When is a handaxe a planned-axe? exploring morphological variability in the Acheulean.

The handaxe is an iconic stone tool form used to define and symbolise both the Acheulean and the wider Palaeolithic. There has long been debate around the extent of its morphological variability between sites, and the role that extrinsic factors (especially raw material, blank type, and the extent of resharpening) have played in driving this variability, but there has been a lack of high-resolution examinations of these factors in the same study. In this paper, we present a 2D geometric morphometric analysis of 1097 handaxes from across Africa, the Levant, and western Europe to examine the patterning of this variability and what it can tell us about hominin behaviour. We replicate the findings of previous studies, that handaxe shape varies significantly between sites and entire continental regions, but we find no evidence for raw material, blank type, or resharpening in determining this pattern. What we do find, however, is that markers of reduction trajectory vary substantially between sites, suggesting that handaxes were deployed differently according to hominin need at a given site. We argue this is reflective of a continuum of reduction strategies, from those focused on the maintenance of a sharp cutting edge (i.e. direct use in cutting activities), to those focused on maintaining tip shapes, and perhaps a corresponding production of flakes. Implications for hominin behavioural flexibility are discussed.

The nature of the last universal common ancestor and its impact on the early Earth system.

The nature of the last universal common ancestor (LUCA), its age and its impact on the Earth system have been the subject of vigorous debate across diverse disciplines, often based on disparate data and methods. Age estimates for LUCA are usually based on the fossil record, varying with every reinterpretation. The nature of LUCA's metabolism has proven equally contentious, with some attributing all core metabolisms to LUCA, whereas others reconstruct a simpler life form dependent on geochemistry. Here we infer that LUCA lived ~4.2 Ga (4.09-4.33 Ga) through divergence time analysis of pre-LUCA gene duplicates, calibrated using microbial fossils and isotope records under a new cross-bracing implementation. Phylogenetic reconciliation suggests that LUCA had a genome of at least 2.5 Mb (2.49-2.99 Mb), encoding around 2,600 proteins, comparable to modern prokaryotes. Our results suggest LUCA was a prokaryote-grade anaerobic acetogen that possessed an early immune system. Although LUCA is sometimes perceived as living in isolation, we infer LUCA to have been part of an established ecological system. The metabolism of LUCA would have provided a niche for other microbial community members and hydrogen recycling by atmospheric photochemistry could have supported a modestly productive early ecosystem.

A small switch in perspective: Comparing weight loss by nutrient balance versus caloric balance.

The establishment of a Caloric balance has been classically discussed as the means to induce weight loss. Recently, the idea of nutrient balance as opposed to Caloric balance has emerged as a better means to induce weight loss. This investigation compared differences in weight loss between a diet based on a nutrient balanced diet compared to a Caloric balance diet. 53 (27M/26F) active overfat individuals (30.7+/- 7.1 years) were randomly (matched for age, gender, training history) assigned within an 8-week intervention to follow either a self-selected diet (control) or a diet based on following a Caloric balance (%Cal/day) or a nutrient balance (g/kg/day) in conjunction with a periodized exercise regimen to determine effectiveness for each diet to induce weight loss. Nutrient balance group had significantly different changes (p < 0.05) in fat-free mass (2.26 (2.02, 2.49) kg versus 0.42 (-0.40, 1.24) kg) and fat mass (-5.96 (-5.34, -6.58) kg versus -4.08 (-3.92, -5.92) kg) relative to the Caloric balance group and was more effective at meeting nutritional requirements for protein (ES = 0.65 (0.48, 0.85)) and lipids (ES = 0.24 (-0.09, 0.98)) than the Caloric balance group. Nutrient balance was subjectively scored as easier to follow and more likely to be self-selected. Using a nutrient balance diet may be more effective at inducing beneficial body compositional changes and shows being a more self-selected dietary method when compared to a Caloric balance diet. Therefore, it may be a better choice for advice when offering treatments to those who are attempting to lose weight or maintain weight loss.

Environmental effects on genetic variance are likely to constrain adaptation in novel environments.

Adaptive plasticity allows populations to cope with environmental variation but is expected to fail as conditions become unfamiliar. In novel conditions, populations may instead rely on rapid adaptation to increase fitness and avoid extinction. Adaptation should be fastest when both plasticity and selection occur in directions of the multivariate phenotype that contain abundant genetic variation. However, tests of this prediction from field experiments are rare. Here, we quantify how additive genetic variance in a multivariate phenotype changes across an elevational gradient, and test whether plasticity and selection align with genetic variation. We do so using two closely related, but ecologically distinct, sister species of Sicilian daisy (Senecio, Asteraceae) adapted to high and low elevations on Mt. Etna. Using a quantitative genetic breeding design, we generated and then reciprocally planted c. 19,000 seeds of both species, across an elevational gradient spanning each species' native elevation, and then quantified mortality and five leaf traits of emergent seedlings. We found that genetic variance in leaf traits changed more across elevations than between species. The high-elevation species at novel lower elevations showed changes in the distribution of genetic variance among the leaf traits, which reduced the amount of genetic variance in the directions of selection and the native phenotype. By contrast, the low-elevation species mainly showed changes in the amount of genetic variance at the novel high elevation, and genetic variance was concentrated in the direction of the native phenotype. For both species, leaf trait plasticity across elevations was in a direction of the multivariate phenotype that contained a moderate amount of genetic variance. Together, these data suggest that where plasticity is adaptive, selection on genetic variance for an initially plastic response could promote adaptation. However, large environmental effects on genetic variance are likely to reduce adaptive potential in novel environments.

Decoding the muscle transcriptome of patients with late onset Pompe disease reveals markers of disease progression.

Late-onset Pompe Disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction due to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage - a classic manifestation of the disease - has been extensively studied by analysing the whole muscle tissue; however, little, if any, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single nuclei RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age and gender matched healthy controls. We matched these changes with histology findings using GeoMx Spatial Transcriptomics to compare the transcriptome of control myofibers from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibers of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibers and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibers, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes, and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. The upregulation of the genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibers. Notably, enzyme replacement therapy - the only available therapy for the disease - showed a tendency to restore metabolism dysregulation, particularly within slow fibers. A combination of single nuclei RNA sequencing and spatial transcriptomics revealed the landscape of normal and the diseased muscle, and highlighted the early abnormalities associated with the disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention.

X marks the spot: catheter aspiration using the Inari FlowTriever device to debulk defibrillator lead vegetations prior to transvenous lead extraction-a case report.

Background: When cardiac implantable electronic device infection occurs, standard therapy is usually total system extraction. Transvenous lead extraction is preferable to open heart surgical extraction, unless contraindicated because of the presence of very large vegetations on the intravenous leads according to the European Society of Cardiology guidelines. Extraction of transvenous leads with vegetations risks distal embolism resulting in obstruction and/or infection in the pulmonary arteries. Catheter aspiration of vegetations or thrombi has been performed prior to transvenous lead extraction using a partial veno-venous extracorporeal bypass circuit. We report the use of a single-access aspiration system using the Inari FlowTriever 24 French system to debulk a defibrillator lead before percutaneous extraction. Case summary: A 79-year-old male presented with fever 18 years after his first implantable cardioverter defibrillator implant and 9 years after his most recent pulse generator change. Two large vegetations were identified on his transvenous defibrillator lead on the atrial aspect, near the tricuspid annulus, which were aspirated using the Inari Medical 24Fr FlowTriever aspiration catheter. We describe anatomical considerations during the approach and a technique to localize the vegetations based on a combination of fluoroscopy and transoesophageal echocardiogram guidance. Discussion: This case demonstrates the safe and effective use of the Inari Medical 24Fr FlowTriever aspiration catheter in debulking a defibrillator lead before transvenous lead extraction. This method uses a single venous puncture and is not dependent on extracorporeal bypass. Apart from reducing complexity, this technique may be advantageous in patients where anticoagulation needs to be minimised.

Remotely sensed crown nutrient concentrations modulate forest reproduction across the contiguous United States.

Global forests are increasingly lost to climate change, disturbance, and human management. Evaluating forests' capacities to regenerate and colonize new habitats has to start with the seed production of individual trees and how it depends on nutrient access. Studies on the linkage between reproduction and foliar nutrients are limited to a few locations and few species, due to the large investment needed for field measurements on both variables. We synthesized tree fecundity estimates from the Masting Inference and Forecasting (MASTIF) network with foliar nutrient concentrations from hyperspectral remote sensing at the National Ecological Observatory Network (NEON) across the contiguous United States. We evaluated the relationships between seed production and foliar nutrients for 56,544 tree-years from 26 species at individual and community scales. We found a prevalent association between high foliar phosphorous (P) concentration and low individual seed production (ISP) across the continent. Within-species coefficients to nitrogen (N), potassium (K), calcium (Ca), and magnesium (Mg) are related to species differences in nutrient demand, with distinct biogeographic patterns. Community seed production (CSP) decreased four orders of magnitude from the lowest to the highest foliar P. This first continental-scale study sheds light on the relationship between seed production and foliar nutrients, highlighting the potential of using combined Light Detection And Ranging (LiDAR) and hyperspectral remote sensing to evaluate forest regeneration. The fact that both ISP and CSP decline in the presence of high foliar P levels has immediate application in improving forest demographic and regeneration models by providing more realistic nutrient effects at multiple scales.

Correction: Ruchaya et al. Transplantation of Skeletal Muscle-Derived Sca-1+/PW1+/Pax7- Interstitial Cells (PICs) Improves Cardiac Function and Attenuates Remodeling in Mice Subjected to Myocardial Infarction. Cells2022, 11, 4050.

In the original publication [...].

Molecular Dating of the Teleost Whole Genome Duplication (3R) Is Compatible With the Expectations of Delayed Rediploidization.

Vertebrate evolution has been punctuated by three whole genome duplication events that have been implicated causally in phenotypic evolution, from the origin of phenotypic novelties to explosive diversification. Arguably, the most dramatic of these is the 3R whole genome duplication event associated with the origin of teleost fishes which comprise more than half of all living vertebrate species. However, tests of a causal relationship between whole genome duplication and teleost diversification have proven difficult due to the challenge of establishing the timing of these phenomena. Here we show, based on molecular clock dating of concatenated gene alignments, that the 3R whole genome duplication event occurred in the early-middle Permian (286.18 to 267.20 million years ago; Ma), 52.02 to 12.84 million years (Myr) before the divergence of crown-teleosts in the latest Permian-earliest Late Triassic (254.36 to 234.16 Ma) and long before the major pulses of teleost diversification in Ostariophysi and Percomorpha (56.37 to 100.17 Myr and at least 139.24 to 183.29 Myr later, respectively). The extent of this temporal gap between putative cause and effect precludes 3R as a deterministic driver of teleost diversification. However, these age constraints remain compatible with the expectations of a prolonged rediploidization process following whole genome duplication which, through the effects of chromosome rearrangement and gene loss, remains a viable mechanism to explain the evolution of teleost novelties and diversification.

Diverse Fgfr1 signaling pathways and endocytic trafficking regulate mesoderm development.

The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1-null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identified processes regulating early mesoderm development by mechanisms involving both canonical and noncanonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.

Controlling In Planta Gold Nanoparticle Synthesis and Size for Catalysis.

Gold nanoparticles (Au-NPs) are used as catalysts for a diverse range of industrial applications. Currently, Au-NPs are synthesized chemically, but studies have shown that plants fed Au deposit, this element naturally as NPs within their tissues. The resulting plant material can be used to make biomass-derived catalysts. In vitro studies have shown that the addition of specific, short (∼10 amino acid) peptide/s to solutions can be used to control the NP size and shape, factors that can be used to optimize catalysts for different processes. Introducing these peptides into the model plant species, Arabidopsis thaliana (Arabidopsis), allows us to regulate the diameter of nanoparticles within the plant itself, consequently influencing the catalytic performance in the resulting pyrolyzed biomass. Furthermore, we show that overexpressing the copper and gold COPPER TRANSPORTER 2 (COPT2) in Arabidopsis increases the uptake of these metals. Adding value to the Au-rich biomass offers the potential to make plant-based remediation and stabilization of mine wastes financially feasible. Thus, this study represents a significant step toward engineering plants for the sustainable recovery of finite and valuable elements from our environment.

Extreme shifts in pyrite sulfur isotope compositions reveal the path to bonanza gold.

Pyrite is the most common sulfide mineral in hydrothermal ore-forming systems. The ubiquity and abundance of pyrite, combined with its ability to record and preserve a history of fluid evolution in crustal environments, make it an ideal mineral for studying the genesis of hydrothermal ore deposits, including those that host critical metals. However, with the exception of boiling, few studies have been able to directly link changes in pyrite chemistry to the processes responsible for bonanza-style gold mineralization. Here, we report the results of high-resolution secondary-ion mass spectrometry and electron microprobe analyses conducted on pyrite from the Brucejack epithermal gold deposit, British Columbia. Our δ34S and trace element results reveal that the Brucejack hydrothermal system experienced abrupt fluctuations in fluid chemistry, which preceded and ultimately coincided with the onset of ultra-high-grade mineralization. We argue that these fluctuations, which include the occurrence of extraordinarily negative δ34S values (e.g., -36.1‰) in zones of auriferous, arsenian pyrite, followed by sharp increases of δ34S values in syn-electrum zones of nonarsenian pyrite, were caused by vigorous, fault valve-induced episodic boiling (flashing) and subsequent inundation of the hydrothermal system by seawater. We conclude that the influx of seawater was the essential step to forming bonanza-grade electrum mineralization by triggering, through the addition of cationic flocculants and cooling, the aggregation of colloidal gold suspensions. Moreover, our study demonstrates the efficacy of employing high-resolution, in situ analytical techniques to map out individual ore-forming events in a hydrothermal system.

Disturbance sensitivity shapes patterns of tree species distribution in Afrotropical lowland rainforests more than climate or soil.

Understanding how tropical forests respond to abiotic environmental changes is critical for preserving biodiversity, mitigating climate change, and maintaining ecosystem services in the coming century. To evaluate the relative roles of the abiotic environment and human disturbance on Central African tree community composition, we employ tree inventory data, remotely sensed climatic data, and soil nutrient data collected from 30 1-ha plots distributed across a large-scale observational experiment in forests that had been differently impacted by logging and hunting in northern Republic of Congo. We show that the composition of Afrotropical plant communities at this scale responds to human disturbance more than to climate, with particular sensitivities to hunting and distance to the nearest village (a proxy for other human activities, including tree-cutting and gathering). These findings contrast neotropical predictions, highlighting the unique ecological, evolutionary, and anthropogenic history of Afrotropical forests.

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.

Sustainable bio-based solid phase extraction adsorbent for the determination of various types of organic compounds.

A sustainable, bio-based, mesoporous material, Starbon A800, was explored for use as an adsorbent in solid phase extraction (SPE). A solution containing seven nitrosamines was first used as a standard to optimise conditions for extraction efficiency with Starbon A800. After optimising conditions, 25 compounds of varying polarity (terpenes, phenolics, pesticides, PAHs, amines, and nitrosamines) were extracted with SPE using either Starbon® A800, C18 or Porous Graphitic Carbon (PGC) as the adsorbent, for comparison purposes. At the same time, 3 different elution solvents (heptane, dichloromethane, and ethanol) were used for each type of adsorbent. Hansen solubility parameters can be used to choose an appropriate elution solvent for the selected SPE adsorbent. The best average SPE recoveries found for the 25 various compounds were 83%, 79%, and 65% using Starbon A800, PGC, and C18 adsorbents respectively and these had dichloromethane as the elution solvent. The identification and quantification of components was carried out using UV-visible spectroscopy, two-dimensional gas chromatography (GCxGC) with time of flight/mass spectrometry (TOF/MS) or a nitrogen chemiluminescence detector (NCD). The optimized method was successfully applied to extract volatile organic compounds from red wine and tap water using Starbon A800. Starbon A800 was shown to be a promising, low-cost, green, scalable, alternative adsorbent for the extraction of various types of organic compounds of a wide range of polarities using SPE.

Identifying potential high-risk zones for land-derived plastic litter to marine megafauna and key habitats within the North Atlantic.

The pervasive use of plastic in modern society has led to plastic litter becoming ubiquitous within the ocean. Land-based sources of plastic litter are thought to account for the majority of plastic pollution in the marine environment, with plastic bags, bottles, wrappers, food containers and cutlery among the most common items found. In the marine environment, plastic is a transboundary pollutant, with the potential to cause damage far beyond the political borders from where it originated, making the management of this global pollutant particularly complex. In this study, the risks of land-derived plastic litter (LDPL) to major groups of marine megafauna - seabirds, cetaceans, pinnipeds, elasmobranchs, turtles, sirenians, tuna and billfish - and a selection of productive and biodiverse biogenic habitats - coral reefs, mangroves, seagrass, saltmarsh and kelp beds - were analysed using a Spatial Risk Assessment approach. The approach combines metrics for vulnerability (mechanism of harm for megafauna group or habitat), hazard (plastic abundance) and exposure (distribution of group or habitat). Several potential high-risk zones (HRZs) across the North Atlantic were highlighted, including the Azores, the UK, the French and US Atlantic coasts, and the US Gulf of Mexico. Whilst much of the modelled LDPL driving risk in the UK originated from domestic sources, in other HRZs, such as the Azores archipelago and the US Gulf of Mexico, plastic originated almost exclusively from external (non-domestic) sources. LDPL from Caribbean islands - some of the largest generators of marine plastic pollution in the dataset of river plastic emissions used in the study - was noted as a significant input to HRZs across both sides of the Atlantic. These findings highlight the potential of Spatial Risk Assessment analyses to determine the location of HRZs and understand where plastic debris monitoring and management should be prioritised, enabling more efficient deployment of interventions and mitigation measures.

Proposed treatment strategy for reactive hypoglycaemia.

Background/aim: Managing reactive hypoglycaemia (RH) poses challenges due to limited and often ineffective treatment options. We report a case series and draw on this to propose a stepwise treatment approach consisting of lifestyle modifications, metformin, GLP-1 analogues, and the use of flash glucose monitoring technology. Method: A retrospective review was conducted to analyse the management of 11 cases presenting with recurrent RH symptoms. Result: Two patients experienced successful resolution of symptoms through lifestyle modifications. Metformin alone was effective in treating seven out of nine patients who received pharmacological treatment. Two patients with previous upper gastrointestinal surgery showed a partial response to metformin and benefited further from additional long-acting GLP-1 analogue. Pharmacological intervention led to significant reductions in insulin and C-peptide levels in repeat mixed meal tolerance tests (P-values 0.043 for insulin and 0.006 for C-peptide). Finally, flash glucose monitoring technology was useful in early detection and preventing episodes of hypoglycaemia in one of these patients with persistent symptoms. Conclusion: These findings highlight the potential efficacy of escalated treatment strategies for RH, including the use of metformin, GLP-1 analogues, and flash glucose monitoring technology.

Plant evolution: Streptophyte multicellularity, ecology, and the acclimatisation of plants to life on land.

Land plants are celebrated as one of the three great instances of complex multicellularity, but new phylogenomic and phenotypic analyses are revealing deep evolutionary roots of multicellularity among algal relatives, prompting questions about the causal basis of this major evolutionary transition.

Diverse Fgfr1 signaling pathways and endocytic trafficking regulate early mesoderm development.

The Fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1 null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth, but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM-interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identify processes regulating early mesoderm development by mechanisms involving both canonical and non-canonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.