Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells.

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.

Microbial biomarkers reveal a hydrothermally active landscape at Olduvai Gorge at the dawn of the Acheulean, 1.7 Ma.

Landscape-scale reconstructions of ancient environments within the cradle of humanity may reveal insights into the relationship between early hominins and the changing resources around them. Many studies of Olduvai Gorge during Pliocene-Pleistocene times have revealed the presence of precession-driven wet-dry cycles atop a general aridification trend, though may underestimate the impact of local-scale conditions on early hominins, who likely experienced a varied and more dynamic landscape. Fossil lipid biomarkers from ancient plants and microbes encode information about their surroundings via their molecular structures and composition, and thus can shed light on past environments. Here, we employ fossil lipid biomarkers to study the paleolandscape at Olduvai Gorge at the emergence of the Acheulean technology, 1.7 Ma, through the Lower Augitic Sandstones layer. In the context of the expansion of savanna grasslands, our results represent a resource-rich mosaic ecosystem populated by groundwater-fed rivers, aquatic plants, angiosperm shrublands, and edible plants. Evidence of a geothermally active landscape is reported via an unusual biomarker distribution consistent with the presence of hydrothermal features seen today at Yellowstone National Park. The study of hydrothermalism in ancient settings and its impact on hominin evolution has not been addressed before, although the association of thermal springs in the proximity of archaeological sites documented here can also be found at other localities. The hydrothermal features and resources present at Olduvai Gorge may have allowed early hominins to thermally process edible plants and meat, supporting the possibility of a prefire stage of human evolution.

Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication.

Zinc pyrithione (1a), together with its analogues 1b-h and ruthenium pyrithione complex 2a, were synthesised and evaluated for the stability in biologically relevant media and anti-SARS-CoV-2 activity. Zinc pyrithione revealed potent in vitro inhibition of cathepsin L (IC50=1.88 ± 0.49 µM) and PLPro (IC50=0.50 ± 0.07 µM), enzymes involved in SARS-CoV-2 entry and replication, respectively, as well as antiviral entry and replication properties in an ex vivo system derived from primary human lung tissue. Zinc complexes 1b-h expressed comparable in vitro inhibition. On the contrary, ruthenium complex 2a and the ligand pyrithione a itself expressed poor inhibition in mentioned assays, indicating the importance of the selection of metal core and structure of metal complex for antiviral activity. Safe, effective, and preferably oral at-home therapeutics for COVID-19 are needed and as such zinc pyrithione, which is also commercially available, could be considered as a potential therapeutic agent against SARS-CoV-2.

Entrectinib-A SARS-CoV-2 Inhibitor in Human Lung Tissue (HLT) Cells.

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify drug candidates that are able to block the entrance of the virus into human cells. By combining virtual screening with in vitro pseudovirus assays and antiviral assays in Human Lung Tissue (HLT) cells, we identify entrectinib as a potential antiviral drug.

KLRG1 expression on natural killer cells is associated with HIV persistence, and its targeting promotes the reduction of the viral reservoir.

Human immunodeficiency virus (HIV) infection induces immunological dysfunction, which limits the elimination of HIV-infected cells during treated infection. Identifying and targeting dysfunctional immune cells might help accelerate the purging of the persistent viral reservoir. Here, we show that chronic HIV infection increases natural killer (NK) cell populations expressing the negative immune regulator KLRG1, both in peripheral blood and lymph nodes. Antiretroviral treatment (ART) does not reestablish these functionally impaired NK populations, and the expression of KLRG1 correlates with active HIV transcription. Targeting KLRG1 with specific antibodies significantly restores the capacity of NK cells to kill HIV-infected cells, reactivates latent HIV present in CD4+ T cells co-expressing KLRG1, and reduces the intact HIV genomes in samples from ART-treated individuals. Our data support the potential use of immunotherapy against the KLRG1 receptor to impact the viral reservoir during HIV persistence.

A symbolic Neanderthal accumulation of large herbivore crania.

This work examines the possible behaviour of Neanderthal groups at the Cueva Des-Cubierta (central Spain) via the analysis of the latter's archaeological assemblage. Alongside evidence of Mousterian lithic industry, Level 3 of the cave infill was found to contain an assemblage of mammalian bone remains dominated by the crania of large ungulates, some associated with small hearths. The scarcity of post-cranial elements, teeth, mandibles and maxillae, along with evidence of anthropogenic modification of the crania (cut and percussion marks), indicates that the carcasses of the corresponding animals were initially processed outside the cave, and the crania were later brought inside. A second round of processing then took place, possibly related to the removal of the brain. The continued presence of crania throughout Level 3 indicates that this behaviour was recurrent during this level's formation. This behaviour seems to have no subsistence-related purpose but to be more symbolic in its intent.

Transfer of median and ulnar nerve fascicles for lesions of the posterior cord in infraclavicular brachial plexus injury: report of 2 cases.

In infraclavicular lesions of brachial plexus, severe lesions of the posterior cord often occur when medial and lateral cord function is preserved to a greater or lesser extent. In these cases, shoulder function may be preserved by activity of the muscles innervated by the suprascapular nerve, but complete paralysis exists in the deltoid, triceps, and brachioradialis, and all wrist and finger extensors. Classical reconstruction procedures consist of nerve grafts, but their results in adults are disappointing. We report an approach transferring: (1) an ulnar nerve fascicle to the motor branch of the long portion of the triceps brachii muscle, (2) a median nerve branch from the pronator teres to the motor branch of the extensor carpi radialis longus, and (3) a median nerve branch from the flexor carpi radialis to the posterior interosseous nerve. We describe the procedure and report 2 clinical cases showing the effectiveness of this technique for restoring extension of the elbow, wrist, and fingers in the common infraclavicular lesions of the brachial plexus affecting the posterior cord.

Neo-taphonomic analysis of the Misiam leopard lair from Olduvai Gorge (Tanzania): understanding leopard-hyena interactions in open settings.

Misiam is a modern wildebeest-dominated accumulation situated in a steep ravine covered with dense vegetation at Olduvai Gorge (Tanzania). It is interpreted here as a leopard lair to which carcasses have been transported for several years. Felid-specific bone damage patterns, felid-typical skeletal part profiles, taxonomic specialization and the physical presence of leopards observed by the authors show that leopards at Misiam can be specialized medium-sized carcass accumulators. Hyenas also intervened at intervals in the modification of the retrieved faunal assemblage. This makes Misiam a carnivore palimpsest. Here, we additionally show that leopards only transport and accumulate carcasses on occasions, that they can seem highly specialized despite being dietary generalists, and that such a behaviour may be prompted by seasonal competition or during the breeding season or both. Misiam is the first open-air leopard lair with a dense bone accumulation reported. There, leopards engaged in intensive accumulation of carcasses during the wet season, when the southern Serengeti short-grass plains undergo the effect of the famous wildebeest migration and this migratory species reaches the gorge. The ecological importance of this behaviour and its relevance as a proxy for reconstructing prehistoric carnivore behaviours are discussed.

Transfer of the nerve to the brachioradialis muscle to the anterior interosseous nerve for treatment for lower brachial plexus lesions: case report.

In lower lesions of the brachial plexus (C8-T1) there is good function of the shoulder, elbow, and wrist, although that of the hand is impaired. Reconstruction of finger flexion is generally obtained by tendon transfer. We present a case report involving transfer of the motor nerve branch of the brachioradialis muscle to the anterior interosseous nerve to restore finger flexion in acute lower brachial plexus lesion.

Punctuated ecological equilibrium in mammal communities over evolutionary time scales.

The study of deep-time ecological dynamics has the ability to inform conservation decisions by anticipating the behavior of ecosystems millions of years into the future. Using network analysis and an exceptional fossil dataset spanning the past 21 million years, we show that mammalian ecological assemblages undergo long periods of functional stasis, notwithstanding high taxonomic volatility due to dispersal, speciation, and extinction. Higher functional richness and diversity promoted the persistence of functional faunas despite species extinction risk being indistinguishable among these different faunas. These findings, and the large mismatch between functional and taxonomic successions, indicate that although safeguarding functional diversity may or may not minimize species losses, it would certainly enhance the persistence of ecosystem functioning in the face of future disturbances.

Peripheral and lung resident memory T cell responses against SARS-CoV-2.

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.

Early Pleistocene faunivorous hominins were not kleptoparasitic, and this impacted the evolution of human anatomy and socio-ecology.

Humans are unique in their diet, physiology and socio-reproductive behavior compared to other primates. They are also unique in the ubiquitous adaptation to all biomes and habitats. From an evolutionary perspective, these trends seem to have started about two million years ago, coinciding with the emergence of encephalization, the reduction of the dental apparatus, the adoption of a fully terrestrial lifestyle, resulting in the emergence of the modern anatomical bauplan, the focalization of certain activities in the landscape, the use of stone tools, and the exit from Africa. It is in this period that clear taphonomic evidence of a switch in diet with respect to Pliocene hominins occurred, with the adoption of carnivory. Until now, the degree of carnivorism in early humans remained controversial. A persistent hypothesis is that hominins acquired meat irregularly (potentially as fallback food) and opportunistically through klepto-foraging. Here, we test this hypothesis and show, in contrast, that the butchery practices of early Pleistocene hominins (unveiled through systematic study of the patterning and intensity of cut marks on their prey) could not have resulted from having frequent secondary access to carcasses. We provide evidence of hominin primary access to animal resources and emphasize the role that meat played in their diets, their ecology and their anatomical evolution, ultimately resulting in the ecologically unrestricted terrestrial adaptation of our species. This has major implications to the evolution of human physiology and potentially for the evolution of the human brain.

Application of artificially intelligent systems for the identification of discrete fossiliferous levels.

The separation of discrete fossiliferous levels within an archaeological or paleontological site with no clear stratigraphic horizons has historically been carried out using qualitative approaches, relying on two-dimensional transversal and longitudinal projection planes. Analyses of this type, however, can often be conditioned by subjectivity based on the perspective of the analyst. This study presents a novel use of Machine Learning algorithms for pattern recognition techniques in the automated separation and identification of fossiliferous levels. This approach can be divided into three main steps including: (1) unsupervised Machine Learning for density based clustering (2) expert-in-the-loop Collaborative Intelligence Learning for the integration of geological data followed by (3) supervised learning for the final fine-tuning of fossiliferous level models. For evaluation of these techniques, this method was tested in two Late Miocene sites of the Batallones Butte paleontological complex (Madrid, Spain). Here we show Machine Learning analyses to be a valuable tool for the processing of spatial data in an efficient and quantitative manner, successfully identifying the presence of discrete fossiliferous levels in both Batallones-3 and Batallones-10. Three discrete fossiliferous levels have been identified in Batallones-3, whereas another three have been differentiated in Batallones-10.

Taphonomic information from the modern vertebrate death assemblage of Doñana National Park, Spain.

Modern death assemblages provide insights about the early stages of fossilization and useful ecological information about the species inhabiting the ecosystem. We present the results of taphonomic monitoring of modern vertebrate carcasses and bones from Doñana National Park, a Mediterranean coastal ecosystem in Andalusia, Spain. Ten different habitats were surveyed. Half of them occur in active depositional environments (marshland, lake margin, river margin, beach and dunes). Most of the skeletal remains belong to land mammals larger than 5 kg in body weight (mainly wild and feral ungulates). Overall, the Doñana bone assemblage shows good preservation with little damage to the bones, partly as a consequence of the low predator pressure on large vertebrates. Assemblages from active depositional habitats differ significantly from other habitats in terms of the higher incidence of breakage and chewing marks on bones in the latter, which result from scavenging, mainly by wild boar and red fox. The lake-margin and river-margin death assemblages have high concentrations of well preserved bones that are undergoing burial and offer the greatest potential to produce fossil assemblages. The spatial distribution of species in the Doñana death assemblage generally reflects the preferred habitats of the species in life. Meadows seem to be a preferred winter habitat for male deer, given the high number of shed antlers recorded there. This study is further proof that taphonomy can provide powerful insights to better understand the ecology of modern species and to infer past and future scenarios for the fossil record.

First Radiological Study of a Complete Dental Ontogeny Sequence of an Extinct Equid: Implications for Equidae Life History and Taphonomy.

The sequence of cheek teeth mineralization, eruption, and replacement of an extinct horse species is here documented with radiological techniques for the first time thanks to the exceptional preservation of Hipparion sp. mandibles from Cerro de los Batallones (Madrid Basin, Spain). The sequence of dental ontogeny in mammals provides valuable insights about life history traits, such as the pace of growth, and about the mode of formation of fossiliferous assemblages. We have determined that the order of permanent cheek teeth mineralization and eruption of hipparionine horses is m1, m2, (p2, p3), p4, m3. Cheek teeth mineralization timing of hipparionine horses coincides with the one observed in modern equids. In turn, there are differences in the eruption timing of the p4 and m3 between horses belonging to the Anchitheriinae and Hipparionini compared to equids of the Equus genus that might be related to the shorter durability of the deciduous tooth dp4 in anchitheriine and hipparionine horses and, more broadly, to an increased durability of equid teeth through their evolutionary history. Based on the dental eruption sequence, hipparionine horses are slow-growing, long-living mammals. The Hipparion sp. assemblage from Batallones-10 conforms to an attritional model, as individuals more vulnerable to natural mortality predominate.