- The Beaker phenomenon and the genomic transformation of northwest Europe. [Journal Article]
- NatNature 2018 Feb 21
- From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a mat...
From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.
- The genomic history of southeastern Europe. [Journal Article]
- NatNature 2018 Feb 21
- Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to under...
Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to understand the dynamics of this process, we analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12000 and 500 bc. We document a west-east cline of ancestry in indigenous hunter-gatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. We show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. We also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.
- Change in ALT levels after administration of HMG-CoA reductase inhibitors to subjects with pretreatment levels three times the upper normal limit in clinical practice. [Journal Article]
- CTCardiovasc Ther 2018 Feb 21
- CONCLUSIONS: It is not clear whether it is safe to prescribe statins to patients with ALT > 3-times the UNL. Our study showed that prescription of statins in combination with HEPA did not cause deleterious effects, suggesting that ALT levels > 3-times the UNL do not have harmful effects. This article is protected by copyright. All rights reserved.
- Evaluating feasibility and accuracy of non-invasive tests for nonalcoholic fatty liver disease in severe and morbid obesity. [Journal Article]
- IJInt J Obes (Lond) 2018 Jan 30
- CONCLUSIONS: 1 H-MRS and TE/CAP had greatest accuracy for NAFLD-related steatosis and fibrosis. Failure rates in obesity significantly diminished diagnostic ability. Use of a combination of serum and imaging tests improved overall feasibility of assessment and diagnostic accuracy in obese individuals.
- Dysfunctional immunoregulation in human liver allograft rejection associated with compromised galectin-1/CD7 pathway function. [Journal Article]
- CDCell Death Dis 2018 Feb 20; 9(3):293
- Regulatory T cells in rejected allograft patients display an inability to control responder T cells. Galectin-1 (Gal1) inhibits responder T cells through binding CD7. We investigated whether the dysf...
Regulatory T cells in rejected allograft patients display an inability to control responder T cells. Galectin-1 (Gal1) inhibits responder T cells through binding CD7. We investigated whether the dysfunctional immunoregulation in liver allograft rejection patients results from reduced regulatory T-cell Gal1 expression and/or responder T-cell CD7 expression. Circulating regulatory T cells and responder T cells were profiled from 31 acute rejection transplant patients, 85 transplant patients in remission, and 40 healthy controls. CD7+ and CD7- responder T cells were co-cultured with regulatory T cells to assess regulatory T-cell suppressor function. Gal1-small interfering RNA was used to silence regulatory T-cell Gal1. The CD7+ cell percentage was inversely correlated with AST, ALT, and GGT levels. The proportions of CD7+ responder T cells and Gal1+ regulatory T cells were higher in healthy controls than in transplant patients in remission and lowest in acute rejection transplant patients. Notably, CD7+ responder T-cell susceptibility to Gal1+ regulatory T-cell control was ranked in the same manner. Silencing Gal1 expression in regulatory T cells reduced their ability to suppress CD7+ (but not CD7-) responder T cells. Additionally, the proportions of CD43+ and CD45+ responder T cells were higher in healthy controls than in acute rejection transplant patients. CD43 co-expression (but not CD45 co-expression) on CD7+ responder T cells promoted their apoptosis in a Gal1-dependent manner. In sum, dysfunctional immunoregulation in liver allograft rejection patients can be partly attributed to reduced regulatory T-cell Gal1 expression and reduced responder T-cell CD7 expression. Responder T-cell CD43 downregulation in acute rejection patients may further contribute to reduced responder T-cell responsiveness to regulatory T-cell control.
- First-in-human Phase 1 Clinical Study of the IL-15 Superagonist Complex ALT-803 to Treat Relapse after Transplantation. [Journal Article]
- BloodBlood 2018 Feb 20
- New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8+T...
New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8+T cell and NK cell anti-tumor responses, and we hypothesized this cytokine may augment anti-leukemia/lymphoma immunity in vivo. To test this, we performed a first-in-human multi-center phase 1 trial (ClinicalTrials.gov NCT01885897) of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the intravenous (IV) or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 mcg/kg). ALT-803 was well-tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host-disease (GVHD) requiring systemic therapy were observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and IFN-γ. To mitigate these effects the subcutaneous (SQ) route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. PK analysis revealed a prolonged (>96 hours) serum concentrations following SQ, but not IV injection. ALT-803 stimulated activation, proliferation, and expansion of NK cells and CD8+T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including one complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+T cell number and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment anti-tumor immunity alone and combined with other immunotherapies.
- Prognosis of hospitalized patients with community-acquired pneumonia. [Journal Article]
- RPRev Port Pneumol (2006) 2018 Feb 17
- CONCLUSIONS: Long-term mortality following hospitalization for CAP is high. Charlson score and lack of fever are potential indicators for decreased long-term survival. As novel parameters, baseline BUN/albumin ratios and ALT levels are significantly associated with late mortality. Further interventions and closer monitoring are necessary for such subgroups of patients.
- Telomere Length Maintenance in Cancer: At the Crossroad between Telomerase and Alternative Lengthening of Telomeres (ALT). [Review]
- IJInt J Mol Sci 2018 Feb 18; 19(2)
- Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in ...
Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation-both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM.
- The effects of intermittent whole-body hypoxic preconditioning on patients with carotid artery stenosis. [Journal Article]
- WNWorld Neurosurg 2018 Feb 17
- CONCLUSIONS: Intermittent hypoxic preconditioning can change the vital signs and hematological indexes of patients with carotid artery stenosis without causing new postoperative complications or organ damage.
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- Wet feed and cold water as heat stress modulators in growing Muscovy ducklings. [Journal Article]
- PSPoult Sci 2018 Feb 14
- In an attempt to alleviate the deleterious effects of high summer temperatures, the present study investigated the effects of wet feed and cold water on the growth performance, carcass and meat quali...
In an attempt to alleviate the deleterious effects of high summer temperatures, the present study investigated the effects of wet feed and cold water on the growth performance, carcass and meat quality, leg problems, physiological responses, and blood parameters of growing Muscovy ducklings. A total of 180 4-week-old ducklings was randomly divided into 6 experimental groups in a 3 × 2 factorial design that included 3 feed systems (AD: ad libitum dry; DW: diurnal wet; and AW: ad libitum wet) and 2 systems of water (TW: tap water; and CW: cold water). Access to wet feed and cold water affected the growth performance, dressed carcass, gizzard, meat quality (tenderness, juiciness, and susceptibility), tonic immobility, body temperature, and blood parameters [albumin: globulin (A: G) ratio and levels of glucose, alanine transferase (ALT), total antioxidant capacity (T-AOC), and malondialdehyde (MDA)] of the ducklings but had no significant effect on plumage condition, shank length, keel bone length, leg problems, or breast blisters. The body weight (BW) of the DW group was 1.97 and 3.12% greater than that of the AD and AW groups, respectively, and the BWG of the DW group was 6.91 and 10.72% greater than that of the AD and AW groups, respectively. Therefore, providing access to wet feed and cold water is highly recommended when raising Muscovy ducks in open houses under high-temperature conditions.