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.

Parsing the Interferon Transcriptional Network and Its Disease Associations.

Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.

Delayed use of bioenergy crops might threaten climate and food security.

The potential of mitigation actions to limit global warming within 2 °C (ref. 1) might rely on the abundant supply of biomass for large-scale bioenergy with carbon capture and storage (BECCS) that is assumed to scale up markedly in the future2-5. However, the detrimental effects of climate change on crop yields may reduce the capacity of BECCS and threaten food security6-8, thus creating an unrecognized positive feedback loop on global warming. We quantified the strength of this feedback by implementing the responses of crop yields to increases in growing-season temperature, atmospheric CO2 concentration and intensity of nitrogen (N) fertilization in a compact Earth system model9. Exceeding a threshold of climate change would cause transformative changes in social-ecological systems by jeopardizing climate stability and threatening food security. If global mitigation alongside large-scale BECCS is delayed to 2060 when global warming exceeds about 2.5 °C, then the yields of agricultural residues for BECCS would be too low to meet the Paris goal of 2 °C by 2200. This risk of failure is amplified by the sustained demand for food, leading to an expansion of cropland or intensification of N fertilization to compensate for climate-induced yield losses. Our findings thereby reinforce the urgency of early mitigation, preferably by 2040, to avoid irreversible climate change and serious food crises unless other negative-emission technologies become available in the near future to compensate for the reduced capacity of BECCS.

A most formidable arsenal: genetic technologies for building a better mouse.

The mouse is one of the most widely used model organisms for genetic study. The tools available to alter the mouse genome have developed over the preceding decades from forward screens to gene targeting in stem cells to the recent influx of CRISPR approaches. In this review, we first consider the history of mice in genetic study, the development of classic approaches to genome modification, and how such approaches have been used and improved in recent years. We then turn to the recent surge of nuclease-mediated techniques and how they are changing the field of mouse genetics. Finally, we survey common classes of alleles used in mice and discuss how they might be engineered using different methods.

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.

Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation.

BACKGROUND: Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH. METHODS: Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH. RESULTS: Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling. CONCLUSIONS: A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.

North American tree migration paced by climate in the West, lagging in the East.

Tree fecundity and recruitment have not yet been quantified at scales needed to anticipate biogeographic shifts in response to climate change. By separating their responses, this study shows coherence across species and communities, offering the strongest support to date that migration is in progress with regional limitations on rates. The southeastern continent emerges as a fecundity hotspot, but it is situated south of population centers where high seed production could contribute to poleward population spread. By contrast, seedling success is highest in the West and North, serving to partially offset limited seed production near poleward frontiers. The evidence of fecundity and recruitment control on tree migration can inform conservation planning for the expected long-term disequilibrium between climate and forest distribution.

Widespread formation of double-stranded RNAs in testis.

The testis transcriptome is highly complex and includes RNAs that potentially hybridize to form double-stranded RNA (dsRNA). We isolated dsRNA using the monoclonal J2 antibody and deep-sequenced the enriched samples from testes of juvenile Dicer1 knockout mice, age-matched controls, and adult animals. Comparison of our data set with recently published data from mouse liver revealed that the dsRNA transcriptome in testis is markedly different from liver: In testis, dsRNA-forming transcripts derive from mRNAs including promoters and immediate downstream regions, whereas in somatic cells they originate more often from introns and intergenic transcription. The genes that generate dsRNA are significantly expressed in isolated male germ cells with particular enrichment in pachytene spermatocytes. dsRNA formation is lower on the sex (X and Y) chromosomes. The dsRNA transcriptome is significantly less complex in juvenile mice as compared to adult controls and, possibly as a consequence, the knockout of Dicer1 has only a minor effect on the total number of transcript peaks associated with dsRNA. The comparison between dsRNA-associated genes in testis and liver with a reported set of genes that produce endogenous siRNAs reveals a significant overlap in testis but not in liver. Testis dsRNAs also significantly associate with natural antisense genes-again, this feature is not observed in liver. These findings point to a testis-specific mechanism involving natural antisense transcripts and the formation of dsRNAs that feed into the RNA interference pathway, possibly to mitigate the mutagenic impacts of recombination and transposon mobilization.

Diversity of thought: public perceptions of genetic testing across ethnic groups in the UK.

Genetic testing is becoming rapidly more accessible to the general populous either through or outside healthcare systems. Few large-scale studies have been carried out to gauge public opinion in this growing area. Here, we undertook the largest cross-sectional study on genetic testing in the UK. The primary purpose of this study is to identify the differences in attitudes toward genetic testing across ethnic groups. A cohort of 6500 individuals from a diverse population completed a 72-item survey in a cross-sectional study. Responses between ethnic minority and white individuals in the UK were compared using a wilcoxon rank-sum and chi-square tests. The white cohort was approximately twice as likely to have taken a genetic test and 13% more had heard about genetic testing before the survey. The ethnic minority cohort appeared more apprehensive about the impact of genetic testing on employability. This study highlights that in the UK, significant differences in opinions regarding genetic testing exist between white individuals and ethnic minority individuals. There is an urgent need to develop more inclusive strategies to equally inform individuals from all backgrounds to avoid disparities in the utilisation of genetic testing.

Nitrogen-Doped Starbons®: Methodology Development and Carbon Dioxide Capture Capability.

Five nitrogen sources (glycine, ß-alanine, urea, melamine and nicotinamide) and three heating methods (thermal, monomodal microwave and multimodal microwave) are used to prepare nitrogen-doped Starbons® derived from starch. The materials are initially produced at 250-300 °C (SNx 300y ), then heated in vacuo to 800 °C to produce nitrogen-doped SNx 800y 's. Melamine gives the highest nitrogen incorporation without destroying the Starbon® pore structure and the microwave heating methods give higher nitrogen incorporations than thermal heating. The carbon dioxide adsorption capacities of the nitrogen-doped Starbons® determined gravimetrically, in many cases exceed those of S300 and S800. The carbon dioxide, nitrogen and methane adsorption isotherms of the most promising materials are measured volumetrically. Most of the nitrogen-doped materials show higher carbon dioxide adsorption capacities than S800, but lower methane and nitrogen adsorption capacities. As a result, the nitrogen-doped Starbons® exhibit significantly enhanced carbon dioxide versus nitrogen and methane versus nitrogen selectivities compared to S800.

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.

Colloidal transport and flocculation are the cause of the hyperenrichment of gold in nature.

Aqueous complexation has long been considered the only viable means of transporting gold to depositional sites in hydrothermal ore-forming systems. A major weakness of this hypothesis is that it cannot readily explain the formation of ultrahigh-grade gold veins. This is a consequence of the relatively low gold concentrations typical of ore fluids (tens of parts per billion [ppb]) and the fact that these "bonanza" veins can contain weight-percent levels of gold in some epithermal and orogenic deposits. Here, we present direct evidence for a hypothesis that could explain these veins, namely, the transport of the gold as colloidal particles and their flocculation in nanoscale calcite veinlets. These gold-bearing nanoveinlets bear a remarkable resemblance to centimeter-scale ore veins in many hydrothermal gold deposits and give unique insight into the scale invariability of colloidal flocculation in forming hyperenriched gold deposits. Using this evidence, we propose a model for the development of bonanza gold veins in high-grade deposits. We argue that gold transport in these systems is largely mechanical and is the result of exceptionally high degrees of supersaturation that preclude precipitation of gold crystals and instead lead to the formation of colloidal particles, which flocculate and form much larger masses. These flocculated masses aggregate locally, where they are seismically pumped into fractures to locally form veins composed largely of gold. This model explains how bonanza veins may form from fluids containing ppb concentrations of gold and does not require prior encapsulation of colloidal gold particles in silica gel, as proposed by previous studies.

BMP pathway regulation of insulin signaling components promotes lipid storage in Caenorhabditis elegans.

A small number of peptide growth factor ligands are used repeatedly in development and homeostasis to drive programs of cell differentiation and function. Cells and tissues must integrate inputs from these diverse signals correctly, while failure to do so leads to pathology, reduced fitness, or death. Previous work using the nematode C. elegans identified an interaction between the bone morphogenetic protein (BMP) and insulin/IGF-1-like signaling (IIS) pathways in the regulation of lipid homeostasis. The molecular components required for this interaction, however, were not fully understood. Here we report that INS-4, one of 40 insulin-like peptides (ILPs), is regulated by BMP signaling to modulate fat accumulation. Furthermore, we find that the IIS transcription factor DAF-16/FoxO, but not SKN-1/Nrf, acts downstream of BMP signaling in lipid homeostasis. Interestingly, BMP activity alters sensitivity of these two transcription factors to IIS-promoted cytoplasmic retention in opposite ways. Finally, we probe the extent of BMP and IIS interactions by testing additional IIS functions including dauer formation, aging, and autophagy induction. Coupled with our previous work and that of other groups, we conclude that BMP and IIS pathways have at least three modes of interaction: independent, epistatic, and antagonistic. The molecular interactions we identify provide new insight into mechanisms of signaling crosstalk and potential therapeutic targets for IIS-related pathologies such as diabetes and metabolic syndrome.

The National COVID Cancer Antibody Survey: a hyper-accelerated study proof of principle for cancer research.

The COVID-19 pandemic has led to a range of novel and adaptive research designs. In this perspective, we use our experience coordinating the National COVID Cancer Antibody Survey to demonstrate how a balance between speed and integrity can be achieved within a hyper-accelerated study design. Using the COVID-19 pandemic as an example, we show this approach is necessary in the face of uncertain and evolving situations wherein reliable information is needed in a timely fashion to guide policy. We identify streamlined participant involvement, healthcare systems integration, data architecture and real-world real-time analytics as key areas that differentiate this design from traditional cancer trials, and enable rapid results. Caution needs to be taken to avoid the exclusion of patient subgroups without digital access or literacy. We summarise the merits and defining features of hyper-accelerated cancer studies.

Genome evolution in plants and the origins of innovation.

Plant evolution has been characterised by a series of major novelties in their vegetative and reproductive traits that have led to greater complexity. Underpinning this diversification has been the evolution of the genome. When viewed at the scale of the plant kingdom, plant genome evolution has been punctuated by conspicuous instances of gene and whole-genome duplication, horizontal gene transfer and extensive gene loss. The periods of dynamic genome evolution often coincide with the evolution of key traits, demonstrating the coevolution of plant genomes and phenotypes at a macroevolutionary scale. Conventionally, plant complexity and diversity have been considered through the lens of gene duplication and the role of gene loss in plant evolution remains comparatively unexplored. However, in light of reductive evolution across multiple plant lineages, the association between gene loss and plant phenotypic diversity warrants greater attention.

Hidden genetic variation in plasticity provides the potential for rapid adaptation to novel environments.

Rapid environmental change is forcing populations into environments where plasticity will no longer maintain fitness. When populations are exposed to novel environments, evolutionary theory predicts that genetic variation in fitness will increase and should be associated with genetic differences in plasticity. If true, then genetic variation in plasticity can increase adaptive potential in novel environments, and population persistence via evolutionary rescue is more likely. To test whether genetic variation in fitness increases in novel environments and is associated with plasticity, we transplanted 8149 clones of 314 genotypes of a Sicilian daisy (Senecio chrysanthemifolius) within and outside its native range, and quantified genetic variation in fitness, and plasticity in leaf traits and gene expression. Although mean fitness declined by 87% in the novel environment, genetic variance in fitness increased threefold and was correlated with plasticity in leaf traits. High fitness genotypes showed greater plasticity in gene expression, but lower plasticity in most leaf traits. Interestingly, genotypes with the highest fitness in the novel environment had the lowest fitness at the native site. These results suggest that standing genetic variation in plasticity could help populations to persist and adapt to novel environments, despite remaining hidden in native environments.

How to measure mast seeding?

The periodic production of large seed crops, or masting, is a widespread phenomenon in perennial plants. This behavior can enhance the reproductive efficiency of plants, leading to increased fitness, and produce ripple effects on food webs. While variability from year to year is a defining characteristic of masting, the methods used to quantify this variability are highly debated. The commonly used coefficient of variation lacks the ability to account for the serial dependence in mast data and can be influenced by zeros, making it a less suitable choice for various applications based on individual-level observations, such as phenotypic selection, heritability, and climate change studies, which rely on individual-plant-level datasets that often contain numerous zeros. To address these limitations, we present three case studies and introduce volatility and periodicity, which account for the variance in the frequency domain by emphasizing the significance of long intervals in masting. By utilizing examples of Sorbus aucuparia, Pinus pinea, Quercus robur, Quercus pubescens, and Fagus sylvatica, we demonstrate how volatility captures the effects of variance at both high and low frequencies, even in the presence of zeros, leading to improved ecological interpretations of the results. The growing availability of long-term, individual-plant datasets promises significant advancements in the field, but requires appropriate tools for analysis, which the new metrics provide.

Ecomorphological patterns in trigeminal canal branching among sauropsids reveal sensory shift in suchians.

The vertebrate trigeminal nerve is the primary mediator of somatosensory information from nerve endings across the face, extending nerve branches through bony canals in the face and mandibles, terminating in sensory receptors. Reptiles evolved several extreme forms of cranial somatosensation in which enhanced trigeminal tissues are present in species engaging in unique mechanosensory behaviors. However, morphology varies by clade and ecology among reptiles. Few lineages approach the extreme degree of tactile somatosensation possessed by crocodylians, the only remaining members of a clade that underwent an ecological transition from the terrestrial to semiaquatic habitat, also evolving a specialized trigeminal system. It remains to be understood how trigeminal osteological correlates inform how adaptations for enhanced cranial sensation evolved in crocodylians. Here we identify an increase in sensory abilities in Early Jurassic crocodylomorphs, preceding the transitions to a semiaquatic habitat. Through quantification of trigeminal neurovascular canal branching patterns in an extant phylogenetic bracket we quantify and identify morphologies associated with sensory behaviors in representative fossil taxa, we find stepwise progression of increasing neurovascular canal density, complexity, and distribution from the primitive archosaurian to the derived crocodilian condition. Model-based inferences of sensory ecologies tested on quantified morphologies of extant taxa with known sensory behaviors indicate a parallel increase in sensory abilities among pseudosuchians. These findings establish patterns of reptile trigeminal ecomorphology, revealing evolutionary patterns of somatosensory ecology.

Mechanistic modeling of climate effects on redistribution and population growth in a community of fish species.

Understanding community responses to climate is critical for anticipating the future impacts of global change. However, despite increased research efforts in this field, models that explicitly include important biological mechanisms are lacking. Quantifying the potential impacts of climate change on species is complicated by the fact that the effects of climate variation may manifest at several points in the biological process. To this end, we extend a dynamic mechanistic model that combines population dynamics, such as species interactions, with species redistribution by allowing climate to affect both processes. We examine their relative contributions in an application to the changing biomass of a community of eight species in the Gulf of Maine using over 30 years of fisheries data from the Northeast Fishery Science Center. Our model suggests that the mechanisms driving biomass trends vary across space, time, and species. Phase space plots demonstrate that failing to account for the dynamic nature of the environmental and biologic system can yield theoretical estimates of population abundances that are not observed in empirical data. The stock assessments used by fisheries managers to set fishing targets and allocate quotas often ignore environmental effects. At the same time, research examining the effects of climate change on fish has largely focused on redistribution. Frameworks that combine multiple biological reactions to climate change are particularly necessary for marine researchers. This work is just one approach to modeling the complexity of natural systems and highlights the need to incorporate multiple and possibly interacting biological processes in future models.

Modelling mood updating: a proof of principle study.

BACKGROUND: Recent developments in computational psychiatry have led to the hypothesis that mood represents an expectation (prior belief) on the likely interoceptive consequences of action (i.e. emotion). This stems from ideas about how the brain navigates its external world by minimising an upper bound on surprisal (free energy) of sensory information and echoes developments in other perceptual domains. AIMS: In this paper we aim to present a simple partial observable Markov decision process that models mood updating in response to stressful or non-stressful environmental fluctuations while seeking to minimise surprisal in relation to prior beliefs about the likely interoceptive signals experienced with specific actions (attenuating or amplifying stress and pleasure signals). METHOD: We examine how, by altering these prior beliefs we can model mood updating in depression, mania and anxiety. RESULTS: We discuss how these models provide a computational account of mood and its related psychopathology and relate it to previous research in reward processing. CONCLUSIONS: Models such as this can provide hypotheses for experimental work and also open up the potential modelling of predicted disease trajectories in individual patients.