抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

Here we report the crystal structure of the humank-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Aresolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human k-OR. Modelling of other important k-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 59-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for k-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human k-OR.

/pdf/structure-of-the-human-k-opioid-receptor-in-complex-with-4c4i5xppri.pdf

Structure of the human κ-opioid receptor in complex with JDTic

https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1151&context=biomedsci_fac

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress.

Background The apelin system is a novel peptidic pathway widely expressed in the
heart and vasculature. In preclinical studies, apelin receptor agonism mediates
nitric oxide-dependent vasodilatation, reduces ventricular preload and afterload and
potently increases myocardial contractility. In preclinical models of heart failure,
expression of the apelin pathway is down regulated but the haemodynamic effects of
apelin receptor agonism are preserved. These changes in expression appear to be
paralleled in patients with chronic heart failure but the cardiovascular actions of
apelin in vivo in man are, to date, unknown. Detailed clinical investigation is
therefore required to establish the role of apelin in human cardiovascular physiology
and pathophysiology and to explore the therapeutic potential of apelin receptor
agonism in patients with heart failure.
Objectives Through a series of in vivo clinical studies: 1) to establish the direct
vascular actions of apelin in the peripheral venous, peripheral arterial and coronary
arterial circulations; 2) to determine the contribution of the endothelium-derived
vasodilators, nitric oxide and prostacyclin, to the vascular actions of apelin; 3) to
establish the effects of apelin on cardiac contractility and systemic haemodynamics;
4) to compare the direct vascular and systemic haemodynamic effects of the fulllength
mature apelin peptide, apelin-36, with a shorter, biologically active carboxyl
(C)-terminal fragment, (Pyr1)apelin-13); and 5) to establish whether the local
vascular and systemic haemodynamic effects of apelin are altered in patients with
chronic heart failure.
Methods The cardiovascular effects of apelin were assessed in 32 healthy
volunteers, 6 patients undergoing elective diagnostic coronary angiography,
18 patients with stable New York Heart Association (NYHA) class II-III chronic
heart failure and 18 age- and sex-matched healthy controls. Dorsal hand vein tone
was assessed by the Aellig hand vein technique during local intravenous
infusions (0.1-3 nmol/min) of apelin-36, (Pyr1)apelin-13, and sodium nitroprusside
(SNP; 0.6 nmol/min). Forearm blood flow was measured by venous occlusion
plethysmography during intrabrachial infusions of apelin-36 and (Pyr1)apelin-13
(0.01-30 nmol/min) and subsequently in the presence or absence of a ‘nitric oxide
clamp’ (nitric oxide synthase inhibitor, L-NG-monomethylarginine (L-NMMA;
8 μmol/min), co-infused with SNP (90-900 ng/min)), or a single oral dose of aspirin
(600 mg) or matched placebo. Coronary blood flow was evaluated by quantitative
coronary angiography (QCA) and Doppler flow wire, and left ventricular pressures
measured by pressure wire before and after intracoronary injection of apelin-36
(20 and 200 nM), 0.9% saline and glyceryl trinitrate (GTN) (100 μg). Blood
pressure, heart rate, cardiac output and peripheral vascular resistance were assessed
by sphygmomanometry and thoracic electrical bioimpedance (TEB) during systemic
intravenous infusion of apelin-36 and (Pyr1)apelin-13 (30-300 nmol/min). Forearm
blood flow and systemic haemodynamic responses to (Pyr1)apelin-13 in patients with
chronic heart failure were then compared with age- and sex-matched healthy
controls.
Results Although SNP caused venodilatation (P<0.0001), apelin-36 and
(Pyr1)apelin-13 had no effect on dorsal hand vein diameter (P=0.2). Both apelin
isoforms caused vasodilatation in forearm resistance vessels (P<0.0001) but the
offset was slower with apelin-36. (Pyr1)apelin-13-mediated vasodilatation was
attenuated by the nitric oxide clamp (P=0.004) but unaffected by aspirin (P=0.7).
Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum
rate of rise in left ventricular pressure, and reduced peak and end-diastolic left
ventricular pressures (all P<0.05). Both (Pyr1)apelin-13 and apelin-36 increased
heart rate and cardiac output whilst reducing peripheral vascular resistance (P<0.01
for all) with no overall effect on blood pressure. Intrabrachial infusions of
(Pyr1)apelin-13, acetylcholine and SNP caused forearm vasodilatation in patients and
controls (P<0.0001 for all). Vasodilatation to acetylcholine (P=0.01) but not apelin
(P=0.3) or SNP (p=0.9) was attenuated in patients with heart failure. Systemic
infusions of (Pyr1)apelin-13 increased cardiac index and lowered mean arterial
pressure and peripheral vascular resistance index in patients and matched controls
(all P<0.01) but increased heart rate only in controls (P<0.01).
Conclusions Although having no apparent effect on venous tone, acute apelin
receptor agonism causes peripheral and coronary vasodilatation and increases cardiac
contractility and output. Local vascular and systemic haemodynamic responses to
apelin are preserved in patients with stable symptomatic chronic heart failure. The
apelin system merits further clinical investigation to determine its role in
cardiovascular homeostasis and represents a novel potential therapeutic target for
patients with heart failure.

Cardiovascular effects of apelin in vivo in man

This disclosure is directed to agonists of the apelin receptor (APJ) and uses of such agonists.

Apelin receptor (apj) agonists and uses thereof

The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity.

Scott P. Runyon

Papers

Apelin receptor (apj) agonists and uses thereof

Therapeutic and Prophylactic Vaccines to Counteract Fentanyl Use Disorders and Toxicity.

The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.

The frequency of early-activated hapten-specific B cell subsets predicts the efficacy of vaccines for nicotine dependence

Doppler indices of vascular impedance as indicators of testicular dysfunction in stallions