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The most essential trademark function is the origin function, which should enable a person to distinguish the goods and services of one undertaking from those of another. For undertakings there is a likewise evident need to make their own product range distinguishable and identifiable. For this purpose, item names are quite common and certainly catchier than item numbers, since long and random sequences of numbers tend to be difficult to remember. However, conflicts may arise where the item name corresponds with a trademark. In Germany, the Federal Supreme Court issued in 2019 two decisions on item names, SAM (case No. I ZR 195/17) and Damen Hose MO (case No. I ZR 108/18), where it was clarified that the assumption of trademark use is not self-evident. This article discusses whether and how this recent German case law still fits in with EU trademark law and which conclusions can be drawn for item names on an EU-wide scale.

Limited therapies exist for neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN). For this reason, the activity of vinblastine (VBL) and methotrexate (MTX) was evaluated in children and young adults with NF1 and PN. Patients ≤ 25 years of age with progressive and/or inoperable NF1-PN received VBL 6 mg/m2 and MTX 30 mg/m2 weekly for 26 weeks, followed by every 2 weeks for 26 weeks. Objective response rate was the primary endpoint. Of 25 participants enrolled, 23 were evaluable. The median age of participants was 6.6 years (range 0.3–20.7). The most frequent toxicities were neutropenia and elevation of transaminases. On two-dimensional (2D) imaging, 20 participants (87%) had stable tumor, with a median time to progression of 41.5 months (95% confidence interval 16.9, 64.9). Two of eight participants (25%) with airway involvement demonstrated functional improvements including decreased positive pressure requirements and apnea-hypopnea index. A post hoc three-dimensional (3D) analysis of PN volumes was completed on 15 participants with amenable imaging; 7 participants (46%) had progressive disease on or by the end of therapy. VBL/MTX was well-tolerated but did not result in objective volumetric response. Furthermore, 3D volumetric analysis highlighted the lack of sensitivity of 2D imaging for PN response evaluation.

Background: Access to pediatric specialty care is a challenge, particularly for medically underserved populations. Introduction: One evolving method that has shown promise in helping ameliorate this disparity is electronic consultations (e-consults). Materials and Methods: This retrospective cohort study compared two groups: patients referred to pediatric cardiology, endocrinology, or pulmonology from a Federally-Qualified Health Center 10 months before the implementation of an evidence-based care pathway and those referred in the 10 months after implementation. The care pathway included evidence-based referral guidelines for common pediatric diagnoses and an e-consult process. Data included patient demographics, dates of referral requests, appointment dates, e-consult response dates and times, diagnosis codes, and consultants' recommendations. Results: Twenty-three percent of all referrals made postimplementation were submitted for an e-consult, with 53% preventing an unnecessary face-to-face visit. The most common reason for an e-consult was heart murmur/chest pain for cardiology, short stature for endocrinology, and asthma for pulmonology. Discussion: Providers used e-consults for nearly one-quarter of all consultations postimplementation, resulting in 17% of consultations not needing a face-to-face visit. The use of e-consults combined with evidence-based referral guidelines provided a useful tool to help front line pediatric primary care providers manage complex problems and identify those not needing to see a specialist in person. Conclusions: Evidence-based care pathways combined with e-consults can help improve access to pediatric specialty care by reducing demand for in-person visits and allowing more care to be delivered in primary care.

In the hippocampal CA1 area, the GABAergic trilaminar cells have their axon distributed locally in three layers and also innervate the subiculum. Trilaminar cells have a high level of somato-dendritic muscarinic M2 acetylcholine receptor, lack somatostatin expression and their presynaptic inputs are enriched in mGluR8a. But the origin of their inputs and their behaviour-dependent activity remain to be characterised. Here we demonstrate that (1) GABAergic neurons with the molecular features of trilaminar cells are present in CA1 and CA3 in both rats and mice. (2) Trilaminar cells receive mGluR8a-enriched GABAergic inputs, e.g. from the medial septum, which are probably susceptible to hetero-synaptic modulation of neurotransmitter release by group III mGluRs. (3) An electron microscopic analysis identifies trilaminar cell output synapses with specialised postsynaptic densities and a strong bias towards interneurons as targets, including parvalbumin-expressing cells in the CA1 area. (4) Recordings in freely moving rats revealed the network state-dependent segregation of trilaminar cell activity, with reduced firing during movement, but substantial increase in activity with prolonged burst firing (> 200 Hz) during slow wave sleep. We predict that the behaviour-dependent temporal dynamics of trilaminar cell firing are regulated by their specialised inhibitory inputs. Trilaminar cells might support glutamatergic principal cells by disinhibition and mediate the binding of neuronal assemblies between the hippocampus and the subiculum via the transient inhibition of local interneurons. Electronic supplementary material The online version of this article (10.1007/s00429-020-02029-2) contains supplementary material, which is available to authorized users.

Eine Marke ist mehr als nur ein betrieblicher Herkunftshinweis: Angereichert mit einem bestimmten Markenimage, hat sich die Marke zu einem wirksamen Werbeträger entwickelt. Doch sind deshalb auch solche Sachverhalte dem Markenrecht zuzuordnen, wenn die Marke nur in dieser Eigenschaft betroffen ist? Diese Arbeit untersucht, ob sich der funktionsorientierte Benutzungsbegriff und die Öffnung zugunsten der weiteren Markenfunktionen noch in das derzeitige Markenrecht einfügen. Hierbei wird u.a. erörtert, inwiefern die Herkunftsfunktion weiterhin als das die Eigenart der Marke konstitutiv bestimmende Merkmal im Markenrecht verankert ist. Alternativ könnten Zeichenverwendungen jenseits der Herkunftsfunktion über das Wettbewerbsrecht erfasst werden.

Background: In the development of indacaterol (IND)/glycopyrronium/mometasone FDC for asthma, the maleate salt of IND was replaced by acetate to avoid post-inhalation cough. We investigated lung function, PK, and safety/tolerability of the two IND salt forms in patients with asthma. Methods: This was a randomized, double-blind, three-period cross-over study. Adult asthma patients with percentage predicted pre-bronchodilator FEV1 ≥50% and ≤90% received IND maleate 150µg od, IND acetate 150µg od and placebo on top of stable background ICS in randomised sequence. Primary endpoint was trough FEV1 after 14 days of treatment. Plasma PK were assessed at steady state after 14 days, while AEs were collected throughout the study. Results: In total, 51 patients (median age, 48 yrs) completed the study. Both IND salts significantly improved lung function vs placebo (Table). Systemic exposure to IND after inhalation of IND acetate and IND maleate were comparable (Table). Both salt forms were safe and well tolerated, with considerable difference in incidence of post-inhalation cough with IND acetate (maleate, 23.5%; acetate, 0%). Conclusions: In patients with asthma, indacaterol acetate and maleate elicited comparable and significant improvements in lung function and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. Indacaterol acetate was not associated with any post-inhalation cough.

Exposure of cells to heat or oxidative stress causes misfolding of proteins. To avoid toxic protein aggregation, cells have evolved nuclear and cytosolic protein quality control (PQC) systems. In response to proteotoxic stress, cells also limit protein synthesis by triggering transient storage of mRNAs and RNA-binding proteins (RBPs) in cytosolic stress granules (SGs). We demonstrate that the SUMO-targeted ubiquitin ligase (StUbL) pathway, which is part of the nuclear proteostasis network, regulates SG dynamics. We provide evidence that inactivation of SUMO deconjugases under proteotoxic stress initiates SUMO-primed, RNF4-dependent ubiquitylation of RBPs that typically condense into SGs. Impairment of SUMO-primed ubiquitylation drastically delays SG resolution upon stress release. Importantly, the StUbL system regulates compartmentalization of an amyotrophic lateral sclerosis (ALS)-associated FUS mutant in SGs. We propose that the StUbL system functions as surveillance pathway for aggregation-prone RBPs in the nucleus, thereby linking the nuclear and cytosolic axis of proteotoxic stress response.

Summary: Signaling by the ubiquitin-related SUMO pathway relies on coordinated conjugation and deconjugation events. SUMO-specific deconjugating enzymes counterbalance SUMOylation, but comprehensive insight into their substrate specificity and regulation is missing. By characterizing SENP6, we define an N-terminal multi-SIM domain as a critical determinant in targeting SENP6 to SUMO chains. Proteomic profiling reveals a network of SENP6 functions at the crossroads of chromatin organization and DNA damage response (DDR). SENP6 acts as a SUMO eraser at telomeric and centromeric chromatin domains and determines the SUMOylation status and chromatin association of the cohesin complex. Importantly, SENP6 is part of the hPSO4/PRP19 complex that drives ATR-Chk1 activation. SENP6 deficiency impairs chromatin association of the ATR cofactor ATRIP, thereby compromising the activation of Chk1 signaling in response to aphidicolin-induced replicative stress and sensitizing cells to DNA damage. We propose a general role of SENP6 in orchestrating chromatin dynamics and genome stability networks by balancing chromatin residency of protein complexes. : SUMO isopeptidases of the SENP family counterbalance cellular SUMOylation, but their substrate specificity is largely unknown. Using in-depth proteomic profiling, Wagner et al. reveal a network of SENP6 functions at the crossroads of chromatin organization and DNA damage response and define a role of SENP6 in balancing chromatin residency of proteins. Keywords: SUMO, StUbL, SENP6, SUMO chains, cohesion, DNA damage checkpoint, ATR, Chk1, hPSO4, PRP19

GABAergic interneurons in the hippocampus provide for local and long-distance coordination of neurons in functionally connected areas. Vasoactive intestinal peptide-expressing (VIP+) interneurons occupy a distinct niche in circuitry as many of them specialize in innervating GABAergic cells, thus providing network disinhibition. In the CA1 hippocampus, VIP+ interneuron-selective cells target local interneurons. Here, we discover a type of VIP+ neuron whose axon innervates CA1 and also projects to the subiculum (VIP-LRPs). VIP-LRPs show specific molecular properties and target interneurons within the CA1 area but both interneurons and pyramidal cells within subiculum. They are interconnected through gap junctions but demonstrate sparse spike coupling in vitro. In awake mice, VIP-LRPs decrease their activity during theta-run epochs and are more active during quiet wakefulness but not coupled to sharp-wave ripples. Together, the data provide evidence for VIP interneuron molecular diversity and functional specialization in controlling cell ensembles along the hippocampo-subicular axis., Long-range GABAergic hippocampal neurons project to cortical and subcortical areas, while vasoactive intestinal peptide (VIP+) interneurons can inhibit other GABAergic neurons. Here, authors discover a VIP+, long-range projecting GABAergic neuron whose activity is associated with quiet wakefulness.

Post‐translational modifications by ubiquitin‐related SUMO modifiers regulate cellular signaling networks and protein homeostasis. While SUMO1 is mainly conjugated to proteins as a monomer, SUMO2/3 can form polymeric chains. Poly‐SUMOylation is best understood in the SUMO‐targeted ubiquitin ligase (StUbL) pathway, where chains prime proteins for subsequent ubiquitylation by StUbLs. SUMO chains typically form in response to genotoxic or proteotoxic stress and are preferentially linked via lysine 11 of SUMO2/3. Here, we report that K11 of SUMO2/3 undergoes reversible acetylation with SIRT1 being the K11 deacetylase. In a purified in vitro system, acetylation of SUMO2/3 impairs chain formation and restricts chain length. In a cellular context, however, K11 acetyl‐mimicking SUMO2 does not affect the StUbL pathway, indicating that in cells non‐canonical chains are more prevalent. MS‐based SUMO proteomics indeed identified non‐canonical chain types under basal and stress conditions. Importantly, mimicking K11 acetylation alters chain architecture by favoring K5‐ and K35‐linked chains, while inhibiting K7 and K21 linkages. These data provide insight into SUMO chain signaling and point to a role of K11 acetylation as a modulator of SUMO2/3 chains.

Summary Dogs are sometimes referred to as “man’s best friend” and with the increase in urbanization and lifestyle changes, dogs are seen by their owners as family members. Society expresses specific concerns about the experimental use of dogs, as they are sometimes perceived to have a special status for humans. This may appear somewhat conflicting with the idea that the intrinsic value of all animals is the same, and that also several other animal species are used in biomedical research and toxicology. This aspect and many others are discussed in an introductory chapter dealing with ethical considerations on the use of dogs as laboratory animals. The report gives an overview on the use of dogs in biomedical research, safety assessment and the drug developmental process and reflects the discussion on the use of dogs as second (non-rodent)species in toxicity testing. Approximately 20,000 dogs are used in scientific procedures in Europe every year, and their distinct genetic, physiological and behavioral characteristics may support their use as models for e.g. behavioral analysis and genetic research. Advances in the 3Rs (Replacement, Reduction and Refinement of experiments using dogs) are described, potential opportunities are discussed and recommendations for further progress in this area are made.

Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its major intracellular receptor, the αβ heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here, we show that oxidation-induced downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both α and β subunits. Collectively, our data establish oxidation–ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.

Agenesis of the corpus callosum (ACC) is among the most frequent human brain malformations with an incidence of 0.5-70 in 10,000. It is a heterogeneous condition, for which several different genetic causes are known, for example, ACC as part of monogenic syndromes or complex chromosomal rearrangements. We systematically evaluated the data of 172 patients with documented corpus callosum abnormalities in the records, and 23 patients with chromosomal rearrangements known to be associated with corpus callosum changes. All available neuroimaging data, including CT and MRI, were re-evaluated following a standardized protocol. Whenever feasible chromosome and subtelomere analyses as well as molecular genetic testing were performed in patients with disorders of the corpus callosum in order to identify a genetic diagnosis. Our results showed that 41 patients with complete absence (agenesis of the corpus callosum-ACC) or partial absence (dysgenesis of the corpus callosum-DCC) were identified. Out of these 28 had ACC, 13 had DCC. In 11 of the 28 patients with ACC, the following diagnoses could be established: Mowat-Wilson syndrome (n = 2), Walker-Warburg syndrome (n = 1), oro-facial-digital syndrome type 1 (n = 1), and chromosomal rearrangements (n = 7), including a patient with an apparently balanced reciprocal translocation, which led to the disruption and a predicted loss of function in the FOXG1B gene. The cause of the ACC in 17 patients remained unclear. In 2 of the 13 patients with DCC, unbalanced chromosomal rearrangements could be detected (n = 2), while the cause of DCC in 11 patients remained unclear. In our series of cases a variety of genetic causes of disorders of the corpus callosum were identified with cytogenetic anomalies representing the most common underlying etiology.

The German Federal Administrative Court recently announced an order (finalized on January 20, 2014) on the neurobiological experiments on primate brains of Prof. Kreiter at the University of Bremen. With this order, a preceding court decision by the Higher Administrative Court of Bremen was established as final and absolute and the last glimmer of hope to end the suffering of the primates in Bremen was extinguished. The court decision had claimed the experiments to be ethically justified. The Federal Administrative Court upheld the court decision and issued the order on the grounds that due to the phrasing of both the former and the current German Animal Welfare Act, authorities had no entitlement to assess the ethical justification of an experiment, but were obliged to approve an application if all formalities were complied with. The impact the order will have on the authorization of animal experiments and testing in Germany caused an outrage in the animal welfare community.

European Union (EU) legislation on the protection of animals used for scientific purposes requires that alternative methods must be used instead of animal tests wherever they are available. Unfortunately, this provision is not implemented to its full extent when it comes to risk assessment of chemicals and new products prior to their authorization and placing on the market in the EU. In this study, we screened data requirements of relevant EU law regarding chemicals (REACH), biocides, pesticides, and food safety (Novel Food) and found that data requirements as part of the risk assessment do not always reflect state-of-the-art science and technology. Most of the data requirements we investigated still include testing on animals for many toxicological endpoints, even though more than 40 alternative testing methods accepted at the level of the EU or the OECD are available. This may be due to a multitude of reasons, including a shortage of both manpower to implement existing knowledge and expertise in the field of alternative methods, as well as unclear and misleading statements on the applicability and state of validation of alternative methods. In conclusion, we strongly suggest a homogeneous EU-wide approach for all areas involving risk assessment of substances with the goal of better implementing the 3Rs and complying with Directive 2010/63/EU. This also would streamline data requirements, save costs on various levels, and enhance product safety for consumers.

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the major cytosolic receptor for NO, catalyzing the conversion of GTP to cGMP. In a search for proteins specifically interacting with human sGC, we have identified the multidomain protein AGAP1, the prototype of an ArfGAP protein with a GTPase-like domain, Ankyrin repeats, and a pleckstrin homology domain. AGAP1 binds through its carboxyl terminal portion to both the α1 and β1 subunits of sGC. We demonstrate that AGAP1 mRNA and protein are co-expressed with sGC in human, murine, and rat cells and tissues and that the two proteins interact in vitro and in vivo. We also show that AGAP1 is prone to tyrosine phosphorylation by Src-like kinases and that tyrosine phosphorylation potently increases the interaction between AGAP1 and sGC, indicating that complex formation is modulated by reversible phosphorylation. Our findings may hint to a potential role of AGAP1 in integrating signals from Arf, NO/cGMP, and tyrosine kinase signaling pathways.