454 research outputs found
Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma
Synthesis of substituted indazole acetic acids by N−N bond forming reactions
Herein, we report on the discovery and development of novel cascade N−N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs
Role of the Cys loop and transmembrane domain in the allosteric modulation of α4β2 nicotinic acetylcholine receptors
Allosteric modulators of pentameric ligand gated ion channels (pLGICs) are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors (nAChRs) and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pLGICs. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4 region) of the α4 subunit. Here, using homology modelling in combination with mutagenesis and electrophysiology, we identified the binding site for potentiating dFBr on the top-half of a cavity between the third (M3) and fourth transmembrane (M4) α-helices of the α4 subunit. We found that the binding sites for βEST and dFBr communicate with the Cys loop, through interactions between the last residue of post-M4 and F170 of the conserved FPF sequence of the Cys loop, and that these interactions affect potentiating efficacy. In addition, interactions between a residue in M3 (Y309) and F167, a residue adjacent to the Cys loop FPF motif, also affect dFBr potentiating efficacy. Thus, the Cys loop acts as a key control element in the allosteric transduction pathway for potentiating βEST and dFBr. Overall, we propose that positive allosteric modulators that bind the M3-M4 cavity or post-M4 region increase the efficacy of channel gating through interactions with the Cys loop
Immigration and Human Development: Evidence from Lebanon
This paper takes Lebanon as a case study to examine the relationship between human
development and immigration. It examines this issue from both ends: the sending and the
receiving countries. The author suggests that by developing the concept of a diasporic civil
society and a diasporic public sphere, a significant aspect of the relationship between human
development and immigration is illuminated especially at the level of political, social and
cultural capitals. The paper also argues that the double impact of the home country and that of
destination has a lot to say about the influence of immigration on human development in
Lebanon. In examining Australia as a destination country, the paper shows the particular impact
that globalisation and September 11 have lately had on the capacity of the Lebanese migrants for
human development. Finally, the paper concludes by showing the extent to which the diasporic
civil society compensates for the ‘negligent’ character of the Lebanese state in the context of
human development
A pilot study to evaluate the application of a generic protein standard panel for quality control of biomarker detection technologies
<p>Abstract</p> <p>Background</p> <p>Protein biomarker studies are currently hampered by a lack of measurement standards to demonstrate quality, reliability and comparability across multiple assay platforms. This is especially pertinent for immunoassays where multiple formats for detecting target analytes are commonly used.</p> <p>Findings</p> <p>In this pilot study a generic panel of six non-human protein standards (50 - 10^7 pg/mL) of varying abundance was prepared as a quality control (QC) material. Simulated "normal" and "diseased" panels of proteins were prepared in pooled human plasma and incorporated into immunoassays using the Meso Scale Discovery<sup>® </sup>(MSD<sup>®</sup>) platform to illustrate reliable detection of the component proteins. The protein panel was also evaluated as a spike-in material for a model immunoassay involving detection of ovarian cancer biomarkers within individual human plasma samples. Our selected platform could discriminate between two panels of the proteins exhibiting small differences in abundance. Across distinct experiments, all component proteins exhibited reproducible signal outputs in pooled human plasma. When individual donor samples were used, half the proteins produced signals independent of matrix effects. These proteins may serve as a generic indicator of platform reliability.</p> <p>Each of the remaining proteins exhibit differential signals across the distinct samples, indicative of sample matrix effects, with the three proteins following the same trend. This subset of proteins may be useful for characterising the degree of matrix effects associated with the sample which may impact on the reliability of quantifying target diagnostic biomarkers.</p> <p>Conclusions</p> <p>We have demonstrated the potential utility of this panel of standards to act as a generic QC tool for evaluating the reproducibility of the platform for protein biomarker detection independent of serum matrix effects.</p
Specific Appetite for Carotenoids in a Colorful Bird
Background: Since carotenoids have physiological functions necessary for maintaining health, individuals should be selected to actively seek and develop a specific appetite for these compounds. Methodology/Principal Findings: Great tits Parus major in a diet choice experiment, both in captivity and the field, preferred carotenoid-enriched diets to control diets. The food items did not differ in any other aspects measured besides carotenoid content. Conclusions/Significance: Specific appetite for carotenoids is here demonstrated for the first time, placing these compounds on a par with essential nutrients as sodium or calcium
From transformation to chronification of migraine : pathophysiological and clinical aspects
Chronic migraine is a neurological disorder characterized by 15 or more headache days per month of which at least 8 days show typical migraine features. The process that describes the development from episodic migraine into chronic migraine is commonly referred to as migraine transformation or chronification. Ample studies have attempted to identify factors associated with migraine transformation from different perspectives. Understanding CM as a pathological brain state with trigeminovascular participation where biological changes occur, we have completed a comprehensive review on the clinical, epidemiological, genetic, molecular, structural, functional, physiological and preclinical evidence available
From transformation to chronification of migraine: Pathophysiological and clinical aspects
Chronic migraine is a neurological disorder characterized by 15 or more headache days per month of which at least 8 days show typical migraine features. The process that describes the development from episodic migraine into chronic migraine is commonly referred to as migraine transformation or chronification. Ample studies have attempted to identify factors associated with migraine transformation fr
GW190425: Pan-STARRS and ATLAS coverage of the skymap and limits on optical emission associated with FRB190425
GW190425 is the second of only two binary neutron star (BNS) merger events to
be significantly detected by the LIGO-Virgo- Kagra gravitational wave
detectors. With a detection only in LIGO Livingston, the skymap containing the
source was large and no plausible electromagnetic counterpart was found in real
time searching in 2019. Here we summarise our ATLAS and Pan-STARRS wide-field
optical coverage of the skymap beginning within 1 hour and 3 hours respectively
of the GW190425 merger time. More recently, a potential coincidence between
GW190425 and a fast radio burst FRB 190425 has been suggested, given their
spatial and temporal coincidence. The smaller sky localisation area of FRB
190425 and its dispersion measure have led to the identification of a likely
host galaxy, UGC 10667 at a distance of 141 +/- 10 Mpc. Our optical imaging
covered the galaxy 6.0 hrs after GW190425 was detected and 3.5 hrs after the
FRB 190425. No optical emission was detected and further imaging at +1.2 and
+13.2 days also revealed no emission. If the FRB 190425 and GW190425
association were real, we highlight our limits on kilonova emission from a BNS
merger in UGC 10667. The model for producing FRB 190425 from a BNS merger
involves a supramassive magnetised neutron star spinning down by dipole
emission on the timescale of hours. We show that magnetar enhanced kilonova
emission is ruled out by optical upper limits. The lack of detected optical
emission from a kilonova in UGC 10667 disfavours, but does not disprove, the
FRB-GW link for this source.Comment: Submitted to MNRAS, 20th Sept 2023, 9 page
- …