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Polar molecules are desirable systems for quantum simulations and cold chemistry. Molecular ions are easily trapped, but a bias electric field applied to polarize them tends to accelerate them out of the trap. We present a general solution to this issue by rotating the bias field slowly enough for the molecular polarization axis to follow but rapidly enough for the ions to stay trapped. We demonstrate Ramsey spectroscopy between Stark-Zeeman subleveis in ¹⁸⁰Hf¹⁹F⁺ with a coherence time of 100 milliseconds. Frequency shifts arising from well-controlled topological (Berry) phases are used to determine magnetic g factors. The rotating-bias-field technique may enable using trapped polar molecules for precision measurement and quantum information science, including the search for an electron electric dipole moment.

AbstractBackgroundVascular function (VF) is a general term used to describe the regulation of blood flow, arterial pressure, capillary recruitment, filtration and central venous pressure, it's well known that age has direct effects on the VF, and this may affect the frailty status. ObjectivesTo analyse the association between Frailty Trait Scale 5 (FTS 5) with VF and its changes at values below and above a nadir. DesignProspective population-based cohort study. Setting and ParticipantsData from 1.230 patients were taken from the first wave (2006–2009) of the Toledo Study for Healthy Aging. MeasurementsFrailty was evaluated using FTS 5, which evaluates 5 items: Body mass index, progressive Romberg, physical activity, usual gait speed and hand grip strength. VF was assessed using the ankle-brachial index (ABI) as an indirect measure of VF. Screening for cardiovascular and cerebrovascular disease was also performed by self-reporting and by searching medical records, and was used as exclusion criteria. ResultsThe optimal ABI cut-off point that maximized the adjusted R2 was 1.071. We observed a statistically significant association for FTS 5 score above and below the ABI cut-off points. For every tenth that the ABI decreased below the cut-off point the patient had an increase in the FTS 5 score of 0.47 points and in every tenth that increased above the cut-off point the increase in the FTS 5 score was 0.41 points. Of all FTS 5 items, the gait speed was the only item that showed a significant association with an ABI changes 0.28 and 0.21 points for every tenth below and above the cut-off point, respectively. ConclusionsFrailty is highly associated with VF. In addition, FTS 5 and its gait speed criteria are useful to detect VF impairments, via changes in ABI.

Land use change is a key component of regional environmental change. In mountain regions, where conditions for agriculture and human life are often difficult, land use trends are dominated by changes in the population's distribution across rural and urban areas and shifts in the main human activities. In the Argentinian puna—a high-elevation subtropical plateau of about 95,000 km2 situated above 3200 masl—land is chiefly used for grazing, mining, and tourism. In this article, we analyze trends in these land uses over the last 57 years in the context of climatic changes toward drier and warmer conditions. Since 1960, the human population grew from 80,000 to 130,000; but this increase largely occurred in the scattered urban centers, while the rural population decreased. The main livestock— sheep—showed a net decrease of around 100,000 animals (–18.5%), with numbers increasing between 1960 and 1980 and then dropping markedly. The number of mining operations declined during the 1970s and 1980s and then rose sharply, reaching a 30% increase since the 1990s. Simultaneously, structural wild vicuña populations increased from a few thousand to around 130,000. These results show that environmental changes over the past half century involved a major wildlife recovery associated with a change from widespread extensive grazing to intensive but spatially limited impacts around mining operations and growing urban centers. Tourism emerged as a new activity over the last decades, but the environmental impacts have been poorly studied. To promote local development and regional conservation, research priorities should include (1) empirical assessments of the ecological consequences of land use changes, such as grazing regimes shifting from domestic to wild herbivores, as well as the impacts of mining, tourism, and urbanization on wetlands and hydrological regimes; (2) modeling of future scenarios of mining and tourism expansion and resulting conflicts with environmental conservation; and (3) coproduction of knowledge about interactions among land uses, climate change, and the different decision-making agents.

There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF(-/-), IFN-gamma(-/-), IL-12(-/-) and RAG-1(-/-) malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses.

Background The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP ( Good Manufacturing Practice ) or clinical grade reagents with the aim of defining their use for human cell therapy. Methods Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-α, IL-β and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced. Results Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3-tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol-DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-γ) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-γ production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells. Conclusions Our results demonstrate contrasting influences of different clinical-grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p  < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

Breast conserving surgery is the preferred treatment for women diagnosed with early stage invasive breast cancer. To ensure successful breast conserving surgeries, efficient tumour margin resection is required for minimizing tumour recurrence. Currently surgeons rely on touch preparation cytology or frozen section analysis to assess tumour margin status intraoperatively. These techniques have suboptimal accuracy and are time-consuming. Tumour margin status is eventually confirmed using postoperative histopathology that takes several days. Thus, there is a need for a real-time, accurate, automated guidance tool that can be used during tumour resection intraoperatively to assure complete tumour removal in a single procedure. In this paper, we evaluate feasibility of a 3-dimensional scanner that relies on Raman Spectroscopy to assess the entire margins of a resected specimen within clinically feasible time. We initially tested this device on a phantom sample that simulated positive tumour margins. This device first scans the margins of the sample and then depicts the margin status in relation to an automatically reconstructed image of the phantom sample. The device was further investigated on breast tissues excised from prophylactic mastectomy specimens. Our findings demonstrate immense potential of this device for automated breast tumour margin assessment to minimise repeat invasive surgeries.

Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B . In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti-CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL.

Background: Steroids improve multiple sclerosis (MS) relapses but therapeutic window and dose, frequency and administration route remain uncertain. Objective: The objective of this paper is to compare the clinical and radiologic efficacy, tolerability and safety of intravenous methylprednisolone (ivMP) vs oral methylprednisolone (oMP), at equivalent high doses, for MS relapse. Methods: Forty-nine patients with moderate or severe relapse within the previous 15 days were randomized in a double-blind, noninferiority, multicenter trial to receive ivMP or oMP and their matching placebos. Expanded Disability Status Scale (EDSS) scores were determined at baseline and weeks 1, 4 and 12. Brain MRI were assessed at baseline and at weeks 1 and 4. Primary endpoint was a noninferiority assessment of EDSS improvement at four weeks (noninferiority margin of one point), with further key efficacy assessments of number and volume of T1 gadolinium-enhancing (Gd+), and new or enlarged T2 lesions at four weeks’ post-treatment initiation. Secondary outcomes were safety and tolerability. Results: The study achieved the main outcome of noninferiority at four weeks for improved EDSS score. No differences were found between ivMP and oMP in the number of Gd+ lesions (0 (0–1) vs 0 (0–0.5), p = 0.630), volume of Gd+ lesions (0 (0–88.0) vs 0 (0–32.9) mm3, p = 0.735), or new or enlarged T2 lesions (0 (0–194) vs 0 (0–123), p = 0.769). MP was well tolerated, and no serious adverse events were reported. Conclusions: This study provides confirmatory evidence that oMP is not inferior to ivMP in reducing EDSS, similar in MRI lesions at four weeks for MS relapses and is equally well tolerated and safe. Trial registration: clinicaltrials.gov identifier: NCT00753792

Land use is central to addressing sustainability issues, including biodiversity conservation, climate change, food security, poverty alleviation, and sustainable energy. In this paper, we synthesize knowledge accumulated in land system science, the integrated study of terrestrial social-ecological systems, into 10 hard truths that have strong, general, empirical support. These facts help to explain the challenges of achieving sustainability in land use and thus also point toward solutions. The 10 facts are as follows: 1) Meanings and values of land are socially constructed and contested; 2) land systems exhibit complex behaviors with abrupt, hard-to-predict changes; 3) irreversible changes and path dependence are common features of land systems; 4) some land uses have a small footprint but very large impacts; 5) drivers and impacts of land-use change are globally interconnected and spill over to distant locations; 6) humanity lives on a used planet where all land provides benefits to societies; 7) land-use change usually entails trade-offs between different benefits—“win–wins” are thus rare; 8) land tenure and land-use claims are often unclear, overlapping, and contested; 9) the benefits and burdens from land are unequally distributed; and 10) land users have multiple, sometimes conflicting, ideas of what social and environmental justice entails. The facts have implications for governance, but do not provide fixed answers. Instead they constitute a set of core principles which can guide scientists, policy makers, and practitioners toward meeting sustainability challenges in land use.