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Friedman, M.

Publications and source records attributed to Friedman, M..

At least 19 recordsLinked to original sources

bifrost: an R package for scalable inference of phylogenetic shifts in multivariate evolutionary dynamics

O_LIHigh-dimensional comparative datasets, including geometric morphometric landmarks, functional traits, and other large trait datasets, are increasingly common in biology. When these datasets include a large number of traits relative to the number of taxa, they pose significant challenges for phylogenetic comparative analysis. In addition, evolutionary dynamics are often heterogeneous across phylogenies, challenging researchers to develop tools that can localize and account for such variation when investigating hypotheses of evolutionary change. C_LIO_LIWe present bifrost, an R package for detecting and characterizing shifts in multivariate trait evolution across phylogenetic trees. bifrost implements a stepwise greedy search over alternative macroevolutionary regime configurations on a phylogeny. Candidate shifts are proposed and assessed at internal nodes, accelerated with parallel model fitting where possible, and aggregated sequentially when they exceed a user-defined information-criterion acceptance threshold. C_LIO_LIThe underlying model is a scalar-rate multivariate Brownian motion process fit by generalized least squares using mvMORPH::mvgls [1]. Our framework also provides support estimates for individual shifts using information-criterion weights. C_LIO_LIWe illustrate the workflow using a fossil-tip-dated phylogeny and high-dimensional landmark data for early bony fish jaws (32,508 scalar coordinate values), and discuss tuning, outputs, and limitations. bifrost extends existing phylogenetic comparative frameworks for evolutionary analysis and provides a scalable pipeline for exploring the phylogenetic natural history of large multivariate datasets. C_LI

evolutionary biology↗

The phylogenetic signal of extinction through the rise and fall of early vertebrates: field of bullets or clustered strike?

We investigate patterns of phylogenetic selectivity of extinction in early aquatic vertebrates from the Silurian to the Carboniferous, an interval punctuated by one of the Big Five mass extinctions and marked by many critical anatomical (e.g. jaws, limbs) and ecological (e.g. macrophagy, terrestrialization) vertebrate evolutionary innovations. Using a new >1300 taxon, formally inferred supertree, we show that phylogenetic extinction clustering in early vertebrates varied through time and between major ecomorphological divisions of the tree. At the end of the Silurian and into the Early Devonian, jawless fishes became marginalized components of vertebrate faunas and show more strongly clustered extinction than jawed fishes, which became ecologically dominant during this interval. Clustered extinction (contemporaneous extinction of close relatives) is typical of most stages of the Devonian, particularly during the Late Devonian extinctions. By contrast, the subsequent early Carboniferous interval of putative recovery is characterized by overdispersed extinction (contemporaneous extinction of distant relatives), consistent with widespread persistence of phylogenetically distinct lineages. This work shows how varying patterns of extinction selectivity pruned the vertebrate tree at the time when the first-order patterns of diversity apparent in modern aquatic vertebrate faunas were first established.

paleontology↗

Endocrine therapy induces oxidative stress in ER+ breast cancer that sensitizes persister cells to ferroptosis

Despite endocrine therapy, recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer remain significant clinical problems. We therefore sought to identify mechanisms underlying endocrine-tolerant persistence. Endocrine-tolerant persister ER+ breast cancer cells were oxidatively stressed during endocrine therapy. Proteomic analysis revealed upregulation of antioxidant-driving enzymes including glutathione peroxidase 4 (GPX4) in persisters. Relief of oxidative stress enhanced persister fitness. The increased oxidative state of persisters enabled lipid peroxidation and ferroptosis. Persisters had an altered lipidome with increased levels of polyunsaturated fatty acids prone to peroxidation, which was attributable in part to increased lysophosphatidylcholine acyltyransferase 3 (LPCAT3, MBOAT5) expression via loss of ER-mediated repression during endocrine therapy. Treatment with the GPX4 inhibitor RSL3 enhanced the anti-persister effects of endocrine-based therapies in xenograft-bearing mice. These findings supporting the development of therapeutic strategies to leverage the oxidative stress induced by endocrine-based therapies and drive ferroptosis as a treatment for ER+ breast cancer. Statement of SignificanceEndocrine therapy increases oxidative stress and sensitizes endocrine-tolerant persister ER+ breast cancer cells to ferroptosis, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence and progression.

cancer biology↗

Tongue bite apparatus highlights functional innovation in a 310-million-year-old ray-finned fish

Gill skeleton modifications for processing prey represent a major source of functional innovation in living ray-finned fishes. Here we present the oldest actinopterygian tongue bite, derived from the gill skeleton, in the Early Pennsylvanian ([~]310 Ma) {dagger}Platysomus parvulus. Unrelated to extant tongue biters, this deep-bodied taxon possesses a large, multipartite basibranchial tooth plate opposing an upper tooth field centered on the vomer. This branchial structure occurs in conjunction with toothed jaws, indicating a role for both in feeding. {dagger}P. parvulus illustrates the assembly of the tongue bite in the geologically younger {dagger}Bobasatraniidae: large opposing dorsal (vomerine) and ventral (basibranchial) crushing plates associated with toothless jaws. The origin of tongue bites falls within the Carboniferous actinopterygian radiation, although postdates the first signs of durophagy in other ray-finned lineages by several million years. This lends support to a protracted long-fuse model of actinopterygian diversification in the aftermath of the End-Devonian Mass Extinction.

paleontology↗

The lower jaw of Devonian ray-finned fishes (Actinopterygii): anatomy, relationships, and functional morphology

Actinopterygii is a major extant vertebrate group, but limited data are available for its earliest members. Here we investigate the morphology of Devonian actinopterygians, focusing on the lower jaw. We use X-Ray Computed Tomography (XCT) to provide comprehensive descriptions of the mandibles of 19 species, which span the whole of the Devonian and represent roughly two thirds of all taxa known from more than isolated or fragmentary material. Our findings corroborate previous reports in part but reveal considerable new anatomical data and represent the first detailed description for roughly half of these taxa. The mandibles display substantial variation in size, spanning more than an order of magnitude. Although most conform to a generalized pattern of a large dentary and one or two smaller infradentaries, XCT data reveal significant differences in the structure of the jaw and arrangement of teeth that may be of functional relevance. We report the presence of a rudimentary coronoid process in several taxa, contributed to by the dentary and/or infradentaries, as well a raised articular region, resulting in a mandible with an offset bite and that functions as a bent level arm. Among the most striking variation is that of tooth morphology: several taxa have heterodont dentary teeth that vary in size and orientation, and multiple variations on enlarged, whorl-like and posteriorly-oriented anterior coronoid dentition are observed. We use these new data to revise morphological characters that may be of phylogenetic significance and consider the possible functional implications of these traits. The observed variation in mandible form and structure suggests previously unappreciated functional diversity among otherwise morphologically homogenous Devonian ray-finned fishes.

paleontology↗

Divergent morphologies with convergent performance in the mandible of pelagiarian fishes

Mandibles represent a key evolutionary innovation that enabled jawed vertebrates to adapt and diversify in response to a range of food sources. Using a phylogenetic comparative approach, we explore the phenotypic disparity and mechanical properties of the lower jaw in Pelagiaria, a morphologically diverse but relatively small clade of open-ocean fishes which are hypothesized to have radiated near the Cretaceous/Paleogene (K/Pg) mass extinction event. We found that body elongation and diet are not significantly correlated with jaw shape, but that habitat depth and tooth type are. Mechanical advantage (MA) is significantly correlated with mandible shape, with jaw-closing MA being most strongly correlated. Pelagiarian jaw shapes fall broadly into six morphotypes, of which two show significantly higher closing MA than other groups, despite differing substantially in shape. The high morphological disparity of pelagiarian mandible shape was established very early in their evolutionary history, and high levels of disparity have been maintained over tens of millions of years; this is consistent with the hypothesis that Pelagiaria represents an ancient adaptive radiation. Our results demonstrate both the mechanical and morphological diversity of the pelagiarian mandible and highlight the crucial role that morphological diversification has played in the trophic radiation of this clade.

evolutionary biology↗

Variable patterns of phenotypic evolution among canonical 'living fossil' lineages

Coelacanths, lungfishes, and holosteans represent three emblematic living fossil lineages, thought to be united by similar patterns of phenotypic change through time. While past studies suggest that diverse evolutionary patterns occur within these groups, it is unclear whether these reflect biological differences or arise from contrasting analytical approaches. Here, we examine these lineages under a common framework to assess variation in the evolution of discrete characters, and morphometric shape data, to test whether living fossils show comparable patterns of phenotypic evolution. Our results suggest different evolutionary modes occur, both among and within lineages, as a function of data type. For lungfishes, rates in discrete characters are highest in the Devonian and monotonically decline over time. Coelacanth rates show multiple early peaks followed by a decline toward the recent. Holostean rates show modest peaks but are broadly comparable over time. Patterns of body shape evolution also differ among clades, with strong support for declining rates over time for coelacanths but mixed evidence for similar dynamics in the other groups. Our results imply idiosyncratic processes of evolutionary change among traditional examples of living fossils and indicate a need to explicitly quantify patterns of change rather than apply informal, often qualitative, macroevolutionary classifications.

evolutionary biology↗

One Health in practice: Multi-season survey of ixodid tick species collected from domestic dogs in Chad

Ticks are medically important vectors of pathogens, many of which are zoonotic or impact domestic animal and/or wildlife health. Climate change, landscape use, and increasing interactions between domestic animals, wildlife, and humans have resulted in changes in tick-host dynamics and the emergence of novel pathogens worldwide. Therefore, it is crucial to describe the host and geographic ranges of vector species to assess disease risk, particularly in areas where research is lacking. This task necessitates adopting a One Health approach. In sub-Saharan Africa, previous work on ticks has focused primarily on those species most relevant to domestic livestock or humans, highlighting a significant knowledge gap concerning species of ticks that infest peri-domestic animals in rural areas. The objective of this study was to investigate the species diversity of ticks on peri-domestic dogs in rural areas of Chad, Africa. From 2019-2022, we collected 3,412 ixodid ticks from 435 peri-domestic dogs from 23 villages in Chad, Africa during both dry and wet seasons. Ticks were identified to species using morphological techniques and/or molecular analyses of the 16S rRNA, 12S rRNA, and cytochrome oxidase I gene regions. We identified 11 species of ticks from dogs including Amblyomma variegatum, Amblyomma marmoreum, Haemaphysalis leachi, a Haemaphysalis sp., Hyalomma impressum, Hyalomma truncatum, Rhipicephalus decoloratus, Rhipicephalus guilhoni, Rhipicephalus muhsamae, Rhipicephalus linnaei (=R. sanguineus tropical lineage), and a Rhipicephalus sp. Several of these tick species are known vectors for important canine and zoonotic pathogens and some are more commonly associated with cattle hosts. Our results show that sampling ticks from peri-domestic dogs provides an opportunity to examine vectors that may infest domestic animals, agricultural animals, wildlife, and humans as hosts in an understudied area. HighlightsO_LITick-borne diseases are significant concern across sub-Saharan Africa C_LIO_LILimited data on ticks of animals and people in Chad, Africa C_LIO_LIA high diversity of tick species infested domestic dogs in Chad C_LIO_LIMany detected tick species associated with important pathogens C_LI

zoology↗

Micro-CT Based Description of Dorsetichthys bechei (Actinopterygii: Teleostei): Cranial Anatomy of an Iconic Early Teleost

Teleost fishes comprise more than 36,000 living vertebrate species and occupy a wide range of aquatic ecosystems. Despite their overwhelming success, extinct taxa outside of the living radiation--stem teleosts--remain poorly understood. Dorsetichthys bechei is an Early Jurassic stem teleost of historic importance. Although D. bechei is well described, its proximity to the teleost crown and relationships with other stem teleosts is challenging due to previous associations with the wastebasket assemblage known as "pholidophorids". Here we present a new, three-dimensionally preserved specimen of Dorsetichthys bechei from the Blue Lias Formation (Sinemurian) Lyme Regis, UK. High-resolution CT scanning of this specimen plus additional material reveals previously unknown internal morphological information, including of the jaw and palate, hyoid arch, and gill skeleton. Importantly, this previously undescribed articulated specimen permits description of the external dermal skeleton and internal endoskeleton for the same individual, clarifying past accounts drawing on composite descriptions of two- and three-dimensionally preserved specimens. We confirm the presence of important teleost synapomorphies such as a mobile premaxilla and quadratojugal process. However, contrasting previous accounts, we find no evidence for dorsal and ventral hypohyals or a postarticular process of the lower jaw. We also confirm the presence of a prearticular. The presence of a mobile upper jaw, elaborate gill rakers and reduced dentition also support a possible facultative filter feeding ecology. These new anatomical data support removal of D. bechei from Pholidophoridae and Pholidophoriformes as currently defined but indicate that finer-scale patterns of relationships among more crownward members of the teleost stem are some way from being resolved.

paleontology↗

Three-dimensional anatomy of the early Eocene {dagger}Whitephippus (Teleostei: Lampriformes) documents parallel conquests of the pelagic environment by multiple teleost lineages

The early Eocene fossil assemblage of the London Clay (Southeastern England) is a key window to the early Paleogene diversification of teleost fishes in the open ocean. Despite their three-dimensional preservation that offers unique insight into skeletal anatomy, the London Clay fossils are still poorly described for the most part. {dagger}Whitephippus tamensis is a fossil teleost from this assemblage, known by several well-preserved specimens. Based on a complete description of the known material, including previously hidden structures (braincase, hyoid and branchial arches) revealed through 3D microtomography, we reinterpret {dagger}Whitephippus as an early member of the teleost group Lampriformes. More specifically, the anatomy of {dagger}Whitephippus indicates that it is likely a member of the so-called pelagic clade including modern opahs and oarfishes. This redescription of {dagger}Whitephippus provides the earliest definitive evidence of lampriforms conquering the pelagic environment, alongside numerous other teleost lineages.

paleontology↗

How to tuna fish: constraint, convergence and integration in the neurocranium of pelagiarian fishes.

Morphological evolution of the vertebrate skull has been explored across a wide range of tetrapod clades, but teleost fishes, accounting for roughly half of all vertebrate species, have largely been overlooked. Here we present the results of a study investigating three-dimensional morphological evolution across 114 species of Pelagiaria, a morphologically diverse clade of open-ocean teleost fishes that includes tuna and mackerel. Despite showing high shape disparity, the majority of taxa are concentrated in fairly restricted regions of morphospace, with taxa from all families falling into three distinct clusters. Phylogenetic signal in shape data is significant but low (Kmult = 0.27, p = 0.001) and a single-rate Ornstein-Uhlenbeck model of evolution is supported, revealing convergence in shape within and between families. Shape is significantly correlated with body elongation (R2 = 0.35, p =0.001), but correlation with size, diet, and habitat depth is weak. Integration of the neurocranium is high, supporting the hypothesis that high integration may promote the evolution of more extreme morphologies. Taken together, these results suggest that shape evolution in the pelagiarian neurocranium is constrained by a number of factors, resulting in the repeated evolution of a restricted range of morphologies.

evolutionary biology↗

Limited Defense of Liver Energy Status in Rats Susceptible to Diet-induced Obesity

Rats that are susceptible to diet-induced obesity have a preexisting reduced capacity for hepatic fatty acid oxidation compared with those resistant to diet-induced obesity. The eating response to administration of a fatty acid oxidation inhibitor is more closely associated with low liver energy status than it is with reduced hepatic fatty acid oxidation, a finding consistent with studies showing that lowered liver energy status stimulates food intake. To evaluate whether susceptibility to diet-induced obesity is associated with a preexisting impairment in liver energy status, we conducted two experiments in obesity-prone (OP) and -resistant (OR) outbred rats. In one experiment, OP rats increased food intake more than did OR rats during refeeding after a 24 h fast. When fasted and refed again, liver energy status (i.e., liver ATP content, ATP:ADP ratio and phosphorylation index) was lower in OP rats after a fast. When OP animals were refed fixed rations of food, liver energy status increased more slowly during refeeding than it did in OR rats. The delay in restoration of liver energy status during refeeding corresponded to the interval during which OP rats ate significantly more food in the intake test. In a second experiment, liver energy status was lower in OP than it was in OR rats after injection of the fructose analogue, 2,5-anhydro-D-mannitol, which depletes liver ATP. These results suggest that liver energy status is more vulnerable in rats susceptible to diet-induced obesity.

physiology↗

Molecular early burst associated with the diversification of birds at the K-Pg boundary

Complex patterns of genome and life-history evolution associated with the end-Cretaceous (K- Pg) mass extinction event limit our understanding of the early evolutionary history of crown group birds [1-9]. Here, we assess molecular heterogeneity across living birds using a technique enabling inferred sequence substitution models to transition across the history of a clade [10]. Our approach identifies distinct and contrasting regimes of molecular evolution across exons, introns, untranslated regions, and mitochondrial genomes. Up to fifteen shifts in the mode of avian molecular evolution map to rapidly diversifying clades near the Cretaceous-Palaeogene boundary, demonstrating a burst of genomic disparity early in the evolutionary history of crown birds [11-13]. Using simulation and machine learning techniques, we show that shifts in developmental mode [14] or adult body mass [4] best explain transitions in the mode of nucleotide substitution. These patterns are related, in turn, to macroevolutionary shifts in the allometric scaling relationship between basal metabolic rate and body mass [15, 16]. In agreement with theoretical predictions, this scaling relationship appears to have weakened across the end-Cretaceous transition. Overall, our study provides evidence that the Chicxulub bolide impact [17] triggered integrated patterns of evolution across avian genomes, physiology, and life history that structured the evolutionary potential of modern birds.

evolutionary biology↗

Exceptional fossil preservation and evolution of the ray-finned fish brain

Brain anatomy provides key evidence for ray-finned fish relationships1, but two key limitations obscure our understanding of neuroanatomical evolution in this major vertebrate group. First, the deepest branching living lineages are separated from the groups common ancestor by hundreds of millions of years, with indications that aspects of their brain morphology-like other aspects of their anatomy2,3-are specialised relative to primitive conditions. Second, there are no direct constraints on brain morphology in the earliest ray-finned fishes beyond the coarse picture provided by cranial endocasts: natural or virtual infillings of void spaces within the skull4-8. Here we report brain and cranial nerve soft-tissue preservation in {dagger}Coccocephalichthys wildi, a [~]319-million-year-old (Myr) ray-finned fish. This oldest example of a well-preserved vertebrate brain provides a unique window into neural anatomy deep within ray-finned fish phylogeny. {dagger}Coccocephalichthys indicates a more complicated pattern of brain evolution than suggested by living species alone, highlighting cladistian apomorphies9 and providing temporal constraints on the origin of traits uniting all extant ray-finned fishes9-11. Our findings, along with a growing set of studies in other animal groups12-16, point to the significance of ancient soft tissue preservation in understanding the deep evolutionary assembly of major anatomical systems outside of the narrow subset of skeletal tissues17-20.

paleontology↗

High lineage survivorship across the end-Devonian Mass Extinction suggested by a remarkable new Late Devonian actinopterygian

A mass extinction at the end of the Devonian is thought to have had a major influence on the evolution of actinopterygians (ray-finned fishes), which comprise half of living vertebrates. This extinction appears to have acted as a bottleneck, paring the early diversity of the group to a handful of survivors. Coupled with increases in taxonomic and morphological diversity in the Carboniferous, this contributes to a model of explosive post-extinction radiation. However, most actinopterygians from within a ~20-million-year (Myr) window surrounding the extinction remain poorly known, contributing to uncertainty about these patterns. An exceptionally preserved fossil of a diminutive fish from 7 Myr before the extinction reveals unexpected anatomical features that suggest a very different story. This new fossil nests within a clade of post-Devonian species and, in an expanded phylogenetic analysis, draws multiple lineages of Carboniferous actinopterygians into the Devonian. This suggests cryptic but extensive lineage diversification in the latest Devonian, followed by more conspicuous feeding and locomotor structure diversification in the Carboniferous. Our revised model matches more complex patterns of divergence, survival, and diversification around the Devonian-Carboniferous boundary in other vertebrate clades. It also fundamentally recalibrates the onset of diversification early in the history of this major radiation.

paleontology↗

Prolonged morphological expansion of spiny-rayed fishes following the end-Cretaceous

Spiny-rayed fishes (Acanthomorpha) dominate modern marine habitats and comprise more than a quarter of all living vertebrate species1-3. It is believed that this dominance resulted from explosive lineage and phenotypic diversification coincident with the Cretaceous-Paleogene (K-Pg) mass-extinction event4. It remains unclear, however, if living acanthomorph diversity is the result of a punctuated burst or gradual accumulation of diversity following the K-Pg. We assess these hypotheses with a time-calibrated phylogeny inferred using ultraconserved elements from a sampling of species that represent over 91% of all acanthomorph families, as well as an extensive body shape dataset of extant species. Our results indicate that several million years after the end-Cretaceous, acanthomorphs underwent a prolonged and significant expansion of morphological disparity primarily driven by changes in body elongation, and that acanthomorph lineages containing the bulk of the living species diversity originated throughout the Cenozoic. These acanthomorph lineages radiated into distinct regions of morphospace and retained their iconic phenotypes, including a large group of laterally compressed reef fishes, fast-swimming open-ocean predators, bottom-dwelling flatfishes, seahorses, and pufferfishes. The evolutionary success of spiny-rayed fishes is the culmination of a post K-Pg adaptive radiation in which rates of lineage diversification were decoupled from periods of high phenotypic disparity.

evolutionary biology↗

Muscle Atrophy: Different Strains of Mice Respond Differently to Single Limb Immobilization

To examine whether genetic variability plays a role in muscle adaption to its mechanical environment, we examined hind limb immobilization in five different strains of mice: CAST/EiJ, NOD/ShiLtJ, NZO/HILtJ, 129S1/SvImJ and A/J. Mice had one limb immobilized by a cast for three weeks. The response to immobilization was dependent on the strain of mice examined. A/J mice lost the most body weight following immobilization and displayed a significant decrease in physical activity. None of the other strains displayed a significant decrease in activity. Food consumption was significantly increased in NOD/ShiLtJ mice. All other strains had non-significant changes in food consumption. Muscle mass/body weight was decreased by immobilization, to varying degrees, in all strains except 1291/SvImJ. Casting decreased absolute muscle mass in both quadriceps and gastrocnemius in NOD/ShiltJ and NZO/HILtJ mice, two strains that can develop diabetes, but not in the other strains. Three weeks of immobilization caused a significant increase in quadriceps levels of atrogenes in CAST/EiJ mice but not in other strains. Immobilization caused a significant increase in quadriceps and gastrocnemius levels of Myh4 in CAST/EiJ mice but not in any other strain. A similar trend was observed for Myh7 in gastrocnemius muscle. Immobilization resulted in a decrease the p-p70S6K1/total p706SK1 ratio in quadriceps of NOD/ShiLtJ mice and the gastrocnemius of A/J mice, but not in other strains. Immobilization did not affect the p-4EBP1/total 4EBP1 ratio in quadriceps of any of the strains examined. However, the p-4EBP1/total 4EBP1 ratio in gastrocnemius was greater in immobilized, relative to control, limbs in CAST/EiJ mice. Muscle mass normalized to body weight in both gastrocnemius and quadriceps displayed the greatest degree of heritability. These results reveal remarkable variability in responsiveness to immobilization across five different genetic strains of mice.

physiology↗

Chemical constituents involved in e-cigarette, or vaping product use-associated lung injury (EVALI)

BackgroundThe Centers for Disease Control (CDC) declared e-cigarette (e-cig), or vaping product use-associated lung injury (EVALI) a national outbreak due to the high incidence of emergency department admissions and deaths. Investigators have identified vitamin E acetate (VEA) as the plausible cause for EVALI, based on compounds found in bronchoalveolar lavage fluid. ObjectivesWe defined the chemical constituents present in e-cig cartridges associated with EVALI and compared constituents to medical-grade and cannabidiol (CBD) containing cartridges. MethodsWe measured chemicals and elemental metals in e-liquid and vapor phases of e-cig counterfeit cartridges by Gas Chromatography (GC) and Mass Spectrometry (MS), EPA method TO-15 by GCMS, and ICP-MS analysis. ResultsWe have identified chemical constituents in e-cig vaping tetrahydrocannabinol (THC)-containing counterfeit cartridges compared to medical-grade and cannabidiol (CBD) containing cartridges. Apart from VEA and THC, other potential toxicants correlated with EVALI included solvent-derived hydrocarbons, silicon conjugated compounds, various terpenes, pesticides/plasticizers/polycaprolactones, and metals. These chemicals are known to cause symptoms, such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea, fatigue, fever, or weight loss, all symptoms presenting in patients with EVALI. ConclusionThis study provides insights into understanding the chemical-induced disease mechanism of acute lung injury.

pharmacology and toxicology↗