Small‐Molecule Proteomimetic Inhibitors of the HIF‐1α–p300 Protein–Protein Interaction

The therapeutically relevant hypoxia inducible factor HIF‐1α–p300 protein–protein interaction can be orthosterically inhibited with α‐helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C‐terminal helix of the HIF‐1α C‐TAD (C‐terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side‐chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF‐1α–p300 PPI inhibitors and the first examples of small‐molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF‐1α, the result is still remarkable in that the mimetic reproduces only three residues from the 42‐residue HIF‐1α C‐TAD from which it is derived.     

Quantitative biology of single neurons

The building blocks of complex biological systems are single cells. Fundamental insights gained from single-cell analysis promise to provide the framework for understanding normal biological systems development as well as the limits on systems/cellular ability to respond to disease. The interplay of cells to create functional systems is not well understood. Until recently, the study of single cells has concentrated primarily on morphological and physiological characterization. With the application of new highly sensitive molecular and genomic technologies, the quantitative biochemistry of single cells is now accessible.     

Effect of coating morphology on the electron stimulated desorption from Ti-Zr-Hf-V nonevaporable-getter-coated stainless steel

The electron stimulated desorption (ESD) was studied for quaternary Ti-Zr-Hf-V alloy coated stainless steel samples with different surface structures: dense on one sample and columnar on another. The ESD yields were measured as a function of electron accumulated dose up to ∼10²³ e⁻/m² or greater and three different NEG coating activation temperatures: 150, 180 and 250 °C. After each ESD experiment the samples were saturated with a mixture of H₂, CO and CO₂. Both samples depicted lower ESD yields for all desorbed species compared to a ternary Ti-Zr-V alloy. It was also shown that although the columnar NEG coating demonstrated better pumping properties and, for NEG activated at 150 °C, lower initial ESD yields, the higher activation temperature may result in a significant H₂ yield increase with dose for the columnar NEG coating. This effect was demonstrated for the first time and should be considered for application in particle accelerators.     

Oscillatory combustion of propene during in situ mechanical activation of solid catalysts

Mechanochemical activation of solids can lead to a strong increase in their activity as catalysts in heterogeneously catalyzed reactions. In the following, we report on the effects of solid catalyst activation during ball milling that lead to oscillatory behavior in CO and CO₂ formation during propene oxidation. The oscillations arise under in situ ball milling conditions over chromium(III) oxide (Cr₂O₃) and cerium(IV) oxide (CeO₂), respectively. The experiments were conducted under continuous gas flow at ambient pressure and temperature, using both a modified steel and a tungsten carbide milling vessel. Abrasion of particles from the steel milling vessel could be eliminated as the sole cause for the oscillations through substitution by a tungsten carbide milling vessel. The intensity and frequency of oscillations are shown to be dependent on the propene-to-oxygen ratio, the milling frequency, milling ball size and metal oxide used. Overall, Cr₂O₃ shows higher activity for oscillatory propene combustion under in situ mechanical activation than CeO₂.     

Cancer-Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery

Nucleic acids are a promising type of therapeutic for the treatment of a wide range of conditions, including cancer, but they also pose many delivery challenges. For efficient and safe delivery to cancer cells, nucleic acids must generally be packaged into a vehicle, such as a nanoparticle, that will allow them to be taken up by the target cells and then released in the appropriate cellular compartment to function. As with other types of therapeutics, delivery vehicles for nucleic acids must also be designed to avoid unwanted side effects; thus, the ability of such carriers to target their cargo to cancer cells is crucial. Classes of nucleic acids, hurdles that must be overcome for effective intracellular delivery, types of nonviral nanomaterials used as delivery vehicles, and the different strategies that can be employed to target nucleic acid delivery specifically to tumor cells are discussed. Additonally, nanoparticle designs that facilitate multiplexed delivery of combinations of nucleic acids are reviewed.     

Mobile device location data reveal human mobility response to state-level stay-at-home orders during the COVID-19 pandemic in the USA

One approach to delaying the spread of the novel coronavirus (COVID-19) is to reduce human travel by imposing travel restriction policies. Understanding the actual human mobility response to such policies remains a challenge owing to the lack of an observed and large-scale dataset describing human mobility during the pandemic. This study uses an integrated dataset, consisting of anonymized and privacy-protected location data from over 150 million monthly active samples in the USA, COVID-19 case data and census population information, to uncover mobility changes during COVID-19 and under the stay-at-home state orders in the USA. The study successfully quantifies human mobility responses with three important metrics: daily average number of trips per person; daily average person-miles travelled; and daily percentage of residents staying at home. The data analytics reveal a spontaneous mobility reduction that occurred regardless of government actions and a ‘floor’ phenomenon, where human mobility reached a lower bound and stopped decreasing soon after each state announced the stay-at-home order. A set of longitudinal models is then developed and confirms that the states'' stay-at-home policies have only led to about a 5% reduction in average daily human mobility. Lessons learned from the data analytics and longitudinal models offer valuable insights for government actions in preparation for another COVID-19 surge or another virus outbreak in the future.     

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.     

Coaxial ion trap mass spectrometer: concentric toroidal and quadrupolar trapping regions

We present the design and results for a new radio-frequency ion trap mass analyzer, the coaxial ion trap, in which both toroidal and quadrupolar trapping regions are created simultaneously. The device is composed of two parallel ceramic plates, the facing surfaces of which are lithographically patterned with concentric metal rings and covered with a thin film of germanium. Experiments demonstrate that ions can be trapped in either region, transferred from the toroidal to the quadrupolar region, and mass-selectively ejected from the quadrupolar region to a detector. Ions trapped in the toroidal region can be transferred to the quadrupole region using an applied ac signal in the radial direction, although it appears that the mechanism of this transfer does not involve resonance with the ion secular frequency, and the process is not mass selective. Ions in the quadrupole trapping region are mass analyzed using dipole resonant ejection. Multiple transfer steps and mass analysis scans are possible on a single population of ions, as from a single ionization/trapping event. The device demonstrates better mass resolving power than the radially ejecting halo ion trap and better sensitivity than the planar quadrupole ion trap.