Hemipiperazines as peptide-derived molecular photoswitches with low-nanomolar cytotoxicity.

Molecular photoswitches transform light energy into reversible structural changes. Their combination with known pharmacophores often allows for photomodulation of the biological activity. The effort to apply such compounds in photopharmacology as light-activated pro-drugs is, however, hampered by serious activity reduction upon pharmacophore modifications, or limited biostability. Here we report that a potent antimitotic agent plinabulin and its derivatives demonstrate up to 56-fold reversible activity photomodulation. Alternatively, irreversible photoactivation with cyan light can enhance the cytotoxicity up to three orders of magnitude-all without compromising the original activity level, as the original pharmacophore structure is unchanged. This occurs due to the presence of a peptide-derived photoswitchable motif hemipiperazine inside the plinabulin scaffold. Furthermore, we systematically describe photochromism of these thermally stable and biocompatible hemipiperazines, as well as a photoswitchable fluorophore derived from plinabulin. The latter may further expand the applicability of hemipiperazine photochromism towards super-resolution microscopy.

Photopharmacology of Antimitotic Agents.

Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.

A Comparison of Wearable Tonometry, Photoplethysmography, and Electrocardiography for Cuffless Measurement of Blood Pressure in an Ambulatory Setting.

OBJECTIVE: While non-invasive, cuffless blood pressure (BP) measurement has demonstrated relevancy in controlled environments, ambulatory measurement is important for hypertension diagnosis and control. We present both in-lab and ambulatory BP estimation results from a diverse cohort of participants. METHODS: Participants (N=1125, aged 21-85, 49.2% female, multiple hypertensive categories) had BP measured in-lab over a 24-hour period with a subset also receiving ambulatory measurements. Radial tonometry, photoplethysmography (PPG), electrocardiography (ECG), and accelerometry signals were collected simultaneously with auscultatory or oscillometric references for systolic (SBP) and diastolic blood pressure (DBP). Predictive models to estimate BP using a variety of sensor-based feature groups were evaluated against challenging baselines. RESULTS: Despite limited availability, tonometry-derived features showed superior performance compared to other feature groups and baselines, yieldingprediction errors of 0.32 ±9.8 mmHg SBP and 0.54 ±7.7 mmHg DBP in-lab, and 0.86 ±8.7 mmHg SBP and 0.75 ±5.9 mmHg DBP for 24-hour averages. SBP error standard deviation (SD) was reduced in normotensive (in-lab: 8.1 mmHg, 24-hr: 7.2 mmHg) and younger (in-lab: 7.8 mmHg, 24-hr: 6.7 mmHg) subpopulations. SBP SD was further reduced 15-20% when constrained to the calibration posture alone. CONCLUSION: Performance for normotensive and younger participants was superior to the general population across all feature groups. Reference type, posture relative to calibration, and controlled vs. ambulatory setting all impacted BP errors. SIGNIFICANCE: Results highlight the need for demographically diverse populations and challenging evaluation settings for BP estimation studies. We present the first public dataset of ambulatory tonometry and cuffless BP over a 24-hour period to aid in future cardiovascular research.

Fluorinated Azobenzenes Switchable with Red Light.

Molecular photoswitches triggered with red or NIR light are optimal for photomodulation of complex biological systems, including efficient penetration of the human body for therapeutic purposes ("therapeutic window"). Yet, they are rarely reported, and even more rarely functional under aqueous conditions. In this work, fluorinated azobenzenes are shown to exhibit efficient E→Z photoisomerization with red light (PSS660nm >75 % Z) upon conjugation with unsaturated substituents. Initially demonstrated for aldehyde groups, this effect was also observed in a more complex structure by incorporating the chromophore into a cyclic dipeptide with propensity for self-assembly. Under physiological conditions, the latter molecule formed a supramolecular material that reversibly changed its viscosity upon irradiation with red light. Our observation can lead to design of new photopharmacology agents or phototriggered materials for in vivo use.

"They don't always think about that": Translational Needs in the Design of Personal Health Informatics Applications.

Personal health informatics continues to grow in both research and practice, revealing many challenges of designing applications that address people's needs in their health, everyday lives, and collaborations with clinicians. Research suggests strategies to address such challenges, but has struggled to translate these strategies into design practice. This study examines translation of insights from personal health informatics research into resources to support designers. Informed by a review of relevant literature, we present our development of a prototype set of design cards intended to support designers in re-thinking potential assumptions about personal health informatics. We examined our design cards in semi-structured interviews, first with 12 student designers and then with 12 health-focused professional designers and researchers. Our results and discussion reveal tensions and barriers designers encounter, the potential for translational resources to inform the design of health-related technologies, and a need to support designers in addressing challenges of knowledge, advocacy, and evidence in designing for health.

Sphingosine-1-Phosphate Lyase Deficient Cells as a Tool to Study Protein Lipid Interactions.

Cell membranes contain hundreds to thousands of individual lipid species that are of structural importance but also specifically interact with proteins. Due to their highly controlled synthesis and role in signaling events sphingolipids are an intensely studied class of lipids. In order to investigate their metabolism and to study proteins interacting with sphingolipids, metabolic labeling based on photoactivatable sphingoid bases is the most straightforward approach. In order to monitor protein-lipid-crosslink products, sphingosine derivatives containing a reporter moiety, such as a radiolabel or a clickable group, are used. In normal cells, degradation of sphingoid bases via action of the checkpoint enzyme sphingosine-1-phosphate lyase occurs at position C2-C3 of the sphingoid base and channels the resulting hexadecenal into the glycerolipid biosynthesis pathway. In case the functionalized sphingosine looses the reporter moiety during its degradation, specificity towards sphingolipid labeling is maintained. In case degradation of a sphingosine derivative does not remove either the photoactivatable or reporter group from the resulting hexadecenal, specificity towards sphingolipid labeling can be achieved by blocking sphingosine-1-phosphate lyase activity and thus preventing sphingosine derivatives to be channeled into the sphingolipid-to-glycerolipid metabolic pathway. Here we report an approach using clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated nuclease Cas9 to create a sphingosine-1-phosphate lyase (SGPL1) HeLa knockout cell line to disrupt the sphingolipid-to-glycerolipid metabolic pathway. We found that the lipid and protein compositions as well as sphingolipid metabolism of SGPL1 knock-out HeLa cells only show little adaptations, which validates these cells as model systems to study transient protein-sphingolipid interactions.