Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNA production.

Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known.

Dark times: iminothioindoxyl--nucleoside fluorescence quenchers with defined location and minimal perturbation in DNA.

Fluorescence quenchers for application in DNA - like the BHQ family - tend to be large molecules which need to be attached, often post-synthetically, long linkers. In this study, we present two new iminothioindoxyl--nucleosidic quenchers which are very compact, feature a native backbone and can be introduced into DNA regular solid-phase synthesis. Especially with d as juxtaposed nucleobase, they have a defined location and orientation in a DNA duplex with minimal perturbation of the structure and hence interaction capabilities.

BODIPY phototether enables oligonucleotide cyclization and subsequent deprotection by tissue-transparent red light.

-methyl-BODIPY photocages release a leaving group upon visible light irradiation but often lack thermal stability. In turn, our thermally-stable, red-shifted BODIPY phototether allows oligonucleotide cyclization, preventing complementary strand hybridization. Hybridization resumes upon red-NIR irradiation, disconnecting the phototether by oxidative cleavage, which is easily monitored by a blue shift in fluorescence.

Discovery and development of BI 1265162, an ENaC inhibitor for the treatment of cystic fibrosis.

Lung selective inhibition of the endothelial sodium channel (ENaC) is a potential mutation agnostic treatment of Cystic Fibrosis (CF). We describe the discovery and development of BI 1265162, the first ENaC inhibitor devoid of the amiloride structural motif that entered clinical trials. The design of BI 1265162 focused on its suitability for inhalation via the Respimat® Soft Mist™ Inhaler and a long duration of action.

Iminothioindoxyl Donors with Exceptionally High Cross Section for Protein Vibrational Energy Transfer.

Various protein functions are related to vibrational energy transfer (VET) as an important mechanism. The underlying transfer pathways can be experimentally followed by ultrafast Vis-pump/IR-probe spectroscopy with a donor-sensor pair of non-canonical amino acids (ncAAs) incorporated in a protein. However, so far only one donor ncAA, azulenylalanine (AzAla), exists, which suffers from a comparably low Vis extinction coefficient.

Targeting of CRISPR-Cas12a crRNAs into human mitochondria.

Mitochondrial gene editing holds great promise as a therapeutic approach for mitochondrial diseases caused by mutations in the mitochondrial DNA (mtDNA). Current strategies focus on reducing mutant mtDNA heteroplasmy levels through targeted cleavage or base editing. However, the delivery of editing components into mitochondria remains a challenge.

Effects of combined exercises on shoulder mobility and strength of the upper extremities in breast cancer rehabilitation: a 3-week randomized controlled trial.

Purpose: The aim of this study was to analyze the effects of mobility training with FIVE® devices in combination with device-supported strength exercises for shoulder mobility and strength of the upper extremities in women with breast cancer.

Methods: We conducted a pretest-posttest intervention study with female breast cancer patients (n = 41) who were randomly assigned to two groups by lot during their stationary follow-up treatment at a rehabilitation clinic in the south of Germany between February and March 2020. As part of exercise therapy, the intervention group (n = 24) performed a mobility training with FIVE® devices combined with device-supported strength training, whereas the control group (n = 17) completed device-supported strength training.

A Blue Light and Two-Photon Activatable Rhodamine Fluorophore.

Photoactivatable fluorophores (PAFs) are powerful tools for biological imaging applications because they provide spatiotemporal control of fluorescence distribution. Many of the existing PAFs can only be activated by UV irradiation. In our study, we present a blue light (1P) and NIR light (2P) activatable rhodamine fluorophore.

Extending the Palette of Green Coumarin Photocages - Oligonucleotide Fragmentation and Superior 5'-Caps.

The possibilities of dicyanocoumarin (DCCM)-modified oligonucleotides are expanded to not just allow their release and therefore activation with green light (OFF→ON) but to also now offer a solution for their fragmentation after exposure to green light (ON→OFF). Furthermore, an answer to the decreasing uncaging quantum yields often faced when working with red-shifted photocages is given and showed that rigidified DCCM 5'-caps outperform their predecessors. Those two new 5'-caps with ATTO 390 motif or julolidine core are compatible with copper(I)-catalyzed alkyne-azide cycloadditions (CuAACs) and therefore suitable for efficient caging through cyclization or more bioconjugation reactions.

Choose your leaving group: selective photodeprotection in a mixture of HP-caged compounds by VIPER excitation.

Photocages are light-triggerable molecular moieties that can locally release a pre-determined leaving group (LG). Finding a suitable photocage for a particular application may be challenging, as the choice may be limited by for instance the optical or physicochemical properties of the system. Using more than one photocage to release different LGs in a reaction mixture may even be more difficult.

Rhodamine-Sensitized Two-Photon Activation of a Red Light-Absorbing BODIPY Photocage.

Two-photon (2P) activatable probes are of high value in biological and medical chemistry since near infrared (NIR) light can penetrate deeply even in blood-perfused tissue and due to the intrinsic three-dimensional activation properties. Designing two-photon chromophores is challenging. However, the two-photon absorption qualities of a photocage can be improved with an intramolecular sensitizer, which transfers the absorbed light onto the cage.

Arterial stiffness and augmentation index are associated with balance function in young adults.

Objective: Arterial stiffness and pulsatile central hemodynamics have been shown to affect various aspects of physical function, such as exercise capacity, gait speed, and motor control. The aim of this study was to examine the potential association between arterial stiffness and balance function in healthy younger men and women.

Methods: 112 participants (age = 21 ± 4 years, n = 78 women) underwent measures of arterial stiffness, pulsatile central hemodynamics, balance function and physical fitness in this cross-sectional study.

Chromatic Selectivity of Coumarin-Caged Oligonucleotides.

A system of two coumarin-based caging groups is presented - one absorbing in the blue (400-450 nm) and the other absorbing in the green (480-550 nm) part of the visible spectrum. Together they form a pair, which allows to selectively photoactivate the one or the other in oligonucleotides. A numerical characterization defining the term "chromatic selectivity" was proposed, and it was shown how chromatically selective uncaging can literally be titrated in a kinetic reaction scheme.

RNA Probes for Visualization of Sarcin/ricin Loop Depurination without Background Fluorescence.

Protein synthesis via ribosomes is a fundamental process in all known living organisms. However, it can be completely stalled by removing a single nucleobase (depurination) at the sarcin/ricin loop of the ribosomal RNA. In this work, we describe the preparation and optimization process of a fluorescent probe that can be used to visualize depurination.

Twenty-Four-Hour Central Hemodynamic Load in Adults With and Without a History of COVID-19.

Background: Although hypertension is a risk factor for severe Coronavirus Disease 2019 (COVID-19) illness, little is known about the effects of COVID-19 on blood pressure (BP). Central BP measures taken over a 24-hour period using ambulatory blood pressure monitoring (ABPM) adds prognostic value in assessing cardiovascular disease (CVD) risk compared with brachial BP measures from a single time point. We assessed CVD risk between adults with and without a history of COVID-19 via appraisal of 24-hour brachial and central hemodynamic load from ABPM.

Inactivation of Competitive Decay Channels Leads to Enhanced Coumarin Photochemistry.

In the development of photolabile protecting groups, it is of high interest to selectively modify photochemical properties with structural changes as simple as possible. In this work, knowledge of fluorophore optimization was adopted and used to design new coumarin- based photocages. Photolysis efficiency was selectively modulated by inactivating competitive decay channels, such as twisted intramolecular charge transfer (TICT) or hydrogen-bonding, and the photolytic release of the neurotransmitter serotonin was demonstrated.

Green-Light Activatable BODIPY and Coumarin 5'-Caps for Oligonucleotide Photocaging.

We synthesized two green-light activatable 5'-caps for oligonucleotides based on the BODIPY and coumarin scaffold. Both bear an alkyne functionality allowing their use in numerous biological applications. They were successfully incorporated in oligonucleotides via solid-phase synthesis.

A long-lived fluorenyl cation: efficiency booster for uncaging and photobase properties.

The photochemistry of fluorenols has been of special interest for many years. This is because both the fluorenol and the fluorenyl cation are antiaromatic in the ground state due to their 4n π-electrons according to the Hückel rule. The photolysis reaction of various fluorene derivatives takes place a cation intermediate and is preferred due to its excited state aromaticity.

Ultrafast and efficient energy transfer in a one- and two-photon sensitized rhodamine-BODIPY dyad: a perspective for broadly absorbing photocages.

In view of the demand for photoactivatable probes that operate in the visible (VIS) to near infrared (NIR) region of the spectrum, we designed a bichromophoric system based on a rhodamine fluorophore and a BODIPY photocage. Two-photon excited fluorescence (TPEF) measurements and quantum chemical calculations reveal excellent two-photon properties of the employed rhodamine derivative. Excitation of the rhodamine unit a one- or two-photon process leads to excitation energy transfer (EET) onto the BODIPY part, which is followed by the liberation of the leaving group.

Visible light-activatable Q-dye molecular beacons for long-term mRNA monitoring in neurons.

Herein, we present a new class of Q-dye molecular beacons (MBs) that can be locally activated with visible light in hippocampal neurons. Our novel architecture increases the available monitoring time for neuronal mRNA from several minutes to 14 hours, since a lower light-sampling rate is required for tracking.

Solid-Phase-Supported Chemoenzymatic Synthesis of a Light-Activatable tRNA Derivative.

Herein, we present a multi-cycle chemoenzymatic synthesis of modified RNA with simplified solid-phase handling to overcome size limitations of RNA synthesis. It combines the advantages of classical chemical solid-phase synthesis and enzymatic synthesis using magnetic streptavidin beads and biotinylated RNA. Successful introduction of light-controllable RNA nucleotides into the tRNA sequence was confirmed by gel electrophoresis and mass spectrometry.

Exposure to 16 h of normobaric hypoxia induces ionic edema in the healthy brain.

Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, stroke, or traumatic brain injury, cerebral edema can develop. The exact nature and genesis of hypoxia-induced edema in healthy individuals remain unresolved. We examined the effects of prolonged, normobaric hypoxia, induced by 16 h of exposure to simulated high altitude, on healthy brains using proton, dynamic contrast enhanced, and sodium MRI.

The RNA chaperone StpA enables fast RNA refolding by destabilization of mutually exclusive base pairs within competing secondary structure elements.

In bacteria RNA gene regulatory elements refold dependent on environmental clues between two or more long-lived conformational states each associated with a distinct regulatory state. The refolding kinetics are strongly temperature-dependent and especially at lower temperatures they reach timescales that are biologically not accessible. To overcome this problem, RNA chaperones have evolved.

Rethinking Uncaging: A New Antiaromatic Photocage Driven by a Gain of Resonance Energy.

Photoactivatable compounds for example photoswitches or photolabile protecting groups (PPGs, photocages) for spatiotemporal light control, play a crucial role in different areas of research. For each application, parameters such as the absorption spectrum, solubility in the respective media and/or photochemical quantum yields for several competing processes need to be optimized. The design of new photochemical tools therefore remains an important task.