Steroid cell tumors are very rare in children. During the past 25years, only 3 cases have been reported in Germany. Symptoms may vary from virilization to signs of precocious puberty and increased growth velocity, making it diagnostically challenging. Due to rarity and the wide morphologic as well as differential diagnostic spectrum, initial clinical features may be misleading. We report on a 2-year-old girl, who initially presented with symptoms of virilization and precocious puberty, i.e.,pubertal hair growth equivalent to Tanner stage P3. Basal hormone profile yielded 10-fold increased testosterone and androstenedione as well as markedly increased estradiol levels in serum. Diagnostic imaging procedures (ultrasound, MRI of the abdomen) revealed a solid tumor in the left ovary, without any signs of peritoneal dissemination or metastases. After salpingo-oophrectomy of the left ovary (en bloc via laparoscopic surgery, without spillage), the diagnosis of an ovarian steroid cell tumor sized 40×25×22 mm producing both testosterone and estradiol was confirmed. The increased serum levels of androgens as well as estradiol decreased toward prepubertal values within 1week after surgery. Hormone-active steroid cell tumors of the ovary are extremely rare in infancy. In our patient, the tumor was classified as clinical stage Ia. We thus opted for clinical, biochemical, and sonographical controls without chemotherapy. We herein present follow-up data until 18months after surgery and discuss them within the context of international literature.

Histone deacetylases (HDACs) play a pivotal role in variousbiologicalpathways and represent interesting drug targets. Therefore, HDAC inhibitors(HDACi) with high isoform selectivity and a zinc-binding group differentfrom hydroxamic acid, because of its low metabolic stability, arerequired. HDAC11, as a highly potent defatty-acylase, differs fromother HDACs in its substrate preference. Starting from this finding,we developed specific inhibitors for HDAC11 based on a peptide containinga fatty-acylated lysine side chain as the selectivity tail. The introductionof different heteroatoms at the fatty acyl residue was used to generatepotent zinc-binding groups in combination with the scissile amidebond, as well as to suppress substrate properties of the resultingcompounds. Further optimization resulted in a highly potent and selectiveHDAC11 inhibitor 31, which exhibits low nanomolar inhibitionagainst HDAC11 without targeting other HDACs and is active in cells.The data presented here may help expand the range of zinc-bindinggroups utilized in HDAC inhibitors. Furthermore, the concept of theselectivity tail was demonstrated to facilitate straightforward accessto selective defatty-acylase inhibitors.

Health economic methods can support the development and evaluation of new healthcare interventions by generating data on the resources used and relating these to a defined benefit. However, the standard methodology of health economic evaluation that is usually used does not do justice to the high degree of complexity of interventions in healthcare. As a result, there is a lack of decision-relevant information, for example, on the preferences of the target group, on spillover effects on the part of carers, or on implementation costs and the role of different contexts in the implementation of interventions into routine care. The UK Medical Research Council's (MRC) standard-setting framework for complex interventions therefore emphasises the need to incorporate health economic aspects more strongly into all phases of the development and evaluation of complex interventions. To make this possible, the MRC's recommendations for expanding and adapting the standard methodology of health economic evaluation must be concretised and supplemented. Building on already established methodological procedures, recommendations should be developed and proposals for necessary further research formulated.

Animal models are essential for studying tumor pathophysiology; however, most lack the capacity for repeated in vivo observation of tumor growth and vascularization over extended periods. This study aimed to establish a novel in vivo model using the mouse dorsal skinfold chamber. Tumor induction was performed using different membrane types (two polytetrafluoroethylene meshes and a polydioxanone plate), followed by monitoring of tumor vascularization via intravital fluorescence microscopy (IVM). Tumors developed successfully over six weeks, demonstrating sustained vascular supply and enabling, for the first time, the investigation of vascular networks in advanced tumors. Among the membranes tested, the polydioxanone membrane facilitated easier chamber preparation but may negatively affect angiogenesis and promote inflammation. IVM revealed persistent microcirculation in manifested tumors over six consecutive days, allowing detailed assessment of microvascular parameters, leukocyte-endothelial interactions, and functional capillary density. This model enables repetitive, high-resolution visualization of tumor microcirculation dynamics in vivo. In conclusion, this improved mouse dorsal skinfold chamber combined with IVM provides a powerful tool for investigating tumor angiogenesis and evaluating therapeutic interventions in advanced tumors.

Arylazopyrazoles (AAPs) are a rapidly emerging classof photoswitches,which stand out due to their distinct absorption maxima of the E- and Z-isomers, the highly Z- or E-isomer-rich photo stationary states upon irradiation byUV- or visible light, respectively, and the long lifetime of the metastable Z-state. Here, we present water-soluble acrylamide copolymersfunctionalized by an AAP dye. This renders them both thermo- and photoresponsiveand enables the reversible modulation of their LCST-type phase transitiontemperature (PTT) in aqueous solution by the E- toZ-isomerization. By alternating irradiation with UV and green light,the PTT is modulated effectively and can be shifted for optimizedAAP contents by up to 27 °C, i.e., much higher than by commonazobenzene photoswitches. The AAP photoswitch and the transition processof the dye-modified polymer are investigated using density functionaltheory calculations, turbidity measurements, and temperature-dependentNMR, EPR, and UV–vis spectroscopies.

Background and ObjectivesBeta-synuclein (beta-syn), synaptosomal-associated protein 25 (SNAP-25), and neurogranin are CSF biomarkers of synaptic damage, which have been poorly investigated in non-neurodegenerative neurologic diseases. In this study, we examined the diagnostic and prognostic role of these markers compared with the neuroaxonal damage marker neurofilament light chain protein (NfL) in infectious and autoimmune inflammatory neurologic diseases (IINDs and AINDs).MethodsThis cohort study included CSF samples from patients with different etiologies of IIND (varicella-zoster virus, herpes simplex virus, tick-borne meningoencephalitis, bacterial meningitis/(meningo)encephalitis, neuroborreliosis, or other/unknown etiology) or AIND (autoimmune encephalitis or other etiology) as well as controls.ResultsA total of 123 patients with IINDs (mean age 55.23 ± 18.04 years, 43.2% female), 22 with AINDs (age 60.41 ± 16.03 years, 81.8% female), and 95 controls (age 52.39 ± 17.94 years, 56.9% female) were enrolled. Compared with the control group, participants with IINDs and AINDs showed higher concentrations of beta-syn (p < 0.001 and p = 0.038, respectively), neurogranin (p = 0.039 and p = 0.002, respectively), and NfL (p < 0.001 and p = 0.001, respectively), with no differences between the 2 latter groups. Overall, synaptic markers and NfL demonstrated poor-to-moderate diagnostic accuracy in discriminating between diagnostic groups (area under the curve 0.366–0.809). All synaptic biomarkers were elevated in participants with IINDs presenting with altered mental status (beta-syn, p < 0.001; SNAP-25, p = 0.002; and neurogranin, p = 0.008), seizures (beta-syn, p = 0.013; SNAP-25, p = 0.005; and neurogranin, p = 0.004), and inflammatory changes on neuroimaging (beta-syn, p = 0.016; SNAP-25, p = 0.029; and neurogranin, p = 0.007). Participants with AINDs requiring intensive care showed higher levels of beta-syn (p = 0.033) and NfL (p = 0.002). Participants with IINDs with a poor functional status (modified Rankin Scale [mRS] scores of 3–6) exhibited higher concentrations of beta-syn (p < 0.001), SNAP-25 (p = 0.022), neurogranin (p = 0.004), and NfL (p < 0.001) compared with those with mRS scores of 0–2. Accordingly, higher levels of synaptic markers were associated with poorer short-term outcomes in patients with IINDs, but not in those with AINDs.DiscussionElevated CSF levels of beta-syn, neurogranin, and NfL may suggest a common pattern of synaptic and neuroaxonal damage in both IINDs and AINDs. Although these biomarkers have limited value in distinguishing between different diseases, they are associated with clinical severity and with short-term outcome, particularly in patients with IINDs.

The influence of high potentials on amorphous nitrogen-free and nitrogen-doped hydrogenated carbon thin film electrodes with thicknesses of 9 to 30 nm is probed toward the vanadium(IV/V) redox reaction by scanning electrochemical cell microscopy (SECCM), which mimics the reaction of the positive side of the all-vanadium redox flow battery (VRFB). Besides the evaluation of the peak separation (EPP) from cyclic voltammograms (CV), the localized probing is adapted in a way that the influence of high overpotentials on the stability of the carbon materials, as well as competitive electrochemical processes, can be analyzed. The sulfate anion insertion process is found to be the predominant process in all samples, with its onset appearing in parallel to the vanadium(IV/V) reaction. The presence of pyridine/pyrrole groups can stabilize the insertion compound, which inhibits the vanadium(IV/V) reaction much more strongly. In all cases, the electrochemical redox features of the vanadium(IV/V) reaction, as well as the initial Raman spectra of the carbon thin films, are fully reconstructed by applying reductive potentials in a suitable time frame, even after polarizing to drastically high potentials (2.5 V vs. RHE). Overall, this competing insertion reaction must be given greater consideration when discussing electrochemical data of the vanadium(IV/V) redox reaction.

Abstract The intersection of actin-filaments with the plasma membrane in plant cells involves lipid-protein interactions by the Arabidopsis class VIII-myosin, ATM2 that are currently not understood. Using pollen tube cells as a model, we describe how ATM2 enables actin-plasma membrane contacts by modulating membrane lipid nano-organization. ATM2 binds both actin and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), a lipid required for ATM2-plasma membrane-attachment. Overexpression of ATM2 unexpectedly stabilized actin-dynamics and altered pollen tube-morphology. Actin-dynamics remained unaltered upon overexpression of a lipid binding-defective ATM2-variant. ATM2-effects on actin-dynamics required PtdIns(4,5)P2, as artificial PtdIns(4,5)P2-depletion in pollen tubes abolished effects of full-length ATM2 on actin dynamics despite its retained plasma membrane-association. ATM2 colocalized and interacted with the PI4P 5-kinase, PIP5K2, which resides at actin-plasma membrane-contacts and forms PtdIns(4,5)P2-nanodomains facilitating ROP-dependent actin-stabilization. Upon ATM2-overexpression, a fluorescent PtdIns(4,5)P2-biosensor decorated an expanded plasma membrane-region in vivo, indicating a promoting effect of ATM2 on PtdIns(4,5)P2-abundance. Moreover, catalytic activity of purified recombinant PIP5K2 protein was enhanced upon coincubation with a purified C-terminal ATM2-fragment in vitro, suggesting that ATM2 contributes to the intrinsic regulation of PtdIns(4,5)P2-formation. Actin-dynamics are, thus, stabilized at the actin-plasma membrane interface by ATM2 locally promoting the formation of PtdIns(4,5)P2-nanodomains, thereby self-reinforcing ATM2-recruitment while also facilitating ROP-activation to stabilize membrane-proximal actin-filaments.