Successful synthesis of a glial-specific blood-brain barrier shuttle peptide following a fragment condensation approach on a solid-phase resin

Successful manual synthesis of the TD2.2 peptide acting as a blood-brain barrier shuttle was achieved. TD2.2 was successfully synthesised by sequential condensation of four protected peptide fragments on solid-phase settings, after several unsuccessful attempts using the stepwise approach. These fragments were chosen to minimize the number of demanding amino acids (in terms of coupling, Fmoc removal) in each fragment that are expected to hamper the overall synthetic process. Thus, the hydrophobic amino acids as well as Fmoc-Arg (Pbf)-OH were strategically spread over multiple fragments rather than having them congested in one fragment. This study shows how a peptide that shows big challenges in the synthesis using the common stepwise elongation methodology can be synthesised with an acceptable purity. It also emphasises that choosing the right fragment with certain amino acid constituents is key for a successful synthesis. It is worth highlighting that lower amounts of reagents were required to synthesise the final peptide with an identical purity to that obtained by the automatic synthesiser

Large spin systematics in CFT

20 pages; v2: version published in JHEPUsing conformal field theory (CFT) arguments we derive an infinite number of constraints on the large spin expansion of the anomalous dimensions and structure constants of higher spin operators. These arguments rely only on analiticity, unitarity, crossing-symmetry and the structure of the conformal partial wave expansion. We obtain results for both, perturbative CFT to all order in the perturbation parameter, as well as non-perturbatively. For the case of conformal gauge theories this provides a proof of the reciprocity principle to all orders in perturbation theory and provides a new "reciprocity" principle for structure constants. We argue that these results extend also to non-conformal theories.Peer reviewe

TCT-338 Spontaneous coronary Artery dissection in sudden death victims and surviving patients: which are the differences?

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Sustainable natural adsorbents for heavy metal removal from wastewater: Lead sorption on pine bark (Pinus radiata D.Don)

Aqueous Pb(II) adsorption on pine bark (Pinus Radiata D.Don), an inexpensive and sustainable natural sorbent material, has been evaluated and the mechanism of metal retention characterized by scanning electron microscopy (SEM), diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and X-ray photoelectron spectroscopy (XPS). Bark pulp densities >1.5 g l-1 achieve near 100% Pb(II) removal from aqueous solutions containing 100 mg l-1 Pb(II). Adsorption rates increased with pulp density, although adsorption capacity diminished at high densities because of blockage of adsorption sites. The effects of washing and sulfuric acid activation were assessed and found to be less important than in previous metal sorption studies. Pb(II) sorption takes place mainly at the lignocellulosic C-O groups, with adsorption at phenolic sites appearing to be most significant

Generalized scaling function from light-cone gauge AdS_5 x S^5 superstring

We revisit the computation of the 2-loop correction to the energy of a folded spinning string in AdS_5 with an angular momentum J in S^5 in the scaling limit log S, J >>1 with J / log S fixed. This correction gives the third term in the strong-coupling expansion of the generalized scaling function. The computation, using the AdS light-cone gauge approach developed in our previous paper, is done by expanding the AdS_5 x S^5 superstring partition function near the generalized null cusp world surface associated to the spinning string solution. The result corrects and extends the previous conformal gauge result of arXiv:0712.2479 and is found to be in complete agreement with the corresponding terms in the generalized scaling function as obtained from the asymptotic Bethe ansatz in arXiv:0805.4615 (and also partially from the quantum O(6) model and the Bethe ansatz data in arXiv:0809.4952). This provides a highly nontrivial strong coupling comparison of the Bethe ansatz proposal with the quantum AdS_5 x S^5 superstring theory, which goes beyond the leading semiclassical term effectively controlled by the underlying algebraic curve. The 2-loop computation we perform involves all the structures in the AdS light-cone gauge superstring action of hep-th/0009171 and thus tests its ultraviolet finiteness and, through the agreement with the Bethe ansatz, its quantum integrability. We do most of the computations for a generalized spinning string solution or the corresponding null cusp surface that involves both the orbital momentum and the winding in a large circle of S^5.Comment: 50 pages, late

Simplifying instanton corrections to N=4 SYM correlators

This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are credited

Structure-activity analysis of a CFTR channel potentiator: Distinct molecular parts underlie dual gating effects.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporter superfamily that functions as an epithelial chloride channel. Gating of the CFTR ion conduction pore involves a conserved irreversible cyclic mechanism driven by ATP binding and hydrolysis at two cytosolic nucleotide-binding domains (NBDs): formation of an intramolecular NBD dimer that occludes two ATP molecules opens the pore, whereas dimer disruption after ATP hydrolysis closes it. CFTR dysfunction resulting from inherited mutations causes CF. The most common CF mutation, deletion of phenylalanine 508 (DeltaF508), impairs both protein folding and processing and channel gating. Development of DeltaF508 CFTR correctors (to increase cell surface expression) and potentiators (to enhance open probability, Po) is therefore a key focus of CF research. The practical utility of 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), one of the most efficacious potentiators of DeltaF508 CFTR identified to date, is limited by its pore-blocking side effect. NPPB-mediated stimulation of Po is unique in that it involves modulation of gating transition state stability. Although stabilization by NPPB of the transition state for pore opening enhances both the rate of channel opening and the very slow rate of nonhydrolytic closure, because of CFTR's cyclic gating mechanism, the net effect is Po stimulation. In addition, slowing of ATP hydrolysis by NPPB delays pore closure, further enhancing Po. Here we show that NPPB stimulates gating at a site outside the pore and that these individual actions of NPPB on CFTR are fully attributable to one or the other of its two complementary molecular parts, 3-nitrobenzoate (3NB) and 3-phenylpropylamine (3PP), both of which stimulate Po: the pore-blocking 3NB selectively stabilizes the transition state for opening, whereas the nonblocking 3PP selectively slows the ATP hydrolysis step. Understanding structure-activity relationships of NPPB might prove useful for designing potent, clinically relevant CFTR potentiators

Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS