Walking through volcanic mud : the 2,100 year-old Acahualina footprints (Nicaragua) II: the Acahualina people, environmental conditions and motivation

We analyzed bare human footprints in Holocene tuff preserved in two pits in the Acahualinca barrio in the northern outskirts of Managua (Nicaragua). Lithology, volcanology, and age of the deposits are discussed in a companion paper (Schmincke et al. Bull Volcanol doi: 10.1007/s00445-008-0235-9, 2008). The footprint layer occurs within a series of rapidly accumulated basaltic–andesitic tephra that is regionally correlated to the Masaya Triple Layer Tephra. The people were probably trying to escape from a powerful volcanic eruption at Masaya Caldera 20 km farther south that occurred at 2.1 ka BP. We subdivided the swath of footprints, up to 5.6 m wide, in the northern pit (Pit I) into (1) a central group of footprints made by about six individuals, the total number being difficult to determine because people walked in each other’s footsteps one behind the other and (2) two marginal groups on either side of the central group with more widely spaced tracks. The western band comprises tracks of three adjacent individuals and an isolated single footprint farther out. The eastern marginal area comprises an inner band of deep footprints made by three individuals and, farther out, three clearly separated individuals. We estimate the total number of people as 15–16. In the southern narrow and smaller pit (Pit II), we recognize tracks of ca. 12 individuals, no doubt made by the same group. The group represented in both pits probably comprised male and female adults, teenagers and children based on differences in length of footprints and of strides and depth of footprints made in the soft wet ash. The smallest footprints (probably made by children) occur in the central group, where protection was most effective. The footprint layer is composed of a lower 5–15-cm thick, coarse-grained vesicle tuff capped by a medium to fine-grained tuff up to 3 cm thick. The surface on which the people walked was muddy, and the soft ash was squeezed up on the sides of the foot imprints and between toes. Especially, deep footprints are mainly due to local thickening of the water-rich ash, multiple track use, and differences in weight of individuals. The excellent preservation of the footprints, ubiquitous mudcracks, sharp and well-preserved squeeze-ups along the margins of the tracks and toe imprints, and the absence of raindrop impressions all suggest that the eruption occurred during the dry season. The people walked at a brisk pace, as judged from the tight orientation of the swath and the length of the strides. The directions of a major erosional channel in the overlying deposits that probably debouched into Lake Managua and the band of footprints are strictly parallel, indicating that people walked together in stride along the eastern margin of a channel straight toward the lake shore, possibly a site with huts and/or boats for protection and/or escape

Late Cenozoic tephrostratigraphy offshore the southern Central American Volcanic Arc: 1. Tephra ages and provenance

We studied the tephra inventory of 18 deep sea drill sites from six DSDP/ODP legs (Legs 84, 138, 170, 202, 205, 206) and two IODP legs (Legs 334 and 344) offshore the southern Central American Volcanic Arc (CAVA). Eight drill sites are located on the incoming Cocos plate and ten drill sites on the continental slope of the Caribbean plate. In total we examined ∼840 ash-bearing horizons and identified ∼650 of these as primary ash beds of which 430 originated from the CAVA. Correlations of ash beds were established between marine cores and with terrestrial tephra deposits, using major and trace element glass compositions with respect to relative stratigraphic order. As a prerequisite for marine-terrestrial correlations we present a new geochemical data set for significant Neogene and Quaternary Costa Rican tephras. Moreover, new Ar/Ar ages for marine tephras have been determined and marine ash beds are also dated using the pelagic sedimentation rates. The resulting correlations and provenance analyses build a tephrochronostratigraphic framework for Costa Rica and Nicaragua that covers the last >8 Myr. We define 39 correlations of marine ash beds to specific tephra formations in Costa Rica and Nicaragua; from the 4.15 Ma Lower Sandillal Ignimbrite to the 3.5 ka Rincón de la Vieja Tephra from Costa Rica, as well as another 32 widely distributed tephra layers for which their specific region of origin along Costa Rica and Nicaragua can be constrained

Late Cenozoic tephrostratigraphy offshore the southern Central American Volcanic Arc: 2. Implications for magma production rates and subduction erosion

Pacific drill sites offshore Central America provide the unique opportunity to study the evolution of large explosive volcanism and the geotectonic evolution of the continental margin back into the Neogene. The temporal distribution of tephra layers established by tephrochonostratigraphy in Part 1 indicates a nearly continuous highly explosive eruption record for the Costa Rican and the Nicaraguan volcanic arc within the last 8 M.y. The widely distributed marine tephra layers comprise the major fraction of the respective erupted tephra volumes and masses thus providing insights into regional and temporal variations of large-magnitude explosive eruptions along the southern Central American Volcanic Arc (CAVA). We observe three pulses of enhanced explosive magmatism between 0-1 Ma at the Cordillera Central, between 1-2 Ma at the Guanacaste and at >3 Ma at the Western Nicaragua segments. Averaged over the long-term the minimum erupted magma flux (per unit arc length) is ∼0.017 g/ms. Tephra ages, constrained by Ar-Ar dating and by correlation with dated terrestrial tephras, yield time-variable accumulation rates of the intercalated pelagic sediments with four prominent phases of peak sedimentation rates that relate to tectonic processes of subduction erosion. The peak rate at >2.3 Ma near Osa particularly relates to initial Cocos Ridge subduction which began at 2.91±0.23 Ma as inferred by the 1.5 M.y. delayed appearance of the OIB geochemical signal in tephras from Barva volcano at 1.42 Ma. Subsequent tectonic re-arrangements probably involved crustal extension on the Guanacaste segment that favored the 2-1 Ma period of unusually massive rhyolite production

Deep Learning for Identification of Acute Illness and Facial Cues of Illness

Background: The inclusion of facial and bodily cues (clinical gestalt) in machine learning (ML) models improves the assessment of patients' health status, as shown in genetic syndromes and acute coronary syndrome. It is unknown if the inclusion of clinical gestalt improves ML-based classification of acutely ill patients. As in previous research in ML analysis of medical images, simulated or augmented data may be used to assess the usability of clinical gestalt. Objective: To assess whether a deep learning algorithm trained on a dataset of simulated and augmented facial photographs reflecting acutely ill patients can distinguish between healthy and LPS-infused, acutely ill individuals. Methods: Photographs from twenty-six volunteers whose facial features were manipulated to resemble a state of acute illness were used to extract features of illness and generate a synthetic dataset of acutely ill photographs, using a neural transfer convolutional neural network (NT-CNN) for data augmentation. Then, four distinct CNNs were trained on different parts of the facial photographs and concatenated into one final, stacked CNN which classified individuals as healthy or acutely ill. Finally, the stacked CNN was validated in an external dataset of volunteers injected with lipopolysaccharide (LPS). Results: In the external validation set, the four individual feature models distinguished acutely ill patients with sensitivities ranging from 10.5% (95% CI, 1.3–33.1% for the skin model) to 89.4% (66.9–98.7%, for the nose model). Specificity ranged from 42.1% (20.3–66.5%) for the nose model and 94.7% (73.9–99.9%) for skin. The stacked model combining all four facial features achieved an area under the receiver characteristic operating curve (AUROC) of 0.67 (0.62–0.71) and distinguished acutely ill patients with a sensitivity of 100% (82.35–100.00%) and specificity of 42.11% (20.25–66.50%). Conclusion: A deep learning algorithm trained on a synthetic, augmented dataset of facial photographs distinguished between healthy and simulated acutely ill individuals, demonstrating that synthetically generated data can be used to develop algorithms for health conditions in which large datasets are difficult to obtain. These results support the potential of facial feature analysis algorithms to support the diagnosis of acute illness

MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection

This work is licensed under a Creative Commons Attribution 4.0 International License.Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-κB dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-κB was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-κB was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-κB repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with α-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-α4 (KPNA4), which is known to translocate the NF-κB protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-κB-p65 subunit. Thereby we propose a model where 4b outcompetes NF-κB for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-κB-mediated innate immune response

SARS Coronavirus 3b Accessory Protein Modulates Transcriptional Activity of RUNX1b

BACKGROUND: The causative agent of severe acute respiratory syndrome, SARS coronavirus (SARS-CoV) genome encodes several unique group specific accessory proteins with unknown functions. Among them, accessory protein 3b (also known as ORF4) was lately identified as one of the viral interferon antagonist. Recently our lab uncovered a new role for 3b in upregulation of AP-1 transcriptional activity and its downstream genes. Thus, we believe that 3b might play an important role in SARS-CoV pathogenesis and therefore is of considerable interest. The current study aims at identifying novel host cellular interactors of the 3b protein. METHODOLOGY/PRINCIPAL FINDINGS: In this study, using yeast two-hybrid and co-immunoprecipitation techniques, we have identified a host transcription factor RUNX1b (Runt related transcription factor, isoform b) as a novel interacting partner for SARS-CoV 3b protein. Chromatin immunoprecipitaion (ChIP) and reporter gene assays in 3b expressing jurkat cells showed recruitment of 3b on the RUNX1 binding element that led to an increase in RUNX1b transactivation potential on the IL2 promoter. Kinase assay and pharmacological inhibitor treatment implied that 3b also affect RUNX1b transcriptional activity by regulating its ERK dependent phosphorylation levels. Additionally, mRNA levels of MIP-1α, a RUNX1b target gene upregulated in SARS-CoV infected monocyte-derived dendritic cells, were found to be elevated in 3b expressing U937 monocyte cells. CONCLUSIONS/SIGNIFICANCE: These results unveil a novel interaction of SARS-CoV 3b with the host factor, RUNX1b, and speculate its physiological relevance in upregulating cytokines and chemokine levels in state of SARS virus infection

Efficient RT-QuIC seeding activity for \u3b1-synuclein in olfactory mucosa samples of patients with Parkinson's disease and multiple system atrophy

Background: Parkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal \u3b1-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either \u3b1-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of \u3b1-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM). Methods: We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant \u3b1-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce \u3b1-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP. Results: Our results showed that a significant percentage of MSA and PD samples induced \u3b1-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination. Conclusions: Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for \u3b1-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages

Rapid Internalization of the Oncogenic K+ Channel KV10.1

KV10.1 is a mammalian brain voltage-gated potassium channel whose ectopic expression outside of the brain has been proven relevant for tumor biology. Promotion of cancer cell proliferation by KV10.1 depends largely on ion flow, but some oncogenic properties remain in the absence of ion permeation. Additionally, KV10.1 surface populations are small compared to large intracellular pools. Control of protein turnover within cells is key to both cellular plasticity and homeostasis, and therefore we set out to analyze how endocytic trafficking participates in controlling KV10.1 intracellular distribution and life cycle. To follow plasma membrane KV10.1 selectively, we generated a modified channel of displaying an extracellular affinity tag for surface labeling by α-bungarotoxin. This modification only minimally affected KV10.1 electrophysiological properties. Using a combination of microscopy and biochemistry techniques, we show that KV10.1 is constitutively internalized involving at least two distinct pathways of endocytosis and mainly sorted to lysosomes. This occurs at a relatively fast rate. Simultaneously, recycling seems to contribute to maintain basal KV10.1 surface levels. Brief KV10.1 surface half-life and rapid lysosomal targeting is a relevant factor to be taken into account for potential drug delivery and targeting strategies directed against KV10.1 on tumor cells

Thiram inhibits angiogenesis and slows the development of experimental tumours in mice

Thiram-tetramethylthiuram disulphide – a chelator of heavy metals, inhibited DNA synthesis and induced apoptosis in cultured bovine capillary endothelial cells. Bovine capillary endothelial cells were 10–60-fold more sensitive to thiram than other cell types. These effects were prevented by addition of antioxidants, indicating involvement of reactive oxygen species. Exogenously added Cu2+ impeded specifically and almost completely the inhibitory effect of thiram for bovine capillary endothelial cells. Moreover, thiram had markedly inhibited human recombinant Cu/Zn superoxide dismutase enzymatic activity (85%) in vitro. Moreover, PC12-SOD cells with elevated Cu/Zn superoxide dismutase were less sensitive to thiram treatment than control cells. These data indicate that the effects of thiram are mediated by inhibition of Cu/Zn superoxide dismutase activity. Oral administration of thiram (13–30 μg mouse−1), inhibited angiogenesis in CD1 nude mice. Tumour development is known to largely depend on angiogenesis. We found that oral administration of thiram (30 μg) to mice caused significant inhibition of C6 glioma tumour development (60%) and marked reduction (by 3–5-fold) in metastatic growth of Lewis lung carcinoma. The data establish thiram as a potential inhibitor of angiogenesis and raise the possibility for its use as therapy in pathologies in which neovascularisation is involved, including neoplasia

The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et a