Structural Determinants for the Interactions of Chemically Modified Nucleic Acids with the Stabilin‑2 Clearance Receptor

The Stabilin receptors are systemic clearance receptors for some classes of chemically modified nucleic acid therapeutics. In this study, the recombinant human secreted ecto-domain of the small isoform of Stabilin-2 (s190) was purified from cell culture and evaluated for direct binding with a multitude of antisense oligonucleotides (ASOs) using a fluorescence polarizationbased assay. The tested ASOs varied in their backbone composition, modification of the ribose 2′ position, overall length of the oligo, and sequence of the nucleotide bases. A fully phosphorothioate (PS) ASO with a 5−10−5 pattern of flanking 2′-O-methoxyethyl modifications was then used to test the effects of pH and salt concentration on receptor binding. These tests concluded that the PS backbone was the primary determinant for ASO binding and that decreasing pH and increasing salt generally increased the rate of ligand dissociation and fit within the biological parameters expected of a constitutive recycling receptor. These results will be useful in the rational design of therapeutic oligonucleotides for enhancing their affinity or avoidance of the Stabilin receptors

HIV taken by STORM : super-resolution fluorescence microscopy of a viral infection

<p>Abstract</p> <p>Background</p> <p>The visualization of viral proteins has been hindered by the resolution limit of conventional fluorescent microscopes, as the dimension of any single fluorescent signal is often greater than most virion particles. Super-resolution microscopy has the potential to unveil the distribution of proteins at the resolution approaching electron microscopy without relying on morphological features of existing characteristics of the biological specimen that are needed in EM.</p> <p>Results</p> <p>Using direct stochastic optical reconstruction microscopy (dSTORM) to achieve a lateral resolution of 15–20 nm, we quantified the 2-D molecular distribution of the major structural proteins of the infectious human immunodeficiency virus type 1 (HIV-1) before and after infection of lymphoid cells. We determined that the HIV-1 matrix and capsid proteins undergo restructuring soon after HIV-1 infection.</p> <p>Conclusions</p> <p>This study provides the proof-of-concept for the use of dSTORM to visualize the changes in the molecular distribution of viral proteins during an infection.</p

Differential Double Excitation Cross Sections in Proton-Helium Collisions Studied by Energy-Loss Spectroscopy

We have measured ion energy-loss spectra for 150 keV proton-helium collisions as a function of the projectile scattering angle. From the data we obtained double excitation cross sections differential in the proton scattering angle as well as the ratios of both double excitation and single ionization to single excitation. In these ratios pronounced peak structures are observed at about 0.7 mrad. Two alternative interpretations of these peak structures are offered: They may be due to binary collisions between the projectile and the target electrons, or they could be a manifestation of an interference between different transition amplitudes leading to the same final state of the collision

Eating Habits, Anxiety and Depression in Patients with Irritable Bowel Syndrome: Clinical and Laboratory Comparisons

Aim: to assess the level of stress hormones (cortisol in saliva), neurotransmitters (serotonin in blood serum, dopamine in blood plasma) in relation to eating habits, anxiety and depression levels in patients with IBS.Materials and methods. An open cohort prospective study was conducted with the inclusion of 263 patients with an established diagnosis of IBS, among them 189 (71.9 %) women and 74 (28.1 %) men. The average age of patients with IBS was 29 [25; 35] years. The control group included 40 healthy volunteers. All individuals included in the study were assessed for diet and eating habits using the WHO CINDI program questionnaire, “Information on Nutrition and Eating Behavior”, the severity of anxiety and depression according to the HADS questionnaire, the level of specific anxiety in relation to gastrointestinal symptoms according to the VSI questionnaire, quality of life according to the IBS-QoL questionnaire. In addition, the enzyme immunoassay method was used to assess the levels of cortisol in the morning and evening portions of saliva, serotonin in the blood serum and dopamine in the blood plasma.Results. Among patients with IBS there is a statistically significantly higher level of cortisol in the morning and evening portions of saliva (U = 19.5, p &lt; 0.001 and U = 111.5, p &lt; 0.001, respectively), serotonin in blood serum (U = 269.0, p = 0.042) and lower plasma dopamine levels (U = 93.5, p = 0.0002) compared with controls. The mean salivary cortisol level among patients with IBS was 45.39 [29.86; 70.10] ng/ml in the morning and 19.21 [13.98; 23.50] ng/ml in the evening, while in the group of healthy individuals it was 19.0 [16.5; 21.7] and 9.7 [8.5; 10.5] ng/ml, respectively. The average content of serotonin in blood serum in patients with IBS was 188.78 [150.41; 230.32] ng/ml, among healthy individuals — 142.80 [130.52; 154.15] ng/ml. The average content of dopamine in blood plasma in patients with IBS was 28.83 [20.08; 41.54] ng/ml, in healthy individuals — 58.20 [48.15; 66.62] ng/ml.Conclusion. In patients with IBS the secretion of the stress hormone (cortisol) and neurotransmitters (serotonin, dopamine) is closely related to the nature of nutrition, the level of anxiety and depression, and is also associated with the clinical variant and severity of the course of the disease

Forst on Reciprocity of Reasons: a Critique

According to Rainer Forst, (i) moral and political claims must meet a requirement of reciprocal and general acceptability (RGA) while (ii) we are under a duty in engaged discursive practice to justify such claims to others, or be able to do so, on grounds that meet RGA. The paper critically engages this view. I argue that Forst builds a key component of RGA, i.e., reciprocity of reasons, on an idea of the reasonable that undermines both (i) and (ii): if RGA builds on this idea, RGA is viciously regressive and a duty of justification to meet RGA fails to be agent transparent. This negative result opens the door for alternative conceptions of reciprocity and generality. I then suggest that a more promising conception of reciprocity and generality needs to build on an idea of the reasonable that helps to reconcile the emancipatory or protective aspirations of reciprocal and general justification with its egalitarian commitments. But this requires to downgrade RGA in the order of justification and to determine on prior, substantive grounds what level of discursive influence in reciprocal and general justification relevant agents ought to have