Combinatorial functions of two chimeric antibodies directed to human CD4 and one directed to the a-chain of the human interleukin-2 receptor

The general feasibility of chimerization of monoclonal antibodies (mAbs) has already been shown for a large number of them. In order to evaluate in vitro parameters relevant to immunosuppressive therapy, we have chimerized and synthesized two anti-CD4 mAbs recognizing two different epitopes on the human T-lymphocyte antigen, CD4. The chimerized mAbs are produced at levels corresponding to those of the original hybridoma cell lines. With respect to activation of human complement, the individual Abs are negative; however, when used in combination, complement activation was performed. When applied in combination, they were found to modulate the CD4 antigen, whereas the individual mAb do not display this property. Individually they mediate an up to 60% inhibition of the mixed lymphocyte reaction (MLR). However, by combination of an anti-CD4 mAb with one directed against the a-chain of the human IL2 receptor, nearly 100% inhibition of the MLR was achieved, even with reduced dosage of the mAbs. Our data suggest that the combination of an anti-CD4 mAb and an anti-IL2Rcc chain mAb is more effective with respect to immunosuppression than each mAb by itself, indicating that this mAb cocktail could be a new strategy for immunosuppressive therapy

LST1 promotes the assembly of a molecular machinery responsible for tunneling nanotube formation

Carefully orchestrated intercellular communication is an essential prerequisite for the development of multicellular organisms. In recent years, tunneling nanotubes (TNT) have emerged as a novel and widespread mechanism of cell-cell communication. However, the molecular basis of their formation is still poorly understood. In the present study we report that the transmembrane MHC class III protein LST1 induces the formation of functional nanotubes and is required for endogenous nanotube generation. Mechanistically, we found LST1 to induce nanotube formation by recruiting the small GTPase RalA to the plasma membrane and promoting its interaction with the exocyst complex. Furthermore, we determined LST1 to recruit the actin-crosslinking protein filamin to the plasma membrane and to interact with M-Sec, myosin and myoferlin. These results allow us to suggest a molecular model for nanotube generation. In this proposal LST1 functions as a membrane scaffold mediating the assembly of a multimolecular complex, which controls the formation of functional nanotubes

Status of earthquake monitoring in Schleswig-Holstein and Mecklenburg-Western Pommerania: Annual report 2024

Das seismologische Stationsnetz in Schleswig-Holstein und Mecklenburg-Vorpommern bestand im Jahr 2024 aus 17 seismologischen Stationen sowie regionalen Netzen auf Helgoland, um Bad Segeberg, auf Rügen und im Raum Lubmin mit 20 weiteren Stationen. Auf dem Darß und an der Schleimünde wurden zu Testzwecken neue Stationen eingerichtet. Wartungs- und Reparaturarbeiten umfassten u.a. die Neueinrichtung der Station Büsum als Bohrlochstation und die Inbetriebnahme einer Raspberryshake Station am Botanischen Garten der Uni Kiel. In MV wurde die Verstetigung der Station Liddow auf Rügen sowie der angestrebte Bau einer Bohrlochstation auf der Greifswalder Oie weiterfolgt. Der seismische Ereigniskatalog 2024 für SH und MV umfasst 577 manuell ausgewertete Ereignisse. Ein Ereignis in der Kadetrinne nördlich von Rostock, ist mit hoher Wahrscheinlichkeit als Explosion einzustufen. Neben tektonischen Ereignissen im Bereich der Tornquist Zone, der zentralen Nordsee und den Gasfördergebieten in Niedersachsen und den Niederlanden, enthält der Katalog vor allem Sprengereignisse in Südschweden sowie im Norden Sachsen-Anhalts. Vier Ereignisse aus den Jahren 2023 und 2024 im Bereich der deutsch-dänischen AWZ Grenze in der Nordsee konnten bisher nicht zweifelsfrei einer natürlichen oder anthropogenen Quelle zugeordnet werden. Eine Bewertung von Hydrofondaten aus der Quellregion unterstützt eine Interpretation als tektonisches Ereignis in der oberen Kruste. Ein Vergleich des deutschen und dänischen Katalogs seismischer Ereignisse in der südwestlichen Ostsee zeigte zum Teil erhebliche Inkonsistenzen in der Lokalisierung und/oder Bewertung des Quelltyps seismischer Ereignisse. Für Ereignisse im Zeitraum 1992-2023 wurden seismische Wellenformen qualitativ neu bewertet und Korrekturen in der Quellbewertung sowie Unsicherheiten in der Lokalisierung diskutiert.In 2024, the seismological station network in Schleswig-Holstein and Mecklenburg-Western Pomerania consisted of 17 seismological stations as well as regional networks on Heligoland, around Bad Segeberg, on Rügen and in the Lubmin area with 20 additional stations. New stations were set up on the Darß and at Schleimünde for test purposes. Maintenance and repair work included the new installation of the Büsum station as a borehole station and the commissioning of a raspberry shake station at the Botanical Garden of Kiel University. In MV, the stabilization of the Liddow station on Rügen and the planned construction of a borehole station on Greifswalder Oie were pursued. The 2024 seismic event catalog for SH and MV comprises 577 manually evaluated events. One event in the Kadet Trough north of Rostock is highly likely to be classified as an explosion. In addition to tectonic events in the Tornquist Zone, the central North Sea and the gas production areas in Lower Saxony and the Netherlands, the catalog mainly contains blast events in southern Sweden and northern Saxony-Anhalt. Four events from 2023 and 2024 in the area of the German-Danish EEZ border in the North Sea could not yet be unequivocally attributed to a natural or anthropogenic source. An evaluation of hydrophone data from the source region supports an interpretation as a tectonic event in the upper crust. A comparison of the German and Danish catalogs of seismic events in the southwestern Baltic Sea showed considerable inconsistencies in the localization and/or evaluation of the source type of seismic events. For events in the period 1992-2023, seismic waveforms were qualitatively re-evaluated and corrections in the source evaluation as well as uncertainties in the localization were discussed

Body Dysmorphic Symptoms in Youth with Obsessive-compulsive Disorder: Prevalence, Clinical Correlates, and Cognitive Behavioral Therapy Outcome

The aims of the study were to estimate the prevalence of body dysmorphic symptoms in a sample of children and adolescents with obsessive-compulsive disorder, possible clinical correlates and whether BDD symptoms predict poorer treatment outcomes after cognitive behavioral therapy. The study included 269 children and adolescents with OCD, aged 7–17 years, from Denmark, Sweden, and Norway, who were treated with 14 weekly sessions of manualized, exposure-based CBT. Twenty-one patients (7.8%) had BDD symptoms. BDD symptoms were associated with older age (p = 0.003) and a higher prevalence of comorbid anxiety disorders (p = 0.025). In addition, patients with BDD symptoms endorsed a greater number of OCD symptoms than did those without BDD symptoms. Having symptoms of BDD did not affect the CBT outcome on OCD. The results of the study suggest that CBT for OCD is equally effective for those with and without comorbid BDD symptoms.acceptedVersio

Remission and Relapse Across Three Years in Pediatric Obsessive-Compulsive Disorder Following Evidence-Based Treatments

Objective: To examine relapse rates following remission in a 3-year follow-up study in pediatric patients with obsessive-compulsive disorder (OCD) treated with cognitive–behavioral therapy (CBT) in a first step, and either continued CBT or sertraline (randomized selection) in a second step. Method: Participants (N ¼ 269) fulfilled DSM-IV OCD criteria with a mean severity on the Children’s Yale–Brown Obsessive Compulsive Scale (CY-BOCS) of 24.6 (SD ¼ 5.1) and were included in analyses according to intent-to-treat principles. CBT used manualized exposure and response prevention (ERP) during both steps 1 and 2, and step 2 sertraline medication used flexible dosing. The follow-up schedules were timed to 6, 12, 24, and 36 months following step 1 CBT. Remission was defined as a CY-BOCS score 10 and relapse as an elevated CY-BOCS score 16 in those who had remitted. Results: A good third of our patients were in stable and full remission at all examinations (n ¼ 98, 36.4%). Further, some in remission following treatment (n ¼ 36, 13.4%) had mild OCD at some examinations. Relapses during follow-up were not uncommon (n ¼ 28, 10.4%), but in many patients these improved again (n ¼ 10, 3.7%) and were in remission at the final 3-year follow-up. Furthermore, a considerable proportion (n ¼ 50, 18.6%) of the patients were initial non-remitters to the treatment but achieved remission at some point during the follow-up. In addition, 11.5% (n ¼ 31) had persistent OCD but reached remission by the last follow-up. Finally, a smaller segment of our sample (9.7%, n ¼ 26), did not attain remission at any point during the study. Conclusion: Our outcome paints a more promising picture of pediatric OCD long-term outcome than previous studies have done. However, both relapse rates and the presence of initial non-remitters and persistent OCD show that treatments need improvement, particularly for those who respond slowly, partially, or not at all. The lack of a general psychiatric interview at follow-up is a marked limitation. Clinical trial registration information: Nordic Long-term Obsessive compulsive disorder (OCD) Treatment Study; https://www.isrctn.com; ISRCTN66385119 Key words: obsessive-compulsive disorder; cognitive-behavioral therapy; serotonin re-uptake inhibitor; stepped care; relapseRemission and Relapse Across Three Years in Pediatric Obsessive-Compulsive Disorder Following Evidence-Based TreatmentspublishedVersio

Dynamic vulnerability revealed in the collapse of an Arctic tidewater glacier

Abstract Glacier flow instabilities can rapidly increase sea level through enhanced ice discharge. Surge-type glacier accelerations often occur with a decadal to centennial cyclicity suggesting internal mechanisms responsible. Recently, many surging tidewater glaciers around the Arctic Barents Sea region question whether external forces such as climate can trigger dynamic instabilities. Here, we identify a mechanism in which climate change can instigate surges of Arctic tidewater glaciers. Using satellite and seismic remote sensing observations combined with three-dimensional thermo-mechanical modeling of the January 2009 collapse of the Nathorst Glacier System (NGS) in Svalbard, we show that an underlying condition for instability was basal freezing and associated friction increase under the glacier tongue. In contrast, continued basal sliding further upstream increased driving stresses until eventual and sudden till failure under the tongue. The instability propagated rapidly up-glacier, mobilizing the entire 450 km2 glacier basin over a few days as the till entered an unstable friction regime. Enhanced mass loss during and after the collapse (5–7 fold compared to pre-collapse mass losses) combined with regionally rising equilibrium line altitudes strongly limit mass replenishment of the glacier, suggesting irreversible consequences. Climate plays a paradoxical role as cold glacier thinning and retreat promote basal freezing which increases friction at the tongue by stabilizing an efficient basal drainage system. However, with some of the most intense atmospheric warming on Earth occurring in the Arctic, increased melt water can reduce till strength under tidewater glacier tongues to orchestrate a temporal clustering of surges at decadal timescales, such as those observed in Svalbard at the end of the Little Ice Age. Consequently, basal terminus freezing promotes a dynamic vulnerability to climate change that may be present in many Arctic tidewater glaciers

Sexual obsessions in children and adolescents : Prevalence, clinical correlates, response to cognitive-behavior therapy and long-term follow up

No funding was received for this study. Publisher Copyright: © 2022 The AuthorsSexual obsessions occur in pediatric and adult OCD including thoughts about sexual acts with family members, sexually inappropriate behavior, or homosexual orientation. They may remain undiagnosed because of embarrassment to report thoughts that are perceived as unacceptable. Prevalence studies of sexual obsessions in pediatric populations are rare. The present study investigated prevalence of sexual obsessions and treatment outcome compared to youth with OCD without sexual obsessions in a large sample. Sexual obsessions and OCD severity were assessed with the Children's Yale-Brown Obsessive- Compulsive Scale in all 269 participants of the Nordic Longterm OCD Treatment study (mean age 12.8 years, 48.7% boys) at baseline, after treatment and three years follow-up. Treatment consisted in individual manualized CBT with exposure and response prevention. Patients with and without sexual obsessions were compared on clinical characteristics and treatment outcomes. Sexual obsessions were reported by 18%, those with sexual obsessions were slightly older (13.5 versus 12.7 years). Both groups had no difference in treatment outcome, suggesting that if addressed, the response to CBT is similar in sexual, as in other obsessions. Clinicians need to be aware that children may need help to disclose and to identify these thoughts as obsessions to address them in treatment.Peer reviewe

LST1 promotes the assembly of a molecular machinery responsible for tunneling nanotube formation

Carefully orchestrated intercellular communication is an essential prerequisite for the development of multicellular organisms. In recent years, tunneling nanotubes (TNT) have emerged as a novel and widespread mechanism of cell-cell communication. However, the molecular basis of their formation is still poorly understood. In the present study we report that the transmembrane MHC class III protein LST1 induces the formation of functional nanotubes and is required for endogenous nanotube generation. Mechanistically, we found LST1 to induce nanotube formation by recruiting the small GTPase RalA to the plasma membrane and promoting its interaction with the exocyst complex. Furthermore, we determined LST1 to recruit the actin-crosslinking protein filamin to the plasma membrane and to interact with M-Sec, myosin and myoferlin. These results allow us to suggest a molecular model for nanotube generation. In this proposal LST1 functions as a membrane scaffold mediating the assembly of a multimolecular complex, which controls the formation of functional nanotubes

The Slab Puzzle of the Alpine‐Mediterranean Region: Insights from a new, High‐Resolution, Shear‐Wave Velocity Model of the Upper Mantle

Mediterranean tectonics since the Lower Cretaceous has been characterized by a multi‐phase subduction and collision history with temporally and spatially‐variable, small‐scale plate configurations. A new shear‐wave velocity model of the Mediterranean upper mantle (MeRE2020), constrained by a very large set of over 200,000 broadband (8‐350 s), inter‐station, Rayleigh‐wave, phase‐velocity curves, illuminates the complex structure and fragmentation of the subducting slabs. Phase‐velocity maps computed using these measurements were inverted for depth‐dependent, shear‐wave velocities using a stochastic particle‐swarm‐optimization algorithm (PSO). The resulting three‐dimensional (3‐D) model makes possible an inventory of slab segments across the Mediterranean. Fourteen slab segments of 200‐800 km length along‐strike are identified. We distinguish three categories of subducted slabs: attached slabs reaching down to the bottom of the model; shallow slabs of shorter length in down‐dip direction, terminating shallower than 300 km depth; and detached slab segments. The location of slab segments are consistent with and validated by the intermediate‐depth seismicity, where it is present. The new high‐resolution tomography demonstrates the intricate relationships between slab fragmentation and the evolution of the relatively small and highly curved subduction zones and collisional orogens characteristic of the Mediterranean realm

Internet-based psychotherapy in children with obsessive-compulsive disorder (OCD): protocol of a randomized controlled trial

Background: Obsessive-compulsive disorder (OCD) in children can lead to a huge burden on the concerned patients and their family members. While successful state-of-the art cognitive behavioral interventions exist, there is still a lack of available experts for treatment at home, where most symptoms manifest. Internet-based cognitive behavioral therapy (iCBT) could overcome these restrictions; however, studies about iCBT in children with OCD are rare and mostly target computerized self-help resources and only email contact with the therapist. Therefore, we intended to build up and to evaluate an iCBT approach for children with OCD, replacing successful elements of traditional in-office face-to-face CBT, with face-to-face teleconferences, online materials, and apps. Methods: With the help of a pilot feasibility study, we developed the iCBT consisting of 14 teleconference sessions with the child and parents. The sessions are supported by an app assessing daily and weekly symptoms and treatment course completed by children and parents. Additionally, we obtain heart rate and activity scores from the child via wristbands during several days and exposure sessions. Using a waiting list randomized control trial design, we aim to treat and analyze 20 children with OCD immediately after a diagnostic session whereas the control group of another set of 20 OCD patients will be treated after waiting period of 16 weeks. We will recruit 30 patients in each group to take account for potential dropouts. Outcomes for the treatment group are evaluated before randomization (baseline, t0), 16 weeks (end of treatment, t1), 32 weeks (follow-up 1, t2), and 48 weeks after randomization (follow-up 2, t3). For the waiting list group, outcomes are measured before the first randomization (baseline), at 16 weeks (waiting list period), 32 weeks (end of treatment), 48 weeks after the first randomization (follow-up I), and 64 weeks after the first randomization (follow-up II). Discussion: Based on our experience of feasibility during the pilot study, we were able to develop the iCBT approach and the current study will investigate treatment effectiveness. Building up an iCBT approach, resembling traditional in-office face-to-face therapy, may ensure the achievement of well-known therapy effect factors, the acceptance in both patients and clinicians, and the wide distribution within the health system. Trial registration: ClinicalTrials.gov NCT05037344 . Registered May 2019, last release August 13th, 2021