Oligoethylene Phosphoramidate-based Kinase Inhibitor Prodrugs - Solubility, Enzyme Inhibition, and Hydrolysis.

The efficiency of kinase inhibiting cancer therapeutics is often limited by their poor solubility in water. PEGylation is one possible strategy to improve the solubility of the drug, however, means to cleave these after reaching the target is important to make use of the therapeutic effects of the native drug. Moreover, the length of the PEG chains will have an effect on the solubility and binding.

Engineering and structures of Crimean-Congo hemorrhagic fever virus glycoprotein complexes.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tickborne virus that can cause severe disease in humans with case fatality rates of 10%-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we use structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn-Gc).

Utilization of health-related data in the regional context for health service planning in the Federal State of Brandenburg, Germany-a qualitative study.

Background: Utilizing regional health data goes hand in hand with challenges: can they be used for health planning, are they applicable to the relevant topics? The study explores current data utilization and needs of stakeholders working in regional health services planning.

Methods: We conducted 16 semi-structured expert-interviews with stakeholders of regional health planning in Brandenburg, a federal state in the north-east of Germany, by telephone or online-meeting tools between 05/2022 and 03/2023. The data were analysed according to qualitative content analysis.

Longitudinal proteome-wide antibody profiling in Marburg virus survivors identifies wing domain immunogen for vaccine design.

Limited knowledge exists on the quality of polyclonal antibody responses generated following Marburg virus (MARV) infection and its evolution in survivors. In this study, we evaluate MARV proteome-wide antibody repertoire longitudinally in convalescent phase approximately every six months for five years following MARV infection in ten human survivors. Differential kinetics were observed for IgM vs IgG vs IgA epitope diversity, antibody binding, antibody affinity maturation and Fc-receptor interaction to MARV proteins.

A Longitudinal Analysis of Memory Immune Responses in Convalescent Crimean-Congo Hemorrhagic Fever Survivors in Uganda.

Evaluating the adaptive immune responses to natural infection with Crimean-Congo hemorrhagic fever (CCHF) virus (CCHFV) in human survivors is critical to the development of medical countermeasures. However, the correlates of protection are unknown. As the most prevalent tick-borne human hemorrhagic fever virus with case fatality rates of 5%-30% and worldwide distribution, there is an urgent need to fill these knowledge gaps.

Helmet Radio Frequency Phased Array Applicators Enhance Thermal Magnetic Resonance of Brain Tumors.

Thermal Magnetic Resonance (ThermalMR) integrates Magnetic Resonance Imaging (MRI) diagnostics and targeted radio-frequency (RF) heating in a single theranostic device. The requirements for MRI (magnetic field) and targeted RF heating (electric field) govern the design of ThermalMR applicators. We hypothesize that helmet RF applicators (HPA) improve the efficacy of ThermalMR of brain tumors versus an annular phased RF array (APA).

Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38.

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection.

A Phosphoramidate Prodrug Platform: One-Pot Amine Functionalization of Kinase Inhibitors with Oligoethylene Glycol for Improved Water-Solubility.

Small molecular kinase inhibitors play a key role in modern cancer therapy. Protein kinases are essential mediators in the growth and progression of cancerous tumors, rendering involved kinases an increasingly important target for therapy. However, kinase inhibitors are almost insoluble in water because of their hydrophobic aromatic nature, often lowering their availability and pharmacological efficacy.

Dihedral Angles and Photoluminescence Quantum Yields: An NMR Analysis.

The synthesis of two different series of donor-acceptor (D-A) molecules is reported, consisting of a series of four structurally related donors and two different acceptors. The subtle differences in the electron density of these D-A-D and D-A compounds are clearly reflected in the different chemical shifts of certain donor protons in the H NMR spectra. These shifts show a cosine squared correlation of the dihedral angle between the donor units and the neighbouring phenyl unit of the acceptor.

Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown.

[An After-Action Review at Municipal Level in the Public Health Service - Lessons Learned at the Corona Unit of the Duesseldorf Public Health Authority after the end of the Covid-19 Pandemic, March 2023].

Background: After-Action Reviews (AARs) represent structured, qualitative evaluations of crisis interventions. Here, we describe the implementation of an AAR to assess the Corona Unit of the Duesseldorf Health Department.

Methods: We employed an after-action review (AAR) using the working group format supplemented by structured interviews with key personnel.

Mixed-method evaluation study of a targeted mass drug administration of long-acting anti-malarials among children aged 3 months to 15 years in the Bossangoa sub-prefecture, Ouham, Central African Republic, during the COVID-19 pandemic.

Background: In 2020, during the COVID-19 pandemic, Médecins Sans Frontières (MSF) initiated three cycles of dihydroartemisin-piperaquine (DHA-PQ) mass drug administration (MDA) for children aged three months to 15 years within Bossangoa sub-prefecture, Central African Republic. Coverage, clinical impact, and community members perspectives were evaluated to inform the use of MDAs in humanitarian emergencies.

Methods: A household survey was undertaken after the MDA focusing on participation, recent illness among eligible children, and household satisfaction.

A Stable Chichibabin Diradicaloid with Near-Infrared Emission.

Conjugated molecules with multiple radical centers such as the iconic Chichibabin diradicaloid hold promise as building blocks in materials for quantum sensing and quantum information processing. However, it is a considerable challenge to design simple analogues of the Chichibabin hydrocarbon that are chemically inert, exhibit high diradical character and emit light at a distinct wavelength that may offer an optical readout of the spin state in functional ensembles. Here we describe the serendipitous discovery of the stable TTM-TTM diradicaloid, which exhibits high diradical character, a striking sky-blue color and near-infrared (NIR) emission (in solution).

Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn-Gc).

Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies.

Monoclonal antibodies (mAbs) are an important class of antiviral therapeutics. MAbs are highly selective, well tolerated, and have long in vivo half-life as well as the capacity to induce immune-mediated virus clearance. Their activities can be further enhanced by integration of their variable fragments (Fvs) into bispecific antibodies (bsAbs), affording simultaneous targeting of multiple epitopes to improve potency and breadth and/or to mitigate against viral escape by a single mutation.

Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38.

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique to , is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection.

Water-Soluble Trityl Radicals for Fluorescence Imaging.

Stable tris(trichlorophenyl)methyl radicals have gained interest as all-organic bioimaging agents combining fluorescent and paramagnetic properties. However, cellular uptake has so far only been reported for nanoparticles, because molecular hydrophobic trityl radicals are not soluble in aqueous media. Here, we report the synthesis and characterization of new water-soluble tris(trichlorophenyl)methyl radical derivatives exhibiting red doublet emission.

Evaluation of a multi-component early warning system for pastoralist populations in Doolo zone, Ethiopia: mixed-methods study.

Background: This study evaluated an early warning, alert and response system for a crisis-affected population in Doolo zone, Somali Region, Ethiopia, in 2019-2021, with a history of epidemics of outbreak-prone diseases. To adequately cover an area populated by a semi-nomadic pastoralist, or livestock herding, population with sparse access to healthcare facilities, the surveillance system included four components: health facility indicator-based surveillance, community indicator- and event-based surveillance, and alerts from other actors in the area. This evaluation described the usefulness, acceptability, completeness, timeliness, positive predictive value, and representativeness of these components.

Long-term Sudan Virus Ebola Survivors Maintain Multiple Antiviral Defense Mechanisms.

Background: The critical issues of sustained memory immunity following ebolavirus disease among long-term survivors are still unclear.

Methods: Here, we examine virus-specific immune and inflammatory responses following in vitro challengd in 12 Sudan virus (SUDV) long-term survivors from Uganda's 2000-2001 Gulu outbreak, 15 years after recovery. Total RNA from isolated SUDV-stimulated and unstimulated peripheral blood mononuclear cells was extracted and analyzed.

Deferral of Estimated Glomerular Filtration Rate Testing Before Contrast-Enhanced CT in Low-Risk Emergency Department Patients: Assessment of Safety and Impact on Throughput.

Objective: To assess the safety and utility of deferring estimated glomerular filtration rate (eGFR) testing before contrast-enhanced CT (CECT) in low-risk emergency department (ED) patients.

Methods: A new question was added to CECT order screens, allowing ordering ED providers to defer eGFR testing in patients deemed low risk for contrast-induced acute kidney injury (AKI). Low risk was defined as no known chronic kidney disease (CKD) or risk factors for AKI or CKD.

Revealing the Origin of Fast Delayed Fluorescence in a Donor Functionalized Bisterpyridine.

A new carbazole-substituted bisterpyridine with pronounced delayed fluorescence is presented. While the molecular donor-acceptor-donor design suggests the origin of this to be thermally activated delayed fluorescence (TADF), results from various photophysical characterizations, OLED characteristics, temperature-dependent NMR spectroscopy, and DFT calculations all point against the involvement of triplet states. The molecule exhibits blue emission at about 440 nm with two or more fast decay channels in the lower nanosecond range in both solution and thin films.