The Role of Canids in Ritual and Domestic Contexts: New Ancient DNA Insights from Complex Hunter-Gatherer Sites in Prehistoric Central California

This study explores the interrelationship between the genus Canis and hunter–gatherers through a case study of prehistoric Native Americans in the San Francisco Bay-Sacramento Delta area. A distinctive aspect of the region\u27s prehistoric record is the interment of canids, variously classified as coyotes, dogs, and wolves. Since these species are difficult to distinguish based solely on morphology, ancient DNA analysis was employed to distinguish species. The DNA study results, the first on canids from archaeological sites in California, are entirely represented by domesticated dogs (including both interments and disarticulated samples from midden deposits). These results, buttressed by stable isotope analyses, provide new insight into the complex interrelationship between humans and canids in both ritual and prosaic contexts, and reveal a more prominent role for dogs than previously envisioned

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Development of heat shock protein 90 (Hsp90) C‐terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Angle of attack: The distance and angle between the N‐methylpiperidine and the biaryl side chain was analyzed in an effort to develop more potent Hsp90 C‐terminal inhibitors. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/1/chem201504955_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/2/chem201504955.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/3/chem201504955-sup-0001-misc_information.pd

Disease and Healing in Ancient Societies: Dental Calculus Residues and Skeletal Pathology Data Indicate Age and Sex-Biased Medicinal Practices among Native Californians

The health of humans is intricately linked to the substances - both food and non-dietary items -we ingest. Adverse health outcomes related to smoking of products like tobacco and other psychoactive substances are clearly established in modern populations but are less well understood for ancient communities. Grasping these dynamics is further complicated by the curative, religious, and medicinal context of many of these substances, which have often been commodified, refined, and altered in recent history. As part of a larger collaboration with the Muwekma Ohlone Tribe dedicated to understanding medicinal plant use among native Californians, we present a summary of new metabolomic data from three Middle and Late-period ancestral heritage Ohlone sites: Thámien Rúmmeytak (CA-SCL-128), ’Ayttakiš ’Éete Hiramwiš Trépam-tak (CA-ALA-677/H/H), and Sii Tuupentak (CA-ALA-565/H/H). Using a UPLC-MS platform, we analyze chemical residues from 95 human dental calculus samples from 50 burials. Employing multivariate statistics, we co-analyzed demographic and skeletal pathology data with chemical residue profiles. We considered skeletal markers for a series of oral and postcranial health conditions. Results indicate sex and age biases in consumption patterns. Periodontitis stands out as the most significant local factor for changes in the oral metabolome. However, while chemical markers of oral diseases may be related to pathogen activity, associations between residues and postcranial conditions such as osteoarthritis suggest traditional curative practices and the ingestion of medicinal substances. Hence, our study yields new insights into the broader context of illness and healing in the past

Disease and Healing in Ancient Societies: Dental Calculus Residues and Skeletal Pathology Data Indicate Age- and Sex-Biased Medicinal Practices among Native Californians

The health of humans is intricately linked to the substances we ingest—both food and nondietary items. Adverse health outcomes related to smoking of such products as tobacco and other psychoactive substances are clearly established in modern populations but are less well understood for ancient communities. Grasping these dynamics is further complicated by the curative, religious, and medicinal context of many of these substances, which have often been commodified, refined, and altered in recent history. As part of a larger collaboration with the Muwekma Ohlone Tribe dedicated to understanding medicinal plant use among Native Californians, this article summarizes new metabolomic data from three Middle- and Late-Period ancestral heritage Ohlone sites: Thámien Rúmmeytak (CA-SCL-128), ’Ayttakiš ’Éete Hiramwiš Trépam-tak (CA-ALA-677/H), and Síi Túupentak (CA-ALA-565/H). The authors used an ultra-performance liquid chromatography-mass spectrometry platform to analyze chemical residues from 95 human dental calculus samples from 50 burials. Using multivariate statistics, they coanalyzed demographic and skeletal pathology data with chemical residue profiles and considered skeletal markers for a series of oral and postcranial health conditions. Results indicate sex and age biases in consumption patterns. Periodontitis stands out as the most significant local factor for changes in the oral metabolome. However, while chemical markers of oral diseases may be related to pathogen activity, associations between residues and postcranial conditions such as osteoarthritis suggest traditional curative practices and the ingestion of medicinal substances. Hence, this study yields new insights into the broader context of illness and healing in the past

Ancient and modern genomics of the Ohlone Indigenous population of California

Traditional knowledge, along with archaeological and linguistic evidence, documents that California supports cultural and linguistically diverse Indigenous populations. Studies that have included ancient genomes in this region, however, have focused primarily on broad-scale migration history of the North American continent, with relatively little attention to local population dynamics. Here, in a partnership involving researchers and the Muwekma Ohlone tribe, we analyze genomic data from ancient and present-day individuals from the San Francisco Bay Area in California: 12 ancient individuals dated to 1905 to 1826 and 601 to 184 calibrated years before the present (cal BP) from two archaeological sites and eight present-day members of the Muwekma Ohlone tribe, whose ancestral lands include these two sites. We find that when compared to other ancient and modern individuals throughout the Americas, the 12 ancient individuals from the San Francisco Bay Area cluster with ancient individuals from Southern California. At a finer scale of analysis, we find that the 12 ancient individuals from the San Francisco Bay Area have distinct ancestry from the other groups and that this ancestry has a component of continuity over time with the eight present-day Muwekma Ohlone individuals. These results add to our understanding of Indigenous population history in the San Francisco Bay Area, in California, and in western North America more broadly

A comparison of proteomic, genomic, and osteological methods of archaeological sex estimation

Sex estimation of skeletons is fundamental to many archaeological studies. Currently, three approaches are available to estimate sex–osteology, genomics, or proteomics, but little is known about the relative reliability of these methods in applied settings. We present matching osteological, shotgun-genomic, and proteomic data to estimate the sex of 55 individuals, each with an independent radiocarbon date between 2,440 and 100 cal BP, from two ancestral Ohlone sites in Central California. Sex estimation was possible in 100% of this burial sample using proteomics, in 91% using genomics, and in 51% using osteology. Agreement between the methods was high, however conflicts did occur. Genomic sex estimates were 100% consistent with proteomic and osteological estimates when DNA reads were above 100,000 total sequences. However, more than half the samples had DNA read numbers below this threshold, producing high rates of conflict with osteological and proteomic data where nine out of twenty conditional DNA sex estimates conflicted with proteomics. While the DNA signal decreased by an order of magnitude in the older burial samples, there was no decrease in proteomic signal. We conclude that proteomics provides an important complement to osteological and shotgun-genomic sex estimation

Summary of the ISEV workshop on extracellular vesicles as disease biomarkers, held in Birmingham, UK, during December 2017

This report summarises the presentations and activities of the ISEV Workshop on extracellular vesicle biomarkers held in Birmingham, UK during December 2017. Among the key messages was broad agreement about the importance of biospecimen science. Much greater attention needs to be paid towards the provenance of collected samples. The workshop also highlighted clear gaps in our knowledge about pre-analytical factors that alter extracellular vesicles (EVs). The future utility of certified standards for credentialing of instruments and software, to analyse EV and for tracking the influence of isolation steps on the structure and content of EVs were also discussed. Several example studies were presented, demonstrating the potential utility for EVs in disease diagnosis, prognosis, longitudinal serial testing and stratification of patients. The conclusion of the workshop was that more effort focused on pre-analytical issues and benchmarking of isolation methods is needed to strengthen collaborations and advance more effective biomarkers

A Study to Assess the Efficacy of Enasidenib and Risk-Adapted Addition of Azacitidine in Newly Diagnosed IDH2-Mutant AML

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe