The chronology of Gezer from the end of the late bronze age to iron age II: A meeting point for radiocarbon, archaeology egyptology and the Bible.

The ancient southern Levantine city of Gezer is well-known from Egyptian, Biblical and Assyrian sources, associated with power struggles, conquests, and intriguing tales involving figures such as Milkilu and Amenhotep III, Merneptah, the Philistines, Solomon and his unidentified pharaonic father-in-law, and Shishak / Sheshonq I. Since the identity of Gezer with "Tell Jezer" is quite literally 'set in stone' by some dozen boundary inscriptions, along with impressive Bronze and Iron Age remains, research at this site provides a unique opportunity to compare text and archaeology, as well as bring to light the undocumented everyday lives of the city's inhabitants. In this endeavour, independent scientific dating is crucial for anchoring the remains chronologically. This paper presents the first substantial radiocarbon dataset and Bayesian chronological analysis for Gezer spanning the last part of the Late Bronze Age (LBA; LB IIB) through Iron Age II. The dataset derives from an essentially continuous stratigraphic sequence exposed in recent years by the Tandy expedition along the central-southern edge of the site. The results allow us for the first time to independently determine the site chronology, test the viability (from a chronological perspective) of proposed historical correlations, and contribute to debates on Philistine and Iron Age chronology.

Threatened North African seagrass meadows have supported green turtle populations for millennia.

"Protect and restore ecosystems and biodiversity" is the second official aim of the current UN Ocean Decade (2021 to 2030) calling for the identification and protection of critical marine habitats. However, data to inform policy are often lacking altogether or confined to recent times, preventing the establishment of long-term baselines. The unique insights gained from combining bioarchaeology (palaeoproteomics, stable isotope analysis) with contemporary data (from satellite tracking) identified habitats which sea turtles have been using in the Eastern Mediterranean over five millennia. Specifically, our analysis of archaeological green turtle (Chelonia mydas) bones revealed that they likely foraged on the same North African seagrass meadows as their modern-day counterparts. Here, millennia-long foraging habitat fidelity has been directly demonstrated, highlighting the significance (and long-term dividends) of protecting these critical coastal habitats that are especially vulnerable to global warming. We highlight the potential for historical ecology to inform policy in safeguarding critical marine habitats.

Immunotherapeutic approach to reduce senescent cells and alleviate senescence-associated secretory phenotype in mice.

Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-ß and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet ß cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro-inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single-nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell-cycle, and senescence-associated pathways in naturally aged mice. Long-term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence-associated diseases.

High-resolution Bayesian chronology of the earliest evidence of domesticated animals in the Dutch wetlands (Hardinxveld-Giessendam archaeological sites).

The archaeological sites of Hardinxveld-Giessendam de Bruin and Polderweg, situated in the Rhine-Meuse delta, are the best-preserved Mesolithic sites in the Netherlands. Due to the early appearance of domesticated animals in their faunal assemblage, they are also integral to the research of the emergence of animal husbandry in the region. This study focuses on the precise chronology of the sites, using radiocarbon dating and Bayesian modelling of both newly acquired and legacy radiocarbon dates. To mitigate the risk of erroneous dates, we dated the bone collagen of 26 herbivorous and one aquatic mammals from clear archaeological contexts and discovered that the most recent occupational phases at both sites are several centuries younger than previously thought. This is consistent with material evidence of lifestyle changes in the final phase at Hardinxveld-Giessendam de Bruin, which is now, according to our chronology, contemporaneous with the similar patterns produced in the region.

Hunting before herding: A zooarchaeological and stable isotopic study of suids (Sus sp.) at Hardinxveld-Giessendam, the Netherlands (5450-4250 cal BC).

Suids (Sus sp.) played a crucial role in the transition to farming in northern Europe and, like in many regions, in the Netherlands pig husbandry became an important subsistence activity at Neolithic sites. Yet little is known about wild boar palaeoecology and hunting in the Late Mesolithic Netherlands with which to contextualize this transition. This paper presents the first multi-proxy analysis of archaeological suid remains in the Netherlands. It explores human-suid interactions at the Swifterbant culture sites of Hardinxveld-Giessendam Polderweg and De Bruin (5450-4250 BC) through biometric analysis, estimation of age-at-death, and stable carbon and nitrogen isotope analysis. The results reveal targeted hunting of adult wild boar in the Late Mesolithic (5450-4850 BC), with a possible shift over time towards more juveniles. The wild boar in this period are demonstrated to be of comparably large size to contemporary northern European populations and exhibiting a wide range of dietary regimes. In the final occupational period (4450-4250 BC), small suids are present, possibly domestic pigs, but there is no evidence of pig management. This study demonstrates that the nature of human-suid interactions varied over time, which may have been connected to changing environmental conditions, human mobility, and wild boar behaviour. This study also contributes the first biometric and dietary baseline for mid-Holocene wild boar in the Netherlands.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells.

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-ß (TGF-ß) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

Evidence for European presence in the Americas in AD 1021.

Transatlantic exploration took place centuries before the crossing of Columbus. Physical evidence for early European presence in the Americas can be found in Newfoundland, Canada1,2. However, it has thus far not been possible to determine when this activity took place3-5. Here we provide evidence that the Vikings were present in Newfoundland in AD 1021. We overcome the imprecision of previous age estimates by making use of the cosmic-ray-induced upsurge in atmospheric radiocarbon concentrations in AD 993 (ref. 6). Our new date lays down a marker for European cognisance of the Americas, and represents the first known point at which humans encircled the globe. It also provides a definitive tie point for future research into the initial consequences of transatlantic activity, such as the transference of knowledge, and the potential exchange of genetic information, biota and pathologies7,8.

A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.

Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.

A revised AMS and tephra chronology for the Late Middle to Early Upper Paleolithic occupations of Ortvale Klde, Republic of Georgia.

The nature and timing of the shift from the Late Middle Paleolithic (LMP) to the Early Upper Paleolithic (EUP) varied geographically, temporally, and substantively across the Near East and Eurasia; however, the result of this process was the archaeological disappearance of Middle Paleolithic technologies across the length and breadth of their geographic distribution. Ortvale Klde rockshelter (Republic of Georgia) contains the most detailed LMP-EUP archaeological sequence in the Caucasus, an environmentally and topographically diverse region situated between southwest Asia and Europe. Tephrochronological investigations at the site reveal volcanic ash (tephra) from various volcanic sources and provide a tephrostratigraphy for the site that will facilitate future correlations in the region. We correlate one of the cryptotephra layers to the large, caldera-forming Nemrut Formation eruption (30,000 years ago) from Nemrut volcano in Turkey. We integrate this tephrochronological constraint with new radiocarbon dates and published ages in an OxCal Bayesian age model to produce a revised chronology for the site. This model increases the ages for the end of the LMP (∼47.5-44.2 ka cal BP) and appearance of the EUP (∼46.7-43.6 ka cal BP) at Ortvale Klde, which are earlier than those currently reported for other sites in the Caucasus but similar to estimates for specific sites in southwest Asia and eastern Europe. These data, coupled with archaeological, stratigraphic, and taphonomic observations, suggest that at Ortvale Klde, (1) the appearance of EUP technologies of bone and stone has no technological roots in the preceding LMP, (2) a LMP population vacuum likely preceded the appearance of these EUP technologies, and (3) the systematic combination of tephra correlations and absolute dating chronologies promises to substantially improve our inter-regional understanding of this critical time interval of human evolution and the potential interconnectedness of hominins at different sites.

The magnitude and impact of the 431 CE Tierra Blanca Joven eruption of Ilopango, El Salvador.

The Tierra Blanca Joven (TBJ) eruption from Ilopango volcano deposited thick ash over much of El Salvador when it was inhabited by the Maya, and rendered all areas within at least 80 km of the volcano uninhabitable for years to decades after the eruption. Nonetheless, the more widespread environmental and climatic impacts of this large eruption are not well known because the eruption magnitude and date are not well constrained. In this multifaceted study we have resolved the date of the eruption to 431 ± 2 CE by identifying the ash layer in a well-dated, high-resolution Greenland ice-core record that is >7,000 km from Ilopango; and calculated that between 37 and 82 km3 of magma was dispersed from an eruption coignimbrite column that rose to ∼45 km by modeling the deposit thickness using state-of-the-art tephra dispersal methods. Sulfate records from an array of ice cores suggest stratospheric injection of 14 ± 2 Tg S associated with the TBJ eruption, exceeding those of the historic eruption of Pinatubo in 1991. Based on these estimates it is likely that the TBJ eruption produced a cooling of around 0.5 °C for a few years after the eruption. The modeled dispersal and higher sulfate concentrations recorded in Antarctic ice cores imply that the cooling would have been more pronounced in the Southern Hemisphere. The new date confirms the eruption occurred within the Early Classic phase when Maya expanded across Central America.

Radiocarbon offsets and old world chronology as relevant to Mesopotamia, Egypt, Anatolia and Thera (Santorini).

The new IntCal20 radiocarbon record continues decades of successful practice by employing one calibration curve as an approximation for different regions across the hemisphere. Here we investigate three radiocarbon time-series of archaeological and historical importance from the Mediterranean-Anatolian region, which indicate, or may include, offsets from IntCal20 (~0-22 14C years). While modest, these differences are critical for our precise understanding of historical and environmental events across the Mediterranean Basin and Near East. Offsets towards older radiocarbon ages in Mediterranean-Anatolian wood can be explained by a divergence between high-resolution radiocarbon dates from the recent generation of accelerator mass spectrometry (AMS) versus dates from previous technologies, such as low-level gas proportional counting (LLGPC) and liquid scintillation spectrometry (LSS). However, another reason is likely differing growing season lengths and timings, which would affect the seasonal cycle of atmospheric radiocarbon concentrations recorded in different geographic zones. Understanding and correcting these offsets is key to the well-defined calendar placement of a Middle Bronze Age tree-ring chronology. This in turn resolves long-standing debate over Mesopotamian chronology in the earlier second millennium BCE. Last but not least, accurate dating is needed for any further assessment of the societal and environmental impact of the Thera/Santorini volcanic eruption.

Radiocarbon-based approach capable of subannual precision resolves the origins of the site of Por-Bajin.

Inadequate resolution is the principal limitation of radiocarbon dating. However, recent work has shown that exact-year precision is attainable if use can be made of past increases in atmospheric radiocarbon concentration or so-called Miyake events. Here, this nascent method is applied to an archaeological site of previously unknown age. We locate the distinctive radiocarbon signal of the year 775 common era (CE) in wood from the base of the Uyghur monument of Por-Bajin in Russia. Our analysis shows that the construction of Por-Bajin started in the summer of 777 CE, a foundation date that resolves decades of debate and allows the origin and purpose of the building to be established.

Mediterranean radiocarbon offsets and calendar dates for prehistory.

A single Northern Hemisphere calibration curve has formed the basis of radiocarbon dating in Europe and the Mediterranean for five decades, setting the time frame for prehistory. However, as measurement precision increases, there is mounting evidence for some small but substantive regional (partly growing season) offsets in same-year radiocarbon levels. Controlling for interlaboratory variation, we compare radiocarbon data from Europe and the Mediterranean in the second to earlier first millennia BCE. Consistent with recent findings in the second millennium CE, these data suggest that some small, but critical, periods of variation for Mediterranean radiocarbon levels exist, especially associated with major reversals or plateaus in the atmospheric radiocarbon record. At high precision, these variations potentially affect calendar dates for prehistory by up to a few decades, including, for example, Egyptian history and the much-debated Thera/Santorini volcanic eruption.

Advancing the understanding of treponemal disease in the past and present.

Syphilis was perceived to be a new disease in Europe in the late 15th century, igniting a debate about its origin that continues today in anthropological, historical, and medical circles. We move beyond this age-old debate using an interdisciplinary approach that tackles broader questions to advance the understanding of treponemal infection (syphilis, yaws, bejel, and pinta). How did the causative organism(s) and humans co-evolve? How did the related diseases caused by Treponema pallidum emerge in different parts of the world and affect people across both time and space? How are T. pallidum subspecies related to the treponeme causing pinta? The current state of scholarship in specific areas is reviewed with recommendations made to stimulate future work. Understanding treponemal biology, genetic relationships, epidemiology, and clinical manifestations is crucial for vaccine development today and for investigating the distribution of infection in both modern and past populations. Paleopathologists must improve diagnostic criteria and use a standard approach for recording skeletal lesions on archaeological human remains. Adequate contextualization of cultural and environmental conditions is necessary, including site dating and justification for any corrections made for marine or freshwater reservoir effects. Biogeochemical analyses may assess aquatic contributions to diet, physiological changes arising from treponemal disease and its treatments (e.g., mercury), or residential mobility of those affected. Shifting the focus from point of origin to investigating who is affected (e.g., by age/sex or socioeconomic status) and disease distribution (e.g., coastal/ inland, rural/urban) will advance our understanding of the treponemal disease and its impact on people through time.

A 5700 year-old human genome and oral microbiome from chewed birch pitch.

The rise of ancient genomics has revolutionised our understanding of human prehistory but this work depends on the availability of suitable samples. Here we present a complete ancient human genome and oral microbiome sequenced from a 5700 year-old piece of chewed birch pitch from Denmark. We sequence the human genome to an average depth of 2.3× and find that the individual who chewed the pitch was female and that she was genetically more closely related to western hunter-gatherers from mainland Europe than hunter-gatherers from central Scandinavia. We also find that she likely had dark skin, dark brown hair and blue eyes. In addition, we identify DNA fragments from several bacterial and viral taxa, including Epstein-Barr virus, as well as animal and plant DNA, which may have derived from a recent meal. The results highlight the potential of chewed birch pitch as a source of ancient DNA.

Radiocarbon dating and cultural dynamics across Mongolia's early pastoral transition.

The emergence of mobile herding lifeways in Mongolia and eastern Eurasia was one of the most crucial economic and cultural transitions in human prehistory. Understanding the process by which this played out, however, has been impeded by the absence of a precise chronological framework for the prehistoric era in Mongolia. One rare source of empirically dateable material useful for understanding eastern Eurasia's pastoral tradition comes from the stone burial mounds and monumental constructions that began to appear across the landscape of Mongolia and adjacent regions during the Bronze Age (ca. 3000-700 BCE). Here, along with presenting 28 new radiocarbon dates from Mongolia's earliest pastoral monumental burials, we synthesise, critically analyse, and model existing dates to present the first precision Bayesian radiocarbon model for the emergence and geographic spread of Bronze Age monument and burial forms. Model results demonstrate a cultural succession between ambiguously dated Afanasievo, Chemurchek, and Munkhkhairkhan traditions. Geographic patterning reveals the existence of important cultural frontiers during the second millennium BCE. This work demonstrates the utility of a Bayesian approach for investigating prehistoric cultural dynamics during the emergence of pastoral economies.

Identification of possible Δ14C anomalies since 14 ka BP: A computational intelligence approach.

Rapid increments in the concentration of the radiocarbon in the atmosphere (Δ14C) have been identified in the years 774-775 CE and 993-994 CE (Miyake events) using annual measurements on known-age tree-rings. The level of cosmic radiation implied by such increases could cause the failure of satellite telecommunication systems, and thus, there is a need to model and predict them. In this work, we investigated several intelligent computational methods to identify similar events in the past. We apply state-of-the-art pattern matching techniques as well as feature representation, a procedure that typically is used in machine learning and classification. To validate our findings, we used as ground truth the two confirmed Miyake events, and several other dates that have been proposed in the literature. We show that some of the methods used in this study successfully identify most of the ground truth events (~1% false positive rate at 75% true positive rate). Our results show that computational methods can be used to identify comparable patterns of interest and hence potentially uncover sudden increments of Δ14C in the past.