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TASK-5 ( KCNK15 ) belongs to the acid-sensitive subfamily of two-pore domain potassium (K 2P ) channels, which includes TASK-1 and TASK-3. TASK-5 stands out as K 2P channel for which there is no functional data available, since it was reported in 2001 as non-functional and thus “silent”. Here we show that TASK-5 channels are indeed non-functional as homodimers, but are involved in the formation of functional channel complexes with TASK-1 and TASK-3. TASK-5 negatively modulates the surface expression of TASK channels, while the heteromeric TASK-5-containing channel complexes located at the plasma membrane are characterized by changes in single-channel conductance, Gq-coupled receptor-mediated channel inhibition, and sensitivity to TASK modulators. The unique pharmacology of TASK-1/TASK-5 heterodimers, affected by a common polymorphism in KCNK15 , needs to be carefully considered in the future development of drugs targeting TASK channels. Our observations provide an access to study TASK-5 at the functional level, particularly in malignant cancers associated with KCNK15 . The TASK-5 potassium channel is thought to be non-functional. Here, the authors show that it forms complexes with TASK family members, resulting in heteromeric channels with unique pharmacology and potential as therapeutic targets.

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been established as a powerful technique for the determination of metal and nonmetal distributions within biological systems with high sensitivity. An imaging LA-ICP-MS technique for Fe, Cu, Zn, and Mn was developed to produce large series of quantitative element maps in native brain sections of mice subchronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) as a model of Parkinson's disease. Images were calibrated using matrix-matched laboratory standards. A software solution allowing a precise delineation of anatomical structures was implemented. Coronal brain sections were analyzed crossing the striatum and the substantia nigra, respectively. Animals sacrificed 2 h, 7 d, or 28 d after the last MPTP injection and controls were investigated. We observed significant decreases of Cu concentrations in the periventricular zone and the fascia dentata at 2 h and 7d and a recovery or overcompensation at 28 d, most pronounced in the rostral periventricular zone (+40%). In the cortex Cu decreased slightly to −10%. Fe increased in the interpeduncular nucleus (+40%) but not in the substantia nigra. This pattern is in line with a differential regulation of periventricular and parenchymal Cu, and with the histochemical localization of Fe, and congruent to regions of preferential MPTP binding described in the rodent brain. The LA-ICP-MS technique yielded valid and statistically robust results in the present study on 39 slices from 19 animals. Our findings underline the value of routine micro-local analytical techniques in the life sciences and affirm a role of Cu availability in Parkinson's disease. Quantitation in 18 animals showed a time profile of periventricular Cu paralleling the course of classical dopaminergic markers at 2 h, 7 d, and 28 d.

The rise of fungal infections in recent years is alarming due to an increase in the vulnerable immunocompromised population, global temperature increase, and limited antifungal treatment options. One of the major hurdles in developing new drugs is the identification of fungal-specific antifungal drug targets due to highly conserved cellular machinery between fungi and humans. Here, we describe a small molecule inhibitor, 4456dh, of the trehalose biosynthesis pathway. This pathway is present in fungi but not in humans. Trehalose plays a critical role in stress responses such as thermotolerance in fungal pathogens and is essential for their virulence. We show that treatment with 4456dh blocks the production of trehalose and renders fungal cells inviable. Thus far, 4456dh is active against two fungal pathogens of critical importance, suggesting broad-spectrum activity.

Background Prostate-specific membrane antigen (PSMA) is an established target for the imaging and treatment of prostate cancer. This study focused on the preclinical evaluation of three novel PSMA inhibitors—P15, P16, and P19—which were structurally modified compared to the clinically used PSMA-617. Two main strategies were pursued: a chemical approach following the so-called reversed synthetic strategy, and the replacement of the naphthyl-based linker moiety with an analogous diphenyl-based moiety. The aim was to assess the impact of these modifications on physicochemical properties, in vitro behaviour, and in vivo pharmacokinetics following radiolabelling with ⁶⁸Ga. Results Radiolabelling of all three novel compounds with ⁶⁸Ga resulted in high radiochemical purity above 98% under physiological pH conditions and above 97% during stability testing in human plasma. All compounds exhibited hydrophilic characteristics based on partition coefficient measurements. Notable differences were observed in plasma protein binding, with P15 and P16 showing significantly lower binding compared to PSMA-617 and P19. In vitro assays using LNCaP prostate cancer cells demonstrated similar cellular uptake and internalization across all tested compounds. In vivo evaluation using Positron Emission Tomography/Computed Tomography (PET/CT) imaging in LNCaP tumour-bearing mice confirmed the tumour-targeting ability of all three inhibitors. These findings were further supported by biodistribution studies, which highlighted efficient and specific accumulation in tumour tissue. Among the tested compounds, P19 demonstrated the most promising overall profile in terms of stability, binding characteristics, and tumour uptake. Conclusions The stereochemical modifications in the linker region significantly influenced the in vitro and in vivo behaviour of the PSMA inhibitors. Despite similar cellular uptake, differences in plasma protein binding and pharmacokinetics were evident. Among the three novel compounds, P19 emerged as a particularly promising candidate for further investigation, also indicating that the diphenyl moiety might serve as a favourable linker building block in analogy to the naphthyl moiety. Our observations suggest potential not only for diagnostic imaging with ⁶⁸Ga, but also for therapeutic applications using 177 Lu, which offers a longer half-life suitable for delayed imaging and treatment intervals in prostate cancer management.

ObjectiveTo estimate the effects of Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), other biologic(b) or conventional synthetic(cs) disease-modifying antirheumatic drugs (DMARDs) on the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA).MethodsCohort study analysing episodes of DMARD-treatment initiated between January 2017 and April 2022 in the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy. Incidence rates (IRs) per 100 patient-years with 95% CIs were calculated for overall patients and those with cardiovascular risk (age ≥50 years and ≥1 cardiovascular risk factor). MACE risk was estimated as HRs by inverse probability of treatment weight-adjusted Andersen-Gill models.ResultsA total of 154 MACE occurred among 14 203 treatment episodes (21 218 patient-years). IRs were 0.68 (0.47; 0.95), 0.62 (0.45; 0.83), 0.76 (0.53; 1.06) and 0.95 (0.68; 1.29) for JAKi, TNFi, bDMARDs and csDMARDs, respectively. IRs were higher in cardiovascular risk patients. Adjusted HRs (95% CI) comparing JAKi, bDMARDs and csDMARDs with TNFi were 0.89 (0.52 to 1.52), 0.76 (0.45; to1.27) and 1.36 (0.85 to 2.19) in overall, and 0.74 (0.41 to 1.31), 0.75 (0.45 to 1.27) and 1.21 (0.74 to 1.98) in cardiovascular risk patients. HRs were not increased in patients ≥65 years, with cardiovascular history or smokers, and also not when using csDMARD as reference instead of TNFi. IRs for baricitinib, tofacitinib and upadacitinib were 0.49 (0.25 to 0.85), 0.98 (0.58 to 1.55) and 0.53 (0.15 to 1.36), respectively.ConclusionIn this German observational cohort study, MACE did not occur more frequently with JAKi compared with other DMARDs. However, individual JAKis showed different unadjusted IRs.

Activation of the complement system promotes the removal of pathogens and tissue damage products from the brain and may also be involved in neuronal cell death in neurodegenerative diseases. Here, we analyzed the expression of C1q, the initial recognition subcomponent of the classic complement cascade, in the substantia nigra pars compacta (SNc) in Parkinson disease (PD) and control cases using immunohistochemistry and in situ hybridization. Microglia were determined to be the only cells that expressed C1q in the SNc and other brain areas. In the SNc of PD cases, there was increased deposition of extracellular neuromelanin in the parenchyma, resulting from degeneration of dopaminergic neurons. Neuromelanin granules and blebs of degenerated neurons seemed to be opsonized by C1q and phagocytosed by C1q-positive microglia and macrophages in the parenchyma and in the perivascular spaces. Neuromelanin-laden C1q-positive cells were also attached to the luminal surfaces of blood vessels in the SNc in PD. Thus, we present evidence suggesting that microglia are capable of phagocytosing and clearing cellular debris of degenerating neurons from the SNc through a C1q-mediated pathway in PD.

The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clinical impact during the last years. 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this molecule represents a rather rarely used acyclic complexing agent with chemical characteristics favourably influencing the biological functionality of the PSMA inhibitor. The simple replacement of HBED-CC by the prominent radiometal chelator DOTA was shown to dramatically reduce the in vivo imaging quality of the respective 68Ga-labelled PSMA-targeted tracer proving that HBED-CC contributes intrinsically to the PSMA binding of the Glu-urea-Lys(Ahx) pharmacophore. Owing to the obvious growing clinical impact, this work aims to reflect the properties of HBED-CC as acyclic radiometal chelator and presents novel preclinical data and relevant aspects of the radiopharmaceutical production process of [68Ga]Ga-PSMA-HBED-CC.

Results from a variety of sources indicate a role for pituitary adenylate cyclase-activating polypeptide (PACAP) in light/glutamate-induced phase resetting of the circadian clock mediated by the retinohypothalamic tract (RHT). Attempts to block or remove PACAP's contribution to clock-resetting have generated phenotypes that differ in their responses to light or glutamate. For example, previous studies of circadian behaviors found that period-maintenance and early-night phase delays are intact in PACAP-null mice, yet there is a consistent deficit in behavioral phase-resetting to light stimulation in the late night. Here we report rodent stimulus-response characteristics of PACAP release from the RHT, and map these to responses of the suprachiasmatic nucleus (SCN) in intact and PACAP-deficient mouse hypothalamus with regard to phase-resetting. SCN of PACAP-null mice exhibit normal circadian rhythms in neuronal activity, but are \"blind\" to glutamate stimulating phase-advance responses in late night, although not in early night, consistent with previously reported selective lack of late-night light behavioral responsiveness of these mice. Induction of CREB phosphorylation, a hallmark of the light/glutamate response of the SCN, also is absent in SCN-containing slices from PACAP-deficient mouse hypothalamus. PACAP replacement to the SCN of PACAP-null mice restored wild-type phase-shifting of firing-rate patterns in response to glutamate applied to the SCN in late night. Likewise, SCN of wild-type mice post-orbital enucleation are unresponsive to glutamate unless PACAP also is restored. Furthermore, we demonstrate that the period of efficacy of PACAP at SCN nerve terminals corresponds to waxing of PACAP mRNA expression in ipRGCs during the night, and waning during the day. These results validate the use of PACAP-deficient mice in defining the role and specificity of PACAP as a co-transmitter with glutamate in ipRGC-RHT projections to SCN in phase advancing the SCN circadian rhythm in late night.

Seasonality is a key environmental factor that regularly promotes life history adaptation. Insects invading cold–temperate climates need to overwinter in a dormant state. We compared the role of temperature and photoperiod in dormancy induction in the laboratory, as well as winter survival and reproduction in the field and the laboratory, of 5 widespread European dung fly species (Diptera: Sepsidae) to investigate their extent of ecological differentiation and thermal adaptation. Unexpectedly, cold temperature is the primary environmental factor inducing winter dormancy, with short photoperiod playing an additional role mainly in species common at high altitudes and latitudes (Sepsis cynipsea, neocynipsea, fulgens), but not in those species also thriving in southern Europe (thoracica, punctum). All species hibernate as adults rather than juveniles. S. thoracica had very low adult winter survivorship under both (benign) laboratory and (harsh) field conditions, suggesting flexible quiescence rather than genetically fixed winter diapause, restricting their distribution towards the pole. All other species appear well suited for surviving cold, Nordic winters. Females born early in the season reproduce before winter while late-born females reproduce after winter, fulgens transitioning earliest before winter and thoracica and punctum latest; a bet-hedging strategy of reproduction during both seasons occurs rarely but is possible physiologically. Fertility patterns indicate that females can store sperm over winter. Winter dormancy induction mechanisms of European sepsids are congruent with their geographic distribution, co-defining their thermal niches. Flexible adult winter quiescence appears the easiest route for insects spreading towards the poles to evolve the necessary overwinter survival.

Background: Co-occurring posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are associated with a more severe course and worse outcome than either disorder alone. In Europe, few treatments have been evaluated for PTSD and SUD. Seeking Safety, a manualized, integrated, cognitive-behavioural treatment, has been shown to be effective in studies in the USA. Objective: To test the efficacy of Seeking Safety plus treatment as usual (TAU) in female outpatients with PTSD and SUD compared to Relapse Prevention Training (RPT) plus TAU and TAU alone. Method: In five German study centres a total of N = 343 women were randomized into one of the three study conditions. PTSD severity (primary outcome), substance use, depression and emotion dysregulation (secondary outcomes) were assessed at baseline, post-treatment, as well as at three months and six months post-treatment. Results: Treatment participants attended M = 6.6 sessions (Seeking Safety) and M = 6.1 sessions (RPT). In an intent-to-treat analysis, Seeking Safety plus TAU, RPT plus TAU and TAU alone showed comparable decreases in PTSD severity over the course of the study. Seeking Safety plus TAU showed superior efficacy to TAU alone on depression and emotion regulation and RPT plus TAU was more effective than TAU alone on number of substance-free days and alcohol severity. Minimum-dose analyses suggest additional effects of both programmes among participants who attended at least eight group sessions. Conclusions: With respect to PTSD symptoms, a brief dose of Seeking Safety and RPT in addition to TAU was not superior to TAU alone in women with PTSD and SUD. However, Seeking Safety and RPT showed greater reductions than TAU alone in other domains of psychopathology and substance use outcomes respectively. Future studies should investigate further variables, such as what aspects of each treatment appeal to particular patients and how best to disseminate them.