Evaluating Pigments as a Biosignature: Abiotic/Prebiotic Synthesis of Pigments and Pigment Mimics in Planetary Environments.

Pigments serve a multitude of functions in biology including light harvesting for photosynthesis, radiation protection, membrane support, and defense. The ubiquity of pigments-especially within extremophiles found in high-radiation, high-salinity, and dry environments-and their detectability via mission-ready techniques have elevated these molecules as promising targets in the search for evidence of life elsewhere. Moreover, the detection of pigments has been proposed as a "smoking gun" for extraterrestrial life as it has been suggested that these molecules cannot be generated abiotically. However, while pigments may hold promise as a biosignature, current understanding of their possible prebiotic origins remains understudied and uncertain. Better understanding of the abiotic synthesis of pigments is critical for evaluating the biogenicity of any pigment detected during missions, including by the Mars Perseverance rover or from returned samples. Compounding this uncertainty is the broad definition of pigment as it includes any compound capable of absorbing visible light and by itself does not specify a particular chemical motif. While not experimentally verified, there are promising prebiotic routes for generating pigments including hemes, chlorophylls, and carotenoids. Herein, we review the biochemistry of pigments, the inherent assumptions made when searching for these molecules in the field, their abiotic synthesis in industry and prebiotic reactions, prebiotically relevant molecules that can mimic their spectral signatures, and implications/recommendations for future work.

Chapter 4: A Geological and Chemical Context for the Origins of Life on Early Earth.

Within the first billion years of Earth's history, the planet transformed from a hot, barren, and inhospitable landscape to an environment conducive to the emergence and persistence of life. This chapter will review the state of knowledge concerning early Earth's (Hadean/Eoarchean) geochemical environment, including the origin and composition of the planet's moon, crust, oceans, atmosphere, and organic content. It will also discuss abiotic geochemical cycling of the CHONPS elements and how these species could have been converted to biologically relevant building blocks, polymers, and chemical networks. Proposed environments for abiogenesis events are also described and evaluated. An understanding of the geochemical processes under which life may have emerged can better inform our assessment of the habitability of other worlds, the potential complexity that abiotic chemistry can achieve (which has implications for putative biosignatures), and the possibility for biochemistries that are vastly different from those on Earth.

Transformation or replacement - Effects of hormone therapy on cardiovascular risk.

Hormone therapy (HT) is important and frequently used both regarding replacement therapy (HRT) and gender affirming therapy (GAHT). While HRT has been effective in addressing symptoms related to hormone shortage, several side effects have been described. In this context, there are some studies that show increased cardiovascular risk. However, there are also studies reporting protective aspects of HT. Nevertheless, the exact impact of HT on cardiovascular risk and the underlying mechanisms remain poorly understood. This article explores the relationship between diverse types of HT and cardiovascular risk, focusing on mechanistic insights of the underlying hormones on platelet and leukocyte function as well as on effects on endothelial and adipose tissue cells.

Manual segmentation of the paraventricular nucleus of the hypothalamus and the dorsal and ventral bed nucleus of stria terminalis using multimodal 7 Tesla structural MRI: probabilistic atlases for a stress-control triad.

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate-high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate-high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.

A Review on Hypothesized Metabolic Pathways on Europa and Enceladus: Space-Flight Detection Considerations.

Enceladus and Europa, icy moons of Saturn and Jupiter, respectively, are believed to be habitable with liquid water oceans and therefore are of interest for future life detection missions and mission concepts. With the limited data from missions to these moons, many studies have sought to better constrain these conditions. With these constraints, researchers have, based on modeling and experimental studies, hypothesized a number of possible metabolisms that could exist on Europa and Enceladus if these worlds host life. The most often hypothesized metabolisms are methanogenesis for Enceladus and methane oxidation/sulfate reduction on Europa. Here, we outline, review, and compare the best estimated conditions of each moon's ocean. We then discuss the hypothetical metabolisms that have been suggested to be present on these moons, based on laboratory studies and Earth analogs. We also detail different detection methods that could be used to detect these hypothetical metabolic reactions and make recommendations for future research and considerations for future missions.

Electron transport chains as a window into the earliest stages of evolution.

The origin and early evolution of life is generally studied under two different paradigms: bottom up and top down. Prebiotic chemistry and early Earth geochemistry allow researchers to explore possible origin of life scenarios. But for these "bottom-up" approaches, even successful experiments only amount to a proof of principle. On the other hand, "top-down" research on early evolutionary history is able to provide a historical account about ancient organisms, but is unable to investigate stages that occurred during and just after the origin of life. Here, we consider ancient electron transport chains (ETCs) as a potential bridge between early evolutionary history and a protocellular stage that preceded it. Current phylogenetic evidence suggests that ancestors of several extant ETC components were present at least as late as the last universal common ancestor of life. In addition, recent experiments have shown that some aspects of modern ETCs can be replicated by minerals, protocells, or organic cofactors in the absence of biological proteins. Here, we discuss the diversity of ETCs and other forms of chemiosmotic energy conservation, describe current work on the early evolution of membrane bioenergetics, and advocate for several lines of research to enhance this understanding by pairing top-down and bottom-up approaches.

Mucoadhesive 3D printed vaginal ovules to treat endometriosis and fibrotic uterine diseases.

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. We show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

Untapped Potential for Female Patients? Comment on Lucà et al. Update on Management of Cardiovascular Diseases in Women. J. Clin. Med. 2022, 11, 1176.

In the recently published review titled "Update on Management of Cardiovascular Diseases in Women", Lucà et al. [...].

Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection.

There have been unprecedented advances in the identification of new treatment targets for chronic hepatitis B that are being developed with the goal of achieving functional cure in patients who would otherwise require lifelong nucleoside analogue treatment. Many of the new investigational therapies either directly target the immune system or are anticipated to impact immunity indirectly through modulation of the viral lifecycle and antigen production. While new viral biomarkers (HBV RNA, HBcAg, small, middle, large HBs isoforms) are proceeding through validation steps in clinical studies, immunological biomarkers are non-existent outside of clinical assays for antibodies to HBs, HBc and HBe. To develop clinically applicable immunological biomarkers to measure mechanisms of action, inform logical combination strategies, and guide clinical management for use and discontinuation of immune-targeting drugs, immune assays must be incorporated into phase I/II clinical trials. This paper will discuss the importance of sample collection, the assays available for immunological analyses, their advantages/disadvantages and suggestions for their implementation in clinical trials. Careful consideration must be given to ensure appropriate immunological studies are included as a primary component of the trial with deeper immunological analysis provided by ancillary studies. Standardising immunological assays and data obtained from clinical trials will identify biomarkers that can be deployed in the clinic, independently of specialised immunology laboratories.

The Analyses of Cetacean Virus-Responsive Genes Reveal Evolutionary Marks in Mucosal Immunity-Associated Genes.

Viruses are the most common and abundant organisms in the marine environment. To better understand how cetaceans have adapted to this virus-rich environment, we compared cetacean virus-responsive genes to those from terrestrial mammals. We identified virus-responsive gene sequences in seven species of cetaceans, which we compared with orthologous sequences in seven terrestrial mammals. As a result of evolution analysis using the branch model and the branch-site model, 21 genes were selected using at least one model. IFN-ε, an antiviral cytokine expressed at mucous membranes, and its receptor IFNAR1 contain cetacean-specific amino acid substitutions that might change the interaction between the two proteins and lead to regulation of the immune system against viruses. Cetacean-specific amino acid substitutions in IL-6, IL-27, and the signal transducer and activator of transcription (STAT)1 are also predicted to alter the mucosal immune response of cetaceans. Since mucosal membranes are the first line of defense against the external environment and are involved in immune tolerance, our analysis of cetacean virus-responsive genes suggests that genes with cetacean-specific mutations in mucosal immunity-related genes play an important role in the protection and/or regulation of immune responses against viruses.

Planetary Minerals Catalyze Conversion of a Polycyclic Aromatic Hydrocarbon to a Prebiotic Quinone: Implications for Origins of Life.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in astrochemical environments and are disbursed into planetary environments via meteorites and extraterrestrial infall where they may interact with mineral phases to produce quinones important for origins of life. In this study, we assessed the potential of the phyllosilicates montmorillonite (MONT) and kaolinite (KAO), and the enhanced Mojave Mars Simulant (MMS) to convert the PAH anthracene (ANTH) to the biologically important 9,10-anthraquinone (ANTHQ). All studied mineral substrates mediate conversion over the temperature range assessed (25-500°C). Apparent rate curves for conversion were sigmoidal for MONT and KAO, but quadratic for MMS. Conversion efficiency maxima for ANTHQ were 3.06% ± 0.42%, 1.15% ± 0.13%, and 0.56% ± 0.039% for MONT, KAO, and MMS, respectively. We hypothesized that differential substrate binding and compound loss account for the apparent conversion kinetics observed. Apparent loss rate curves for ANTH and ANTHQ were exponential for all substrates, suggesting a pathway for wide distribution of both compounds in warmer prebiotic environments. These findings improve upon our previously reported ANTHQ conversion efficiency on MONT and provide support for a plausible scenario in which PAH-mineral interactions could have produced prebiotically relevant quinones in early Earth environments.

Phylogenomic analyses of the genus Drosophila reveals genomic signals of climate adaptation.

Many Drosophila species differ widely in their distributions and climate niches, making them excellent subjects for evolutionary genomic studies. Here, we have developed a database of high-quality assemblies for 46 Drosophila species and one closely related Zaprionus. Fifteen of the genomes were newly sequenced, and 20 were improved with additional sequencing. New or improved annotations were generated for all 47 species, assisted by new transcriptomes for 19. Phylogenomic analyses of these data resolved several previously ambiguous relationships, especially in the melanogaster species group. However, it also revealed significant phylogenetic incongruence among genes, mainly in the form of incomplete lineage sorting in the subgenus Sophophora but also including asymmetric introgression in the subgenus Drosophila. Using the phylogeny as a framework and taking into account these incongruences, we then screened the data for genome-wide signals of adaptation to different climatic niches. First, phylostratigraphy revealed relatively high rates of recent novel gene gain in three temperate pseudoobscura and five desert-adapted cactophilic mulleri subgroup species. Second, we found differing ratios of nonsynonymous to synonymous substitutions in several hundred orthologues between climate generalists and specialists, with trends for significantly higher ratios for those in tropical and lower ratios for those in temperate-continental specialists respectively than those in the climate generalists. Finally, resequencing natural populations of 13 species revealed tropics-restricted species generally had smaller population sizes, lower genome diversity and more deleterious mutations than the more widespread species. We conclude that adaptation to different climates in the genus Drosophila has been associated with large-scale and multifaceted genomic changes.

Determining the "Biosignature Threshold" for Life Detection on Biotic, Abiotic, or Prebiotic Worlds.

The field of prebiotic chemistry has demonstrated that complex organic chemical systems that exhibit various life-like properties can be produced abiotically in the laboratory. Understanding these chemical systems is important for astrobiology and life detection since we do not know the extent to which prebiotic chemistry might exist or have existed on other worlds. Nor do we know what signatures are diagnostic of an extant or "failed" prebiotic system. On Earth, biology has suppressed most abiotic organic chemistry and overprints geologic records of prebiotic chemistry; therefore, it is difficult to validate whether chemical signatures from future planetary missions are remnant or extant prebiotic systems. The "biosignature threshold" between whether a chemical signature is more likely to be produced by abiotic versus biotic chemistry on a given world could vary significantly, depending on the particular environment, and could change over time, especially if life were to emerge and diversify on that world. To interpret organic signatures detected during a planetary mission, we advocate for (1) gaining a more complete understanding of prebiotic/abiotic chemical possibilities in diverse planetary environments and (2) involving experimental prebiotic samples as analogues when generating comparison libraries for "life-detection" mission instruments.

Testing Abiotic Reduction of NAD+ Directly Mediated by Iron/Sulfur Minerals.

Life emerged in a geochemical context, possibly in the midst of mineral substrates. However, it is not known to what extent minerals and dissolved inorganic ions could have facilitated the evolution of biochemical reactions. Herein, we have experimentally shown that iron sulfide minerals can act as electron transfer agents for the reduction of the ubiquitous biological protein cofactor nicotinamide adenine dinucleotide (NAD+) under anaerobic prebiotic conditions, observing the NAD+/NADH redox transition by using ultraviolet-visible spectroscopy and 1H nuclear magnetic resonance. This reaction was mediated with iron sulfide minerals, which were likely abundant on early Earth in seafloor and hydrothermal settings; and the NAD+/NADH redox reaction occurred in the absence of UV light, peptide ligand(s), or dissolved mediators. To better understand this reaction, thermodynamic modeling was also performed. The ability of an iron sulfide mineral to transfer electrons to a biochemical cofactor that is found in every living cell demonstrates how geologic materials could have played a direct role in the evolution of certain cofactor-driven metabolic pathways.

A Proposed Geobiology-Driven Nomenclature for Astrobiological In Situ Observations and Sample Analyses.

As the exploration of Mars and other worlds for signs of life has increased, the need for a common nomenclature and consensus has become significantly important for proper identification of nonterrestrial/non-Earth biology, biogenic structures, and chemical processes generated from biological processes. The fact that Earth is our single data point for all life, diversity, and evolution means that there is an inherent bias toward life as we know it through our own planet's history. The search for life "as we don't know it" then brings this bias forward to decision-making regarding mission instruments and payloads. Understandably, this leads to several top-level scientific, theoretical, and philosophical questions regarding the definition of life and what it means for future life detection missions. How can we decide on how and where to detect known and unknown signs of life with a single biased data point? What features could act as universal biosignatures that support Darwinian evolution in the geological context of nonterrestrial time lines? The purpose of this article is to generate an improved nomenclature for terrestrial features that have mineral/microbial interactions within structures and to confirm which features can only exist from life (biotic), features that are modified by biological processes (biogenic), features that life does not affect (abiotic), and properties that can exist or not regardless of the presence of biology (abiogenic). These four categories are critical in understanding and deciphering future returned samples from Mars, signs of potential extinct/ancient and extant life on Mars, and in situ analyses from ocean worlds to distinguish and separate what physical structures and chemical patterns are due to life and which are not. Moreover, we discuss hypothetical detection and preservation environments for extant and extinct life, respectively. These proposed environments will take into account independent active and ancient in situ detection prospects by using previous planetary exploration studies and discuss the geobiological implications within an astrobiological context.

The whale shark genome reveals how genomic and physiological properties scale with body size.

The endangered whale shark (Rhincodon typus) is the largest fish on Earth and a long-lived member of the ancient Elasmobranchii clade. To characterize the relationship between genome features and biological traits, we sequenced and assembled the genome of the whale shark and compared its genomic and physiological features to those of 83 animals and yeast. We examined the scaling relationships between body size, temperature, metabolic rates, and genomic features and found both general correlations across the animal kingdom and features specific to the whale shark genome. Among animals, increased lifespan is positively correlated to body size and metabolic rate. Several genomic traits also significantly correlated with body size, including intron and gene length. Our large-scale comparative genomic analysis uncovered general features of metazoan genome architecture: Guanine and cytosine (GC) content and codon adaptation index are negatively correlated, and neural connectivity genes are longer than average genes in most genomes. Focusing on the whale shark genome, we identified multiple features that significantly correlate with lifespan. Among these were very long gene length, due to introns being highly enriched in repetitive elements such as CR1-like long interspersed nuclear elements, and considerably longer neural genes of several types, including connectivity, activity, and neurodegeneration genes. The whale shark genome also has the second slowest evolutionary rate observed in vertebrates to date. Our comparative genomics approach uncovered multiple genetic features associated with body size, metabolic rate, and lifespan and showed that the whale shark is a promising model for studies of neural architecture and lifespan.

Effects of Amino Acids on Iron-Silicate Chemical Garden Precipitation.

Understanding the structure and behavior of chemical gardens is of interest for materials science, for understanding organic-mineral interactions, and for simulating geological mineral structures in hydrothermal systems on Earth and other worlds. Herein, we explored the effects of amino acids on inorganic chemical garden precipitate systems of iron chloride and sodium silicate to determine if/how the addition of organics can affect self-assembling morphologies or crystal growth. Amino acids affect chemical garden growth and morphology at the macro-scale and at the nanoscale. In this reaction system, the concentration of amino acid had a greater impact than the amino acid side chain, and increasing concentrations of organics caused structures to have smoother exteriors as amino acids accumulated on the outside surface. These results provide an example of how organic compounds can become incorporated into and influence the growth of inorganic self-organizing precipitates in far-from-equilibrium systems. Additionally, sample handing methods were developed to successfully image these delicate structures.

Apcdd1 is a dual BMP/Wnt inhibitor in the developing nervous system and skin.

Animal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling (Shimomura et al., 2010), here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish. Furthermore, we find that Apcdd1 has an evolutionarily novel protein domain. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways that are central to animal development and human disease.

Whole Genome Analysis of the Red-Crowned Crane Provides Insight into Avian Longevity.

The red-crowned crane (Grus japonensis) is an endangered, large-bodied crane native to East Asia. It is a traditional symbol of longevity and its long lifespan has been confirmed both in captivity and in the wild. Lifespan in birds is known to be positively correlated with body size and negatively correlated with metabolic rate, though the genetic mechanisms for the red-crowned crane's long lifespan have not previously been investigated. Using whole genome sequencing and comparative evolutionary analyses against the grey-crowned crane and other avian genomes, including the long-lived common ostrich, we identified redcrowned crane candidate genes with known associations with longevity. Among these are positively selected genes in metabolism and immunity pathways (NDUFA5, NDUFA8, NUDT12, SOD3, CTH , RPA1, PHAX, HNMT , HS2ST1 , PPCDC , PSTK CD8B, GP9, IL-9R, and PTPRC). Our analyses provide genetic evidence for low metabolic rate and longevity, accompanied by possible convergent adaptation signatures among distantly related large and long-lived birds. Finally, we identified low genetic diversity in the red-crowned crane, consistent with its listing as an endangered species, and this genome should provide a useful genetic resource for future conservation studies of this rare and iconic species.