Energy and environmental stability are positively correlated with species richness along broad‐scale spatial gradients in terrestrial ecosystems, so their relative importance in generating and ...preserving diversity cannot be readily disentangled. This study seeks to exploit the negative correlation between energy and stability along the oceanic depth gradient to better understand their relative contribution in shaping broadscale biodiversity patterns. We develop a conceptual framework by simulating speciation and extinction along energy and stability gradients to generate expected patterns of biodiversity for a suite of complementary phylogenetic diversity metrics. Using a time‐calibrated molecular phylogeny for New Zealand marine ray‐finned fishes and a replicated community ecological sampling design, we then modelled these metrics along large‐scale depth and latitude gradients. Our results indicate that energy‐rich shallow waters may be an engine of diversity for percomorphs, but also suggest that recent speciation occurs in ancient fish lineages in the deep sea, hence questioning the role of energy as a key driver of speciation. Despite potentially facing high extinction early in their evolution, ancient phylogenetic lineages specialized for the deep‐sea were likely preserved by environmental stability during the Cenozoic. Furthermore, intermediate depths might be a ‘museum’ (or zone of overlap) for distinct lineages that occur predominantly in either shallow or deep‐sea waters. These intermediate depths (500–900 m) may form a ‘phylogenetic diversity bank’, perhaps providing a refuge during ancient (Mesozoic) extreme anoxic events affecting the deep sea and more recent (Pliocene–Pleistocene) climatic events occurring in shallow ecosystems. Finally, the phylogenetic structures observed in fish communities at intermediate depths suggest other processes might restrict the co‐occurrence of closely related species. Overall, by combining a conceptual framework with models of empirical phylogenetic diversity patterns, our study paves the way for understanding the determinants of biodiversity across the largest habitat on earth.
Joint replacement is a major orthopaedic procedure used to treat joint osteoarthritis. Aseptic loosening and infection are the two most significant causes of prosthetic implant failure. The ideal ...implant should be able to promote osteointegration, deter bacterial adhesion and minimize prosthetic infection. Recent developments in material science and cell biology have seen the development of new orthopaedic implant coatings to address these issues. Coatings consisting of bioceramics, extracellular matrix proteins, biological peptides or growth factors impart bioactivity and biocompatibility to the metallic surface of conventional orthopaedic prosthesis that promote bone ingrowth and differentiation of stem cells into osteoblasts leading to enhanced osteointegration of the implant. Furthermore, coatings such as silver, nitric oxide, antibiotics, antiseptics and antimicrobial peptides with anti-microbial properties have also been developed, which show promise in reducing bacterial adhesion and prosthetic infections. This review summarizes some of the recent developments in coatings for orthopaedic implants.
We report here a photochemical process for the selective modification of tryptophan (Trp) residues in peptides and small proteins using electron-responsive N-carbamoylpyridinium salts and UV–B light. ...Preliminary mechanistic experiments suggest that the photoconjugation process proceeds through photoinduced electron transfer (PET) between Trp and the pyridinium salt, followed by fragmentation of the pyridinium N–N bond and concomitant transfer of this group to Trp. The reaction displays excellent site selectivity for Trp and is tolerant to other, redox-active amino-acid residues. Moreover, the reaction proceeds in pure aqueous conditions without the requirement of organic cosolvents or photocatalysts, is enhanced by glutathione, and operates efficiently over a wide range of peptide concentrations (10–700 μM). The scope of the process was explored through the labeling of 6-Trp-containing peptides and proteins ranging from 1 to 14 kDa. We demonstrate the versatility of the N-carbamoylpyridinium salt both by tuning the electrochemical and photochemical properties of the pyridinium scaffold to enable challenging photoconjugation reactions and by using the carbamoyl moiety to tether a plethora of productive functional groups, including reactive handles, purification tags, and removable protecting groups.
The FDA-approved entrectinib on August 15, 2019, for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (
) ...gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory alternative therapy. Approval was based on demonstration of a durable overall response rate of 57% (95% confidence interval: 43-71), including a complete response rate of 7%, among 54 entrectinib-treated patients with 10 different tumor types harboring an
fusion enrolled in one of three single-arm clinical trials. The durations of response ranged from 2.8 months to 26.0+ months; 68% of responses lasted ≥ 6 months. The most serious toxicities of entrectinib are congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Adverse reactions were manageable through dose interruptions (46%), dose reductions (29%), or discontinuation of entrectinib (9%). This is the third approval of a cancer drug for treatment of a tissue agnostic, biomarker-defined cancer.
Lipotoxicity is defined as cellular toxicity observed in the presence of an abnormal accumulation of fat and adipocyte-derived factors in non-fat tissues. Palmitic acid (PA), an abundant fatty acid ...in the bone marrow and particularly in osteoporotic bones, affects osteoblastogenesis and osteoblast function, decreasing their survival through induction of apoptosis and dysfunctional autophagy. In this study, we hypothesized that PA also has a lipotoxic effect on osteocytes in vitro.
Initially, we tested the effect of PA on osteocyte-derived factors DKK1, sclerostin and RANKL. Then, we tested whether PA affects survival and causes apoptosis in osteocytes. Subsequently, we investigated the effect of PA on autophagy by detecting the membrane component LC3-II (Western blot) and staining it and lysosomes with Lysotracker Red dye.
PA decreases RANKL, DKK1 and sclerostin expression in osteocytes. In addition, we found that PA induces apoptosis and reduces osteocyte survival. PA also caused autophagy failure identified by a significant increase in LC3-II and a reduced number of autophagosomes/lysosomes in the cytoplasm.
In addition to the effects of PA on RANKL, DKK1 and sclerostin expression, which could have significant deleterious impact on bone cell coupling and bone turnover, PA also induced apoptosis and reduced autophagy in osteocytes. Considering that apoptosis and cell dysfunction are two common changes occurring in the osteocytes of osteoporotic bone, our findings suggest that PA could play a role in the pathogenesis of the disease. Suppression of these effects could bring new potential targets for therapeutic interventions in the future.
•Lipotoxicity is defined as cellular toxicity observed in the presence adipocyte-derived factors in non-fat tissues.•Fatty acids affect osteocyte function and survival.•Suppression of lipotoxicity could bring new potential targets for therapeutic interventions for osteoporosis in the future.
•We show how correlational niche models extrapolate when projected into novel areas.•Extrapolation was visualized using novel single-variable and multi-variable plots.•We amend the Multivariate ...Environmental Similarity Surface metric currently used.
Correlational models of species’ ecological niches are commonly used to transfer model rules onto other sets of conditions to evaluate species’ distributional potential. As with any model fitting exercise, however, interpretation of model predictions outside the range of the independent variables on which models were calibrated is perilous, herein denoted as strict extrapolation to distinguish from extrapolation onto novel combinations of variables. We use novel visualization techniques to characterize model response surfaces for several niche modeling algorithms for a virtual species (wherein the truth is known) and for two transfer-based studies published by one of our group. All modeling algorithms for each species showed strict extrapolation, such that biologically unrealistic response surfaces were reconstructed. We discuss the implications of these results for calibration and interpretation of niche models and analysis of ecological niche evolution. We present Mobility-Oriented Parity (MOP), a modification and extension of the Multivariate Environmental Similarity Surface (MESS) metric currently in use, as a means of both quantifying environmental similarity between calibration and transfer regions and highlighting regions in geographic space where strict extrapolation occurs.
Diagnosis and Management of Ovarian Cancer Doubeni, Chyke A; Doubeni, Anna R; Myers, Allison E
American family physician,
06/2016, Letnik:
93, Številka:
11
Journal Article
Recenzirano
Ovarian cancer is the most lethal gynecologic cancer. Less than one-half of patients survive for more than five years after diagnosis. Ovarian cancer affects women of all ages but is most commonly ...diagnosed after menopause. More than 75% of affected women are diagnosed at an advanced stage because early-stage disease is usually asymptomatic and symptoms of late-stage disease are nonspecific. The strongest risk factors are advancing age and family history of ovarian and breast cancer. Women who have symptoms concerning for ovarian cancer should undergo a physical examination, transvaginal ultrasonography, and measurement of biomarkers such as cancer antigen 125. If results are suspicious for ovarian cancer, the patient should be referred to a gynecologic oncologist. Despite the low rate of early diagnosis, guidelines recommend against routine screening for ovarian cancer in average-risk women because screening, including routine pelvic examinations, is ineffective and associated with harm. However, a recent trial found a potential benefit of annual screening using an algorithm based on serial cancer antigen 125 measurements followed by transvaginal ultrasonography for women at increased risk, as determined by the algorithm. Women with an increased-risk family history should be referred for genetic counseling and, if genetic mutations (e.g., BRCA mutations) are identified, bilateral salpingo-oophorectomy can be considered for risk reduction. In both average- and high-risk women, long-term hormonal contraceptive use reduces risk by about 50%. The treatment of ovarian cancer usually involves surgery, with or without intraperitoneal and intravenous chemotherapy. Primary care physicians have important roles in posttreatment surveillance and end-of-life care.
Magnetic reconnection, in which magnetic field lines break and reconnect to change their topology, occurs throughout the universe. The essential feature of reconnection is that it energizes plasma ...particles by converting magnetic energy. Despite the long history of reconnection research, how this energy conversion occurs remains a major unresolved problem in plasma physics. Here we report that the energy conversion in a laboratory reconnection layer occurs in a much larger region than previously considered. The mechanisms for energizing plasma particles in the reconnection layer are identified, and a quantitative inventory of the converted energy is presented for the first time in a well-defined reconnection layer; 50% of the magnetic energy is converted to particle energy, 2/3 of which transferred to ions and 1/3 to electrons. Our results are compared with simulations and space measurements, for a key step towards resolving one of the most important problems in plasma physics.
Adaptation to mechanical loading has been studied extensively in cortical, but not cancellous bone. However, corticocancellous sites are more relevant to osteoporosis and related fracture risk of the ...hip and spine. We tested the hypotheses that adaptation in a long bone would be greater at cancellous than cortical sites and would depend on the term of daily in vivo cyclic axial loading. We applied compressive loads to the adolescent, 10-week old, male C57BL/6 mouse tibia to examine the skeletal response immediately prior to attainment of peak bone mass. Adaptation was quantified at the completion of either 2-week (
n = 8) or 6-week (
n = 12) loading terms by directly comparing volumetric bone mineral content between loaded and contralateral limbs by microcomputed tomography. The increase in mineral content was site specific with a greater response found in the corticocancellous proximal metaphysis (14%) than the cortical mid-shaft (2%) after 6 weeks of loading. Furthermore, bone volume fraction and average trabecular thickness of cancellous bone in the proximal tibia increased after 6 weeks by 15% and 12% respectively. Diaphyseal response was only evident proximal to the mid-shaft as indicated by an 8% increase in maximum principal moment of inertia. Both loading terms produced similar results for mineral content, volume fraction, and moments of inertia. Our finding that non-invasive loading increases the bone volume and fraction at a corticocancellous site by as much as 15% motivates exploring the use of mechanical loading to attain greater peak bone mass and inhibit osteoporosis.
Perceptual decisions occur after the evaluation and integration of momentary sensory inputs, and dividing attention between spatially disparate sources of information impairs decision performance. ...However, it remains unknown whether dividing attention degrades the precision of sensory signals, precludes their conversion into decision signals, or dampens the integration of decision information toward an appropriate response. Here we recorded human electroencephalographic (EEG) activity while participants categorized one of two simultaneous and independent streams of visual gratings according to their average tilt. By analyzing trial-by-trial correlations between EEG activity and the information offered by each sample, we obtained converging behavioral and neural evidence that dividing attention between left and right visual fields does not dampen the encoding of sensory or decision information. Under divided attention, momentary decision information from both visual streams was encoded in slow parietal signals without interference but was lost downstream during their integration as reflected in motor mu- and beta-band (10-30 Hz) signals, resulting in a "leaky" accumulation process that conferred greater behavioral influence to more recent samples. By contrast, sensory inputs that were explicitly cued as irrelevant were not converted into decision signals. These findings reveal that a late cognitive bottleneck on information integration limits decision performance under divided attention, and places new capacity constraints on decision-theoretic models of information integration under cognitive load.
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