Self-generating autocatalytic networks: structural results, algorithms and their relevance to early biochemistry.

The concept of an autocatalytic network of reactions that can form and persist, starting from just an available food source, has been formalized by the notion of a reflexively autocatalytic and food-generated (RAF) set. The theory and algorithmic results concerning RAFs have been applied to a range of settings, from metabolic questions arising at the origin of life, to ecological networks, and cognitive models in cultural evolution. In this article, we present new structural and algorithmic results concerning RAF sets, by studying more complex modes of catalysis that allow certain reactions to require multiple catalysts (or to not require catalysis at all), and discuss the differing ways catalysis has been viewed in the literature. We also focus on the structure and analysis of minimal RAFs and derive structural results and polynomial-time algorithms. We then apply these new methods to a large metabolic network to gain insights into possible biochemical scenarios near the origin of life.

Towards a scientific community consensus on designating Vulnerable Marine Ecosystems from imagery.

Management of deep-sea fisheries in areas beyond national jurisdiction by Regional Fisheries Management Organizations/Arrangements (RFMO/As) requires identification of areas with Vulnerable Marine Ecosystems (VMEs). Currently, fisheries data, including trawl and longline bycatch data, are used by many RFMO/As to inform the identification of VMEs. However, the collection of such data creates impacts and there is a need to collect non-invasive data for VME identification and monitoring purposes. Imagery data from scientific surveys satisfies this requirement, but there currently is no established framework for identifying VMEs from images. Thus, the goal of this study was to bring together a large international team to determine current VME assessment protocols and establish preliminary global consensus guidelines for identifying VMEs from images. An initial assessment showed a lack of consistency among RFMO/A regions regarding what is considered a VME indicator taxon, and hence variability in how VMEs might be defined. In certain cases, experts agreed that a VME could be identified from a single image, most often in areas of scleractinian reefs, dense octocoral gardens, multiple VME species' co-occurrence, and chemosynthetic ecosystems. A decision flow chart is presented that gives practical interpretation of the FAO criteria for single images. To further evaluate steps of the flow chart related to density, data were compiled to assess whether scientists perceived similar density thresholds across regions. The range of observed densities and the density values considered to be VMEs varied considerably by taxon, but in many cases, there was a statistical difference in what experts considered to be a VME compared to images not considered a VME. Further work is required to develop an areal extent index, to include a measure of confidence, and to increase our understanding of what levels of density and diversity correspond to key ecosystem functions for VME indicator taxa. Based on our results, the following recommendations are made: 1. There is a need to establish a global consensus on which taxa are VME indicators. 2. RFMO/As should consider adopting guidelines that use imagery surveys as an alternative (or complement) to using bycatch and trawl surveys for designating VMEs. 3. Imagery surveys should also be included in Impact Assessments. And 4. All industries that impact the seafloor, not just fisheries, should use imagery surveys to detect and identify VMEs.

Labor induction with a combined method (pharmacologic and mechanical): A randomized controlled trial.

INTRODUCTION: The aim of this study was to compare the effectiveness of a combined misoprostol-Foley catheter induction of labor protocol against the current guidelines of our department. MATERIAL AND METHODS: A randomized trial was conducted comparing two cervical ripening study groups: combined misoprostol-cervical Foley and the current department practice (misoprostol alone or dinoprostone alone). Women were stratified randomly according to parity for the two intervention groups. The primary outcome was defined as time to delivery (in hours). Secondary outcomes were cesarean delivery rate, time to active labor (defined as dilatation 6 cm or greater), delivery within 12 h, delivery within 24 h, maternal length of stay and indication for cesarean delivery. A composite of maternal morbidity and neonatal morbidity were also analyzed. RESULTS: 142 women were randomized into one of the two groups (74 for treatment group and 68 for control group). Demographic and clinical characteristics were similar among the two groups. The primary outcome, the average time to delivery, was faster in the treatment group (22.7 h vs 27.2 h, p = 0.03) and this difference was higher in the nulliparous subgroup (24.2 h vs 29.2 h, p = 0.03). Active phase of labor was achieved faster in the treatment group (17.9 h vs 22.7 h, p = 0.008). The risk for cesarean section was similar in both groups (OR 0.801 (0.527-1.217) vs OR 1.203 (0.871-1.662), p = 0.278). CONCLUSIONS: Our study suggests that the combined method of cervical Foley with vaginal misoprostol for women presenting to induction of labor with unfavorable Bishop scores reduces time to delivery safely. The risk for cesarean section was similar in both groups.

A modelling framework to assess multiple metals impacts on marine food webs: Relevance for assessing the ecological implications of deep-sea mining based on a systematic review.

Industrial deep-sea mining will release plumes containing metals that may disperse over long distances; however, there is no general understanding of metal effects on marine ecosystems. Thus, we conducted a systematic review in search of models of metal effects on aquatic biota with the future perspective to support Environmental Risk Assessment (ERA) of deep-sea mining. According to results, the use of models to study metal effects is strongly biased towards freshwater species (83% freshwater versus 14% marine); Cu, Hg, Al, Ni, Pb, Cd and Zn are the best-studied metals, and most studies target few species rather than entire food webs. We argue that these limitations restrain ERA on marine ecosystems. To overcome this gap of knowledge, we suggest future research directions and propose a modelling framework to predict the effects of metals on marine food webs, which in our view is relevant for ERA of deep-sea mining.

Decision-making support systems on extended hospital length of stay: Validation and recalibration of a model for patients with AMI.

Background: Cardiovascular diseases are still a significant cause of death and hospitalization. In 2019, circulatory diseases were responsible for 29.9% of deaths in Portugal. These diseases have a significant impact on the hospital length of stay. Length of stay predictive models is an efficient way to aid decision-making in health. This study aimed to validate a predictive model on the extended length of stay in patients with acute myocardial infarction at the time of admission. Methods: An analysis was conducted to test and recalibrate a previously developed model in the prediction of prolonged length of stay, for a new set of population. The study was conducted based on administrative and laboratory data of patients admitted for acute myocardial infarction events from a public hospital in Portugal from 2013 to 2015. Results: Comparable performance measures were observed upon the validation and recalibration of the predictive model of extended length of stay. Comorbidities such as shock, diabetes with complications, dysrhythmia, pulmonary edema, and respiratory infections were the common variables found between the previous model and the validated and recalibrated model for acute myocardial infarction. Conclusion: Predictive models for the extended length of stay can be applied in clinical practice since they are recalibrated and modeled to the relevant population characteristics.

Vulvar High-Grade Squamous Intraepithelial Lesion and the Risk of Recurrence and Progression to Cancer.

OBJECTIVE: This study aimed to analyze which clinical characteristics are associated with recurrence and progression of vulvar high-grade squamous intraepithelial lesion (vHSIL). MATERIALS AND METHODS: This was a retrospective cohort study, including all women with vHSIL followed in 1 center between 2009 and 2021. Women with a concomitant diagnosis of invasive vulvar cancer were excluded. Medical records were reviewed for demographic factors, clinical data, treatment type, histopathologic results, and follow-up information. RESULTS: A total of 30 women were diagnosed with vHSIL. The median follow-up time was 4 years (range = 1-12 years). More than half of the women (56.7% [17/30]) underwent excisional treatment, whereas 26.7% (8/30) underwent combined (excisional plus medical) treatment, and 16.7% (5/30) only had medical treatment (imiquimod). Six women had recurrence of vHSIL (20% [6/30]), with a mean time to recurrence of 4.7 ± 2.88 years. The progression rate to invasive vulvar cancer was 13.3% (4/30), with a mean time to progression of 1.8 ± 0.96 years. Multifocal disease was associated with progression to vulvar cancer ( p = .035). We did not identify other variables associated with progression; no differences were found between women with and without recurrences. CONCLUSIONS: Multifocality of the lesions was the only variable associated with progression to vulvar cancer. This reinforces the idea that these lesions are a challenge in both treatment and surveillance, involving a more difficult therapeutic decision with greater associated morbidity.

Biodiversity, environmental drivers, and sustainability of the global deep-sea sponge microbiome.

In the deep ocean symbioses between microbes and invertebrates are emerging as key drivers of ecosystem health and services. We present a large-scale analysis of microbial diversity in deep-sea sponges (Porifera) from scales of sponge individuals to ocean basins, covering 52 locations, 1077 host individuals translating into 169 sponge species (including understudied glass sponges), and 469 reference samples, collected anew during 21 ship-based expeditions. We demonstrate the impacts of the sponge microbial abundance status, geographic distance, sponge phylogeny, and the physical-biogeochemical environment as drivers of microbiome composition, in descending order of relevance. Our study further discloses that fundamental concepts of sponge microbiology apply robustly to sponges from the deep-sea across distances of >10,000 km. Deep-sea sponge microbiomes are less complex, yet more heterogeneous, than their shallow-water counterparts. Our analysis underscores the uniqueness of each deep-sea sponge ground based on which we provide critical knowledge for conservation of these vulnerable ecosystems.

What Wilhelm Ostwald meant by "Autokatalyse" and its significance to origins-of-life research: Facilitating the search for chemical pathways underlying abiogenesis by reviving Ostwald's thought that reactants may also be autocatalysts: Facilitating the search for chemical pathways underlying abiogenesis by reviving Ostwald's thought that reactants may also be autocatalysts.

A closer look at Wilhelm Ostwald's articles that originally proposed the concept of autocatalysis reveals that he accepted reactants, not just products, as potential autocatalysts. Therefore, that a process is catalyzed by some of its products, which is the common definition of autocatalysis, is only a proper subset of what Ostwald meant by "Autokatalyse." As a result, it is necessary to reconsider the definition of autocatalysis, which is especially important for origins-of-life research because autocatalysis provides an abiotic mechanism that yields reproduction-like dynamics. Here, we translate and briefly review the two key publications on autocatalysis by Ostwald to revive his understanding of autocatalysis, and we introduce the concepts of recessive and expansive autocatalysis. Then we discuss the twofold significance of such a revival: first, facilitating the search for candidate processes underlying the origins of life, and second, updating our view of autocatalysis in complex reaction networks and metabolism.

Habitat variability and faunal zonation at the Ægir Ridge, a canyon-like structure in the deep Norwegian Sea.

The Ægir Ridge System (ARS) is an ancient extinct spreading axis in the Nordic seas extending from the upper slope east of Iceland (∼550 m depth), as part of its Exclusive Economic Zone (EEZ), to a depth of ∼3,800 m in the Norwegian basin. Geomorphologically a rift valley, the ARS has a canyon-like structure that may promote increased diversity and faunal density. The main objective of this study was to characterize benthic habitats and related macro- and megabenthic communities along the ARS, and the influence of water mass variables and depth on them. During the IceAGE3 expedition (Icelandic marine Animals: Genetics and Ecology) on RV Sonne in June 2020, benthic communities of the ARS were surveyed by means of a remotely-operated vehicle (ROV) and epibenthic sledge (EBS). For this purpose, two working areas were selected, including abyssal stations in the northeast and bathyal stations in the southwest of the ARS. Video and still images of the seabed were usedtoqualitatively describebenthic habitats based on the presence of habitat-forming taxa and the physical environment. Patterns of diversity and community composition of the soft-sediment macrofauna, retrieved from the EBS, were analyzed in a semiquantitative manner. These biological data were complemented by producing high-resolution bathymetric maps using the vessel's multi-beam echosounder system. As suspected, we were able to identify differences in species composition and number of macro- and megafaunal communities associated with a depth gradient. A biological canyon effect became evident in dense aggregates of megafaunal filter feeders and elevated macrofaunal densities. Analysis of videos and still images from the ROV transects also led to the discovery of a number ofVulnerable Marine Ecosystems (VMEs) dominated by sponges and soft corals characteristic of the Arctic region. Directions for future research encompass a more detailed, quantitative study of the megafauna and more coherent sampling over the entire depth range in order to fully capture the diversity of the habitats and biota of the region. The presence of sensitive biogenic habitats, alongside seemingly high biodiversity and naturalness are supportive of ongoing considerations of designating part of the ARS as an "Ecologically and Biologically Significant Area" (EBSA).

Germline allelic expression of genes at 17q22 locus associates with risk of breast cancer.

INTRODUCTION: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative case-control analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes. METHODS: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples. Then we used in-silico and in-vitro analysis to map and functionally characterised candidate causal variants. RESULTS: We found a significant shift in the AE patterns of STXBP4 (rs2628315) and COX11 (rs17817901) in the normal breast tissue of cases and healthy controls. Preferential expression of the G-rs2628315 and A-rs17817901 alleles, more often observed in cases, was associated with an increased risk for BC. Analysis of blood samples from cases and controls found a similar association. Furthermore, we identified two putative cis-regulatory variants - rs17817901 and rs8066588 - that affect a miRNA and a transcription factor binding site, respectively. CONCLUSION: We propose causal variants and target genes for the 17q22 BC risk locus and show that using AE ratios in case-control association studies is helpful in identifying risk and mapping causal variants.

Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant.

PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER-, PR-, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.

Small-molecule autocatalytic networks are universal metabolic fossils.

Life and the genetic code are self-referential and so are autocatalytic networks made of simpler, small molecules. Several origins of life theories postulate autocatalytic chemical networks preceding the primordial genetic code, yet demonstration with biochemical systems is lacking. Here, small-molecule reflexively autocatalytic food-generated networks (RAFs) ranging in size from 3 to 619 reactions were found in all of 6683 prokaryotic metabolic networks searched. The average maximum RAF size is 275 reactions for a rich organic medium and 93 for a medium with a single organic cofactor, NAD. In the rich medium, all universally essential metabolites are produced with the exception of glycerol-1-p (archaeal lipid precursor), phenylalanine, histidine and arginine. The 300 most common reactions, present in at least 2732 RAFs, are mostly involved in amino acid biosynthesis and the metabolism of carbon, 2-oxocarboxylic acid and purines. ATP and NAD are central in generating network complexity, and because ATP is also one of the monomers of RNA, autocatalytic networks producing redox and energy currencies are a strong candidate niche of the origin of a primordial information-processing system. The wide distribution of small-molecule autocatalytic networks indicates that molecular reproduction may be much more prevalent in the Universe than hitherto predicted. This article is part of the theme issue 'Emergent phenomena in complex physical and socio-technical systems: from cells to societies'.

Energy at Origins: Favorable Thermodynamics of Biosynthetic Reactions in the Last Universal Common Ancestor (LUCA).

Though all theories for the origin of life require a source of energy to promote primordial chemical reactions, the nature of energy that drove the emergence of metabolism at origins is still debated. We reasoned that evidence for the nature of energy at origins should be preserved in the biochemical reactions of life itself, whereby changes in free energy, ΔG, which determine whether a reaction can go forward or not, should help specify the source. By calculating values of ΔG across the conserved and universal core of 402 individual reactions that synthesize amino acids, nucleotides and cofactors from H2, CO2, NH3, H2S and phosphate in modern cells, we find that 95-97% of these reactions are exergonic (ΔG ≤ 0 kJ⋅mol-1) at pH 7-10 and 80-100°C under nonequilibrium conditions with H2 replacing biochemical reductants. While 23% of the core's reactions involve ATP hydrolysis, 77% are ATP-independent, thermodynamically driven by ΔG of reactions involving carbon bonds. We identified 174 reactions that are exergonic by -20 to -300 kJ⋅mol-1 at pH 9 and 80°C and that fall into ten reaction types: six pterin dependent alkyl or acyl transfers, ten S-adenosylmethionine dependent alkyl transfers, four acyl phosphate hydrolyses, 14 thioester hydrolyses, 30 decarboxylations, 35 ring closure reactions, 31 aromatic ring formations, and 44 carbon reductions by reduced nicotinamide, flavins, ferredoxin, or formate. The 402 reactions of the biosynthetic core trace to the last universal common ancestor (LUCA), and reveal that synthesis of LUCA's chemical constituents required no external energy inputs such as electric discharge, UV-light or phosphide minerals. The biosynthetic reactions of LUCA uncover a natural thermodynamic tendency of metabolism to unfold from energy released by reactions of H2, CO2, NH3, H2S, and phosphate.

G-spot: Fact or Fiction?: A Systematic Review.

INTRODUCTION: The G-spot, a putative erogenous area in the anterior vaginal wall, is a widely accepted concept in the mainstream media, but controversial in medical literature. AIM: Review of the scientific data concerning the existence, location, and size of the G-spot. METHODS: Search on Pubmed, Pubmed Central, Cochrane, clinicaltrials.gov and Google Scholar from inception to November 2020 of studies on G-spot's existence, location and nature. Surveys, clinical, physiological, imaging, histological and anatomic studies were included. MAIN OUTCOME MEASURE: Existence, location, and nature of the G-spot. RESULTS: In total, 31 eligible studies were identified: 6 surveys, 5 clinical, 1 neurophysiological, 9 imaging, 8 histological/anatomical, and 2 combined clinical and histological. Most women (62.9%) reported having a G-spot and it was identified in most clinical studies (55.4% of women); in 2 studies it was not identified in any women. Imaging studies had contradictory results in terms of its existence and nature. Some showed a descending of the anterior vaginal wall, that led to the concept of clitourethrovaginal complex. In anatomic studies, one author could systematically identify the G-spot, while another group did not find it. Studies on innervation of the vaginal walls did not systematically identify an area with richer innervation. CONCLUSION: The different studies did systematically agree on the existence of the G-spot. Among the studies in which it was considered to exist, there was no agreement on its location, size, or nature. The existence of this structure remains unproved. Vieira-Baptista P, Lima-Silva J, Preti M, et al. G-spot: Fact or Fiction?: A Systematic Review. Sex Med 2021;9:100435.

The metabolic network of the last bacterial common ancestor.

Bacteria are the most abundant cells on Earth. They are generally regarded as ancient, but due to striking diversity in their metabolic capacities and widespread lateral gene transfer, the physiology of the first bacteria is unknown. From 1089 reference genomes of bacterial anaerobes, we identified 146 protein families that trace to the last bacterial common ancestor, LBCA, and form the conserved predicted core of its metabolic network, which requires only nine genes to encompass all universal metabolites. Our results indicate that LBCA performed gluconeogenesis towards cell wall synthesis, and had numerous RNA modifications and multifunctional enzymes that permitted life with low gene content. In accordance with recent findings for LUCA and LACA, analyses of thousands of individual gene trees indicate that LBCA was rod-shaped and the first lineage to diverge from the ancestral bacterial stem was most similar to modern Clostridia, followed by other autotrophs that harbor the acetyl-CoA pathway.

The Autotrophic Core: An Ancient Network of 404 Reactions Converts H2, CO2, and NH3 into Amino Acids, Bases, and Cofactors.

The metabolism of cells contains evidence reflecting the process by which they arose. Here, we have identified the ancient core of autotrophic metabolism encompassing 404 reactions that comprise the reaction network from H2, CO2, and ammonia (NH3) to amino acids, nucleic acid monomers, and the 19 cofactors required for their synthesis. Water is the most common reactant in the autotrophic core, indicating that the core arose in an aqueous environment. Seventy-seven core reactions involve the hydrolysis of high-energy phosphate bonds, furthermore suggesting the presence of a non-enzymatic and highly exergonic chemical reaction capable of continuously synthesizing activated phosphate bonds. CO2 is the most common carbon-containing compound in the core. An abundance of NADH and NADPH-dependent redox reactions in the autotrophic core, the central role of CO2, and the circumstance that the core's main products are far more reduced than CO2 indicate that the core arose in a highly reducing environment. The chemical reactions of the autotrophic core suggest that it arose from H2, inorganic carbon, and NH3 in an aqueous environment marked by highly reducing and continuously far from equilibrium conditions. Such conditions are very similar to those found in serpentinizing hydrothermal systems.

Rare earth and trace elements in deep-sea sponges of the North Atlantic.

The available data on trace elements (TE) of deep-sea organisms is scarce and nonexistent for rare earth elements (REE). Hence, this study characterizes REE and TE in five porifera genera (Jaspis, Geodia, Hamacantha, Leiodermatium, Poliopogon) collected in deep-sea areas (between 481 and 2656 m) of the North Atlantic. Aluminium was the most common TE while lead was the less abundant. These sponges showed an increased accumulation of TE compared with other probably influenced by volcanic activity. Poliopogon amadou sampled at the deepest location presented the highest concentration of all REE. All studied species exhibited a Light REE enrichment in comparison to Heavy REE and showed a negative Ce anomaly with a less conspicuous Eu depletion. Besides the establishment of a baseline for future comparisons, this study provides the first record of REE in a sessile deep-sea marine invertebrate group.

Gene Duplications Trace Mitochondria to the Onset of Eukaryote Complexity.

The last eukaryote common ancestor (LECA) possessed mitochondria and all key traits that make eukaryotic cells more complex than their prokaryotic ancestors, yet the timing of mitochondrial acquisition and the role of mitochondria in the origin of eukaryote complexity remain debated. Here, we report evidence from gene duplications in LECA indicating an early origin of mitochondria. Among 163,545 duplications in 24,571 gene trees spanning 150 sequenced eukaryotic genomes, we identify 713 gene duplication events that occurred in LECA. LECA's bacterial-derived genes include numerous mitochondrial functions and were duplicated significantly more often than archaeal-derived and eukaryote-specific genes. The surplus of bacterial-derived duplications in LECA most likely reflects the serial copying of genes from the mitochondrial endosymbiont to the archaeal host's chromosomes. Clustering, phylogenies and likelihood ratio tests for 22.4 million genes from 5,655 prokaryotic and 150 eukaryotic genomes reveal no evidence for lineage-specific gene acquisitions in eukaryotes, except from the plastid in the plant lineage. That finding, and the functions of bacterial genes duplicated in LECA, suggests that the bacterial genes in eukaryotes are acquisitions from the mitochondrion, followed by vertical gene evolution and differential loss across eukaryotic lineages, flanked by concomitant lateral gene transfer among prokaryotes. Overall, the data indicate that recurrent gene transfer via the copying of genes from a resident mitochondrial endosymbiont to archaeal host chromosomes preceded the onset of eukaryotic cellular complexity, favoring mitochondria-early over mitochondria-late hypotheses for eukaryote origin.