Precision RNAi using synthetic shRNAmir target sites.

Loss-of-function genetic tools are widely applied for validating therapeutic targets, but their utility remains limited by incomplete on- and uncontrolled off-target effects. We describe artificial RNA interference (ARTi) based on synthetic, ultra-potent, off-target-free shRNAs that enable efficient and inducible suppression of any gene upon introduction of a synthetic target sequence into non-coding transcript regions. ARTi establishes a scalable loss-of-function tool with full control over on- and off-target effects.

Nonclinical safety evaluation of a novel ionizable lipid for mRNA delivery.

mRNA vaccines hold tremendous potential in disease control and prevention for their flexibility with respect to production, application, and design. Recent breakthroughs in mRNA vaccination would have not been possible without major advances in lipid nanoparticles (LNPs) technologies. We developed an LNP containing a novel ionizable cationic lipid, Lipid-1, and three well known excipients.

approaches in organ toxicity hazard assessment: Current status and future needs for predicting heart, kidney and lung toxicities.

The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on and approaches. This paper reviews the current state of the art in predicting these organ toxicities.

approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity.

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed.

Laminar differences in response to simple and spectro-temporally complex sounds in the primary auditory cortex of ketamine-anesthetized gerbils.

In mammals, acoustic communication plays an important role during social behaviors. Despite their ethological relevance, the mechanisms by which the auditory cortex represents different communication call properties remain elusive. Recent studies have pointed out that communication-sound encoding could be based on discharge patterns of neuronal populations.

Mechanical stability of talin rod controls cell migration and substrate sensing.

Cells adhere to the surrounding tissue and probe its mechanical properties by forming cell-matrix adhesions. Talin is a critical adhesion protein and participates in the transmission of mechanical signals between extracellular matrix and cell cytoskeleton. Force induced unfolding of talin rod subdomains has been proposed to act as a cellular mechanosensor, but so far evidence linking their mechanical stability and cellular response has been lacking.

Quantification of mid and late evoked sinks in laminar current source density profiles of columns in the primary auditory cortex.

Current source density (CSD) analysis assesses spatiotemporal synaptic activations at somatic and/or dendritic levels in the form of depolarizing current sinks. Whereas many studies have focused on the short (<50 ms) latency sinks, associated with thalamocortical projections, sinks with longer latencies have received less attention. Here, we analyzed laminar CSD patterns for the first 600 ms after stimulus onset in the primary auditory cortex of Mongolian gerbils.

Bat auditory cortex – model for general mammalian auditory computation or special design solution for active time perception?

Audition in bats serves passive orientation, alerting functions and communication as it does in other vertebrates. In addition, bats have evolved echolocation for orientation and prey detection and capture. This put a selective pressure on the auditory system in regard to echolocation-relevant temporal computation and frequency analysis.

Detection of adverse drug reactions in a neurological department: comparison between intensified surveillance and a computer-assisted approach.

Objectives: Adverse drug reactions (ADRs) leading to hospitalisation or occurring during hospital stay contribute significantly to patient morbidity and mortality as well as representing an additional cost for healthcare systems. The aim of this study was to provide data about the type and incidence of ADRs in a neurological department and to compare two different methodological approaches to collecting information on ADRs.

Methods: The two methods used were intensified surveillance of neurological wards by daily ward rounds and computer-assisted screening for ADRs by means of pathological laboratory parameters.