A contact binary satellite of the asteroid (152830) Dinkinesh.

Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky-O'Keefe-Radzievskii-Paddack effect)1 to be a notable factor in their evolution2. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 AU; its S-type spectrum3,4 is typical of bodies in this part of the main belt5. Here we report observations by the Lucy spacecraft6,7 as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event.

Connecting Scientometrics: Dimensions as a Route to Broadening Context for Analyses.

Modern cloud-based data infrastructures open new vistas for the deployment of scientometric data into the hands of practitioners. These infrastructures lower barriers to entry by making data more available and compute capacity more affordable. In addition, if data are prepared appropriately, with unique identifiers, it is possible to connect many different types of data. Bringing broader world data into the hands of practitioners (policymakers, strategists, and others) who use scientometrics as a tool can extend their capabilities. These ideas are explored through connecting Dimensions and World Bank data on Google BigQuery to study international collaboration between countries of different economic classification.

Measuring Research Information Citizenship Across ORCID Practice.

Over the past 10 years, stakeholders across the scholarly communications community have invested significantly not only to increase the adoption of ORCID adoption by researchers, but also to build the broader infrastructures that are needed both to support ORCID and to benefit from it. These parallel efforts have fostered the emergence of a "research information citizenry" between researchers, publishers, funders, and institutions. This paper takes a scientometric approach to investigating how effectively ORCID roles and responsibilities within this citizenry have been adopted. Focusing specifically on researchers, publishers, and funders, ORCID behaviors are measured against the approximated research world represented by the Dimensions dataset.

Scaling Scientometrics: Dimensions on Google BigQuery as an Infrastructure for Large-Scale Analysis.

Cloud computing has the capacity to transform many parts of the research ecosystem, from particular research areas to overall strategic decision making and policy. Scientometrics sits at the boundary between research and the decision-making, policy-making, and evaluation processes that underpin research. One of the biggest challenges in research policy and strategy is having access to data in a way that allows for analysis that can respond in an iterative way to inform decisions. Many decisions are based on "global" measures such as benchmark metrics that are hard to source and hence are often nonspecific or outdated. The use of cloud technologies may be promising in addressing this area of providing data for research strategy and policy decisions. A novel visualisation technique is introduced and used as a means to explore the potential for scaling scientometrics by democratising both access to data and compute capacity using the cloud.

Exploiting a Rose Bengal-bearing, oxygen-producing nanoparticle for SDT and associated immune-mediated therapeutic effects in the treatment of pancreatic cancer.

Sonodynamic therapy (SDT) is an emerging stimulus-responsive approach for the targeted treatment of solid tumours. However, its ability to generate stimulus-responsive cytotoxic reactive oxygen species (ROS), is compromised by tumour hypoxia. Here we describe a robust means of preparing a pH-sensitive polymethacrylate-coated CaO2 nanoparticle that is capable of transiently alleviating tumour hypoxia. Systemic administration of particles to animals bearing human xenograft BxPC3 pancreatic tumours increases oxygen partial pressures (PO2) to 20-50 mmHg for over 40 min. RT-qPCR analysis of expression of selected tumour marker genes in treated animals suggests that the transient production of oxygen is sufficient to elicit effects at a molecular genetic level. Using particles labelled with the near infra-red (nIR) fluorescent dye, indocyanine green, selective uptake of particles by tumours was observed. Systemic administration of particles containing Rose Bengal (RB) at concentrations of 0.1 mg/mg of particles are capable of eliciting nanoparticle-induced, SDT-mediated antitumour effects using the BxPC3 human pancreatic tumour model in immuno-compromised mice. Additionally, a potent abscopal effect was observed in off-target tumours in a syngeneic murine bilateral tumour model for pancreatic cancer and an increase in tumour cytotoxic T cells (CD8+) and a decrease in immunosuppressive tumour regulatory T cells [Treg (CD4+, FoxP3+)] was observed in both target and off-target tumours in SDT treated animals. We suggest that this approach offers significant potential in the treatment of both focal and disseminated (metastatic) pancreatic cancer.

Pharmaceutical Formulation and Characterization of Dipeptide Nanotubes for Drug Delivery Applications.

Peptide nanotubes are promising materials for a variety of biomedical applications with ultrashort (≤7 amino acids) forms providing particular promise for clinical translation. The manufacture of peptide nanotubes has, however, been associated with toxic organic solvents restricting clinical use. The purpose of this work is to formulate dipeptide nanotubes using mild techniques easily translated to industrial upscale and to characterize their physiochemical and biological properties. Phenylalanine-phenylalanine variants can be successfully formulated using distilled water as demonstrated here. Formulations are homogenous in shape (tubular), with apparent size (50-260 nm) and a zeta potential of up to +30 mV. L-(H2 N-FF-COOH), and D-enantiomers (H2 N-ff-COOH) demonstrate no toxicity against glioblastoma cells and are explored for ability to deliver a model hydrophilic molecule, sodium fluorescein, at pH 5.5 (tumor) and 7.4 (physiological). Peptide nanotubes loaded with >85% sodium fluorescein, demonstrate burst release characteristics, fitting the Weibull model of drug release. This research provides important data contributing to the pharmaceutical formulation of peptide nanotubes as drug delivery platforms for hydrophilic drugs.

Rose Bengal-Amphiphilic Peptide Conjugate for Enhanced Photodynamic Therapy of Malignant Melanoma.

Malignant melanoma is an aggressive skin cancer with poor survival outcomes for patients diagnosed at an advanced stage. While targeted serine/threonine-protein kinase B-Raf (BRAF) and immune checkpoint inhibitors have improved survival outcomes for a proportion of these patients, response rates remain variable. There is a need, therefore, for more effective treatments to bolster the options available for melanoma patients. In this manuscript, we covalently attached Rose Bengal (RB) to the amphipathic peptide (AMP) C(KLAKLAK)2 and determined the effectiveness of the resulting RB-C(KLAKLAK)2 conjugate as a photodynamic therapy (PDT) sensitizer. RB-C(KLAKLAK)2-mediated PDT treatment of subcutaneous B16-F10-Luc2 tumors in C57 mice resulted in lesions that were 479% smaller at the end of the study than animals treated with RB-mediated PDT. The synergistic effect between RB and C(KLAKLAK)2 has been attributed to the AMP sensitizing cells to reactive oxygen species (ROS), making them more susceptible to ROS-induced oxidative stress.

Real-Time Bibliometrics: Dimensions as a Resource for Analyzing Aspects of COVID-19.

Dimensions was built as a platform to allow stakeholders in the research community, including academic bibliometricians, to more easily create and understand the context of different types of research object through the linkages between these objects. Links between objects are created via persistent identifiers and machine learning techniques, while additional context is introduced via data enhancements such as per-object categorisations and person and institution disambiguation. While these features make analytical use cases accessible for end users, the COVID-19 crisis has highlighted a different set of needs to analyze trends in scholarship as they occur: Real-time bibliometrics. The combination of full-text search, daily data updates, a broad set of scholarly objects including pre-prints and a wider set of data fields for analysis, broadens opportunities for a different style of analysis. A subset of these emerging capabilities is discussed and three basic analyses are presented as illustrations of the potential for real-time bibliometrics.

Development of a teaching model to advance skills in industrial pharmaceutical formulation and regulatory aspects.

BACKGROUND AND PURPOSE: To design and critically evaluate a laboratory-scale pharmaceutical formulation practical that enables pharmaceutical science students to develop work-based skills relating to industrial pharmacy such as problem solving, pharmaceutical calculations, research, legal checking, communication, practical aptitude, handling of medicinal products, record keeping, and ability to interpret, analyze and report data. EDUCATIONAL ACTIVITY AND SETTING: Nine laboratory practical sessions were designed whereby students formulated a range of dosage forms and conducted corrective and preventative actions (CAPAs) exercises. A master batch formula outlined the specifications for each product and a practical sheet was provided for the students to record their activities. Student evaluation of the exercise was performed via a self-administered 17-item questionnaire in the final week. FINDINGS: Twenty-four students completed the workshops over two year groups (2015 year group n = 11, 2016 year group n = 13). The mean score across both groups was 15.6 out of 20. DISCUSSION: The questionnaire had a 100% response rate and the majority of students agreed that the classes were a useful teaching method and that they fostered key skills required for pharmaceutical formulation and regulation. SUMMARY: Laboratory classes effectively delivered course content relating to industrial-based pharmaceutical formulation and helped to develop relevant skills.

Self-assembling diphenylalanine peptide nanotubes selectively eradicate bacterial biofilm infection.

Biofilms present a major problem to industry and healthcare worldwide. Composed of a population of surface-attached microbial cells surrounded by a protective extracellular polysaccharide matrix, they are responsible for increased tolerance to antibiotics, treatment failure and a resulting rise in antimicrobial resistance. Here we demonstrate that self-assembled peptide nanostructures composed of a diphenylalanine motif provide sufficient antibacterial activity to eradicate mature biofilm forms of bacteria widely implicated in hospital infections. Modification of terminal functional groups to amino (-NH2), carboxylic acid (-COOH) or both modalities, and switch to d-isomers, resulted in changes in antibacterial selectivity and mammalian cell toxicity profiles. Of the three peptide nanotubes structures studied (NH2-FF-COOH, NH2-ff-COOH and NH2-FF-NH2), NH2-FF-COOH demonstrated the most potent activity against both planktonic (liquid, free-floating) and biofilm forms of bacteria, possessing minimal mammalian cell toxicity. NH2-FF-COOH resulted in greater than 3 Log10 CFU/mL viable biofilm reduction (>99.9%) at 5 mg/mL and total biofilm kill at 10 mg/mL against Staphylococcus aureus after 24 h exposure. Scanning electron microscopy proved that antibiofilm activity was primarily due to the formation of ion channels and/or surfactant-like action, with NH2-FF-COOH and NH2-ff-COOH capable of degrading the biofilm matrix and disrupting cell membranes, leading to cell death in Gram-positive bacterial isolates. Peptide-based nanotubes are an exciting platform for drug delivery and engineering applications. This is the first report of using peptide nanotubes to eradicate bacterial biofilms and provides evidence of a new platform that may alleviate their negative impact throughout society. STATEMENT OF SIGNIFICANCE: We outline, for the first time, the antibiofilm activity of diphenylalanine (FF) peptide nanotubes. Biofilm bacteria exhibit high tolerance to antimicrobials 10-10,000 times that of free-flowing planktonic forms. Biofilm infections are difficult to treat using conventional antimicrobial agents, leading to a rise in antimicrobial resistance. We discovered nanotubes composed of NH2-FF-COOH demonstrated potent activity against staphylococcal biofilms implicated in hospital infections, resulting in complete kill at concentrations of 10 mg/mL. Carboxylic acid terminated FF nanotubes were able to destroy the exopolysaccharide architecture of staphylococcal biofilms expressing minimal toxicity, highlighting their potential for use in patients. Amidated (NH2-FF-NH2) forms demonstrated reduced antibiofilm efficacy and significant toxicity. These results contribute significantly to the development of innovative antibacterial technologies and peptide nanomaterials.

Ultrashort Self-Assembling Peptide Hydrogel for the Treatment of Fungal Infections.

The threat of antimicrobial resistance to society is compounded by a relative lack of new clinically effective licensed therapies reaching patients over the past three decades. This has been particularly problematic within antifungal drug development, leading to a rise in fungal infection rates and associated mortality. This paper highlights the potential of an ultrashort peptide, (naphthalene-2-ly)-acetyl-diphenylalanine-dilysine-OH (NapFFKK-OH), encompassing hydrogel-forming and antifungal properties within a single peptide motif, thus overcoming formulation (e.g., solubility, drug loading) issues associated with many currently employed highly hydrophobic antifungals. A range of fungal susceptibility (colony counts) and cell cytotoxicity (MTS cell viability, LIVE/DEAD staining® with fluorescent microscopy, haemolysis) assays were employed. Scanning electron microscopy confirmed the nanofibrous architecture of our self-assembling peptide, existing as a hydrogel at concentrations of 1% w/v and above. Broad-spectrum activity was demonstrated against a range of fungi clinically relevant to infection (Aspergillus niger, Candida glabrata, Candida albicans, Candida parapsilosis and Candida dubliniensis) with greater than 4 log10 CFU/mL reduction at concentrations of 0.5% w/v and above. We hypothesise antifungal activity is due to targeting of anionic components present within fungal cell membranes resulting in membrane disruption and cell lysis. NapFFKK-OH demonstrated reduced toxicity against mammalian cells (NCTC 929, ARPE-19) suggesting increased selectivity for fungal cells. However, further studies relating to safety for systemic administration is required, given the challenges toxicity has presented in the wider context of antimicrobial peptide drug development. Overall this study highlights the promise of NapFFKK-OH hydrogels, particularly as a topical formulation for the treatment of fungal infections relating to the skin and eyes, or as a hydrogel coating for the prevention of biomaterial related infection.

Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients.

Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somatostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or monotherapy for prostate and breast cancer, and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutical industry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers.

Addressing selective polypharmacology of antipsychotic drugs targeting the bioaminergic receptors through receptor dynamic conformational ensembles.

Selective polypharmacology, where a drug acts on multiple rather than a single molecular target involved in a disease, emerges to develop a structure-based system biology approach to design drugs selectively targeting a disease-active protein network. We focus on the bioaminergic receptors that belong to the group of G-protein-coupled receptors (GPCRs) and represent targets for therapeutic agents against schizophrenia and depression. Among them, it has been shown that the serotonin (5-HT(2A) and 5-HT6) and dopamine (D2 and D3) receptors induce a cognition-enhancing effect (group 1), while the histamine (H1) and serotonin (5-HT(2C)) receptors lead to metabolic side effects and the 5-HT(2B) serotonin receptor causes pulmonary hypertension (group 2). Thus, the problem arises to develop an approach that allows identifying drugs targeting only the disease-active receptors, i.e. group 1. The recent release of several crystal structures of the bioaminergic receptors, involving the D3 and H1 receptors, provides the possibility to model the structures of all receptors and initiate a study of the structural and dynamic context of selective polypharmacology. In this work, we use molecular dynamics simulations to generate a conformational space of the receptors and subsequently characterize its binding properties applying molecular probe mapping. All-against-all comparison of the generated probe maps of the selected diverse conformations of all receptors with the Tanimoto similarity coefficient (Tc) enable the separation of the receptors of group 1 from group 2. The pharmacophore built based on the Tc-selected receptor conformations, using the multiple probe maps discovers structural features that can be used to design molecules selective toward the receptors of group 1. The importance of several predicted residues to ligand selectivity is supported by the available mutagenesis and ligand structure-activity relationship studies. In addition, the Tc-selected conformations of the receptors for group 1 show good performance in isolation of known ligands from a random decoy. Our computational structure-based protocol to tackle selective polypharmacology of antipsychotic drugs could be applied for other diseases involving multiple drug targets, such as oncologic and infectious disorders.