Development of Macrocyclic Neurotensin Receptor Type 2 (NTS2) Opioid-Free Analgesics.

The opioid crisis has highlighted the urgent need to develop non-opioid alternatives for managing pain, with an effective, safe, and non-addictive pharmacotherapeutic profile. Using an extensive structure-activity relationship approach, here we have identified a new series of highly selective neurotensin receptor type 2 (NTS2) macrocyclic compounds that exert potent, opioid-independent analgesia in various experimental pain models. To our knowledge, the constrained macrocycle in which the Ile residue of NT(7-12) was substituted by cyclopentylalanine, Pro and Pro were replaced by allyl-glycine followed by side-chain to side-chain cyclization is the most selective analog targeting NTS2 identified to date (K 2.

Safety and immunogenicity of escalating dosages of a single oral administration of peru-15 pCTB, a candidate live, attenuated vaccine against enterotoxigenic Escherichia coli and Vibrio cholerae.

Enterotoxigenic Escherichia coli (ETEC) organisms are a leading cause of infectious diarrhea in developing countries. A live, attenuated cholera strain that expresses high levels of the nontoxic B subunit of cholera toxin, which might also serve as an ETEC protective antigen, was evaluated for safety, excretion, and immunogenicity in healthy volunteers. We enrolled four inpatient dose-escalation cohorts of 15 to 16 eligible subjects to randomly (3:1) receive a single oral dose of vaccine or placebo (buffer alone), evaluating 1 ×10(7), 1 ×10(8), 1 ×10(9), and 1 ×10(10) CFU of the vaccine.

Cholestatic liver disease in children.

Inherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of chronic liver disease and the prime indication for liver transplantation in children. Our understanding of the pathogenesis of these diseases has increased substantially by the discovery of genetic mutations in children with intrahepatic cholestasis and the findings that inflammatory circuits are operative at the time of diagnosis of biliary atresia. Building on this solid foundation, recent studies provide new insight into genotype-phenotype relationships and how mutations produce altered bile composition and cholestasis.

Nonimmune complications after transplantation.

As posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes. The incidence of, and risk factors for these complications may vary by transplanted organ based on immunosuppressive protocols and preexisting risk factors. This article discusses the relevant nonimmune complications associated with posttransplant care, with a focus on risk factors and management strategies.

Solution structure of proinsulin: connecting domain flexibility and prohormone processing.

The folding of proinsulin, the single-chain precursor of insulin, ensures native disulfide pairing in pancreatic beta-cells. Mutations that impair folding cause neonatal diabetes mellitus. Although the classical structure of insulin is well established, proinsulin is refractory to crystallization.

Crystal structure of a "nonfoldable" insulin: impaired folding efficiency despite native activity.

Protein evolution is constrained by folding efficiency ("foldability") and the implicit threat of toxic misfolding. A model is provided by proinsulin, whose misfolding is associated with beta-cell dysfunction and diabetes mellitus. An insulin analogue containing a subtle core substitution (Leu(A16) --> Val) is biologically active, and its crystal structure recapitulates that of the wild-type protein.

The lived experience of hope among parents of a child with Duchenne muscular dystrophy: perceiving the human being beyond the illness.

Objectives: Duchenne muscular dystrophy (DMD) is genetically determined, progressive and incurable. Our study's primary objective was to describe the lived experience of hope among parents of a child with DMD.

Methods: Semi-structured interviews were conducted with 12 parents having a child with DMD.

Kinematic and electromyographic parameters of the cervical flexion-relaxation phenomenon: the effect of trunk positioning.

Background: The cervical flexion-relaxation phenomenon (FRP) is a neck extensor myoelectric "silence" that occurs during complete cervical flexion. The aim of this study was to assess the presence of this phenomenon in the cervical region and to explore the kinematics and EMG parameters in two different experimental conditions.

Patients And Methods: Nineteen young healthy adults (22.

Cytokine removal with a novel adsorbent polymer.

Background/aims: We sought to characterize a novel adsorbent polymer in terms of cytokine removal.

Methods: We challenged 50 rats with lipopolysaccharide to obtain cytokine-rich blood and circulated this through cartridges containing polymer. In separate experiments, cell-free supernatants were passed through cartridges containing polymer.

Geochemical characterization of acid mine drainage from a waste rock pile, Mine Doyon, Québec, Canada.

Water quality in the unsaturated and saturated zones of a waste rock pile containing sulphides was investigated. The main objectives of the project were (1) the evaluation of geochemical trends including the acid mine drainage (AMD)-buffering mechanism and the role of secondary minerals, and (2) the investigation of the use of stable isotopes for the interpretation of physical and geochemical processes in waste rock. Pore water in unsaturated zone was sampled from suction lysimeters and with piezometers in underlying saturated rocks.

Expression, purification, and PC1-mediated processing of (H10D, P28K, and K29P)-human proinsulin.

Our previous methods for the generation of recombinant human proinsulin were inadequate in terms of reproducibility and yield. In addition, it was difficult to perform structure/function studies on proinsulin because of its tendency to form hexamers. We have developed an improved procedure, which overcomes many of the technical purification problems, and results in a potentially monomeric version of modified proinsulin.

Retinoic acid receptor alpha1 variants, RARalpha1DeltaB and RARalpha1DeltaBC, define a new class of nuclear receptor isoforms.

Retinoic acid (RA) binds and activates retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimers, which regulate the transcription of genes that have retinoic acid response elements (RARE). The RAR isotypes (alpha, beta and gamma) are comprised of six regions designated A-F. Two isoforms of RARalpha, 1 and 2, have been identified in humans, which have different A regions generated by differential promoter usage and alternative splicing.

The next step from high-flux dialysis: application of sorbent technology.

The current foci of renal replacement therapy with dialysis are middle molecular weight toxins, consisting of small proteins, polypeptides and products of glycosylation and lipoxygenation. Conventional high-flux dialysis is not efficient at removing these molecules, explaining the increased interest in using sorbents to supplement dialysis techniques. Prototype biocompatible sorbents have been developed and investigated for middle molecule removal; these have been shown, in man, to remove beta(2)-microglobulin, angiogenin, leptin, cytokines and other molecules, without reducing platelets and leukocytes.