Pharmacology and Mechanism of Action of Suzetrigine, a Potent and Selective Na1.8 Pain Signal Inhibitor for the Treatment of Moderate to Severe Pain.

Introduction: There is a high unmet need for safe and effective non-opioid medicines to treat moderate to severe pain without risk of addiction. Voltage-gated sodium channel 1.8 (Na1.

T cell margination: investigating the detour of T cells following forimtamig treatment in humanized mice.

T cell bispecific antibodies (TCBs) are a promising new class of therapeutics for relapsed/refractory multiple myeloma. A frequently observed, yet incompletely understood effect of this treatment is the transient reduction of circulating T cell counts, also known as T cell margination (TCM). After administration of the GPRC5D-targeting TCB forimtamig (RG6234), TCM occurred in patients and correlated with cytokine release and soluble B cell maturation antigen decrease.

Critical assessment of LC3/GABARAP ligands used for degrader development and ligandability of LC3/GABARAP binding pockets.

Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome.

From the brain's encoding of input dynamics to its behavior: neural dynamics shape bias in decision making.

The human brain is tightly connected to the individual's environment and its input dynamics. How the dynamics of periodic environmental stimuli influence neural activity and subsequent behavior via neural entrainment or alignment is not fully clear yet, though. This study explores how periodic environmental stimuli influence neural activity and behavior.

Friends and Foes: Bacteria of the Hydroponic Plant Microbiome.

Hydroponic greenhouses and vertical farms provide an alternative crop production strategy in regions that experience low temperatures, suboptimal sunlight, or inadequate soil quality. However, hydroponic systems are soilless and, therefore, have vastly different bacterial microbiota than plants grown in soil. This review highlights some of the most prevalent plant growth-promoting bacteria (PGPB) and destructive phytopathogenic bacteria that dominate hydroponic systems.

Spectral peak analysis and intrinsic neural timescales as markers for the state of consciousness.

Resting state EEG in patients with disorders of consciousness (DOC) is characterized by an increase of power in the delta frequency band and a concurrent decrease in the alpha range, equivalent to a weakening or disappearance of the alpha peak. Prolongation of Intrinsic Neural Timescales (INTs) is also associated with DOCs. Together, this raises the question whether the decreased alpha peak relates to the prolonged INTs and, importantly, how that can be used for diagnosing the state of consciousness in DOC individuals.

Methylphenidate differentially affects the social ultrasonic vocalizations of wild-type and prodromal Parkinsonian rats.

Prodromal signs of Parkinson's disease (PD), including vocal communication deficits, are poorly understood and do not respond adequately to current pharmacologic treatments. Norepinephrine dysfunction is involved early in PD; thus, drug therapies targeting norepinephrine may be useful as a treatment of prodromal signs. This study used a validated, translational rodent model of prodromal PD, the male -/- rat, which exhibits ultrasonic vocalization (USV) deficits as early as 2 months of age.

Abnormal resting-state EEG phase dynamics distinguishes major depressive disorder and bipolar disorder.

Changes in EEG have been reported in both major depressive disorder (MDD) and bipolar disorder (BD). Specifically, power changes in EEG alpha and theta frequency bands during rest and task are known in both disorders. This leaves open whether there are changes in yet another component of the electrophysiological EEG signal, namely phase-related processes that may allow for distinguishing MDD and BD.

Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics.

Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus.

The activation thresholds and inactivation kinetics of poking-evoked PIEZO1 and PIEZO2 currents are sensitive to subtle variations in mechanical stimulation parameters.

PIEZO1 and PIEZO2 are mechanically activated ion channels that confer mechanosensitivity to various cell types. PIEZO channels are commonly examined using the so-called poking technique, where currents are recorded in the whole-cell configuration of the patch-clamp technique, while the cell surface is mechanically stimulated with a small fire-polished patch pipette. Currently, there is no gold standard for mechanical stimulation, and therefore, stimulation protocols differ significantly between laboratories with regard to stimulation velocity, angle, and size of the stimulation probe.

Contribution of mechanoreceptors to spinal cord injury-induced mechanical allodynia.

Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors.

Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics.

Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App.

Vocal and tongue exercise in early to mid-stage Parkinson disease using the Pink1-/- rat.

Vocal and swallowing deficits are common in Parkinson disease (PD). Because these impairments are resistant to dopamine replacement therapies, vocal and lingual exercise are the primary treatment, but not all individuals respond to exercise and neural mechanisms of treatment response are unclear. To explore putative mechanisms, we used the progressive Pink1-/- rat model of early to mid-stage PD and employed vocal and lingual exercises at 6- and 10-months of age in male Pink1-/- and wild type (WT) rats.

OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage.

Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents.

Nuclear Charge Radius of ^{26m}Al and Its Implication for V_{ud} in the Quark Mixing Matrix.

Collinear laser spectroscopy was performed on the isomer of the aluminium isotope ^{26m}Al. The measured isotope shift to ^{27}Al in the 3s^{2}3p ^{2}P_{3/2}^{○}→3s^{2}4s ^{2}S_{1/2} atomic transition enabled the first experimental determination of the nuclear charge radius of ^{26m}Al, resulting in R_{c}=3.130(15)  fm.

Intrinsic neural timescales relate to the dynamics of infraslow neural waves.

The human brain is a highly dynamic organ that operates across a variety of timescales, the intrinsic neural timescales (INT). In addition to the INT, the neural waves featured by its phase-related processes including their cycles with peak/trough and rise/fall play a key role in shaping the brain's neural activity. However, the relationship between the brain's ongoing wave dynamics and INT remains yet unclear.

Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease.

Parkinson disease (PD) causes voice and swallow dysfunction even in early stages of the disease. Treatment of this dysfunction is limited, and the neuropathology underlying this dysfunction is poorly defined. Targeted exercise provides the greatest benefit for offsetting voice and swallow dysfunction, and previous data suggest the hypoglossal nucleus and noradrenergic-locus coeruleus (LC) may be involved in its early pathology.

A region-resolved proteomic map of the human brain enabled by high-throughput proteomics.

Substantial efforts are underway to deepen our understanding of human brain morphology, structure, and function using high-resolution imaging as well as high-content molecular profiling technologies. The current work adds to these approaches by providing a comprehensive and quantitative protein expression map of 13 anatomically distinct brain regions covering more than 11,000 proteins. This was enabled by the optimization, characterization, and implementation of a high-sensitivity and high-throughput microflow liquid chromatography timsTOF tandem mass spectrometry system (LC-MS/MS) capable of analyzing more than 2,000 consecutive samples prepared from formalin-fixed paraffin embedded (FFPE) material.

Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1-/- rats.

Background: Parkinson disease (PD) is the fastest growing neurodegenerative disease. The molecular pathology of PD in the prodromal phase is poorly understood; as such, there are no specific prognostic or diagnostic tests. A validated genetic knockout rat was used to model early-onset and progressive PD.

High-Throughput Screening and Proteomic Characterization of Compounds Targeting Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population of incompletely differentiated immune cells. They are known to suppress T cell activity and are implicated in multiple chronic diseases, which make them an attractive cell population for drug discovery. Here, we characterized the baseline proteomes and phospho-proteomes of mouse MDSC differentiated from a progenitor cell line to a depth of 7000 proteins and phosphorylation sites.

Selective Inhibition of Na1.8 with VX-548 for Acute Pain.

Background: The Na1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na1.

Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid.

Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy.

Temporal imprecision and phase instability in schizophrenia resting state EEG.

Schizophrenia is characterized by temporal imprecision and irregularities on neuronal, psychological cognitive, and behavioral levels which are usually tested during task-related activity. This leaves open whether analogous temporal imprecision and irregularities can already be observed in the brain's spontaneous activity as measured during the resting state; this is the goal of our study. Building on recent task-related data, we, using EEG, aimed to investigate the temporal precision and regularity of phase coherence over time in healthy, schizophrenia, and bipolar disorder participants.