The PfRCR complex bridges malaria parasite and erythrocyte during invasion.

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The PfPCRCR complex1, containing PfRH5 (refs. 2,3), PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies3-6 or nanobodies1 against each of these conserved proteins, making them the leading blood-stage malaria vaccine candidates. However, little is known about how PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex7,8, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. We test the hypothesis that PfRH5 opens to insert into the membrane9, instead showing that a rigid, disulfide-locked PfRH5 can mediate efficient erythrocyte invasion. We show, through modelling and an erythrocyte-binding assay, that PfCyRPA-binding antibodies5 neutralize invasion through a steric mechanism. We determine the structure of PfRIPR, showing that it consists of an ordered, multidomain core flexibly linked to an elongated tail. We also show that the elongated tail of PfRIPR, which is the target of growth-neutralizing antibodies6, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. A modular PfRIPR is therefore linked to the merozoite membrane through an elongated tail, and its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides fresh insight into the molecular mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.

Lateral Flow Assays in Infectious Disease Diagnosis.

BACKGROUND: Lateral flow immunoassays are widely used as diagnostic tests in many applications in human and other diagnostic areas. Assays for human applications have been commercially available since the 1980s and initially were primarily used to identify pregnancy by measuring human chorionic gonadotropin in urine and serum/plasma. CONTENT: The first infectious disease lateral flow assays were commercialized in the late 1980s identifying the presence of Group A Streptococcus pyogenes collected with throat swabs; innumerable other applications followed in the intervening decades. The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) pandemic has brought a vast number of new assays for which emergency use authorization (EUA) has been requested in the USA. These assays have been designed for detection of the antibody response to an infection and viral antigens in respiratory samples. In view of the onslaught of new tests, this review will focus on the use of rapid lateral flow immunoassays for infectious diseases. Principles of lateral flow assays and approaches to the production of high-sensitivity point-of-care assays are presented. Market trends, customer requirements, and future directions of lateral flow assay technology and its applications in the infectious disease diagnostic space are discussed. SUMMARY: Lateral flow immunoassays play an important role in infectious disease diagnostics. Advancements in technology have led to improved performance of these assays and acceptance by professional users. With the advent of the SARS-CoV-2 pandemic, the market has reached new levels requiring hundreds of millions of tests per year for professional and even home use.

Rethinking Educational Space(s): Exploring the Impact of Co-Curricular Programming on Undergraduate Belonging, Career Exploration, and Interprofessional Education.

This mixed-methods study examined the impact of educational space on undergraduate belonging and learning by analyzing the post-event evaluations of 259 healthcare living-learning program (LLP) students who attended co-curricular programming designed to enhance belonging, career exploration, and interprofessional awareness. Students were broken into two groups based on program location. Post-event evaluations were analyzed using a Mann Whitney U-test and thematic analysis. Themes of career exploration and interprofessional awareness/identity formation emerged in the open-ended responses of both groups. Belonging was enhanced/muted by program location. Seemingly superficial, this variable actually reflects the institution's performance of educational space. The study includes a short discussion regarding the goal of constructing more inclusive educational spaces that support student belonging and success for all students.

Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting.

The receptor tyrosine kinase family of fibroblast growth factor receptors (FGFRs) play crucial roles in embryonic development, metabolism, tissue homeostasis and wound repair via stimulation of intracellular signalling cascades. As a consequence of FGFRs' influence on cell growth, proliferation and differentiation, FGFR signalling is frequently dysregulated in a host of human cancers, variously by means of overexpression, somatic point mutations and gene fusion events. Dysregulation of FGFRs is also the underlying cause of many developmental dysplasias such as hypochondroplasia and achondroplasia. Accordingly, FGFRs are attractive pharmaceutical targets, and multiple clinical trials are in progress for the treatment of various FGFR aberrations. To effectively target dysregulated receptors, a structural and mechanistic understanding of FGFR activation and regulation is required. Here, we review some of the key research findings from the last couple of decades and summarise the strategies being explored for therapeutic intervention.

NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 3 in apo state and in complex with inhibitor PD173074.

Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074. Analysis of chemical shift changes upon inhibitor binding highlights a characteristic pattern of allosteric network perturbations that is of relevance for future drug discovery activities aimed at development of conformationally-selective FGFR inhibitors.

Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System.

Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface. We determine the architecture of the client kinase/Cdc37 complex and demonstrate, together with site-specific information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and interactions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deactivates the kinase and presents it, in a specific orientation established in the complex, for direct recognition by Hsp90.

Enhanced PEDOT adhesion on solid substrates with electrografted P(EDOT-NH2).

Conjugated polymers, such as poly(3,4-ethylene dioxythiophene) (PEDOT), have emerged as promising materials for interfacing biomedical devices with tissue because of their relatively soft mechanical properties, versatile organic chemistry, and inherent ability to conduct both ions and electrons. However, their limited adhesion to substrates is a concern for in vivo applications. We report an electrografting method to create covalently bonded PEDOT on solid substrates. An amine-functionalized EDOT derivative (2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)methanamine (EDOT-NH2), was synthesized and then electrografted onto conducting substrates including platinum, iridium, and indium tin oxide. The electrografting process was performed under slightly basic conditions with an overpotential of ~2 to 3 V. A nonconjugated, cross-linked, and well-adherent P(EDOT-NH2)-based polymer coating was obtained. We found that the P(EDOT-NH2) polymer coating did not block the charge transport through the interface. Subsequent PEDOT electrochemical deposition onto P(EDOT-NH2)-modified electrodes showed comparable electroactivity to pristine PEDOT coating. With P(EDOT-NH2) as an anchoring layer, PEDOT coating showed greatly enhanced adhesion. The modified coating could withstand extensive ultrasonication (1 hour) without significant cracking or delamination, whereas PEDOT typically delaminated after seconds of sonication. Therefore, this is an effective means to selectively modify microelectrodes with highly adherent and highly conductive polymer coatings as direct neural interfaces.

Poly[3,4-ethylene dioxythiophene (EDOT) -co- 1,3,5-tri[2-(3,4-ethylene dioxythienyl)]-benzene (EPh)] copolymers (PEDOT-co-EPh): optical, electrochemical and mechanical properties.

PEDOT-co-EPh copolymers with systematic variations in composition were prepared by electrochemical polymerization from mixed monomer solutions in acetonitrile. The EPh monomer is a trifunctional crosslinking agent with three EDOTs around a central benzene ring. With increasing EPh content, the color of the copolymers changed from blue to yellow to red due to decreased absorption in the near infrared (IR) spectrum and increased absorption in the visible spectrum. The surface morphology changed from rough and nanofibrillar to more smooth with rounded bumps. The electrical transport properties dramatically decreased with increasing EPh content, resulting in coatings that either substantially lowered the impedance of the electrode (at the lowest EPh content), leave the impedance nearly unchanged (near 1% EPh), or significantly increase the impedance (at 1% and above). The mechanical properties of the films were substantially improved with EPh content, with the 0.5% EPh films showing an estimated 5x improvement in modulus measured by AFM nanoindentation. The PEDOT-co-EPh copolymer films were all shown to be non-cytotoxic toward and promote the neurite outgrowth of PC12 cells. Given these results, we expect that the films of most interest for neural interface applications will be those with improved mechanical properties that maintain the improved charge transport performance (with 1% EPh and below).

Lateral Flow Technology for Field-Based Applications-Basics and Advanced Developments.

In terms of their ability to provide accurate information there is a traditional continuum in diagnostics that ranges from highly accurate methods requiring infrastructure and a centralized approach to testing to less accurate technologies that can be used in a decentralized or point of care testing strategy and that require little to no supporting infrastructure. Today's lateral flow assays marry the utility of a truly field deployable, simple to use technology with the high performance of many laboratory based assay formats. Advances in recent years have allowed for the extension of performance of lateral flow assays into applications that require high accuracy and sensitivity while still maintaining the advantages of the technology from the perspective of infrastructure requirements and user friendliness. This has allowed for improved application of this technology in decentralized testing environments; veterinary, medical and otherwise. The lateral flow assay, once considered less accurate and less capable than infrastructure-heavy, laboratory based formats, is being viewed more and more as a truly versatile technology, capable of more than adequate performance at all ends of the diagnostic continuum. This article discusses the state of the art in lateral flow technology and outlines the utility of the technology in a variety of field based applications.

Precipitation of silver/palladium alloy platelets from homogeneous solutions.

Dispersed silver/palladium (Ag/Pd) nanoplatelets were prepared by delivering in parallel solutions of mixed metal nitrates and L-ascorbic acid into a nitric acid solution containing Arabic gum. The shape and size of bimetallic nanoparticles varied with the silver/palladium weight ratio and the concentration of nitric acid. The optimum conditions for platelets formation were a palladium content of ~2.0 wt.% and nitric acid concentrations above 1.0 mol dm(-3). The data presented show that both parameters play a critical role in the nucleation and growth of AgPd particles. A mechanism explaining the formation of the bimetallic nanoplatelets is proposed.