Fat residue and use-wear found on Acheulian biface and scraper associated with butchered elephant remains at the site of Revadim, Israel

The archaeological record indicates that elephants must have played a significant role in early human diet and culture during Palaeolithic times in the Old World. However, the nature of interactions between early humans and elephants is still under discussion. Elephant remains are found in Palaeolithic sites, both open-air and cave sites, in Europe, Asia, the Levant, and Africa. In some cases elephant and mammoth remains indicate evidence for butchering and marrow extraction performed by humans. Revadim Quarry (Israel) is a Late Acheulian site where elephant remains were found in association with characteristic Lower Palaeolithic flint tools. In this paper we present results regarding the use of Palaeolithic tools in processing animal carcasses and rare identification of fat residue preserved on Lower Palaeolithic tools. Our results shed new light on the use of Palaeolithic stone tools and provide, for the first time, direct evidence (residue) of animal exploitation through the use of an Acheulian biface and a scraper. The association of an elephant rib bearing cut marks with these tools may reinforce the view suggesting the use of Palaeolithic stone tools in the consumption of large game

Effective action in spherical domains

The effective action on an orbifolded sphere is computed for minimally coupled scalar fields. The results are presented in terms of derivatives of Barnes zeta-functions and it is shown how these may be evaluated. Numerical values are shown. An analytical, heat-kernel derivation of the Ces\`aro-Fedorov formula for the number of symmetry planes of a regular solid is also presented.Comment: 18 pages, Plain TeX (Mailer oddities possibly corrected.

Passive and catalytic antibodies and drug delivery

Antibodies are one of the most promising components of the biotechnology repertoire for the purpose of drug delivery. On the one hand, they are proven agents for cell-selective delivery of highly toxic agents in a small but expanding number of cases. This technology calls for the covalent attachment of the cytotoxin to a tumor-specific antibody by a linkage that is reversible under appropriate conditions (antibody conjugate therapy, ACT —"passive delivery”). On the other hand, the linker cleavage can be accomplished by a protein catalyst attached to the tumor-specific antibody ("catalytic delivery”). Where the catalyst is an enzyme, this approach is known as antibody-directed enzyme prodrug therapy (ADEPT). Where the transformation is brought about by a catalytic antibody, it has been termed antibody-directed abzyme prodrug therapy (ADAPT). These approaches will be illustrated with emphasis on how their demand for new biotechnology is being realized by structure-based protein engineerin

Interferon β-1a in relapsing multiple sclerosis: four-year extension of the European IFNβ-1a Dose-C omparison Study

Background: Multiple sclerosis (MS) is a chronic disease requiring long-term monitoring of treatment. Objective: To assess the four-year clinical efficacy of intramuscular (IM) IFNb-1a in patients with relapsing MS from the European IFNb-1a Dose-C omparison Study. Methods: Patients who completed 36 months of treatment (Part 1) of the European IFNb-1a Dose-C omparison Study were given the option to continue double-blind treatment with IFNb-1a 30 mcg or 60 mcg IM once weekly (Part 2). Analyses of 48-month data were performed on sustained disability progression, relapses, and neutralizing antibody (NA b) formation. Results: O f 608/802 subjects who completed 36 months of treatment, 493 subjects continued treatment and 446 completed 48 months of treatment and follow-up. IFNb-1a 30 mcg and 60 mcg IM once weekly were equally effective for up to 48 months. There were no significant differences between doses over 48 months on any of the clinical endpoints, including rate of disability progression, cumulative percentage of patients who progressed (48 and 43, respectively), and annual relapse rates; relapses tended to decrease over 48 months. The incidence of patients who were positive for NAbs at any time during the study was low in both treatment groups. Conclusion: C ompared with 60-mcg IM IFNb-1a once weekly, a dose of 30 mcg IM IFNb-1a once weekly maintains the same clinical efficacy over four years

Exploring conformational energy landscape of glassy disaccharides by CPMAS 13C NMR and DFT/GIAO simulations. I. Methodological aspects

The aim of this article is to assess the ability of chemical shift surfaces to provide structural information on conformational distributions of disaccharides in glassy solid state. The validity of the general method leading to a simulation of inhomogeneous 13C chemical shift distributions is discussed in detail. In particular, a proper consideration of extrema and saddle points of the chemical shift map correctly accounts for the observed discontinuities in the experimental CPMAS spectra. Provided that these basic requirements are met, DFT/GIAO chemical shift maps calculated on relaxed conformations lead to a very satisfactory description of the experimental lineshapes. On solid-state trehalose as a model of amorphous disaccharide, this simulation approach defines unambiguously the most populated sugar conformation in the glass, and can help in discriminating the validity of different models of intramolecular energy landscape. Application to other molecular systems with broad conformational populations is foreseen to produce a larger dependence of the calculated chemical shift distribution on the conformational map

From time series to visibility algorithms: A novel approach to study the spread of SARS-CoV-2 in wastewater

The detection of SARS-CoV-2 in faeces encouraged various studies exploring wastewater as a disease surveillance tool from a wastewater-based epidemiology (WBE) perspective. Virus concentration data in wastewater are collected and arranged in time series and generally analysed by using statistical approaches. However, for studying complex and non-linear phenomena, this procedure may not be effective. In this regard, the present work introduces an alternative and innovative approach to analyse time series of SARS-CoV-2 concentration in wastewater based on visibility algorithms. The temporal evolution of the epidemic is transformed into a visibility graph that allows the study of time series from a nonlinear perspective. The connectivity structure of the visibility graph encapsulates significant information of the starting time series. By investigating the topological characteristics of the graph, it is possible to extract nontrivial evidence to give a physical interpretation of the phenomenon and to identify the factors that mainly influence the virus transmission. The proposed approach has been applied to the time series data collected at ten wastewater treatment plants to interpret the trend of the epidemic and attempt to forecast the phenomenon in the analysed basins. Overall, using visibility algorithms to study COVID-19 in sewage is a valuable tool for monitoring the community, with potential for predicting epidemics and community behaviours

The effect of timing and composition of gestational weight gain in obese pregnant women on infant birth weight: A prospective cohort study.

Introduction: CK2 is a protein kinase implicated in several essential cellular processes, over-expressed in cancer and described to regulate insulin signaling cascade. Recently CK2 has been described to negatively regulate thermogenesis (Shinoda K et al, 2015, Cell Metabolism) and to inhibit insulin release (Rossi M et al, 2015, PNAS). Nevertheless, the role of CK2 in adipose tissue (AT) and its involvement in human obesity development and therapy has been poorly investigated. Methods: Our multi-disciplinary team performed biochemical analysis of signaling pathways by WB and in vitro kinase activity assays, and glucose handling studies using glucose uptake assay and IF in adipocyte cultures and glucose and insulin tolerance test in mice. Moreover we quantify CK2 expression/activity in human AT specimens of 27 obese patients, clinically characterized, in 12 obese patients underwent relevant weight loss and 11 normal-weight controls. Results: We proved that CK2 amount and activity were not influenced by insulin stimulation and that CK2 activity was efficiently inhibited by specific inhibitors, structurally unrelated. We worked with CX-4945, a CK2 inhibitor currently used in cancer clinical trials, using the minimal concentration (2.5 \u192 dM) and pre-treatment time (1hr) able to efficiently inhibit CK2 activity, avoiding any cytotoxic effect. Pharmacological inhibition of CK2 did not significantly affect in vitro adipogenic differentiation or expression profiling of mature adipocytes. Conversely, we showed that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. We compared CK2 expression and activity in different mouse tissues highlighted that white skeletal muscle fibres and liver contained the highest quantity of this kinase. CK2 was expressed more in brown AT than in white AT depots. We show that CK2 promotes insulin-signaling in mouse AT, liver and skeletal muscle and that in vivo acute treatment with CX-4945 impairs glucose- tolerance in mice. Studies in tissues of ob/ob and db/db mice highlights an up-regulation of CK2 expression and activity only in WAT. CK2 hyper-activation is strongly evident also in SAT and VAT of obese patients and weight loss obtained by bariatric surgery or hypocaloric diet reverts CK2 up-regulation to normal level. Conclusion: We show that CK2 is involved in insulin sensitivity, glucose handling and remodeling of WAT. Moreover we identify CK2 hyper-activation as a hallmark of human obesity, suggesting a new potential therapeutic target for metabolic diseases

The fate of microplastics during the anaerobic digestion of thermally pretreated sludge

The presence of microplastics (MPs) in the water environment has raised as an issue of great concern, mainly due to their persistence and potential adverse effects on biota. Municipal wastewater treatment plants have been claimed among the most important point source of MPs. Nevertheless, they act as a barrier for the spread of MPs in water, since a significant amount of these pollutants concentrates in the sludge originating from wastewater treatment. This study focuses on the presence of MPs in sewage sludge, with the main aim of assessing their fate during the mesophilic anaerobic digestion of thermally pretreated sludge. MP abundance in the digestate as well as the anaerobic biodegradability of the pretreated substrates were assessed. Experimental results addressed preliminary considerations on the effects of high temperature on the MPs as well as on their influence on anaerobic degradation processes

Cidofovir for BK Virus-Associated Hemorrhagic Cystitis: A Retrospective Study

Background.BK virus-associated hemorrhagic cystitis (BKV-HC) is a severe complication after allogeneic hematopoietic stem cell transplantation (HSCT), but antiviral treatment for this condition has not been evaluated. Methods.We conducted a retrospective survey on the safety and outcome of cidofovir treatment for patients with BKV-HC in centers affiliated with the European Group for Blood and Marrow Transplantation. Results.From 1 April 2004 to 31 December 2007, 62 patients received a diagnosis of BKV-HC after a median interval of 35 days after HSCT (range, 3-577 days). Fifty-seven patients (92%) received intravenous cidofovir, whereas 5 patients received cidofovir intravesically. Complete response (CR) was recorded in 38 (67%) of 57 patients with HC treated with intravenous cidofovir, whereas partial response (PR) was documented in 7 patients (12%). CR was documented in 3 patients and PR in 1 patient with HC treated with intravesical cidofovir. A reduction of 1-3 logs in BKV load was documented in 8 of the 10 patients achieving CR. Mild-to-moderate toxic effects were recorded in 18 of 57 patients who received intravenous cidofovir administration. In a multivariate analysis, the factors significantly associated with response to cidofovir were the stem cell source (P=.01) and the use of total body irradiation (P=.03). After a median follow-up of 287 days, overall survival and total treatment-related mortality rates were 63% and 40% for patients achieving CR, compared with 14% and 72% for patients with PR or no response to cidofovir, respectively (P<.001 and P=.001, respectively). Conclusions.Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trial