Endosomal Escape of Antisense Oligonucleotides Internalized by Stabilin Receptors Is Regulated by Rab5C and EEA1 During Endosomal Maturation

Second-generation (Gen 2) Antisense oligonucleotides (ASOs) show increased nuclease stability and affinity for their RNA targets, which has translated to improved potency and therapeutic index in the clinic. Gen 2 ASOs are typically modified using the phosphorothioate (PS) backbone modification, which enhances ASO interactions with plasma, cell surface, and intracellular proteins. This facilitates ASO distribution to peripheral tissues and also promotes cellular uptake after injection into animals. Previous work identified that Stabilin receptors specifically internalize PS-ASOs in the sinusoidal endothelial cells of the liver and the spleen. By modulating expression of specific proteins involved in the trafficking and maturation of the endolysosomal compartments, we show that Rab5C and EEA1 in the early endosomal pathway, and Rab7A and lysobisphosphatidic acid in the late endosomal pathway, are important for trafficking of PS-ASOs and facilitate their escape from endolysosomal compartments after Stabilin-mediated internalization. In conclusion, this work identifies key ratelimiting proteins in the pathway for PS-ASO translocation and escape from the endosome

Source amplitudes for active exterior cloaking

The active cloak comprises a discrete set of multipole sources that destructively interfere with an incident time harmonic scalar wave to produce zero total field over a finite spatial region. For a given number of sources and their positions in two dimensions it is shown that the multipole amplitudes can be expressed as infinite sums of the coefficients of the incident wave decomposed into regular Bessel functions. The field generated by the active sources vanishes in the infinite region exterior to a set of circles defined by the relative positions of the sources. The results provide a direct solution to the inverse problem of determining the source amplitudes. They also define a broad class of non-radiating discrete sources.Comment: 21 pages, 17 figure

Inverting the Sachs-Wolfe Formula: an Inverse Problem Arising in Early-Universe Cosmology

The (ordinary) Sachs-Wolfe effect relates primordial matter perturbations to the temperature variations $\delta T/T$ in the cosmic microwave background radiation; $\delta T/T$ can be observed in all directions around us. A standard but idealised model of this effect leads to an infinite set of moment-like equations: the integral of $P(k) j_\ell^2(ky)$ with respect to k ($0<k<\infty$) is equal to a given constant, $C_\ell$, for $\ell=0,1,2,...$. Here, P is the power spectrum of the primordial density variations, $j_\ell$ is a spherical Bessel function and y is a positive constant. It is shown how to solve these equations exactly for ~$P(k)$. The same solution can be recovered, in principle, if the first ~m equations are discarded. Comparisons with classical moment problems (where $j_\ell^2(ky)$ is replaced by $k^\ell$) are made.Comment: In Press Inverse Problems 1999, 15 pages, 0 figures, Late

3-\u3ci\u3eO\u3c/i\u3e sulfation of heparin leads to hepatotropism and longer circulatory half-life

Introduction: Heparins are common blood anticoagulants that are critical for many surgical and biomedical procedures used in modern medicine. In contrast to natural heparin derived from porcine gut mucosa, synthetic heparins are homogenous by mass, polymer length, and chemistry. Materials & methods: Stable cell lines expressing the human and mouse Stabilin receptors were used to evaluate endocytosis of natural and synthetic heparin. We chemoenzymatically produced synthetic heparin consisting of 12 sugars (dodecamers) containing 14 sulfate groups resulting in a non-3-O sulfated structure (n12mer). Half of the n12mer was modified with a 3-O sulfate on a single GlcNS sugar producing the 3-O sulfated heparin (12mer). Wildtype (WT), Stabilin-1 knock-out (KO), and Stabilin-2 KO C57BL/6 mice were developed and used for metabolic studies and provided as a source for primary liver sinusoidal endothelial cells. Results & conclusions: Human and mouse Stabilin-2 receptors had very similar endocytosis rates of both the 12mer and n12mer, suggesting that they are functionally similar in primary cells. Subcutaneous injections of the n12mer and 12mer revealed that the 12mer had a much longer half-life in circulation and a higher accumulation in liver. The n12mer never accumulated in circulation and was readily excreted by the kidneys before liver accumulation could occur. Liver sinusoidal endothelial cells from the Stabilin-2 KO mice had lower uptake rates for both dodecamers, whereas, the Stabilin-1 KO mice had lower endocytosis rates for the 12mer than the n12mer. 3-O sulfation of heparin is correlated to both a longer circulatory half-life and hepatotropism which is largely performed by the Stabilin receptors

S-wave Meson-Meson Scattering from Unitarized U(3) Chiral Lagrangians

An investigation of the s-wave channels in meson-meson scattering is performed within a U(3) chiral unitary approach. Our calculations are based on a chiral effective Lagrangian which includes the eta' as an explicit degree of freedom and incorporates important features of the underlying QCD Lagrangian such as the axial U(1) anomaly. We employ a coupled channel Bethe-Salpeter equation to generate poles from composed states of two pseudoscalar mesons. Our results are compared with experimental phase shifts up to 1.5 GeV and effects of the eta' within this scheme are discussed.Comment: 18 pages, 6 figure

Another look at ππ\pi\pi scattering in the scalar channel

We set up a general framework to describe $\pi\pi$ scattering below 1 GeV based on chiral low-energy expansion with possible spin-0 and 1 resonances. Partial wave amplitudes are obtained with the $N/D$ method, which satisfy unitarity, analyticity and approximate crossing symmetry. Comparison with the phase shift data in the J=0 channel favors a scalar resonance near the $\rho$ mass.Comment: 17 pages, 5 figures, REVTe

Multimorbidity in bipolar disorder and under-treatment of cardiovascular disease: a cross sectional study

Background: Individuals with serious mental disorders experience poor physical health, especially increased rates of cardiometabolic morbidity and premature morbidity. Recent evidence suggests that individuals with schizophrenia have numerous comorbid physical conditions which may be under-recorded and under-treated but to date very few studies have explored this issue for bipolar disorder. Methods:We conducted a cross-sectional analysis of a dataset of 1,751,841 registered patients within 314 primary-care practices in Scotland, U.K. Bipolar disorder was identified using Read Codes recorded within electronic medical records. Data on 32 common chronic physical conditions were also assessed. Potential prescribing inequalities were evaluated by analyzing prescribing data for coronary heart disease (CHD) and hypertension. Results: Compared to controls, individuals with bipolar disorder were significantly less likely to have no recorded physical conditions (OR 0.59, 95% CI 0.54-0.63) and significantly more likely to have one physical condition (OR 1.27, 95% CI 1.16-1.39), two physical conditions (OR 1.45, 95% CI 1.30-1.62) and three or more physical conditions (OR 1.44, 95% CI 1.30-1.64). People with bipolar disorder also had higher rates of thyroid disorders, chronic kidney disease, chronic pain, chronic obstructive airways disease and diabetes but, surprisingly, lower recorded rates of hypertension and atrial fibrillation. People with bipolar disorder and comorbid CHD or hypertension were significantly more likely to be prescribed no antihypertensive or cholesterol-lowering medications compared to controls, and bipolar individuals with CHD or hypertension were significantly less likely to be on 2 or more antihypertensive agents. Conclusions: Individuals with bipolar disorder are similar to individuals with schizophrenia in having a wide range of comorbid and multiple physical health conditions. They are also less likely than controls to have a primary-care record of cardiovascular conditions such as hypertension and atrial fibrillation. Those with a recorded diagnosis of CHD or hypertension were less likely to be treated with cardiovascular medications and were treated less intensively. This study highlights the high physical healthcare needs of people with bipolar disorder, and provides evidence for a systematic under-recognition and under-treatment of cardiovascular disease in this group

Meson-Meson Scattering in the Quark Model: Spin Dependence and Exotic Channels

We apply a quark interchange model to spin-dependent and exotic meson-meson scattering. The model includes the complete set of standard quark model forces, including OGE spin-orbit and tensor and scalar confinement spin-orbit. Scattering amplitudes derived assuming SHO and Coulomb plus linear plus hyperfine meson wavefunctions are compared. In I=2 pi pi we find approximate agreement with the S-wave phase shift from threshold to 1.5 GeV, where we predict an extremum that is supported by the data. Near threshold we find rapid energy dependence that may reconcile theoretical estimates of small scattering lengths with experimental indications of larger ones based on extrapolation of measurements at moderate kpi^2. In PsV scattering we find that the quark-quark L*S and T forces map into L*S and T meson-meson interactions, and the P-wave L*S force is large. Finally we consider scattering in J^PC-exotic channels, and note that some of the Deck effect mechanisms suggested as possible nonresonant origins of the pi_1(1400) signal are not viable in this model.Comment: 51 pages, 10 figures, uses epsf.sty epsfig.st