Renewed excavations at the Neolithic site of Beisamoun (Upper Jordan Valley, Israel) has resulted in the discovery of the earliest occurrence of an intentional cremation in the Near East directly ...dated to 7031-6700 cal BC (Pre-Pottery Neolithic C, also known as Final PPNB, which spans ca. 7100-6400 cal BC). The funerary treatment involved in situ cremation within a pyre-pit of a young adult individual who previously survived from a flint projectile injury. In this study we have used a multidisciplinary approach that integrates archaeothanatology, spatial analysis, bioanthropology, zooarchaeology, soil micromorphological analysis, and phytolith identification in order to reconstruct the different stages and techniques involved in this ritual: cremation pit construction, selection of fuel, possible initial position of the corpse, potential associated items and funerary containers, fire management, post-cremation gesture and structure abandonment. The origins and development of cremation practices in the region are explored as well as their significance in terms of Northern-Southern Levantine connections during the transition between the 8th and 7th millennia BC.
Lyme disease is the most common tick-borne disease in North America and Europe, however, current biomarkers inconsistently detect the disease. In this issue of the JCI, Gwynne et al. revealed how the ...Lyme disease agent Borrelia burgdorferi relies on host lipids for growth. The authors used a murine model to show that B. burgdorferi infection led to the production of antibodies against phospholipids, possibly as a consequence of incorporation into the spirochete membrane. Antibodies were induced against phosphatidic acid, phosphatidylcholine, and phosphatidylserine. Notably, no antibodies against cardiolipin were found, distinguishing Lyme disease from syphilis and some other diseases. Sera samples from patients with Lyme disease suggested that these antibodies may help diagnose B. burgdorferi infection and that antibody titers may effectively indicate the response to treatment. These findings suggest that B. burgdorferi-induced anti-lipid antibodies, in conjunction with a careful clinical assessment, may aid in the diagnosis of Lyme disease.
Pathogens possess the ability to adapt and survive in some host species but not in others-an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, ...the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Since Naomi Miller’s first discussion of dung fuel within macro-botanical samples from Malyan, Iran, considerations of dung fuel across Southwest Asia have become commonplace, yet archaeobotanists ...remain divided on: (1) the extent to which dung fuel contributed to archaeobotanical assemblages relative to remnants of repeated crop processing and household activities; and (2) the plant-based, middle-range theories that should be used to infer the presence of dung within macro-botanical assemblages. Here we present a case-study integrating a simple, well-established geo-archaeological approach to assess the presence and relative abundance of dung spherulites within paired sediment and flotation samples from Ubaid period Tell Zeidan, Syria (5300–5100 BC). Spherulite data generated from “sediment smears” are integrated with macro-botanical and phytolith data to assess elevated concentrations of dung within samples. Our analyses demonstrate that plant-based depositional processes across a site are complex, reflecting the rich nature of plant use in antiquity. By using a multi-proxy approach, it is possible to differentiate between predominantly fuel-based deposits and those resulting from predominantly crop-processing processes with greater resolution. This study documents the use of wood fuels in hearths and dung fuel within pyrotechnic features and an oven during the Ubaid period, thereby contributing to discussions of fuel selection and the Secondary Products Revolution. When spherulites are preserved within sediment in abundance, they are also present in floated material, so it is possible to use this approach to consider the presence of dung within archived macro-botanical samples and resolve decade-old debates.
Lyme disease is the most common vector-borne infectious disease in the United States, in part because a vaccine against it is not currently available for humans. We propose utilizing the lipid ...nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) platform to generate a Lyme disease vaccine like the successful clinical vaccines against SARS-CoV-2. Of the antigens expressed by Borrelia burgdorferi, the causative agent of Lyme disease, outer surface protein A (OspA) is the most promising candidate for vaccine development. We have designed and synthesized an OspA-encoding mRNA-LNP vaccine and compared its immunogenicity and protective efficacy to an alum-adjuvanted OspA protein subunit vaccine. OspA mRNA-LNP induced superior humoral and cell-mediated immune responses in mice after a single immunization. These potent immune responses resulted in protection against bacterial infection. Our study demonstrates that highly efficient mRNA vaccines can be developed against bacterial targets.
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Pardi and colleagues developed a nucleoside-modified mRNA vaccine against Lyme disease. The OspA-targeting vaccine induced robust T cell, germinal center B cell, memory B cell, long-lived plasma cell, and durable antibody responses in mice. Importantly, the vaccine induced a high level of protection from Borrelia burgdorferi infection after a single immunization.
Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial ...infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.
We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.
Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening.
Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)
The caries lesion, the most commonly observed sign of dental caries disease, is the cumulative result of an imbalance in the dynamic demineralization and remineralization process that causes a net ...mineral loss over time. A classification system to categorize the location, site of origin, extent, and when possible, activity level of caries lesions consistently over time is necessary to determine which clinical treatments and therapeutic interventions are appropriate to control and treat these lesions.
In 2008, the American Dental Association (ADA) convened a group of experts to develop an easy-to-implement caries classification system. The ADA Council on Scientific Affairs subsequently compiled information from these discussions to create the ADA Caries Classification System (CCS) presented in this article.
The ADA CCS offers clinicians the capability to capture the spectrum of caries disease presentations ranging from clinically unaffected (sound) tooth structure to noncavitated initial lesions to extensively cavitated advanced lesions. The ADA CCS supports a broad range of clinical management options necessary to treat both noncavitated and cavitated caries lesions.
The ADA CCS is available for implementation in clinical practice to evaluate its usability, reliability, and validity. Feedback from clinical practitioners and researchers will allow system improvement. Use of the ADA CCS will offer standardized data that can be used to improve the scientific rationale for the treatment of all stages of caries disease.
Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional ...pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3
CD8
cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68
macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68
HLA-DR
) macrophages than nonactivated (CD68
HLA-DR
) macrophages (
< 0.0001). CTLs were further in proximity from proliferating SOX10
melanoma cells than nonproliferating ones (
< 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (
= 0.0038 and
= 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (
= 0.0147 and
= 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR
CTLs (
= 0.0005). CTL distance to HLA-DR
macrophages associated with poor DSS (
= 0.0016), whereas distance to Ki67
tumor cells associated inversely with DSS (
= 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (
= 0.009) and merits further development as a biomarker for clinical application.
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Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host's skin following a tick bite, and then disseminates to distant organs, ...leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
Archaeologists use survey artifacts to study any number of interesting topics. The focus of this study is to test the usefulness of starch grains and phytoliths found on artifacts recovered during ...archaeological survey. Phytolith and starch grain analysis was used to determine the level of environmental contamination on three types of medieval ceramics collected during survey work from plowed fields in the parish of Wicken, Northamptonshire, England. The plant residues found on these artifacts were compared with their surrounding soil and with contemporaneous excavated artifacts recovered from under the floorboards of a medieval house in nearby Wyton, Cambridgeshire, England. Through the use of the “piggyback” approach pioneered by Chandler-Ezell and Pearsall, phytoliths and starch grains were systematically removed from the artifacts surface. Residues associated with contamination were removed from the outermost layer of the artifact surface while potentially uncontaminated residues were removed from the innermost layer of the artifact surface. Matching phytoliths and starch grains were found on the outermost surface of the survey artifacts and in the surrounding soils. No phytoliths and starch grains were found on the innermost surface of the survey artifacts suggesting that residues from the surrounding soils did not penetrate into the pores and crevices of the artifacts. The overall results suggest that, although they are preliminary, there is potential for plant residue analysis of survey artifacts.
► Survey artifacts were analyzed for starch grain and phytolith contamination. ► Contamination did not penetrate to the deepest layers of the artifacts surfaces. ► Contamination does not always occur on all survey artifacts. ► Survey artifacts can be used for analysis if soil is systematically removed.
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