Synthesis of Small Molecule Derivatives of CK-666 as Potential Inhibitors of the Arp2/3 Complex

The Actin-Related Protein (Arp) 2/3 Complex is an actin nucleating factor intrinsically involved in cellular regulation of actin networks during life-essential processes such as motility. Overexpression of the Arp2/3 complex has indicated as a factor allowing the proliferation of certain metastatic cancers. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. The molecules are designed based off of the structure of known Arp2/3 inhibitor CK-666, which was discovered via high-throughput screening. Details of the synthesis of the tryptamine derivatives are discussed, and the bulk actin polymerization assay used to determine potency of the new compounds is discussed

Assessment of Human Trabecular Architecture in the Pubis by Three Radiographic Modalities

This poster discusses technical aspects of an investigation into the use of non-destructive radiological analyses of pubic cancellous bone structure to estimate age-at-death from human skeletal remains. This study stems from findings, in X-ray plain films, of increased rarification and orientation of trabeculae with age [1]; likely in concert with the macroscopic remodelling of the symphyseal surface currently used in estimation of age-at-death. The study uses three non-destructive X-ray imaging modalities: plain film radiography, computed tomography (CT), and micro-CT (μCT). Plain film radiography has greater spatial resolution than CT [2] and is relatively inexpensive, widely available, and, with portable X-ray units, even accessible in the field for archaeological and forensic applications. CT scanners are largely restricted to clinical settings due to the size, sensitivity, and cost of the machine, but offer a greater contrast resolution than plain film radiography [2]. More expensive and more precise, μCTscanners are further restricted in their availability and accessibility, but CT andμCTmodalities provide volumetric data, avoiding the confusion of overlying cortical and cancellous structures and the apparent increases in density with element thickness seen in plain film radiography

\u3cem\u3eIn Vitro\u3c/em\u3e Determination of Potency of Small Molecule Inhibitors of Arp2/3 Complex

Actin is a key protein building block of actin microfilaments, which are constructed and deconstructed in response to cellular signaling pathways to regulate cellular processes such as motility, division, and endocytosis. Arp2/3 Complex is a 7-subunit protein complex that is in involved in cellular construction of branched actin networks, functioning by attaching to the side of a pre-existing actin filament and nucleating a daughter branch. Overexpression of Arp2/3 complex has been linked to the ability of certain metastatic cancers to proliferate. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. A bulk actin polymerization assay is used as the key method to determine the potency of inhibitor candidates. Structure-activity relationships derived from these results are also discussed

Constraining the near-core rotation of the gamma Doradus star 43 Cygni using BRITE-Constellation data

Photometric time series of the $\gamma$ Dor star 43 Cyg obtained with the BRITE-Constellation nano-satellites allow us to study its pulsational properties in detail and to constrain its interior structure. We aim to find a g-mode period spacing pattern that allows us to determine the near-core rotation rate of 43 Cyg and redetermine the star's fundamental atmospheric parameters and chemical composition. We conducted a frequency analysis using the 156-days long data set obtained with the BRITE-Toronto satellite and employed a suite of MESA/GYRE models to derive the mode identification, asymptotic period spacing and near-core rotation rate. We also used high-resolution, high signal-to-noise ratio spectroscopic data obtained at the 1.2m Mercator telescope with the HERMES spectrograph to redetermine the fundamental atmospheric parameters and chemical composition of 43 Cyg using the software Spectroscopy Made Easy (SME). We detected 43 intrinsic pulsation frequencies and identified 18 of them to be part of a period spacing pattern consisting of prograde dipole modes with an asymptotic period spacing $\Delta \Pi_{l=1}$ of $2970^{+700}_{-570} \rm s$. The near-core rotation rate was determined to be $f_{\rm rot} = 0.56^{+0.12}_{-0.14}\,\rm d^{-1}$. The atmosphere of 43 Cyg shows solar chemical composition at an effective temperature of 7150 $\pm$ 150 K, a log g of 4.2 $\pm$ 0.6 dex and a projected rotational velocity, $v {\rm sin}i$, of 44 $\pm$ 4 kms$^{-1}$. The morphology of the observed period spacing patterns shows indications of the presence of a significant chemical gradient in the stellar interior.Comment: 9 pages, 8 figures, accepted by A&

Detection and Degradation of Adenosine Monophosphate in Perchlorate-Spiked Martian Regolith Analogue, by Deep-Ultraviolet Spectroscopy

The search for organic biosignatures on Mars will depend on finding material protected from the destructive ambient radiation. Solar ultraviolet can induce photochemical degradation of organic compounds, but certain clays have been shown to preserve organic material. We examine how the SHERLOC instrument on the upcoming Mars 2020 mission will use deep-ultraviolet (UV) (248.6 nm) Raman and fluorescence spectroscopy to detect a plausible biosignature of adenosine 5′-monophosphate (AMP) adsorbed onto Ca-montmorillonite clay. We found that the spectral signature of AMP is not altered by adsorption in the clay matrix but does change with prolonged exposure to the UV laser over dosages equivalent to 0.2–6 sols of ambient martian UV. For pure AMP, UV exposure leads to breaking of the aromatic adenine unit, but in the presence of clay the degradation is limited to minor alteration with new Raman peaks and increased fluorescence consistent with formation of 2-hydroxyadenosine, while 1 wt % Mg perchlorate increases the rate of degradation. Our results confirm that clays are effective preservers of organic material and should be considered high-value targets, but that pristine biosignatures may be altered within 1 sol of martian UV exposure, with implications for Mars 2020 science operations and sample caching

Acute Renal Replacement Therapy in Children with Diarrhea-Associated Hemolytic Uremic Syndrome: A Single Center 16 Years of Experience

Acute kidney injury (AKI) is becoming more prevalent among hospitalized children, its etiologies are shifting, and new treatment modalities are evolving; however, diarrhea-associated hemolytic uremic syndrome (D+HUS) remains the most common primary disease causing AKI in young children. Little has been published about acute renal replacement therapy (ARRT) and its challenges in this population. We describe our single center's experience managing 134 pediatric patients with D+HUS out of whom 58 (43%) required ARRT over the past 16 years. In our cohort, all but one patient were started on peritoneal dialysis (PD). Most patients, 47 (81%), received acute PD on a pediatric inpatient ward. The most common recorded complications in our cohort were peritoneal fluid leaks 13 (22%), peritonitis 11 (20%), and catheter malfunction 5 (9%). Nine patients (16%) needed surgical revision of their PD catheters. There were no bleeding events related to PD despite a mean platelets count of 40.9 (±23.5) × 103/mm3 and rare use of platelets infusions. Despite its methodological limitations, this paper adds to the limited body of evidence supporting the use of acute PD as the primary ARRT modality in children with D+HUS

The UQAM Mummy – The Use of Non-Destructive Imaging to Reconstruct an Ancient Osteobiography and to Document Modern Malfeasance

An Egyptian mummy and her coffin dating to the 26th Dynasty were donated to the École de Beaux Arts in Montreal in 1927. This mummy has been in the collection of the Université du Québec à Montréal since 1967. Inscriptions on the elaborate coffin identify the individual as Hetep-Bastet. In 1969, the mummy was attacked by a protester, who caused extensive damage. The mummy was scanned once over a decade ago. However, computed tomography (CT) technology has advanced a great deal since that time, and some conclusions reached were somewhat suspect (e.g. that she suffered from a large dental abscess caused by “drinking too much beer”). Thus, when Hetep-Bastet was transported to Gatineau in the fall of 2008 to be part of the “Tombs for Eternity” exhibit at the Canadian Museum of Civilization, we took the opportunity to rescan her. The specific goals of our study were: to assess the damage done by the protester in 1969 to investigate the specific details of how she was mummified as part of an ongoing study of variability in mummification practice to gather osteological and paleopathological data in order to reconstruct her osteobiography to segment the skull from the CT data in order to create a facial reconstruction to examine her coffin as part of an ongoing study of the use of CT scans to characterize different materials associated with Egyptian mummies Damag

The ROM / UWO Mummy Project: A Microcosm of Progress in Mummy Research

The beginnings of the Royal Ontario Museum can be traced back to the excavations and collections of Charles Trick Currelly, a staff member of the Egyptian Exploration Fund in the early 1900s. Currelly excavated with Sir Flinders Petrie at Abydos and with Edouard Naville at Deir el Bahari. With the assistance of Robert Mond and others, Currelly amassed a rich and diverse collection that became the basis for the ROM, which opened its doors in 1914. Part of that collection included several Egyptian mummies (Currelly 1971) . The Egyptologicalholdings at the ROM include eight mummies: one dating to the Predynastic Period, five from the Pharaonic Period, one from the Roman Period and one without context. Two of these, Nakht and Djedmaatesankh, have been well studied by Peter Lewin and associates, while three more are the subjects of the current investigation. The objectives of this poster are to review the work and accomplishments of the previous research, to describe the preliminary results of the current research project and to outline directions for future work

Research needs for optimising wastewater-based epidemiology monitoring for public health protection

This is the final version. Available on open access from IWA Publishing via the DOI in this recordData availability statement: All relevant data are included in the paper or its Supplementary Information.Wastewater-based epidemiology (WBE) is an unobtrusive method used to observe patterns in illicit drug use, poliovirus, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The pandemic and need for surveillance measures have led to the rapid acceleration of WBE research and development globally. With the infrastructure available to monitor SARS-CoV-2 from wastewater in 58 countries globally, there is potential to expand targets and applications for public health protection, such as other viral pathogens, antimicrobial resistance (AMR), pharmaceutical consumption, or exposure to chemical pollutants. Some applications have been explored in academic research but are not used to inform public health decision-making. We reflect on the current knowledge of WBE for these applications and identify barriers and opportunities for expanding beyond SARS-CoV-2. This paper critically reviews the applications of WBE for public health and identifies the important research gaps for WBE to be a useful tool in public health. It considers possible uses for pathogenic viruses, AMR, and chemicals. It summarises the current evidence on the following: (1) the presence of markers in stool and urine; (2) environmental factors influencing persistence of markers in wastewater; (3) methods for sample collection and storage; (4) prospective methods for detection and quantification; (5) reducing uncertainties; and (6) further considerations for public health use.Natural Environment Research Council (NERC)Engineering and Physical Sciences Research Council (EPSRC