PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine ...diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our ...understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
Specificity of interactions between two DNA strands, or between protein and DNA, is often achieved by varying bases or side chains coming off the DNA or protein backbone-for example, the bases ...participating in Watson-Crick pairing in the double helix, or the side chains contacting DNA in TALEN-DNA complexes. By contrast, specificity of protein-protein interactions usually involves backbone shape complementarity
, which is less modular and hence harder to generalize. Coiled-coil heterodimers are an exception, but the restricted geometry of interactions across the heterodimer interface (primarily at the heptad a and d positions
) limits the number of orthogonal pairs that can be created simply by varying side-chain interactions
. Here we show that protein-protein interaction specificity can be achieved using extensive and modular side-chain hydrogen-bond networks. We used the Crick generating equations
to produce millions of four-helix backbones with varying degrees of supercoiling around a central axis, identified those accommodating extensive hydrogen-bond networks, and used Rosetta to connect pairs of helices with short loops and to optimize the remainder of the sequence. Of 97 such designs expressed in Escherichia coli, 65 formed constitutive heterodimers, and the crystal structures of four designs were in close agreement with the computational models and confirmed the designed hydrogen-bond networks. In cells, six heterodimers were fully orthogonal, and in vitro-following mixing of 32 chains from 16 heterodimer designs, denaturation in 5 M guanidine hydrochloride and reannealing-almost all of the interactions observed by native mass spectrometry were between the designed cognate pairs. The ability to design orthogonal protein heterodimers should enable sophisticated protein-based control logic for synthetic biology, and illustrates that nature has not fully explored the possibilities for programmable biomolecular interaction modalities.
Polymerase chain reaction (PCR) assessment of clonal T-cell receptor (TCR) and immunoglobulin (Ig) gene rearrangements is an important diagnostic tool in mature T-cell neoplasms. However, lack of ...standardized primers and PCR protocols has hampered comparability of data in previous clonality studies. To obtain reference values for Ig/TCR rearrangement patterns, 19 European laboratories investigated 188 T-cell malignancies belonging to five World Health Organization-defined entities. The TCR/Ig spectrum of each sample was analyzed in duplicate in two different laboratories using the standardized BIOMED-2 PCR multiplex tubes accompanied by international pathology panel review. TCR clonality was detected in 99% (143/145) of all definite cases of T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, peripheral T-cell lymphoma (unspecified) and angioimmunoblastic T-cell lymphoma (AILT), whereas nine of 43 anaplastic large cell lymphomas did not show clonal TCR rearrangements. Combined use of TCRB and TCRG genes revealed two or more clonal signals in 95% of all TCR clonal cases. Ig clonality was mostly restricted to AILT. Our study indicates that the BIOMED-2 multiplex PCR tubes provide a powerful strategy for clonality assessment in T-cell malignancies assisting the firm diagnosis of T-cell neoplasms. The detected TCR gene rearrangements can also be used as PCR targets for monitoring of minimal residual disease.
WASP-39b is a hot Saturn-mass exoplanet with a predicted clear atmosphere based on observations in the optical and infrared. Here, we complete the transmission spectrum of the atmosphere with ...observations in the near-infrared (NIR) over three water absorption features with the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) G102 (0.8-1.1 m) and G141 (1.1-1.7 m) spectroscopic grisms. We measure the predicted high-amplitude H2O feature centered at 1.4 m and the smaller amplitude features at 0.95 and 1.2 m, with a maximum water absorption amplitude of 2.4 planetary scale heights. We incorporate these new NIR measurements into previously published observational measurements to complete the transmission spectrum from 0.3 to 5 m. From these observed water features, combined with features in the optical and IR, we retrieve a well constrained temperature Teq = 1030 K, and atmospheric metallicity solar, which is relatively high with respect to the currently established mass-metallicity trends. This new measurement in the Saturn-mass range hints at further diversity in the planet formation process relative to our solar system giants.
The COVID-19 pandemic has placed significant pressure on health and social care. Survivors of COVID-19 may be left with substantial functional deficits requiring ongoing care. We aimed to determine ...whether pre-admission frailty was associated with increased care needs at discharge for patients admitted to hospital with COVID-19.
Patients were included if aged over 18 years old and admitted to hospital with COVID-19 between 27 February and 10 June 2020. The Clinical Frailty Scale (CFS) was used to assess pre-admission frailty status. Admission and discharge care levels were recorded. Data were analysed using a mixed-effects logistic regression adjusted for age, sex, smoking status, comorbidities, and admission CRP as a marker of severity of disease.
Thirteen hospitals included patients: 1671 patients were screened, and 840 were excluded including, 521 patients who died before discharge (31.1%). Of the 831 patients who were discharged, the median age was 71 years (IQR, 58-81 years) and 369 (44.4%) were women. The median length of hospital stay was 12 days (IQR 6-24). Using the CFS, 438 (47.0%) were living with frailty (≥ CFS 5), and 193 (23.2%) required an increase in the level of care provided. Multivariable analysis showed that frailty was associated with an increase in care needs compared to patients without frailty (CFS 1-3). The adjusted odds ratios (aOR) were as follows: CFS 4, 1.99 (0.97-4.11); CFS 5, 3.77 (1.94-7.32); CFS 6, 4.04 (2.09-7.82); CFS 7, 2.16 (1.12-4.20); and CFS 8, 3.19 (1.06-9.56).
Around a quarter of patients admitted with COVID-19 had increased care needs at discharge. Pre-admission frailty was strongly associated with the need for an increased level of care at discharge. Our results have implications for service planning and public health policy as well as a person's functional outcome, suggesting that frailty screening should be utilised for predictive modelling and early individualised discharge planning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Polymerase chain reaction (PCR) assessment of clonal immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements is an important diagnostic tool in mature B-cell neoplasms. However, lack of ...standardized PCR protocols resulting in a high level of false negativity has hampered comparability of data in previous clonality studies. In order to address these problems, 22 European laboratories investigated the Ig/TCR rearrangement patterns as well as t(14;18) and t(11;14) translocations of 369 B-cell malignancies belonging to five WHO-defined entities using the standardized BIOMED-2 multiplex PCR tubes accompanied by international pathology panel review. B-cell clonality was detected by combined use of the IGH and IGK multiplex PCR assays in all 260 definitive cases of B-cell chronic lymphocytic leukemia (n=56), mantle cell lymphoma (n=54), marginal zone lymphoma (n=41) and follicular lymphoma (n=109). Two of 109 cases of diffuse large B-cell lymphoma showed no detectable clonal marker. The use of these techniques to assign cell lineage should be treated with caution as additional clonal TCR gene rearrangements were frequently detected in all disease categories. Our study indicates that the BIOMED-2 multiplex PCR assays provide a powerful strategy for clonality assessment in B-cell malignancies resulting in high Ig clonality detection rates particularly when IGH and IGK strategies are combined.
Catalog of Nearby Exoplanets Butler, R. P; Wright, J. T; Marcy, G. W ...
The Astrophysical journal,
07/2006, Letnik:
646, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We present a catalog of nearby exoplanets. It contains the 172 known low-mass companions with orbits established through radial velocity and transit measurements around stars within 200 pc. We ...include five previously unpublished exoplanets orbiting the stars HD 11964, HD 66428, HD 99109, HD 107148, and HD 164922. We update orbits for 83 additional exoplanets, including many whose orbits have not been revised since their announcement, and include radial velocity time series from the Lick, Keck, and Anglo-Australian Observatory planet searches. Both these new and previously published velocities are more precise here due to improvements in our data reduction pipeline, which we applied to archival spectra. We present a brief summary of the global properties of the known exoplanets, including their distributions of orbital semimajor axis, minimum mass, and orbital eccentricity.
Abstract
A high-resolution primitive equation model simulation is used to form an energy budget for the principal semidiurnal tide (M2) over a region of the Hawaiian Ridge from Niihau to Maui. This ...region includes the Kaena Ridge, one of the three main internal tide generation sites along the Hawaiian Ridge and the main study site of the Hawaii Ocean Mixing Experiment. The 0.01°–horizontal resolution simulation has a high level of skill when compared to satellite and in situ sea level observations, moored ADCP currents, and notably reasonable agreement with microstructure data. Barotropic and baroclinic energy equations are derived from the model’s sigma coordinate governing equations and are evaluated from the model simulation to form an energy budget. The M2 barotropic tide loses 2.7 GW of energy over the study region. Of this, 163 MW (6%) is dissipated by bottom friction and 2.3 GW (85%) is converted into internal tides. Internal tide generation primarily occurs along the flanks of the Kaena Ridge and south of Niihau and Kauai. The majority of the baroclinic energy (1.7 GW) is radiated out of the model domain, while 0.45 GW is dissipated close to the generation regions. The modeled baroclinic dissipation within the 1000-m isobath for the Kaena Ridge agrees to within a factor of 2 with the area-weighted dissipation from 313 microstructure profiles. Topographic resolution is important, with the present 0.01° resolution model resulting in 20% more barotropic-to-baroclinic conversion compared to when the same analysis is performed on a 4-km resolution simulation. A simple extrapolation of these results to the entire Hawaiian Ridge is in qualitative agreement with recent estimates based on satellite altimetry data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
β-galactomannans found in soy-based broiler feed are known to cause physiological effects that are hypothesized to be related to gut inflammation. Previous studies have shown that the ...incorporation of β-mannanase in the diet or as a supplement results in improvements to certain performance parameters related to gut health and feed conversion. Using kinome analysis, we characterized the mechanism of β-galactomannan activity and supplementation with β-mannanase on the gut of commercial broilers to understand the mode of action. Two doses of β-mannanase (200 and 400 g/ton of feed) with and without inclusion of additional β-galactomannan (3,000 ppm) were tested at 3 time points (d 14, d 28, and d 42 post hatch). Broilers were fed starter (d 0 to 14), grower (d 15 to 28), and finisher diets (d 29 to 42). Jejuna were collected from birds from each treatment condition and time point. Cluster analysis of the kinome data showed that birds clustered first by age, then predominantly by whether β-mannanase had been included in the diet. Biological pathway analysis showed that the inclusion of additional β-galactomannan into the diet resulted in increased signaling related to immune response, relative to our normal control diet (with reduced soybean meal). The addition of β-mannanase to the enhanced β-galactomannan diet eliminated the majority of this immune-related signaling, indicating that the feed-induced immune response within the jejuna had been eliminated by the addition of β-mannanase. We also saw changes in specific metabolic and gut function pathways in birds fed β-mannanase. These observed changes in β-mannanase-fed birds are likely the mechanism for the enhanced performance and feed conversion observed in birds given β-mannanase in their diets.
PDF
