Maternal vgll4a regulates zebrafish epiboly through Yap1 activity.

Gastrulation in zebrafish embryos commences with the morphogenetic rearrangement of blastodermal cells, which undergo a coordinated spreading from the animal pole to wrap around the egg at the vegetal pole. This rearrangement, known as epiboly, relies on the orchestrated activity of maternal transcripts present in the egg, compensating for the gradual activation of the zygotic genome. Epiboly involves the mechano-transducer activity of yap1 but what are the regulators of yap1 activity and whether these are maternally or zygotically derived remain elusive. Our study reveals the crucial role of maternal vgll4a, a proposed Yap1 competitor, during zebrafish epiboly. In embryos lacking maternal/zygotic vgll4a (MZvgll4a), the progression of epiboly and blastopore closure is delayed. This delay is associated with the ruffled appearance of the sliding epithelial cells, decreased expression of yap1-downstream targets and transient impairment of the actomyosin ring at the syncytial layer. Our study also shows that, rather than competing with yap1, vgll4a modulates the levels of the E-cadherin/ß-catenin adhesion complex at the blastomeres' plasma membrane and hence their actin cortex distribution. Taking these results together, we propose that maternal vgll4a acts at epiboly initiation upstream of yap1 and the E-cadherin/ß-catenin adhesion complex, contributing to a proper balance between tissue tension/cohesion and contractility, thereby promoting a timely epiboly progression.

Optic cup morphogenesis across species and related inborn human eye defects.

The vertebrate eye is shaped as a cup, a conformation that optimizes vision and is acquired early in development through a process known as optic cup morphogenesis. Imaging living, transparent teleost embryos and mammalian stem cell-derived organoids has provided insights into the rearrangements that eye progenitors undergo to adopt such a shape. Molecular and pharmacological interference with these rearrangements has further identified the underlying molecular machineries and the physical forces involved in this morphogenetic process. In this Review, we summarize the resulting scenarios and proposed models that include common and species-specific events. We further discuss how these studies and those in environmentally adapted blind species may shed light on human inborn eye malformations that result from failures in optic cup morphogenesis, including microphthalmia, anophthalmia and coloboma.

Post-Austronesian migrational wave of West Polynesians to Micronesia.

This study examines Y-chromosome and mtDNA markers in the population of the island of Kiritimati in the context of geographically targeted reference populations from the Pacific. Kiritimati derives its population from the atoll islands of the Gilbert Archipelago and representsa geographicaltransitional region between Micronesia, Polynesia and Melanesia that likely played a critical role during theAustronesian expansion. The large presence(84.1%)of individuals withO-M175, O2a-M324 and O2a2b-P164 sub-haplogroups, 69.9% being O2a2b-P164, the Y-STR homogeneity within O2a2b-P164 and the very recent age of the sub-haplogroup(363-548 years ago)inKiritimati suggestthe arrival ofa genetically homogenous population to the Gilberteses followed by a population expassion.The close Y-STR haplotype affinities with profiles from the Samoa and Tonga Archipelagos point to an unprecedented massive post-Austronesian expansionexodus from West Polynesia.Contrasting the abundance of AustronesianO2a2b-P164 sub-haplogroup, the most abundantMelanesian/Papuansub-haplogroup,C-M130is present at a frequency of 13.5%. Thenetwork topology suggests that C-M130 arrived to theKiribati Archipelago from West Polynesia, specifically from West Samoa, Tonga and/or Tutuila subsequent to the Austronesian expansion about 832-1408 years ago. The haplotype affinities withinO2a2b-P164 argue for anoriginal source in Taiwan and its dispersal to West Polynesia and then to Southeast Micronesia. The present investigation provides an understanding of the genetic composition and complex migration history of an understudied region of the Pacific and provides evidence for recent dispersals towards Micronesia from West Polynesia subsequent to the initial Austronesian expansion.

Low anti-SARS-CoV-2 S antibody levels predict increased mortality and dissemination of viral components in the blood of critical COVID-19 patients.

BACKGROUND: Anti-SARS-CoV-2 S antibodies prevent viral replication. Critically ill COVID-19 patients show viral material in plasma, associated with a dysregulated host response. If these antibodies influence survival and viral dissemination in ICU-COVID patients is unknown. PATIENTS/METHODS: We studied the impact of anti-SARS-CoV-2 S antibodies levels on survival, viral RNA-load in plasma, and N-antigenaemia in 92 COVID-19 patients over ICU admission. RESULTS: Frequency of N-antigenaemia was >2.5-fold higher in absence of antibodies. Antibodies correlated inversely with viral RNA-load in plasma, representing a protective factor against mortality (adjusted HR [CI 95%], p): (S IgM [AUC ≥ 60]: 0.44 [0.22; 0.88], 0.020); (S IgG [AUC ≥ 237]: 0.31 [0.16; 0.61], <0.001). Viral RNA-load in plasma and N-antigenaemia predicted increased mortality: (N1-viral load [≥2.156 copies/ml]: 2.25 [1.16; 4.36], 0.016); (N-antigenaemia: 2.45 [1.27; 4.69], 0.007). CONCLUSIONS: Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. Our findings support that these antibodies contribute to prevent systemic dissemination of SARS-CoV-2.

Comparison of real-time and droplet digital PCR to detect and quantify SARS-CoV-2 RNA in plasma.

BACKGROUND: The presence of SARS-CoV-2 RNA in plasma has been linked to disease severity and mortality. We compared RT-qPCR to droplet digital PCR (ddPCR) to detect SARS-CoV-2 RNA in plasma from COVID-19 patients (mild, moderate, and critical disease). METHODS: The presence/concentration of SARS-CoV-2 RNA in plasma was compared in three groups of COVID-19 patients (30 outpatients, 30 ward patients and 30 ICU patients) using both RT-qPCR and ddPCR. Plasma was obtained in the first 24h following admission, and RNA was extracted using eMAG. ddPCR was performed using Bio-Rad SARS-CoV-2 detection kit, and RT-qPCR was performed using GeneFinder™ COVID-19 Plus RealAmp Kit. Statistical analysis was performed using Statistical Package for the Social Science. RESULTS: SARS-CoV-2 RNA was detected, using ddPCR and RT-qPCR, in 91% and 87% of ICU patients, 27% and 23% of ward patients and 3% and 3% of outpatients. The concordance of the results obtained by both methods was excellent (Cohen's kappa index = 0.953). RT-qPCR was able to detect 34/36 (94.4%) patients positive for viral RNA in plasma by ddPCR. Viral RNA load was higher in ICU patients compared with the other groups (P < .001), by both ddPCR and RT-qPCR. AUC analysis revealed Ct values (RT-qPCR) and viral RNA load values (ddPCR) can similarly differentiate between patients admitted to wards and to the ICU (AUC of 0.90 and 0.89, respectively). CONCLUSION: Both methods yielded similar prevalence of RNAemia between groups, with ICU patients showing the highest (>85%). RT-qPCR was as useful as ddPCR to detect and quantify SARS-CoV-2 RNAemia in plasma.

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.

BACKGROUND: COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response. METHODS: A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients. RESULTS: The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia). CONCLUSIONS: SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.

East Asian warm season temperature variations over the past two millennia.

East Asia has experienced strong warming since the 1960s accompanied by an increased frequency of heat waves and shrinking glaciers over the Tibetan Plateau and the Tien Shan. Here, we place the recent warmth in a long-term perspective by presenting a new spatially resolved warm-season (May-September) temperature reconstruction for the period 1-2000 CE using 59 multiproxy records from a wide range of East Asian regions. Our Bayesian Hierarchical Model (BHM) based reconstructions generally agree with earlier shorter regional temperature reconstructions but are more stable due to additional temperature sensitive proxies. We find a rather warm period during the first two centuries CE, followed by a multi-century long cooling period and again a warm interval covering the 900-1200 CE period (Medieval Climate Anomaly, MCA). The interval from 1450 to 1850 CE (Little Ice Age, LIA) was characterized by cooler conditions and the last 150 years are characterized by a continuous warming until recent times. Our results also suggest that the 1990s were likely the warmest decade in at least 1200 years. The comparison between an ensemble of climate model simulations and our summer reconstructions since 850 CE shows good agreement and an important role of internal variability and external forcing on multi-decadal time-scales.

Simultaneous immobilization of metals and arsenic in acidic polluted soils near a copper smelter in central Chile.

INTRODUCTION: Acidic and metal(oid)-rich topsoils resulted after 34 years of continuous operations of a copper smelter in the Puchuncaví valley, central Chile. Currently, large-scale remediation actions for simultaneous in situ immobilization of metals and As are needed to reduce environmental risks of polluted soils. Aided phytostabilization is a cost-effective alternative, but adequate local available soil amendments have to be identified and management options have to be defined. MATERIALS AND METHODS: Efficacy of seashell grit (SG), biosolids (B), natural zeolite (Z), and iron-activated zeolite (AZ), either alone or in mixtures, was evaluated for reducing metal (Cu and Zn) and As solubilization in polluted soils under laboratory conditions. Perennial ryegrass was used to test phytotoxicity of experimental substrates. RESULTS: Soil neutralization to a pH of 6.5 with SG, with or without incorporation of AZ, significantly reduces metal (Cu and Zn) solubilization without affecting As solubilization in soil pore water; furthermore, it eliminates phytotoxicity and excessive metal(oid) accumulation in aerial plant tissues. Addition of B or Z to SG-amended soil does not further reduce metal solubilization into soil pore water, but increase As solubilization due to excessive soil neutralization (pH > 6.5); however, no significant As increase occurs in aerial plant tissues. CONCLUSION: Simultaneous in situ immobilization of metal(oid) in acidic topsoils is possible through aided phytostabilization.

[Toll-like receptor 2 R753Q polymorphisms are associated with an increased risk of infective endocarditis]. / El polimorfismo R753Q del toll-like receptor 2 se asocia a un aumento en el riesgo de sufrir endocarditis infecciosa.

The ability to respond to the ligands of toll-like receptors (TLR) could be affected by single nucleotide polymorphisms in TLR codifying genes. The influence of the polymorphisms TLR2 (R753Q, R677W), TLR4 (D299G, T399I) and CD14 (C-159T) was consecutively studied in 65 patients with infective endocarditis. The control group (n=66) consisted of healthy volunteers. All the polymorphisms were genotyped by means of restriction analysis after their amplification. An association between endocarditis and variants of TLR2 R753Q (P <.001) was observed, but no association with other polymorphisms was found. The TLR2 R753Q co-dominant (odds ratio=13.33), recessive (odds ratio=9.12) and dominant (odds ratio=3.65) genotypes showed a positive association with the infective endocarditis phenotype. The polymorphism TLR2 R753Q was associated with a greater susceptibility towards the development of infective endocarditis. Further studies are required to validate these results and identify other genetic risk factors.

Efficacy of lime, biosolids, and mycorrhiza for the phytostabilization of sulfidic copper tailings in Chile: a greenhouse experiment.

Inadequate abandonment of copper mine tailings under semiarid Mediterranean climate type conditions has posed important environmental risks in Chile due to wind and rain erosion. There are cost-effective technologies for tailings stabilization such as phytostabilization. However, this technology has not been used in Chile yet. This study evaluated in a greenhouse assay the efficacy of biosolids, lime, and a commercial mycorrhiza to improve adverse conditions of oxidized Cu mine tailings for adequate establishment and grow of Lolium perenne L. var nui. Chemical characterization of experimental substrates and pore water samples were performed; plant density, biomass production, chlorophyll content, and metal content in shoots was evaluated in rye grass plants after an eight-week growth period. Results showed that neutralization of tailings and superficial application of biosolids increased both aerial biomass production and chlorophyll content of rye grass. Increased Cu solubilization and translocation to shoots occurred after biosolids application (mixed), particularly on unlimed tailings, due to formation of soluble organometallic complexes with dissolved organic carbon (DOC) which can be readily absorbed by plant roots. Positive effects of mycorrhizal inoculation on rye grass growth were restricted to treatments with superficial application of biosolids, probably due to Cu toxicity effects on commercial mycorrhiza used (Glomulus intraradices).

Soil acidification as a confounding factor on metal phytotoxicity in soils spiked with copper-rich mine wastes.

Pollution of soil with mine wastes results in both Cu enrichment and soil acidification. This confounding effect may be very important in terms of phytotoxicity, because pH is a key parameter influencing Cu solubility in soil solution. Laboratory toxicity tests were used to assess the effect of acidification by acidic mine wastes on Cu solubility and on root elongation of barley (Hordeum vulgare L.). Three contrasting substrates (two soils and a commercial sand) and two acidic, Cu-rich mine wastes (oxidized tailings [OxT] and smelter dust [SmD]) were selected as experimental materials. Substrates were spiked with a fixed amount of either SmD or OxT, and the pH of experimental mixtures was then modified in the range of 4.0 to 6.0 and 7.0 using PIPES (piperazine-1,4-bis(2-ethanesulfonic acid)), MES (2-(N-morpholino)ethanesulfonic acid), and MOPS (3-(N-Morpholino)-propanesulfonic acid) buffers. Chemical (pore-water Cu and pH) and toxicological (root length of barley plants) parameters were determined for experimental mixtures. Addition of SmD and OxT to substrates resulted in acidification (0.11-1.16 pH units) and high levels of soluble Cu and Zn. Neutralization of experimental mixtures with MES (pH 6.0) and MOPS (pH 7.0) buffers resulted in a marked decrease in soluble Cu and Zn, but the intensity of the effect was substrate-dependent. Adjustment of soil pH above the range normally considered to be toxic to plants (pH in water extract, > 5.5) significantly reduced metal toxicity in barley, but phytotoxicity was not completely eliminated. The present results stress the importance of considering confounding effects on derivation of toxicity thresholds to plants when using laboratory phytotoxicity tests.

Agricultural soils spiked with copper mine wastes and copper concentrate: implications for copper bioavailability and bioaccumulation.

A better understanding of exposure to and effects of copper-rich pollutants in soils is required for accurate environmental risk assessment of copper. A greenhouse experiment was conducted to study copper bioavailability and bioaccumulation in agricultural soils spiked with different types of copper-rich mine solid wastes (copper ore, tailing sand, smelter dust, and smelter slag) and copper concentrate. A copper salt (copper sulfate, CuSO4) that frequently is used to assess soil copper bioavailability and phytotoxicity also was included for comparison. Results showed that smelter dust, tailing sand, and CuSO4 are more likely to be bioavailable and, thus, toxic to plants compared with smelter slag, concentrate, and ore at equivalent total copper concentrations. Differences may be explained by intrinsic differences in copper solubilization from the source materials, but also by their capability to decrease soil pH (confounding effect). The copper toxicity and bioaccumulation in plants also varied according to soil physicochemical characteristics (e.g., pH and total organic carbon) and the available levels of plant nutrients, such as nitrogen, phosphorus, and potassium. Chemistry/mineralogy of mine materials, soil/pore-water chemistry, and plant physiological status thus should be integrated for building adequate models to predict phytotoxicity and environmental risk of copper.

Micro-spatial variation of soil metal pollution and plant recruitment near a copper smelter in Central Chile.

Soil chemical changes produced by metal smelters have mainly been studied on a large scale. In terms of plant survival, determination of small scale variability may be more important because less toxic microhabitats may represent safe sites for successful recruitment and thus for plant survival. Three dominant microhabitats (open spaces and areas below the canopy of Sphaeralcea obtusiloba and Baccharis linearis shrubs) were defined in a heavily polluted area near a copper smelter and characterised in terms of microclimate, general soil chemistry, total and extractable metal concentrations in the soil profile (A0 horizon, 0-5 and 15-20 cm depth), and seedling densities. Results indicated a strong variability in microclimate and soil chemistry not only in the soil profile but also among microhabitats. Air/soil temperatures, radiation and wind speed were much lower under the canopy of shrubs, particularly during the plant growth season. Soil acidification was detected on top layers (0-5 cm depth) of all microhabitats while higher concentrations of N, Cu and Cd were detected on litter and top soil layers below shrubs when compared to open spaces; however, high organic matter content below shrubs decreased bioavailability of metals. Plant recruitment was concentrated under shrub canopies; this may be explained as a result of the nursery effect exerted by shrubs in terms of providing a more favourable microclimate, along with better soil conditions in terms of macronutrients and metal bioavailability.