Palaeodata in synthesis form are needed as benchmarks for the Palaeoclimate Modelling Intercomparison Project (PMIP). Advances since the last synthesis of terrestrial palaeodata from the last glacial ...maximum (LGM) call for a new evaluation, especially of data from the tropics. Here pollen, plant-macrofossil, lake-level, noble gas (from groundwater) and δ^sup 18^O (from speleothems) data are compiled for 18±2ka (^sup 14^C), 32°N-33°S. The reliability of the data was evaluated using explicit criteria and some types of data were re-analysed using consistent methods in order to derive a set of mutually consistent palaeoclimate estimates of mean temperature of the coldest month (MTCO), mean annual temperature (MAT), plant available moisture (PAM) and runoff (P-E). Cold-month temperature (MAT) anomalies from plant data range from -1 to -2K near sea level in Indonesia and the S Pacific, through -6 to -8K at many high-elevation sites to -8 to -15K in S China and the SE USA. MAT anomalies from groundwater or speleothems seem more uniform (-4 to -6K), but the data are as yet sparse; a clear divergence between MAT and cold-month estimates from the same region is seen only in the SE USA, where cold-air advection is expected to have enhanced cooling in winter. Regression of all cold-month anomalies against site elevation yielded an estimated average cooling of -2.5 to -3K at modern sea level, increasing to asymptotically =-6K by 3000m. However, Neotropical sites showed larger than the average sea-level cooling (-5 to -6K) and a non-significant elevation effect, whereas W and S Pacific sites showed much less sea-level cooling (-1K) and a stronger elevation effect. These findings support the inference that tropical sea-surface temperatures (SSTs) were lower than the CLIMAP estimates, but they limit the plausible average tropical sea-surface cooling, and they support the existence of CLIMAP-like geographic patterns in SST anomalies. Trends of PAM and lake levels indicate wet LGM conditions in the W USA, and at the highest elevations, with generally dry conditions elsewhere. These results suggest a colder-than-present ocean surface producing a weaker hydrological cycle, more arid continents, and arguably steeper-than-present terrestrial lapse rates. Such linkages are supported by recent observations on freezing-level height and tropical SSTs; moreover, simulations of "greenhouse" and LGM climates point to several possible feedback processes by which low-level temperature anomalies might be amplified aloft.PUBLICATION ABSTRACT
An essential role of enzymes is to catalyze various chemical reactions in the human body and inhibition of the enzymatic activity by small molecules is the mechanism of action of many drugs or tool ...compounds used to study biological processes. Here, we investigate the effect on the dynamics of the serine protease α-chymotrypsin when in complex with two different covalently bound inhibitors using elastic incoherent neutron scattering. The results show that the inhibited enzyme displays enhanced dynamics compared to the free form. The difference was prominent at higher temperatures (240-310 K) and the type of motions that differ include both small amplitude motions, such as hydrogen atom rotations around a methyl group, and large amplitude motions, such as amino acid side chain movements. The measurements were analyzed with multivariate methods in addition to the standard univariate methods, allowing for a more in-depth analysis of the types of motions that differ between the two forms. The binding strength of an inhibitor is linked to the changes in dynamics occurring during the inhibitor-enzyme binding event and thus these results may aid in the deconvolution of this fundamental event and in the design of new inhibitors.
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Oral vaccines present an attractive alternative to injectable vaccines for enteric diseases due to ease of delivery and the induction of intestinal immunity at the site of infection. ...However, susceptibility to gastrointestinal proteolysis, limited transepithelial uptake and a lack of clinically acceptable adjuvants present significant challenges. A further challenge to mass vaccination in developing countries is the very expensive requirement to maintain the cold chain. We recently described the effectiveness of a Single Multiple Pill® (SmPill®) adjuvanted capsule approach to enhance the effectiveness of a candidate enterotoxigenic Escherichia coli (ETEC) oral vaccine. Here it was demonstrated that this delivery system maintains the antigenicity of ETEC colonisation factor antigen I (CFA/I) and the immunostimulatory activity of the orally active α-Galactosylceramide (α-GalCer) adjuvant after storage of SmPill® minispheres under room temperature and extreme storage conditions for several months. In addition, the internal structure of the cores of SmPill® minispheres and antigen release features at intestinal pH were found to be preserved under all these conditions. However, changes in the surface morphology of SmPill® minispheres leading to the antigen release at gastric pH were observed after a few weeks of storage under extreme conditions. Those modifications were prevented by the introduction of an Opadry® White film coating layer between the core of SmPill® minispheres and the enteric coating. Under these conditions, protection against antigen release at gastric pH was maintained even under high temperature and humidity conditions. These results support the potential of the SmPill® minisphere approach to maintain the stability of an adjuvanted whole cell killed oral vaccine formulation.
As forward genetic screens in zebrafish become more common, the number of mutants that cannot be identified by gross morphology or through transgenic approaches, such as many nervous system defects, ...has also increased. Screening for these difficult-to-visualize phenotypes demands techniques such as whole-mount
hybridization (WISH) or antibody staining, which require tissue fixation. To date, fixed tissue has not been amenable for generating libraries for whole genome sequencing (WGS). Here, we describe a method for using genomic DNA from fixed tissue and a bioinformatics suite for WGS-based mapping of zebrafish mutants. We tested our protocol using two known zebrafish mutant alleles,
and
, both of which cause myelin defects. As further proof of concept we mapped a novel mutation,
, identified in a zebrafish WISH screen for myelination defects. We linked
to chromosome 1 and identified a candidate nonsense mutation in the
(
) gene. Importantly,
mutants phenocopy previously described
mutants, and knockdown of
in wild-type animals produced similar defects, demonstrating that
disrupts
Together, these data show that our mapping protocol can map and identify causative lesions in mutant screens that require tissue fixation for phenotypic analysis.
We measured ratios of van der Waals potential coefficients (C3) for different atoms (Li, Na, K, and Rb) interacting with the same surface by studying atom diffraction from a nanograting. These ...measurements are a sensitive test of atomic structure calculations because C3 ratios are strongly influenced by core electrons and only weakly influenced by the permittivity and geometry of the surface. Our measurement uncertainty of 2% in the ratio C(3)(K)/C(3)(Na) is close to the uncertainty of the best theoretical predictions, and some of these predictions are inconsistent with our measurement.
In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients ...with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double‐blinded, placebo‐controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients ≥50 years with type 2 diabetes receiving anti‐diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow‐up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
Head-injured patients admitted to a trauma center may or may not have associated facial fractures. Most head-injured patients undergo head computed tomography (CT) scan early in their evaluation. The ...question of adding a facial CT at the time of the head CT can be unclear. The aims of our study are 1) to analyze how the facial CT is used in conjunction with the head CT in facial fracture trauma patients, 2) to recognize unique identifiers that would aid the surgeon’s decision-making process to order a facial CT in continuity with a head CT, and 3) to examine what is characteristic of head trauma patients who receive a facial CT separately, at some point after the head CT.
Data were retrospectively reviewed for a 5-year period at a level I trauma center in which all patients who present with craniomaxillofacial trauma are managed by the oral and maxillofacial surgery (OMFS) service. Included patients must have obtained a head CT during initial resuscitation and be diagnosed with a facial fracture during the same hospital stay. These patients were divided into 3 groups: those who had a 1) head CT only, 2) head CT and facial CT at the same time, and 3) head CT with the facial CT performed at a later time.
A total of 9,871 patients were admitted to the trauma service during a 5-year period and 4,926 patients (49.9%) had head CT performed. Of this group, 12% had facial fractures, and the most common associated injury in this group was facial lacerations and concussions. The nasal fracture followed by the orbital fracture was the most common fracture type. Eighty-four percent of the time, the facial CT was used to help diagnose facial fractures in this patient population. The 3 different groups showed unique trends.
Six points were identified in our study that can augment the physical examination in patients who require head CT. The following points can help prompt the clinician to order a combination head and facial CT: 1) 12% of trauma patients who require a head CT will have a facial fracture, whereas half of these patients will have multiple facial fractures. 2) Orbital fractures are commonly missed in this group and often require a secondary scan such as coronal views for accurate diagnosis. 3) Facial lacerations correlate with ordering a combination head and facial CT. 4) The most common facial fracture identified among patients receiving a trauma head CT is the nasal fracture. 5) The use of the facial CT in more severely injured patients tended to be delayed and was related to increased hospital and intensive care unit days. 6) Only 16% of facial fracture patients who had received an initial trauma head CT did not require further facial CT scanning.
Cholera is a major global health problem, causing approximately 100,000 deaths annually, about half of which occur in sub-Saharan Africa. Although early-generation parenteral cholera vaccines were ...abandoned as public health tools owing to their limited efficacy, newer-generation oral cholera vaccines have attractive safety and protection profiles. Both killed and live oral vaccines have been licensed, although only killed oral vaccines are currently manufactured and available. These killed oral vaccines not only provide direct protection to vaccinated individuals, but also confer herd immunity. The combination of direct vaccine protection and vaccine herd immunity effects makes these vaccines highly cost-effective and, therefore, attractive for use in developing countries. Administration of these oral vaccines does not require qualified medical personnel, which makes their use practical--even in developing countries. Although new-generation oral cholera vaccines should not be considered in isolation from other preventive approaches, especially improved water quality and sanitation, they represent important tools in the public health armamentarium to control both endemic and epidemic cholera.
Angiogenesis is activated during multistage tumorigenesis prior to the emergence of solid tumors. Using a transgenic mouse model, we have tested the proposition that treatment with angiogenesis ...inhibitors can inhibit the progression of tumorigenesis after the switch to the angiogenic phenotype. In this model, islet cell carcinomas develop from multifocal, hyperproliferative nodules that show the histological hallmarks of human carcinoma in situ. Mice were treated with a combination of the angiogenesis inhibitor AGM-1470 (TNP-470), the antibiotic minocycline, and interferon α /β . The treatment regimen markedly attenuated tumor growth but did not prevent tumor formation; tumor volume was reduced to 11% and capillary density to 40% of controls. The proliferation index of tumor cells in treated and control mice was similar, whereas the apoptotic index was doubled in treated tumors. This study shows that de novo tumor progression can be restricted solely by antiangiogenic therapy. The results suggest that angiogenesis inhibitors represent a valid component of anticancer strategies aimed at progression from discrete stages of tumorigenesis and demonstrate that transgenic mouse models can be used to evaluate efficacy of candidate antiangiogenic agents.
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