c-Src links a RANK/αvβ3 integrin complex to the osteoclast cytoskeleton

RANK ligand (RANKL), by mechanisms unknown, directly activates osteoclasts to resorb bone. Because c-Src is key to organizing the cell's cytoskeleton, we asked if the tyrosine kinase also mediates RANKL-stimulated osteoclast activity. RANKL induces c-Src to associate with RANK(369–373) in an αvβ3-dependent manner. Furthermore, RANK(369–373) is the only one of six putative TRAF binding motifs sufficient to generate actin rings and activate the same cytoskeleton-organizing proteins as the integrin. While c-Src organizes the cell's cytoskeleton in response to the cytokine, it does not participate in RANKL-stimulated osteoclast formation. Attesting to their collaboration, αvβ3 and activated RANK coprecipitate, but only in the presence of c-Src. c-Src binds activated RANK via its Src homology 2 (SH2) domain and αvβ3 via its SH3 domain, suggesting the kinase links the two receptors. Supporting this hypothesis, deletion or inactivating point mutation of either the c-Src SH2 or SH3 domain obviates the RANK/αvβ3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to αvβ3, organizes the cell's cytoskeleton

Quantitative features of multifractal subtleties in time series

Based on the Multifractal Detrended Fluctuation Analysis (MFDFA) and on the Wavelet Transform Modulus Maxima (WTMM) methods we investigate the origin of multifractality in the time series. Series fluctuating according to a qGaussian distribution, both uncorrelated and correlated in time, are used. For the uncorrelated series at the border (q=5/3) between the Gaussian and the Levy basins of attraction asymptotically we find a phase-like transition between monofractal and bifractal characteristics. This indicates that these may solely be the specific nonlinear temporal correlations that organize the series into a genuine multifractal hierarchy. For analyzing various features of multifractality due to such correlations, we use the model series generated from the binomial cascade as well as empirical series. Then, within the temporal ranges of well developed power-law correlations we find a fast convergence in all multifractal measures. Besides of its practical significance this fact may reflect another manifestation of a conjectured q-generalized Central Limit Theorem

Pre-exposure prophylaxis for preventing acquisition of HIV: A cross-sectional study of patients, prescribers, uptake, and spending in the United States, 2015-2016

BACKGROUND: In 2015, there were approximately 40,000 new HIV diagnoses in the United States. Pre-exposure prophylaxis (PrEP) is an effective strategy that reduces the risk of HIV acquisition; however, uptake among those who can benefit from it has lagged. In this study, we 1) compared the characteristics of patients who were prescribed PrEP with individuals newly diagnosed with HIV infection, 2) identified the specialties of practitioners prescribing PrEP, 3) identified metropolitan statistical areas (MSAs) within the US where there is relatively low uptake of PrEP, and 4) reported median amounts paid by patients and third-party payors for PrEP. METHODS AND FINDINGS: We analyzed prescription drug claims for individuals prescribed PrEP in the Integrated Dataverse (IDV) from Symphony Health for the period of September 2015 to August 2016 to describe PrEP patients, prescribers, relative uptake, and payment methods in the US. Data were available for 75,839 individuals prescribed PrEP, and findings were extrapolated to approximately 101,000 individuals, which is less than 10% of the 1.1 million adults for whom PrEP was indicated. Compared to individuals with newly diagnosed HIV infection, PrEP patients were more likely to be non-Hispanic white (45% versus 26.2%), older (25% versus 19% at ages 35-44), male (94% versus 81%), and not reside in the South (30% versus 52% reside in the South).Using a ratio of the number of PrEP patients within an MSA to the number of newly diagnosed individuals with HIV infection, we found MSAs with relatively low uptake of PrEP were concentrated in the South. Of the approximately 24,000 providers who prescribed PrEP, two-thirds reported primary care as their specialty. Compared to the types of payment methods that people living with diagnosed HIV (PLWH) used to pay for their antiretroviral treatment in 2015 to 2016 reported in the Centers for Disease Control and Prevention (CDC) HIV Surveillance Special Report, PrEP patients were more likely to have used commercial health insurance (80% versus 35%) and less likely to have used public healthcare coverage or a publicly sponsored assistance program to pay for PrEP (12% versus 45% for Medicaid). Third-party payors covered 95% of the costs of PrEP. Overall, we estimated the median annual per patient out-of-pocket spending on PrEP was approximately US$72. Limitations of this study include missing information on prescription claims of patients not included in the database, and for those included, some patients were missing information on patient diagnosis, race/ethnicity, educational attainment, and income (34%-36%). CONCLUSIONS: Our findings indicate that in 2015-2016, many individuals in the US who could benefit from being on PrEP were not receiving this HIV prevention medication, and those prescribed PrEP had a significantly different distribution of characteristics from the broader population that is at risk for acquiring HIV. PrEP patients were more likely to pay for PrEP using commercial or private insurance, whereas PLWH were more likely to pay for their antiretroviral treatment using publicly sponsored programs. Addressing the affordability of PrEP and otherwise promoting its use among those with indications for PrEP represents an important opportunity to help end the HIV epidemic

Mean-field Study of Charge, Spin, and Orbital Orderings in Triangular-lattice Compounds ANiO2 (A=Na, Li, Ag)

We present our theoretical results on the ground states in layered triangular-lattice compounds ANiO2 (A=Na, Li, Ag). To describe the interplay between charge, spin, orbital, and lattice degrees of freedom in these materials, we study a doubly-degenerate Hubbard model with electron-phonon couplings by the Hartree-Fock approximation combined with the adiabatic approximation. In a weakly-correlated region, we find a metallic state accompanied by \sqroot3x\sqroot3 charge ordering. On the other hand, we obtain an insulating phase with spin-ferro and orbital-ferro ordering in a wide range from intermediate to strong correlation. These phases share many characteristics with the low-temperature states of AgNiO2 and NaNiO2, respectively. The charge-ordered metallic phase is stabilized by a compromise between Coulomb repulsions and effective attractive interactions originating from the breathing-type electronphonon coupling as well as the Hund's-rule coupling. The spin-orbital-ordered insulating phase is stabilized by the cooperative effect of electron correlations and the Jahn-Teller coupling, while the Hund's-rule coupling also plays a role in the competition with other orbital-ordered phases. The results suggest a unified way of understanding a variety of low-temperature phases in ANiO2. We also discuss a keen competition among different spin-orbital-ordered phases in relation to a puzzling behavior observed in LiNiO2

Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shedding of its ectodomain

AbstractAngiotensin-converting enzyme-2 (ACE2) is a regulatory protein of the renin–angiotensin system (RAS) and a receptor for the causative agent of severe-acute respiratory syndrome (SARS), the SARS-coronavirus. We have previously shown that ACE2 can be shed from the cell surface in response to phorbol esters by a process involving TNF-α converting enzyme (TACE; ADAM17). In this study, we demonstrate that inhibitors of calmodulin also stimulate shedding of the ACE2 ectodomain, a process at least partially mediated by a metalloproteinase. We also show that calmodulin associates with ACE2 and that this interaction is decreased by calmodulin inhibitors

Origin and pressure dependence of ferromagnetism in A2Mn2O7 pyrochlores (A=Y, In, Lu, and Tl)

Non-conventional mechanisms have been recently invoked in order to explain the ferromagnetic ground state of A2Mn2O7 pyrochlores (A=Y, In, Lu and Tl) and the puzzling decrease of their Curie temperatures with applied pressure. Here we show, using a perturbation expansion in the Mn-O hopping term, that both features can be understood within the superexhange model, provided that the intra-atomic oxygen interactions are properly taken into account. An additional coupling between the Mn ions mediated by the In(5s)/Tl(6s) bands yields the higher Tc's of these two compounds, this mechamism enhancing their ferromagnetism for higher pressures.Comment: 7 pages and 2 figures submitted to Phys. Rev. B, missing text adde

The Importance of Human FcγRI in Mediating Protection to Malaria

The success of passive immunization suggests that antibody-based therapies will be effective at controlling malaria. We describe the development of fully human antibodies specific for Plasmodium falciparum by antibody repertoire cloning from phage display libraries generated from immune Gambian adults. Although these novel reagents bind with strong affinity to malaria parasites, it remains unclear if in vitro assays are predictive of functional immunity in humans, due to the lack of suitable animal models permissive for P. falciparum. A potentially useful solution described herein allows the antimalarial efficacy of human antibodies to be determined using rodent malaria parasites transgenic for P. falciparum antigens in mice also transgenic for human Fc-receptors. These human IgG1s cured animals of an otherwise lethal malaria infection, and protection was crucially dependent on human FcγRI. This important finding documents the capacity of FcγRI to mediate potent antimalaria immunity and supports the development of FcγRI-directed therapy for human malaria

The response of Tampa Bay to a legacy mining nutrient release in the year following the event

IntroductionCultural eutrophication threatens numerous ecological and economical resources of Florida’s coastal ecosystems, such as beaches, mangroves, and seagrasses. In April 2021, an infrastructure failure at the retired Piney Point phosphorus mining retention reservoir garnered national attention, as 814 million liters of nutrient rich water were released into Tampa Bay, Florida over 10 days. The release of nitrogen and phosphorus-rich water into Tampa Bay – a region that had been known as a restoration success story since the 1990s – has highlighted the potential for unexpected challenges for coastal nutrient management.MethodsFor a year after the release, we sampled bi-weekly at four sites to monitor changes in nutrients, stable isotopes, and phytoplankton communities, complemented with continuous monitoring by multiparameter sondes. Our data complement the synthesis efforts of regional partners, the Tampa Bay and Sarasota Bay Estuary Programs, to better understand the effects of anthropogenic nutrients on estuarine health.ResultsPhytoplankton community structure indicated an initial diatom bloom that dissipated by the end of April 2021. In the summer, the bay was dominated by Karenia brevis, with conditions improving into the fall. To determine if there was a unique carbon (C) and nitrogen (N) signature of the discharge water, stable isotope values of carbon (δ13C) and nitrogen (δ15N) were analyzed in suspended particulate material (SPM). The δ15N values of the discharge SPM were −17.88‰ ± 0.76, which is exceptionally low and was unique relative to other nutrient sources in the region. In May and early June of 2021, all sites exhibited a decline in the δ15N values of SPM, suggesting that discharged N was incorporated into SPM after the event. The occurrence of very low δ15N values at the reference site, on the Gulf Coast outside of the Bay, indicates that some of the discharge was transported outside of Tampa Bay.DiscussionThis work illustrates the need for comprehensive nutrient management strategies to assess and manage the full range of consequences associated with anthropogenic nutrient inputs into coastal ecosystems. Ongoing and anticipated impacts of climate change – such as increasing tropical storm intensity, temperatures, rainfall, and sea level rise – will exacerbate this need

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

<p>Abstract</p> <p>Background</p> <p>The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in <it>in vivo </it>experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their <it>in vitro </it>complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).</p> <p>Results</p> <p>New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)₂(H₂O)₂] (<b>1</b>) and [Pb(Sal)(NO₃)] (<b>2</b>), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield <b>1</b>. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex <b>2 </b>consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.</p> <p>Conclusion</p> <p>The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.</p

Unique Phase Transition on Spin-2 Triangular Lattice of Ag2MnO2

Ag2MnO2 is studied as a possible candidate compound for an antiferromagnetic XY spin model on a triangular lattice. In spite of the large Curie-Weiss temperature of -430 K found in magnetic susceptibi-lity, Mn3+ spins with S = 2 do not undergo a conventional long-range order down to 2 K probably owing to the geometrical frustration and two dimensionality in the system. Instead, a unique phase transition is found at 80 K, where specific heat exhibits a clear sign of a second-order phase transition, while magnetic susceptibility changes smoothly without a distinct anomaly. We think that this transition is related to the chirality degree of freedom associated with a short-range order, which has been expected for the classical XY spin model on a triangular lattice. On further cooling, spin-glass-like behavior is observed below 22 K, possibly corresponding to a quasi-long-range order.Comment: to appear in J. Phys. Soc. Jpn, Vol. 77, No.