In one of the arguments about the Early Cycladic (EC) III “gap” in material culture, Jeremy Rutter recognized the Anatolianizing Kastri/Lefkandi I assemblage to be of great importance for ...developments in ceramics on the Early Helladic mainland. Now accepted by most scholars as having appeared in the EC/Early Helladic (EH) IIB period, rather than EC/EH III, the Kastri/Lefkandi I assemblage is not thought to be a coherent, unified package of material and social culture. Instead, there is great variation among regions of mainland Greece in how (and when) various components of the Kastri/Lefkandi I assemblage were adopted. This article explores the impact of Kastri/Lefkandi I shapes on the material culture and feasting practices of the Early Helladic mainland.
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Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via ...targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%.
COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction.
The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval CI, -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio OR, 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo.
In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology.
NCT04510194.
This article examines the palatial and nonpalatial organization of craft production and exchange in the Late Bronze Age Argolid. The Late Bronze Age elites controlled markers of status and prestige, ...which were institutionalized in palatial control of the production and consumption of prestige goods. At Mycenae, the existence of attached ceramic workshops is evidence for palatial interest in the production and distribution of a wider range of ceramics than existed at the palace at Pylos, which was interested only in kylikes. Communities in Mycenae’s territory, such as Tsoungiza, used ceramic assemblages nearly identical to those of the palatial elites. Given the quantities of ceramic vessels needed annually to supply the entire polity, it is unlikely that these were allocated via mechanisms of palatial control. Instead, we must consider multiple mechanisms of distribution in addition to redistribution, including market exchange. Likewise, we must consider one individual to be engaged in transactions both with the palace (redistribution, tax payments) and with the surrounding communities (reciprocity and market exchange). Markets serve to horizontally integrate households in a community or region and to vertically integrate those households with the center. Other evidence for market exchange, such as weights and measures and the road network, is explored.
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Mutations at solvent-inaccessible core positions in proteins can impact function through many biophysical mechanisms including alterations to thermodynamic stability and protein dynamics. As these ...properties of proteins are difficult to investigate, the impacts of core mutations on protein function are poorly understood for most systems. Here, we determined the effects of alanine mutations at all 15 core positions in ubiquitin on function in yeast. The majority (13 of 15) of alanine substitutions supported yeast growth as the sole ubiquitin. Both the two null mutants (I30A and L43A) were less stable to temperature-induced unfolding in vitro than wild type (WT) but were well folded at physiological temperatures. Heteronuclear NMR studies indicated that the L43A mutation reduces temperature stability while retaining a ground-state structure similar to WT. This structure enables L43A to bind to common ubiquitin receptors in vitro. Many of the core alanine ubiquitin mutants, including one of the null variants (I30A), exhibited an increased accumulation of high-molecular-weight species, suggesting that these mutants caused a defect in the processing of ubiquitin-substrate conjugates. In contrast, L43A exhibited a unique accumulation pattern with reduced levels of high-molecular-weight species and undetectable levels of free ubiquitin. When conjugation to other proteins was blocked, L43A ubiquitin accumulated as free ubiquitin in yeast. Based on these findings, we speculate that ubiquitin's stability to unfolding may be required for efficient recycling during proteasome-mediated substrate degradation.
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•Diverse core mutant effects indicate complex coupling between function and dynamics.•L43A mutant only accumulated in yeast if conjugation was prevented.•L43A can adopt WT structure and binds to proteasomal ubiquitin receptors.•We speculate that L43A may be deficient for recycling during substrate degradation.
Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ...ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID.
We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194.
Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37–54) and median BMI was 29·8 kg/m2 (IQR 27·0–34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2–8·2) in participants who received metformin and 10·4% (7·8–12·9) in those who received identical metformin placebo (hazard ratio HR 0·59, 95% CI 0·39–0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15–0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59–1·64) or fluvoxamine (1·36, 0·78–2·34) compared with placebo.
Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe.
Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.
Alepotrypa Cave at Diros Bay, Lakonia, Greece, is a massive karstic formation of consecutive chambers ending at a lake. The cave was excavated by G. Papathanassopoulos from 1970 to 2006. In ...conjunction with the surrounding area, it was used as a complementary habitation area, burial site, and place for ceremonial activity during the Neolithic c 6000 to 3200 BC. As a sealed, single-component, archaeological site, the Neolithic settlement complex of Alepotrypa Cave is one of the richest sites in Greece and Europe in terms of number of artifacts, preservation of biological materials, volume of undisturbed deposits, and horizontal exposure of archaeological surfaces of past human activity and this publication is an important contribution to ongoing archaeological research of the Neolithic Age in Greece in particular, but also in Anatolia, the Balkans and Europe in general. This edited volume offers a full scholarly interdisciplinary study and interpretation of the results of approximately 40 years of excavation and analysis. It includes numerous chemical analyses and a much needed long series of radiocarbon dates, the corresponding microstratigraphic, stratigraphic and ceramic sequence, the human burials, stone and bone tools, faunal and floral remains, isotopic analyses, specific locations of human activities and ceremonies inside the cave, as well as a site description and the history of the excavation conducted by G. Papathanasopoulos.
This article examines redistribution as formulated by scholars of the later Mycenaean palatial economies to ascertain its applicability to the Early Bronze Age (EBA) mainland. Lacking textual sources ...in the EBA, the emphasis is on archaeological correlates of redistribution as both a mode of transaction and as an institution. Three areas are examined: mobilization of goods as suggested through the evidence for staple vs. wealth finance, scale and control of production on the basis of evidence for household production vs. craft specialization, and centralized control of economic and political transactions using evidence for administration and feasting. While the data leave much to be desired in terms of suitability and completeness, only a limited number of the transaction types and institutional forms of redistribution as posited for the Mycenaean palatial economies are apparent in the EBA mainland. Thus, the political economies of the Mycenaean palaces may well represent transformations not just of scale but also of forms from the political economies of the EBA chiefdoms.
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This volume brings together an international group of researchers to address how Mycenaean and Minoan states controlled the economy. The contributions, originally delivered at the 2007 Langford ...Conference at the Florida State University, examine the political economies of state (and pre-state) entities within the Aegean Bronze Age, including the issues of centralization and multiple scales of production, distribution, and consumption within a polity; importance of extraregional trade; craft specialization; the role of non-elite institutions, and the political economy before the emergence of the palaces. The contributors address these issues from an explicitly comparative perspective, both within and across Minoan and Mycenaean contexts. The conclusions reached in this volume shed new light on the essential differences between and among "Minoan" and "Mycenaean" states through their political economies.
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