesian phylogenetic comparative techniques to the hominin fossil record to test the effect of climatic and environmental pressures (C-E) on brain size evolution, whilst simultaneously accounting for body mass and chronological age. We find that colder and more variable temperatures have a positive within-species effect on brain size evolution, likely related to biological adaptations to mitigate against hypothermia. However, in Homo, the strength of this effect diminishes over time suggesting that in later species (Homo sapiens and Homo neanderthalensis) brain sizes were less affected by C-E conditions.

evolutionary biology↗

bioRxiv2024

Identification of novel bone-resorption markers by osteoclasts in vitro and in vivo

Bone resorption involves dissolution of mineral and enzymatic degradation of bone matrix. The primary enzyme is cathepsin K but other proteases including matrix metalloproteinases are involved. Some cleavage products of cathepsin K have been partially identified, including crossed-linked telopeptides of type I collagen. However, the pathway of type I bone collagen degradation has not been fully elucidated. The aim of this study was to comprehensively characterise the entire complement of bone breakdown products resulting from osteoclast action under controlled conditions in vitro. Complete characterisation of these breakdown products will advance understanding of osteoclast biology and has the potential to reveal new biomarkers of bone resorption. We analysed extracellular media from osteoclasts cultured on dentine substrates, using untargeted liquid chromatography mass spectrometry. We discovered 22 breakdown products resulting from osteoclastic action. These products were peptide fragment sequences that mapped to various collagen proteins present in bone and dentine matrix. Nine peptide fragments mapped exclusively to collagen I alpha-1 chain (COL1A1), the most abundant protein in bone. Analysis of the reported cleavage sites in the COL1A1 protein sequence indicated 7/9 COL1A1-specific fragments not explained by known proteolytic events. We subsequently showed that 14 of the fragment products were present in human serum and/or urine from metabolomic datasets obtained from patients with the inherited metabolic disease alkaptonuria (serum) and lung cancer (urine). Two products were at higher concentration (P <0.05, fold change >2) in urine from patients with bone metastasis (29/112) from the lung cancer cohort. The range of collagen peptide fragments we discovered as a direct result of osteoclast activity indicates a complexity of bone resorption pathways not previously known. Monitoring the concentrations of these novel bone markers in biofluids has the potential to capture multiple pathways of bone resorption activity beyond the existing assays based on Cathepsin K. Lay summaryBreakdown of bone tissue is performed by specialised bone cells called osteoclasts in a process known as bone resorption. Knowledge of specific molecules produced from osteoclasts acting on bone is important for a) understanding bone resorption in health and disease, and b) clinical tests of bone resorption from measurement of these breakdown products. Here we aimed to characterise the entire complement of bone breakdown products resulting from osteoclast action under controlled conditions in the laboratory. We found a total of 22 breakdown products produced from osteoclasts cultured on wafers of dentine, a tissue with almost identical composition to bone. Analysis of the structures of these products revealed fragments of varying size produced from digestion of specific proteins present in bone. We then showed that 14/22 bone protein fragments observed in our cell culture experiments were also present in human blood and/or urine. In our analysis of urine from patients with lung cancer, we found that two of the protein fragments we identified were higher in a subset (29/112) of patients with bone metastasis. Our findings provide new insights into the mechanisms of bone resorption and show the potential for monitoring the range of urine bone protein fragments in bone disorders.

biochemistry↗

bioRxiv2024

Intraspecies warfare restricts strain coexistence in human skin microbiomes

Determining why only a fraction of encountered or applied strains engraft in a given persons microbiome is crucial for understanding and engineering these communities. Previous work has established that metabolic competition can restrict colonization success in vivo, but the relevance of bacterial warfare in preventing commensal engraftment has been less explored. Here, we demonstrate that intraspecies warfare presents a significant barrier to strain coexistence in the human skin microbiome by profiling 14,884 pairwise interactions between Staphylococcus epidermidis isolates cultured from eighteen people from six families. We find that intraspecies antagonisms are abundant, mechanistically diverse, independent of strain relatedness, and consistent with rapid evolution via horizontal gene transfer. Critically, these antagonisms are significantly depleted among strains residing on the same person relative to random assemblages, indicating a significant in vivo role. Together, our results emphasize that accounting for intraspecies warfare may be essential to the design of long-lasting probiotic therapeutics.

microbiology↗

bioRxiv2024

Single cell resolution analysis of multi-tissue derived human iNKT cells reveals novel transcriptional paradigms

Invariant natural killer T (iNKT) cells are evolutionarily conserved innate lymphocytes important for host defense against pathogens. Further, they are increasingly recognized to play a role in tumor immune surveillance and in protection against graft versus host disease, and they are of particular importance as a universal donor for cellular therapies. Therefore, a thorough understanding of the biology of iNKT cells is critical. Murine studies have revealed the existence of transcriptionally and functionally distinct subsets, similar to T helper cell subsets. However, a comprehensive study of human iNKT cell heterogeneity is lacking. Herein, we define the transcriptomic heterogeneity of human iNKT cells derived from multiple immunologically relevant tissues, including peripheral blood, cord blood, bone marrow, and thymus, using single cell RNA-sequencing. We describe human iNKT cells with a naive/precursor transcriptional pattern, a Th2-like signature, and Th1/17/NK-like gene expression. This combined Th1/17 pattern of gene expression differs from previously described murine iNKT subsets in which Th1- and Th17- like iNKT cells are distinct populations. We also describe transcription factors regulating human iNKT cells with distinct gene expression patterns not previously described in mice. Further, we demonstrate a novel T effector memory RA+ (TEMRA)-like pattern of expression in some human iNKT cells. Additionally, we provide an in-depth transcriptional analysis of human CD8+ iNKT cells, revealing cells with two distinct expression patterns--one consistent with naive/precursor cells and one consistent with Th1/17/NK-like cells. Collectively, our data provide critical insights into the transcriptional heterogeneity of human iNKT cells, providing a platform to facilitate future functional studies and to inform the development of iNKT-based cellular therapies.

immunology↗

bioRxiv2024

Hominin brain size increase has emerged from within-species encephalization

The fact that rapid brain size increase was clearly a key aspect of human evolution has prompted many studies focussing on this phenomenon1-4, and many suggestions as to the underlying evolutionary patterns and processes5-10. No study to date has however separated out the contributions of change through time within-vs. between-hominin species whilst simultaneously incorporating effects of body size. Using a phylogenetic approach never applied before to palaeoanthropological data, we show that brain size increase across ~ 7 million years of hominin evolution arose from increases within individual species which account for an observed overall increase in relative brain size. Variation among species in brain size after accounting for this effect is associated with body mass differences but not time. In addition, our analysis also reveals that the within-species trend escalated in more recent lineages, implying an overall pattern of accelerating brain size increase through time.

paleontology↗

bioRxiv2024

A Macroscopic Quantum Heat Engine: Nested Resonant Structures and the Entropic Stability of Life

Biological systems are fundamentally containers of thermally fluctuating atoms that through unknown mechanisms are structurally layered across many thermal scales from atoms to amino acids to primary, secondary, and tertiary structures to functional proteins to functional macromolecular assemblies and up. Understanding how chemical thermodynamics sc ales across these layered structures is central to describing biological structure and function. Muscle - with chemical thermodynamics well-defined on two different thermal scales - provides a clear solution to this problem. In 1938, A.V. Hill made the extraordinary observation that the mechanics and chemistry of muscle contraction is defined independent of the structural components of muscle, implying that the mechanics and chemistry of myosin motor proteins within muscle do not classically scale up to muscle. We have demonstrated experimentally that thermal scaling bridges Hills top-down thermodynamics and the bottom-up philosophy of molecular biologists. That is, with thermal scaling N individual myosin motor switches physically collapse into an ensemble of N myosin motor switches creating a functional entropy within the ensemble well defined by the statistical mechanics of a binary system of switches. This ensemble entropy stabilizes the resonant ensemble structure of muscle and energetically drives the irreversible kinetics and energetics of muscle contraction. Here I develop a general model of thermal scaling and show that it occurs when the ensemble state of a system is defined, at which point the number of ways constituent molecules can account for the ensemble state contributes to the entropy of the ensemble state. At that point, the statistical occupancy of molecular states physically replaces the physical occupancy of molecular states. This is not a classical mechanism and as shown here results in many quantum-like phenomena, which consistent with Hills observation means that biological function cannot be described by classical molecular mechanisms.

biophysics↗

bioRxiv2024

Highly-resolved within-species dynamics in the human facial skin microbiome

Adult human facial skin microbiomes are remarkably similar at the species-level, dominated by Cutibacterium acnes and Staphylococcus epidermidis, yet each person harbors a unique community of strains. Understanding how person-specific communities assemble is critical for designing microbiome-based therapies. Here, using 4,055 isolate genomes and 360 metagenomes, we reconstruct on-person evolutionary history to reveal on and between-person strain dynamics. We find that multiple cells are typically involved in transmission, indicating ample opportunity for migration. Despite this accessibility, family members share only some of their strains. S. epidermidis communities are dynamic, with each strain persisting for an average of only 2 years. C. acnes strains are more stable and have a higher colonization rate during the transition to an adult facial skin microbiome, suggesting this window could facilitate engraftment of therapeutic strains. These previously undetectable dynamics may influence the design of microbiome therapeutics and motivate the study of their effects on hosts.

microbiology↗

bioRxiv2023

Stochastic Force Generation in an Isometric Binary Mechanical System: A Thermodynamic Model of Muscle Force Generation

With implications for both clean energy technologies and human health, models of muscle contraction provide insights into the inner workings of one of the most energy-efficient engines on the planet and into the modifications to that engine that lead to human diseases. However, only scientific methods can provide these insights. A binary mechanical model is a recently developed thermodynamic model of muscle contraction that implies a novel entropic kinetic formalism, provides a solution to a paradox that has perplexed scientists for over a century, and accounts for many mechanical and energetic aspects of muscle contraction. Here we use this model to perform discrete state chemical simulations of isometric force generation under different conditions and show explicitly that force generating kinetics are bounded by thermodynamic equations, that four phases of force generation occur as four separate thermodynamic processes, and that periodic force generation emerges with amplitudes and periodicities that bifurcate between constant and stochastic values through mechanisms easily understood relative to ideal thermodynamic processes. We discuss these results relative to experimental observations of spontaneous oscillatory contractions (SPOCs) in muscle and periodic force generation in small myosin ensembles. Significance StatementMost models of muscle contraction to date are based on the obsolete 17th century scientific philosophy that the force of the system is determined by the force of the molecules in that system. A new thermodynamic model of muscle provides a completely different interpretation of muscle mechanics and chemistry, implies a novel thermodynamic kinetic formalism, and has solved a paradigm that has intrigued scientists for over a century. Here, we use this model to simulate muscle force generation and show that force generating kinetics are constrained by thermodynamic equations that provide a clear mechanism for the periodic force generation that emerges from these stochastic simulations.

biophysics↗

bioRxiv2023

Four Phases of a Force Transient Emerge from a Binary Mechanical System

Models of muscle contraction are important for guiding drug discovery, drug validation, and clinical decision-making with the goal of improving human health. Models of muscle contraction are also key to discovering clean energy technologies from one of the most efficient and clean-burning machines on the planet. However, these important goals can only be met through muscle models that are based on science. Most every model and mechanism (e.g., a molecular power stroke) of muscle contraction described in the literature to date is based on a corpuscular mechanic philosophy that has been challenged by science for over two decades. A thermodynamic model and mechanisms (e.g., a molecular switch) of muscle contraction is supported by science but has not yet been tested against experimental data. Here, I show that following a rapid perturbation to the free energy of a thermodynamic muscle system, a transient force response emerges with four phases, each corresponding to a different clearly-defined thermodynamic (not molecular) process. I compare these four phases to those observed in two classic muscle transient experiments. The observed consistency between model and data implies that the simplest possible model of muscle contraction (a binary mechanical system) accurately describes muscle contraction.

biophysics↗

bioRxiv2023

The Kinetic and Energetic Pull of Chemical Entropy On Small Ensembles of Proteins

Biological systems are fundamentally containers of thermally fluctuating atoms that through unknown mechanisms are structurally layered across many thermal scales from atoms to amino acids to primary, secondary, and tertiary structures to functional proteins to functional macromolecular assemblies and up. Understanding how the irreversible kinetics (i.e., the arrow of time) of biological systems emerge from the equilibrium kinetics of constituent structures defined on smaller thermal scales is central to describing biological function. Muscles irreversible power stroke - with its mechanochemistry defined on both the thermal scale of muscle and the thermal scale of myosin motors - provides a clear solution to this problem. Individual myosin motors function as reversible force-generating switches induced by actin binding and gated by the release of inorganic phosphate, Pi. As shown in a companion article, when N individual switches thermally scale up to an ensemble of N switches in muscle, the entropy of a binary system of switches is created. We have shown in muscle that a change in state of this binary system of switches entropically drives actin-myosin binding (the switch) and muscles irreversible power stroke, and that this simple two-state model accurately accounts for most key aspects of muscle contraction. Extending this observation beyond muscle, here I show that the chemical kinetics of an ensemble of N molecules differs fundamentally from a conventional chemical analysis of N individual molecules, describing irreversible chemical reactions as being pulled into the future by the a priori defined entropy of a binary system rather than being pushed forward by the physical occupancy of chemical states (e.g., mass action).

biophysics↗

bioRxiv2023

Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice

Endocytosis, or internalization through endosomes is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of Phosphatidylinositol (3,5)biphosphate (PtdIns(3,5)P2), and has been implicated in virus trafficking via the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus in vitro and in vivo. PIKfyve inhibitors, Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in a MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, whilst improving the cell integrity of human nasal air liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2mg/ml), when intranasally treated, exhibited significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated anti-viral effects in RSV A2 infected human nasal epithelium in vitro and mouse in vivo, with equivalent effect to that of ribavirin. AM also showed anti-viral effects against human rhinovirus and seasonal coronavirus in vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for pan-viral approach against respiratory viruses.

microbiology↗

bioRxiv2023

Taste shaped the use of botanical drugs

The perception of taste and flavour (a combination of taste, smell and chemesthesis) here also referred to as chemosensation, enables animals to find high-value foods and avoid toxins. Humans have learned to use unpalatable and toxic substances as medicines, yet the importance of chemosensation in this process is poorly understood. Here we generate tasting-panel data for botanical drugs and apply phylogenetic generalised linear mixed models to test whether intensity and complexity of chemosensory qualities as well as particular tastes and flavours can predict ancient Graeco-Roman drug use. We found chemosensation to be strongly predictive of therapeutic use: botanical drugs with high therapeutic versatility have simple yet intense tastes and flavours, and 21 of 22 chemosensory qualities predicted at least one therapeutic use. In addition to the common notion of bitter tasting medicines, we also found starchy, musky, sweet, cooling, and soapy drugs associated with versatility. In ancient Greece and Rome, illness was thought to arise from imbalance in bodily fluids or humours, yet our study suggests that uses of drugs were based on observed physiological effects that are often consistent with modern understanding of chemesthesis and taste receptor pharmacology.

evolutionary biology↗

bioRxiv2023

Co-evolutionary dynamics of mammalian brain and body size

Despite decades of comparative studies, fundamental questions remain about how brain and body size co-evolved. Divergent explanations exist concurrently in the literature for phenomena such as variation in brain relative to body size, variability in the scaling relationship across taxonomic levels and between taxonomic groups, and purported evolutionary trends. Here we resolve these issues using a comprehensive dataset of brain and body masses across the mammal radiation, and a method enabling us to study brain relative to body mass evolution while estimating their evolutionary rates along the branches of a phylogeny. Contrary to the rarely questioned assumption of a log-linear relationship, we find that a curvilinear model best describes the evolutionary relationship between log brain mass and log body mass. This model greatly simplifies our understanding of mammalian brain-body co-evolution: it can simultaneously explain both the much-discussed taxon-level effect and variation in slopes and intercepts previously attributed to complex scaling patterns. We also document substantial variation in rates of relative brain mass evolution, with bursts of change scattered through the tree. General trends for increasing relative brain size over time are found in only three mammalian orders, with the most extreme case being primates, setting the stage for the uniquely rapid directional increase that ultimately produced the computational powers of the human brain.

evolutionary biology↗

bioRxiv2023

Extracellular release of damaged mitochondria induced by cytotoxic conditioning exacerbates GVHD

Despite therapeutic advancements, GVHD is a major complication of HSCT. In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing Pathogen Associated Molecular Patterns (PAMPs), result in activation of host antigen-presenting cells (APC) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APC. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of MHC-II, co-stimulatory CD86, and pro-inflammatory cytokines, resulting in increased donor T cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggests that pre-HSCT conditioning results in extracellular release of damaged mitochondria which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria following conditioning could serve as a novel strategy for GVHD prevention.

immunology↗

bioRxiv2023

SARS-CoV-2 Spike Protein Reduces Burst Activities in Neurons Measured by Micro-Electrode Arrays

SARS-CoV-2 caused a large-scale global pandemic between 2020 and 2022. Despite efforts to understand its biology and mechanisms of pathogenicity, the viral impact on the neurological systems remains unclear. The main goal of this study was to quantify the neurological phenotypes induced by SARS-CoV-2 spike protein in neurons, measured by in-vitro multi-well micro-electrode arrays (MEAs). We extracted the whole-brain neurons from the newborn P1 mice and plated them on multi-well micro-electrode arrays and administered purified recombinant spike proteins (S1 and S2 subunits respectively) from the SARS-CoV-2 virus. The signals from the MEAs were transmitted from an amplifier to a high-performance computer for recording and analysis. We used an in-house developed algorithm to quantify neuronal phenotypes. Among all the phenotypic features analyzed, we discovered that the S1 protein of SARS-CoV-2 decreased the mean burst numbers observed on each electrode; This effect was not observed for the spike 2 protein (S2) and could be rescued by an anti-S1 antibody. Finally, our data strongly suggest that the receptor binding domain (RBD) of S1 is responsible for the reduction of burst activities in neurons. Overall, our results strongly indicate that spike proteins may play an important role in altering neuronal phenotypes, specifically the burst patterns, when neurons are exposed during early development.

microbiology↗

bioRxiv2022

Single-cell Transcriptomics Reveal Different Maturation Stages and Sublineages Commitment of Human Thymic Invariant Natural Killer T cells

Invariant natural killer T (iNKT) cells are a subset of heterogenous T-cells with potent cytotoxic and immunomodulatory properties. During thymic development, murine iNKT cells go through different maturation stages and differentiate into distinct sublineages, namely iNKT1, iNKT2, and iNKT17 cells. To define maturation stages and to assess sublineage commitment of human iNKT cells during thymic development, we performed single-cell RNA sequencing analysis on human thymic iNKT cells. We show that these iNKT cells displayed heterogeneity and unsupervised analysis identified two clusters: one with an immature profile with high expression of genes that are important for iNKT cell development and enriched in cells expressing an iNKT2 signature, whereas a second cluster displayed a mature, terminally differentiated profile resembling murine iNKT1 cells. Trajectory analysis suggested an ontological relationship between the two clusters. Our work provides the first single cell transcriptomic analysis of thymic human iNKT cells offering new insights into their developmental process in humans.

cell biology↗

bioRxiv2022

Integrated Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease

CD4+FOXP3+ regulatory T cells have demonstrated efficacy in graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCR, TCR{beta} genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal restriction and that Treg did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire, however, markedly suppressed their expansion. Transcriptomic analysis revealed that Treg predominantly affected the transcriptome of CD4 Tcon and to a lesser extent of CD8 Tcon, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach. Key Points- Regulatory T cells modulate conventional T cells transcriptome during GvHD suppression by affecting several, non-redundant pathways. - Regulatory T cells undergo activation and clonal expansion during GvHD suppression.

immunology↗