Palaeoclimate inferred from δ18O and palaeobotanical indicators in freshwater tufa of Lake Äntu Sinijärv, Estonia

We investigated a 3.75-m-long lacustrine sediment record from Lake Äntu Sinijärv, northern Estonia, which has a modeled basal age >12,800 cal yr BP. Our multi-proxy approach focused on the stable oxygen isotope composition (δ18O) of freshwater tufa. Our new palaeoclimate information for the Eastern Baltic region, based on high-resolution δ18O data (219 samples), is supported by pollen and plant macrofossil data. Radiocarbon dates were used to develop a core chronology and estimate sedimentation rates. Freshwater tufa precipitation started ca. 10,700 cal yr BP, ca. 2,000 years later than suggested by previous studies on the same lake. Younger Dryas cooling is documented clearly in Lake Äntu Sinijärv sediments by abrupt appearance of diagnostic pollen (Betula nana, Dryas octopetala), highest mineral matter content in sediments (up to 90 %) and low values of δ18O (less than −12 ‰). Globally recognized 9.3- and 8.2-ka cold events are weakly defined by negative shifts in δ18O values, to −11.3 and −11.7 ‰, respectively, and low concentrations of herb pollen and charcoal particles. The Holocene thermal maximum (HTM) is palaeobotanically well documented by the first appearance and establishment of nemoral thermophilous taxa and presence of water lilies requiring warm conditions. Isotope values show an increasing trend during the HTM, from −11.5 to −10.5 ‰. Relatively stable environmental conditions, represented by only a small-scale increase in δ18O (up to 1 ‰) and high pollen concentrations between 5,000 and 3,000 cal yr BP, were followed by a decrease in δ18O, reaching the most negative value (−12.7 ‰) recorded in the freshwater tufa ca. 900 cal yr BP

Langevin dynamics encapsulate the microscopic and emergent macroscopic properties of midge swarms

In contrast with bird flocks, fish schools and animal herds, midge swarms maintain cohesion but do not process global order. High-speed imaging techniques are now revealing that these swarms have surprisingly properties. Here I show that simple models found on the Langevin equation are consistent with this wealth of recent observations. The models predict correctly that large accelerations, exceeding 10 g, will be common and they predict correctly the co-existence of core condensed phases surrounded by dilute vapour phases. The models also provide new insights into the influence of environmental conditions on swarm dynamics. They predict that correlations between midges increase the strength of the effective force binding the swarm together. This may explain why such correlations are absent in laboratory swarms but present in natural swarms which contend with the wind and other disturbances. Finally, the models predict that swarms have fluid-like macroscopic mechanical properties and will slosh rather than slide back-and-forth after being abruptly displaced. This prediction offers a promising avenue for future experimentation that goes beyond current quasi-static testing which has revealed solid-like responses

Genetically Engineered Alginate Lyase-PEG Conjugates Exhibit Enhanced Catalytic Function and Reduced Immunoreactivity

Alginate lyase enzymes represent prospective biotherapeutic agents for treating bacterial infections, particularly in the cystic fibrosis airway. To effectively deimmunize one therapeutic candidate while maintaining high level catalytic proficiency, a combined genetic engineering-PEGylation strategy was implemented. Rationally designed, site-specific PEGylation variants were constructed by orthogonal maleimide-thiol coupling chemistry. In contrast to random PEGylation of the enzyme by NHS-ester mediated chemistry, controlled mono-PEGylation of A1-III alginate lyase produced a conjugate that maintained wild type levels of activity towards a model substrate. Significantly, the PEGylated variant exhibited enhanced solution phase kinetics with bacterial alginate, the ultimate therapeutic target. The immunoreactivity of the PEGylated enzyme was compared to a wild type control using in vitro binding studies with both enzyme-specific antibodies, from immunized New Zealand white rabbits, and a single chain antibody library, derived from a human volunteer. In both cases, the PEGylated enzyme was found to be substantially less immunoreactive. Underscoring the enzyme's potential for practical utility, >90% of adherent, mucoid, Pseudomonas aeruginosa biofilms were removed from abiotic surfaces following a one hour treatment with the PEGylated variant, whereas the wild type enzyme removed only 75% of biofilms in parallel studies. In aggregate, these results demonstrate that site-specific mono-PEGylation of genetically engineered A1-III alginate lyase yielded an enzyme with enhanced performance relative to therapeutically relevant metrics.Cystic Fibrosis Foundation (Research Development Program)National Center for Research Resources (U.S.) (P20RR018787-06

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

On the relevance of the “genetics-based” approach to medicine for sociological perspectives on medical specialization

This paper draws on a study on the development of medical genetics as a medical specialism in the UK and Canada to reflect on how local and national contexts affect specialty formation. The paper begins by supporting earlier findings in the literature that stress, first, technological innovations as driving specialty formation, and, second, the domination of physicians in the division of medical labour. Beyond this, however, the paper explores the specific circumstances under which geneticists set about turning their work into a medical specialism based on a “genetics-based approach” to illness and how “medical genetics” as a specialism was assessed and configured to fit national and regional health service requirements

Tephrochronology

Tephrochronology is the use of primary, characterized tephras or cryptotephras as chronostratigraphic marker beds to connect and synchronize geological, paleoenvironmental, or archaeological sequences or events, or soils/paleosols, and, uniquely, to transfer relative or numerical ages or dates to them using stratigraphic and age information together with mineralogical and geochemical compositional data, especially from individual glass-shard analyses, obtained for the tephra/cryptotephra deposits. To function as an age-equivalent correlation and chronostratigraphic dating tool, tephrochronology may be undertaken in three steps: (i) mapping and describing tephras and determining their stratigraphic relationships, (ii) characterizing tephras or cryptotephras in the laboratory, and (iii) dating them using a wide range of geochronological methods. Tephrochronology is also an important tool in volcanology, informing studies on volcanic petrology, volcano eruption histories and hazards, and volcano-climate forcing. Although limitations and challenges remain, multidisciplinary applications of tephrochronology continue to grow markedly

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil)

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.7 cal kyBP (95.4% interval). An ultra-filtered AMS age determination on a fragment of the sphenoid provided an age range of 9.1-9.4 cal kyBP (95.4% interval) for Burial 26. The interment was composed of an articulated cranium, mandible and first six cervical vertebrae. Cut marks with a v-shaped profile were observed in the mandible and sixth cervical vertebra. The right hand was amputated and laid over the left side of the face with distal phalanges pointing to the chin and the left hand was amputated and laid over the right side of the face with distal phalanges pointing to the forehead. Strontium analysis comparing Burial 26's isotopic signature to other specimens from Lapa do Santo suggests this was a local member of the group. Therefore, we suggest a ritualized decapitation instead of trophy-taking, testifying for the sophistication of mortuary rituals among hunter-gatherers in the Americas during the early Archaic period. In the apparent absence of wealth goods or elaborated architecture, Lapa do Santo's inhabitants seemed to use the human body to express their cosmological principles regarding death

Efficient, non‐toxic anion transport by synthetic carriers in cells and epithelia

Transmembrane anion transporters (anionophores) have potential for new modes of biological activity, including therapeutic applications. In particular they might replace the activity of defective anion channels in conditions such as cystic fibrosis. However, data on the biological effects of anionophores are scarce, and it remains uncertain whether such molecules are fundamentally toxic. Here, we report a biological study of an extensive series of powerful anion carriers. Fifteen anionophores were assayed in single cells by monitoring anion transport in real time through fluorescence emission from halide-sensitive yellow fluorescent protein. A bis-(p-nitrophenyl)ureidodecalin shows especially promising activity, including deliverability, potency and persistence. Electrophysiological tests show strong effects in epithelia, close to those of natural anion channels. Toxicity assays yield negative results in three cell lines, suggesting that promotion of anion transport may not be deleterious to cells. We therefore conclude that synthetic anion carriers are realistic candidates for further investigation as treatments for cystic fibrosis.info:eu-repo/semantics/publishe

A novel treatment of cystic fibrosis acting on-target:cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes