Explore the vast range of titles available.

The Paleocene–Eocene Thermal Maximum (PETM) (55.6 Mya) was a geologically rapid carbon-release event that is considered the closest natural analog to anthropogenic CO₂ emissions. Recent work has used boron-based proxies in planktic foraminifera to characterize the extent of surface-ocean acidification that occurred during the event. However, seawater acidity alone provides an incomplete constraint on the nature and source of carbon release. Here, we apply previously undescribed culture calibrations for the B/Ca proxy in planktic foraminifera and use them to calculate relative changes in seawater-dissolved inorganic carbon (DIC) concentration, surmising that Pacific surface-ocean DIC increased by + 1 , 010 − 646 + 1 , 415 μmol/kg during the peak-PETM. Making reasonable assumptions for the pre- PETM oceanic DIC inventory, we provide a fully data-driven estimate of the PETM carbon source. Our reconstruction yields a mean source carbon δ13C of −10‰and a mean increase in the oceanic C inventory of +14,900 petagrams of carbon (PgC), pointing to volcanic CO₂ emissions as the main carbon source responsible for PETM warming.

Interactions between predators and prey are often characterized by strong selection pressures that shape extreme physiological adaptations. Venom resistance in large-bodied South American opossums (Clade Didelphini) is a striking example, as these marsupials prey on venomous snakes and exhibit remarkable resistance to their venom. While resistance is well documented in Didelphini, relatively little is known about venom resistance in the smaller, more diverse members of Didelphidae, which inhabit the same regions and encounter the same predators. Moreover, resistance of opossum von Willebrand factor (VWF) to the venom C-type lectin-like proteins has not been previously studied under simulated vascular flow states. Here, we use microfluidic devices to investigate venom resistance in the small-bodied opossum, Monodelphis domestica, examining platelet adhesion and fibrin deposition in response to purified venom components. Additionally, we conduct platelet aggregometry and assays of serum protease inhibitors in the presence of venom from sympatric and allopatric vipers to examine patterns of species-specificity and adaptation. Our results show that M. domestica resists venom-induced disruptions to platelet function in the presence of platelet-disrupting venom components botrocetin and convulxin, while aspercetin disrupts platelet and fibrin function similarly in opossum and human samples. Whole blood aggregometry and serum protease inhibition showed patterns consistent with species-specific adaptation of mammals to their local snake venom. Unexpectedly, we find that M. domestica VWF requires increased shear force to elongate, a previously unknown aspect of opossum blood physiology that may contribute to venom resistance and may have relevance to human coagulopathies. Our findings demonstrate resistance under natural shear stress, and document venom resistance beyond large-bodied Didelphini, suggesting it is a widespread trait in South American marsupials.

Aging results in systemic changes that leave older adults at much higher risk for adverse outcomes following respiratory infections. Much work has been done over the years to characterize and describe the varied changes that occur with aging from the molecular/cellular up to the organismal level. In recent years, the systemic accumulation of senescent cells has emerged as a key mediator of many age-related declines and diseases of aging. Many of these age-related changes can impair the normal function of the respiratory system and its capability to respond appropriately to potential pathogens that are encountered daily. In this review, we aim to establish the effects of cellular senescence on the disruption of normal lung function with aging and describe how these effects compound to leave an aged respiratory system at great risk when exposed to a pathogen. We will also discuss the role cellular senescence may play in the inability of most vaccines to confer protection against respiratory infections when administered to older adults. We posit that cellular senescence may be the point of convergence of many age-related immunological declines. Enhanced investigation into this area could provide much needed insight to understand the aging immune system and how to effectively ameliorate responses to pathogens that continue to disproportionately harm this vulnerable population.

Despite widespread influenza vaccination programs, influenza remains a major cause of morbidity and mortality in older adults. Age-related changes in multiple aspects of the adaptive immune response to influenza have been well-documented including a decline in antibody responses to influenza vaccination and changes in the cell-mediated response associated with immune senescence. This review will focus on T cell responses to influenza and influenza vaccination in older adults, and how increasing frailty or coexistence of multiple (≥2) chronic conditions contributes to the loss of vaccine effectiveness for the prevention of hospitalization. Further, dysregulation of the production of pro- and anti-inflammatory mediators contributes to a decline in the generation of an effective CD8 T cell response needed to clear influenza virus from the lungs. Current influenza vaccines provide only a weak stimulus to this arm of the adaptive immune response and rely on re-stimulation of CD8 T cell memory related to prior exposure to influenza virus. Efforts to improve vaccine effectiveness in older adults will be fruitless until CD8 responses take center stage.

Abstract Tandem duplication of genes can play a critical role in the evolution of functional novelty, yet our understanding is limited concerning the role of gene duplication in coevolution between species. Much is known about the evolution and function of tandemly duplicated snake venom genes, however, the potential of gene duplication to fuel venom resistance within prey species is poorly understood. The SERPINA subfamily of genes produces globular serine protease inhibitors and carrier molecules, and SERPINA1 has previously been shown to inhibit snake venom serine proteases. In this study, we characterize patterns of duplication within the tandem array of SERPINA, documenting trends in copy number evolution between species. We find the hallmarks of rapid birth-death evolution of SERPINA1-like and SERPINA3-like genes within and between rodent lineages, and evidence for diversifying selection acting on rodent genes. To explore the functional significance of copy number evolution, we recombinantly expressed the full set of 12 paralogous duplicates of SERPINA3 found in the genome of the Big-eared woodrat (Neotoma macrotis), a species known for resistance to protease-rich rattlesnake venoms. Two SERPINA3 paralogs inhibited venom serine proteases, indicating that these proteins may serve as resistance factors. In addition, functional variation is apparent among paralogs, including neofunctionalization to inhibit both chymotrypsin-like and trypsin-like proteases simultaneously for one venom-inhibiting paralog. Our results provide further evidence that the rapid evolution of SERPINA1 and SERPINA3 gene copy number across rodents has adaptive potential by producing functionally diverse venom inhibitors.

The serine protease inhibitor (SERPIN) plasminogen activator inhibitor-1 (PAI-1) is a key regulator of the fibrinolytic system, inhibiting the serine proteases tissue- and urokinase-type plasminogen activator (tPA and uPA, respectively). Missense variants render PAI-1 non-functional through misfolding, leading to its turnover as a protease substrate, or to a more rapid transition to the latent/inactive state. Deep mutational scanning was performed to evaluate the impact of amino acid sequence variation on PAI-1 inhibition of uPA using an M13 filamentous phage display system. Error prone PCR was used to construct a mutagenized PAI-1 library encompassing ~ 70% of potential single amino acid substitutions. The relative effects of 27% of all possible missense variants on PAI-1 inhibition of uPA were determined using high-throughput DNA sequencing. 826 missense variants demonstrated conserved inhibitory activity while 1137 resulted in loss of PAI-1 inhibitory function. The least evolutionarily conserved regions of PAI-1 were also identified as being the most tolerant of missense mutations. The results of this screen confirm previous low-throughput mutational studies, including those of the reactive center loop. These data provide a powerful resource for explaining structure–function relationships for PAI-1 and for the interpretation of human genomic sequence variants.

Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10-20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1α, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4 days post flu infection, while increases in Proteobacteria were evident at 7 days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

Infection with the respiratory pathogen influenza A virus (IAV) causes significant morbidity and mortality each year. While host genotype is thought to contribute to severity of disease, naturally occurring genetic determinants remain mostly unknown. Moreover, more severe disease is seen in women compared with men, but genetic mechanisms underlying this sex difference remain obscure. Here, using IAV infection in a mouse model of naturally selected genetic diversity, namely C57BL6/J (B6) mice carrying chromosomes (Chr) derived from the wild-derived and genetically divergent PWD/PhJ (PWD) mouse strain (B6.Chr PWD consomic mice), we examined the effects of genotype and sex on severity of IAV-induced disease. Compared with B6, parental PWD mice were completely protected from IAV-induced disease, a phenotype that was fully recapitulated in the B6.Chr16 PWD strain carrying the PWD-derived allele of Mx1 . In contrast, several other consomic strains, including B6.Chr3 PWD and B6.Chr5 PWD , demonstrated greatly increased susceptibility. Notably, B6.Chr5 PWD and B6.ChrX.3 PWD strains, the latter carrying the distal one-third of ChrX from PWD, exhibited increased morbidity and mortality specifically in male but not female mice. Follow up analyses focused on B6 and B6.ChrX.3 PWD strains demonstrated moderately elevated viral load in B6.ChrX3 PWD male, but not female mice. Transcriptional profiling demonstrated genotype- and sex-specific gene expression profiles in the infected lung, with male B6.ChrX.3 mice exhibiting the most significant changes, including upregulation of a proinflammatory gene expression program associated with myeloid cells, and altered sex-biased expression of several X-linked genes that represent positional candidates, including Tlr13 and Slc25a53 . Taken together, our results identify novel loci on autosomes and the X chromosome regulating IAV susceptibility and demonstrate that sex differences in IAV susceptibility are genotype-dependent, suggesting that future genetic association studies need to consider sex as a covariate.

It is well known that aging is associated with dysregulated metabolism. This is seen both in terms of systemic metabolism, as well as at the cellular level with clear mitochondrial dysfunction. More recently, the importance of cellular metabolism in immune cells, or immunometabolism, has been highlighted as a major modifier of immune cell function. Indeed, T cell activation, differentiation, and effector function partly depend on alterations in metabolic pathways with different cell types and functionality favoring either glycolysis or oxidative phosphorylation. While immune system dysfunction with aging is well described, what remains less elucidated is how the integral networks that control immune cell metabolism are specifically affected by age. In recent years, this significant gap has been identified and work has begun to investigate the various ways immunometabolism could be impacted by both chronological age and age-associated symptoms, such as the systemic accumulation of senescent cells. Here, in this mini-review, we will examine immunometabolism with a focus on T cells, aging, and interventions, such as mTOR modulators and senolytics. This review also covers a timely perspective on how immunometabolism may be an ideal target for immunomodulation with aging.

The collection of delinquent fines is a vast and ongoing public administration challenge. In the United Kingdom, unpaid fines amount to more than 500 million pounds. Managing noncompliant accounts and dispatching bailiffs to collect fines in person is costly. This paper reports the results of a large randomized controlled trial, led by the UK Cabinet Offices Behavioural Insights Team, which was designed to test the effectiveness of mobile phone text messaging as an alternative method of inducing people to pay their outstanding fines. An adaptive trial design was used, first to test the effectiveness of text messaging against no treatment and then to test the relative effectiveness of alternative messages. Text messages, which are relatively inexpensive, are found to significantly increase average payment of delinquent fines. We found text messages to be especially effective when they address the recipient by name.