Search

Članek predstavlja priporočila za obravnavo bolnikov z rinitisom v Sloveniji. Predstavljeno je zdravljenje alergijskega in nealergijskega rinitisa ter rinosinuzitisa z nosnimi polipi ali brez njih. Obravnava tudi upravljanje z alergijami, uporabo imunoterapije z alergeni in njen učinek pri zmanjševanju simptomov. Nacionalna priporočila temeljijo na mednarodnih smernicah in priporočilih in ponujajo celovit pregled farmakoloških in nefarmakoloških možnosti zdravljenja teh stanj. Članek poudarja pomen kliničnega odločanja, sodelovanja bolnika in zdravstvenih delavcev na vseh ravneh in rednega spremljanja. Nacionalna priporočila si prizadevajo podpreti strokovnjake na vseh ravneh pri zagotavljanju z dokazi utemeljene oskrbe bolnikov z rinitisom in z njim povezanimi stanji.

Abstract Migraine is a disabling neurovascular disorder among people of all ages, with the highest prevalence in the fertile years, and in women. Migraine impacts the quality of life of affected individuals tremendously and, in addition, it is associated with highly prevalent metabolic diseases, such as obesity, diabetes mellitus and thyroid dysfunction. Also, the clinical response to drugs might be affected in patients with metabolic disease due to body composition and metabolic change. Therefore, the efficacy of antimigraine drugs could be altered in patients with both migraine and metabolic disease. However, knowledge of the pharmacology and the related clinical effects of antimigraine drugs in patients with metabolic disease are limited. Therefore, and given the clinical relevance, this article provides a comprehensive overview of the current research and hypotheses related to the influence of metabolic state and body composition on the action of antimigraine drugs. In addition, the influence of antimigraine drugs on metabolic functioning and, vice versa, the influence of metabolic diseases and its hormonal modulating medication on migraine activity is outlined. Future exploration on personalizing migraine treatment to individual characteristics is necessary to enhance therapeutic strategies, especially given its increasing significance in recent decades.

Innovation management is an essential prerequisite for the effective and efficient generation, planning, and implementation of ideas and thus for the further development of companies in a dynamic market and competitive environment. In order to investigate the internal innovation potential of production and service companies, this article examines basic success factors and challenges of innovation management in German small and medium-sized enterprises (SMEs) with a view to the sector to which they belong. On the basis of a questionnaire and interviews with experts, companies were considered with regard to their assessment of their innovative capacity. Based on an analysis of data from 30 participants, we show that the innovation capacity of SMEs with regard to success factors and challenges in production companies differs significantly from that of service companies. We also find that there is a discrepancy in the assessment of the potential for improvement of success factors and challenges. Our study shows that in the field of German SMEs, there is no “best way” to increase innovative capacity, but it depends on a combination of different factors.

Abstract Large high pressure die castings (HPDC), recently referred to as mega-castings, can replace plenty of steel metal sheets usually employed for body-in-white (BIW) structures. They can save manufacturing expense and unleash additional lightweight potential thanks to additional design freedom and material properties. The BIW plays a major role in automotive design since it must fulfill numerous structural targets ranging from stiffness for vehicle dynamics, dynamic responses for NVH (noise, vibration, harshness), driving comfort standards and several passive safety requirements. The use of mega-casting structures leads to additional requirements with respect to castability and material quality. Achieving a lightweight design considering requirements related to crash or castability is a challenge on its own, due to the high computational cost of related simulation techniques. Considering multiple requirements simultaneously, therefore often leads to non-weight-optimal structures. To exploit the full lightweight potential, we present a generative multidisciplinary optimization pipeline for the structural design of automotive mega-casting parts in this paper. The approach combines established methods in automotive industry such as topology optimization and response-surface-based (RSM) optimization and enhances the latter by machine learning (ML) based clustering and classification. In a first step topology optimization is employed to derive optimal load-paths for multidisciplinary loading conditions. For this purpose, casting manufacturing constraints as well as more than hundred linearized loads are used to incorporate NVH and passive safety requirements. In a next step the optimal thickness distribution and rib orientation of the structure is achieved using RSM optimization algorithms for the computationally expensive nonlinear crash and casting simulations. Performance indicators are treated by unsupervised learning based on clustering. This enables classification constraints based on simulation field results from hundreds of samples to be included into RSM optimization. It resolves a typical risk of pure scalar, regression-type targets, where supposed optimal results fail when domain experts examine the full field result of the corresponding simulation. It is shown how this approach is superior in achieving a weight-optimal design and turnaround time compared to a design workflow classically used for BIW structures.

Introducing genetic material into hard-to-transfect mammalian cell lines and primary cells is often best achieved through retroviral infection. An ideal retroviral vector should offer a compact, selectable, and screenable marker while maximizing transgene delivery capacity. However, a previously published retroviral vector featuring an EGFP/Puromycin fusion protein failed to meet these criteria in our experiments. We encountered issues such as low infection efficiency, weak EGFP fluorescence, and selection against infected cells. To address these shortcomings, we developed a novel retroviral vector based on the Moloney murine leukemia virus. This vector includes a compact bifunctional EGFP and Puromycin resistance cassette connected by a 2A peptide. Our extensively tested vector demonstrated superior EGFP expression, efficient Puromycin selection, and no growth penalty in infected cells compared with the earlier design. These benefits were consistent across multiple mammalian cell types, underscoring the versatility of our vector. In summary, our enhanced retroviral vector offers a robust solution for efficient infection, reliable detection, and effective selection in mammalian cells. Its improved performance and compact design make it an ideal choice for a wide range of applications involving precise genetic manipulation and characterization in cell-based studies.

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations.

Abstract Plant-parasitic nematodes are one of the most economically impactful pests in agriculture resulting in billions of dollars in realized annual losses worldwide. Soybean cyst nematode (SCN) is the number one biotic constraint on soybean production making it a priority for the discovery, validation and functional characterization of native plant resistance genes and genetic modes of action that can be deployed to improve soybean yield across the globe. Here, we present the discovery and functional characterization of a soybean resistance gene, GmSNAP02. We use unique bi-parental populations to fine-map the precise genomic location, and a combination of whole genome resequencing and gene fragment PCR amplifications to identify and confirm causal haplotypes. Lastly, we validate our candidate gene using CRISPR-Cas9 genome editing and observe a gain of resistance in edited plants. This demonstrates that the GmSNAP02 gene confers a unique mode of resistance to SCN through loss-of-function mutations that implicate GmSNAP02 as a nematode virulence target. We highlight the immediate impact of utilizing GmSNAP02 as a genome-editing-amenable target to diversify nematode resistance in commercially available cultivars.

Abstract Background Monoclonal antibodies (mAbs) targeting the Calcitonin Gene-Related Peptide (CGRP) pathway are safe and effective treatments for migraine prevention. However, the high cost of these novel therapies has led to reimbursement policies requiring patients to try multiple traditional preventives before access. In Germany, a recent change in insurance policy significantly expanded coverage for the CGRP receptor mAb erenumab, enabling migraine patients who failed just one prior prophylactic medication to receive this mAb. Here, we compare the clinical response to treatment with erenumab in migraine patients treated using the old and new coverage policy. Methods In this retrospective cohort study, we included CGRP-mAb naïve patients with episodic or chronic migraine, who started erenumab at our headache center according to either the old or the new insurance policy and received at least 3 consecutive injections. Headache diaries and electronic documentation were used to evaluate reductions in monthly headache and migraine days (MHD and MMD) and ≥ 50% and ≥ 30% responder rates at month 3 (weeks 9–12) of treatment. Results We included 146 patients who received erenumab according to the old policy and 63 patients that were treated using the new policy. At weeks 9–12 of treatment, 37.7% of the old policy group had a 50% or greater reduction in MHD, compared to 63.5% of the new policy group (P

Spectral imaging allows to analyze optical tissue properties that are invisible to the naked eye. Different spectral setups have been introduced in the last years to allow intraoperative image-guidance. All systems suffer from different disadvantages, such as lack of real-time capability, limited spectral coverage or low resolution. We present a novel approach using two multispectral snapshot cameras covering different spectral ranges as a stereo-system. The proposed method allows for continuous hyperspectral imaging of the surgical scene, while also enabling 3D scene reconstruction. The study demonstrates the feasibility of this approach and its potential applications in real-time monitoring and tissue identification of surgical interventions. The paper also discusses the technical challenges and future directions for improving the imaging system.

BackgroundTherapeutic options for migraine prevention in non-responders to monoclonal antibodies (mAbs) targeting Calcitonin Gene-Related Peptide (CGRP) and its receptor are often limited. Real-world data have shown that non-responders to the CGRP-receptor mAb erenumab may benefit from switching to a CGRP ligand mAb. However, it remains unclear whether, vice versa, erenumab is effective in non-responders to CGRP ligand mAbs. In this study, we aim to assess the efficacy of erenumab in patients who have previously failed a CGRP ligand mAb.MethodsThis monocentric retrospective cohort study included patients with episodic or chronic migraine in whom a non-response (< 30% reduction of monthly headache days during month 3 of treatment compared to baseline) to the CGRP ligand mAbs galcanezumab or fremanezumab led to a switch to erenumab, and who had received at least 3 administrations of erenumab. Monthly headache days were retrieved from headache diaries to assess the ≥30% responder rates and the absolute reduction of monthly headache days at 3 and 6 months of treatment with erenumab in this cohort.ResultsFrom May 2019 to July 2022, we identified 20 patients who completed 3 months of treatment with erenumab after non-response to a CGRP ligand mAb. Fourteen patients continued treatment for ≥6 months. The ≥30% responder rate was 35% at 3 months, and 45% at 6 months of treatment with erenumab, respectively. Monthly headache days were reduced from 18.6 ± 5.9 during baseline by 4.1 ± 3.1 days during month 3, and by 7.0 ± 4.8 days during month 6 compared to the month before treatment with erenumab (p < 0.001, respectively). Responders and non-responders to erenumab did not differ with respect to demographic or headache characteristics.ConclusionSwitching to erenumab in non-responders to a CGRP ligand mAb might be beneficial in a subgroup of resistant patients, with increasing responder rates after 6 months of treatment. Larger prospective studies should aim to predict which subgroup of patients benefit from a switch.

Summary: The African trypanosome survives the immune response of its mammalian host by antigenic variation of its major surface antigen (the variant surface glycoprotein or VSG). Here we describe the antibody repertoires elicited by different VSGs. We show that the repertoires are highly restricted and are directed predominantly to distinct epitopes on the surface of the VSGs. They are also highly discriminatory; minor alterations within these exposed epitopes confer antigenically distinct properties to these VSGs and elicit different repertoires. We propose that the patterned and repetitive nature of the VSG coat focuses host immunity to a restricted set of immunodominant epitopes per VSG, eliciting a highly stereotyped response, minimizing cross-reactivity between different VSGs and facilitating prolonged immune evasion through epitope variation.

Summary: Poorly immunogenic small molecules pose challenges for the production of clinically efficacious vaccines and antibodies. To address this, we generate an immunization platform derived from the immunogenic surface coat of the African trypanosome. Through sortase-based conjugation of the target molecules to the variant surface glycoprotein (VSG) of the trypanosome surface coat, we develop VSG-immunogen array by sortase tagging (VAST). VAST elicits antigen-specific memory B cells and antibodies in a murine model after deploying the poorly immunogenic molecule fentanyl as a proof of concept. We also develop a single-cell RNA sequencing (RNA-seq)-based computational method that synergizes with VAST to specifically identify memory B cell-encoded antibodies. All computationally selected antibodies bind to fentanyl with picomolar affinity. Moreover, these antibodies protect mice from fentanyl effects after passive immunization, demonstrating the ability of these two coupled technologies to elicit therapeutic antibodies to challenging immunogens.

Purpose: Anticoagulation Stewardship is urgently needed to improve anticoagulation management and bend the current, negative trajectory on anticoagulation-related harm. This manuscript catalogs the origins and the progression of the Anticoagulation Stewardship model and serves as a call to action for healthcare providers and organizations committed to improving the quality and safety of anticoagulation management. Key elements: Tens of millions of patients around the world currently require anticoagulant therapy to prevent or treat thrombotic events. Concerningly, there is a growing body of evidence confirming that increasing volume and complexity of anticoagulant use is significantly impacting the therapeutic landscape, posing major challenges to safe prescribing and management of these high-risk, yet essential therapies, and leading to increased patient harm including life-threatening bleeding and thrombotic complications across the continuum of care. In response, anticoagulation stewardship programs, modeled after highly successful antimicrobial stewardship efforts, are gaining increased traction to counteract this growing health concern. Conclusions: The current health care system is inadequate to protect patients from avoidable harms and to maximize the benefits of therapy. Apart from anticoagulation stewardship, there does not currently exist another cross-setting, multidisciplinary model for achieving maximum quality and safety for patients. If we are to collectively meet the challenge that stands before us, we must commit ourselves (as individuals and organizations) to leveraging the available resources to advance the anticoagulation stewardship model while also contributing to the burden of evidence and the effective articulation of the stewardship message.

Z dokumentom želimo smernice, ki jih predlaga GINA, vključiti v slovenski prostor. Želimo, da bi dokument služil enotnemu in dogovorjenemu pristopu k obravnavi bolnikov z astmo na primarni in specialistični pulmološki ravni.

Calcitonin gene-related peptide-targeted monoclonal antibodies (CGRP mAbs) are increasingly being used as preventive treatments for migraine. Their effectiveness and safety were established through numerous randomized placebo-controlled trials and real-world studies, yet a significant proportion of patients do not respond to this treatment, and currently, there is a lack of accepted predictors of response to guide expectations, as data from studies so far are lacking and inconsistent. We searched Embase and MEDLINE databases for studies reporting on predictors of response to CGRP and/or CGRP-receptor (CGRP-R) mAbs, defined as a 30% or 50% reduction in monthly headache or migraine days at varying durations of follow-up. Quantitative synthesis was performed where applicable. We found 38 real-world studies that investigated the association between various predictors and response rates. Based on these studies, good response to triptans and unilateral pain with or without unilateral autonomic symptoms are predictors of a good response to CGRP(-R) mAbs. Conversely, obesity, interictal allodynia, the presence of daily headaches, a higher number of non-successful previous prophylactic medications, and psychiatric comorbidities including depression are predictive of a poor response to CGRP(-R) mAbs. Future studies should confirm these results and help to generate more tailored treatment strategies in patients with migraine.

Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse spastic (spa). In spastic mice, the GlyR number is reduced due to a β subunit gene (Glrb) mutation resulting in aberrant splicing of GlyRβ transcripts. Via direct physical interaction with the GlyR anchoring protein gephyrin, this subunit is crucially involved in the postsynaptic clustering of heteromeric GlyRs. We show that the mutation differentially affects aspects of the pain-related behavior of homozygous Glrbspa/Glrbspa mice. While response latencies to noxious heat were unchanged, chemically induced pain-related behavior revealed a reduction of the licking time and an increase in flinching in spastic homozygotes during both phases of the formalin test. Mechanically induced nocifensive behavior was reduced in spastic mice, although hind paw inflammation (by zymosan) resulted in allodynia comparable to wild-type mice. Immunohistochemical staining of the spinal cord revealed a massive reduction of dotted GlyRα subunit immunoreactivity in both ventral and dorsal horns, suggesting a reduction of clustered receptors at synaptic sites. Transcripts for all GlyRα subunit variants, however, were not reduced throughout the dorsal horn of spastic mice. These findings suggest that the loss of functional GlyRβ subunits and hence synaptically localized GlyRs compromises sensory processing differentially, depending on stimulus modality.

Pobudo »Alergijski rinitis in njegov vpliv na astmo« – (angl. Allergic Rhinitis and its Impact on Asthma, ARIA) – so leta 1999 ustanovili na delavnici Svetovne zdravstvene organizacije – World Health Organization (WHO). Njeni prvotni cilji so bili: 1. predlagati novo klasifikacijo alergijskega rinitisa, 2. spodbujati koncept večobolevnosti pri astmi in rinitisu ter 3. skupaj z vsemi deležniki razviti smernice, namenjene globalni uporabi v vseh državah in vsem skupinam bolnikov. Pobuda ARIA se uporablja v 70 državah, trenutno pa se osredinja na uporabo novih tehnologij za individualizirano in napovedno medicino. Mreža MASK – nadzorna mreža MACVIA (Proti kroničnim boleznim za aktivno staranje, franc. – Contre les Maladies Chroniques pour un Vieillissement Actif) in ARIA (angl. ARIA Sentinel NetworK) uporablja mobilno tehnologijo za razvoj klinične poti, ki bi bolnikom, multidisciplinarnim ekipam zdravnikov in raziskovalcem omogočila nadzor rinitisa in astme. Mobilna aplikacija (Android in iOS) je na voljo v 20 državah in 15 jezikih. Uporablja vizualno analogno lestvico za oceno nadzora nad simptomi in oceno delovne zmožnosti in ponuja sistem, ki pomaga pri kliničnem odločanju. Aplikacija omogoča povezovanje z zdravnikom ali drugimi zdravstvenimi delavci. Ta strategija upošteva priporočila Evropskega partnerstva za inovacije za aktivno in zdravo staranje (angl. European Innovation Partnership on Active and Healthy Ageing, EIP on AHA). Cilj novega pristopa pobude ARIA je zagotoviti aktivno in zdravo življenje bolnikov z rinitisom ne glede na njihovo starost, spol ali družbenogospodarski položaj zato, da bi se zmanjšali zdravstvena in družbena neenakost, ki sta posledici te bolezni.

Summary: GABAA and glycine receptors are thought to compete for gephyrin-binding sites at mixed inhibitory synapses. Changes in the occupancy of one receptor type are therefore expected to have opposite effects on the clustering of the other receptors. This does not explain, however, whether different receptors can be regulated independently from one another. Here we show that cAMP-dependent signaling reduces gephyrin phosphorylation at residue S270 in spinal cord neurons. Although no ultrastructural changes of the synaptic scaffold were detected using super-resolution imaging, gephyrin de-phosphorylation was associated with a selective increase in GABAAR diffusion and the loss of the receptors from synapses. As opposed to the PKA-dependent dispersal of α3-containing GlyRs, the regulation of gephyrin phosphorylation and GABAAR dynamics acts via non-canonical EPAC signaling. Subtype-specific changes in receptor mobility can thus differentially contribute to changes in inhibitory synaptic strength, such as the disinhibition of spinal cord neurons during inflammatory processes. : Molecular Neuroscience; Cellular Neuroscience; Sensory Neuroscience Subject Areas: Molecular Neuroscience, Cellular Neuroscience, Sensory Neuroscience

Background: Neonatal drug-resistant epilepsy is often caused by perinatal epileptogenic insults such as stroke, ischemia, hemorrhage, and/or genetic defects. Rapid seizure control is particularly important for cognitive development. Since early surgical intervention and thus a short duration of epilepsy should lead to an optimal developmental outcome, we present our experience with hemispherotomy in an infant at the corrected age of 1 week.Methods: We report successful hemispherotomy for drug-resistant epilepsy in an infant with hemimegalencephaly at a corrected age of 1 week.Results: The infant was diagnosed with drug-resistant lesional epilepsy due to hemimegalencephaly affecting the left hemisphere. Given congruent electroclinical findings, we performed a left vertical parasagittal transventricular hemispherotomy after critical interdisciplinary discussion. No complications occurred during the surgery. Intraoperatively; 118 ml of red blood cells (30 ml/kg) and 80 ml of plasma were transfused. The patient has been seizure-free since discharge without further neurological deficits.Conclusion: We demonstrate that early epilepsy surgery is a safe procedure in very young infants if performed in a specialized center experienced with age-specific surgical conditions and perioperative management. The specific surgical difficulties should be weighed against the risk of life-long developmental drawbacks of ongoing detrimental epilepsy.

Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.

Background: Hemispherotomy is an epilepsy surgery procedure applied to cure particularly pharmacorefractory lesional epilepsy due to unihemispheric pathologies. Such a disconnection of an entire hemisphere is followed by reorganizational processes.Methods: We describe an acute aggravation of behavioral problems following a hemispherotomy in a patient treated with valproic acid, which subsided once valproate was discontinued.Results: A 9-year-old boy with drug-resistant epilepsy caused by the residua of a perinatal stroke treated for several years with valproic acid and lamotrigine underwent hemispherotomy. Shortly after surgery, minimal preoperative behavioral problems intensified dramatically, and aggression occurred as a new symptom. Assuming a correlation between valproate treatment and the postoperative altered neuronal network, we tapered off valproate. The behavioral problems decreased in intensity with the reduction of valproate dose and disappeared after drug discontinuation.Conclusion: We describe severe behavioral problems after hemispherotomy that subsided when valproate was tapered off. While we cannot rule out a spontaneous correction of a post-hemispherotomy network dysregulation, our report raises awareness to possible altered effects of the anticonvulsant valproic acid parallel to reorganizational processes after hemispherotomy.

Transmissible spongiform encephalopathies are incurable neurodegenerative diseases, associated with the conversion of the physiological prion protein to its disease-associated counterpart. Even though immunization against transmissible spongiform encephalopathies has shown great potential, immune tolerance effects impede the use of active immunization protocols for successful prophylaxis. In this study, we evaluate the use of trypanosomes as biological platforms for the presentation of a prion antigenic peptide to the host immune system. Using the engineered trypanosomes in an immunization protocol without the use of adjuvants led to the development of a humoral immune response against the prion protein in wild type mice, without the appearance of adverse reactions. The immune reaction elicited with this protocol displayed in vitro therapeutic potential and was further evaluated in a bioassay where immunized mice were partially protected in a representative murine model of prion diseases. Further studies are underway to better characterize the immune reaction and optimize the immunization protocol.

Pyramidal neurons (PNs) are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization, but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 PNs of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.

Abstract Background To assess the educational impact of a one-to-one tablet PC (TPC) program by analysing university students’ learning skills and related scores of the National Dental Examination (NDE) in Germany. Methods The study design was a mixed-method approach consisting of a survey and a comparison of NDE scores. Students received a loaned non-preloaded and non-managed TPC during three consecutive orthodontic semesters. Usability and learning benefits in clinical and nonclinical settings were assessed by a survey. After the participating students had passed the NDE in a standard period of study, their grades were compared with those of students from the semester prior to TPC introduction. Results One hundred and eight students (36 females and 72 males) received an TPC and participated in the survey. Of these, 53 passed the NDE in a standard period of study. 64 students from the semester before TPC introduction, who passed in the regular period of study, were chosen as non-TPC control group. Survey: Students’ expectations concerning TPC benefits increased significantly after TPC usage (P = 0.000). TPCs were rated more useful for learning at places outside the clinic setting than for inside (P = 0.000). PDFs and communication applications were used more in nonclinical settings (P = 0.008 and 0.000, respectively). NDE scores: Concerning the examination parts relating to theoretical knowledge and clinical knowledge, students with full TPC use achieved higher scores than did those without TPC use (P = 0.006 and 0.002, respectively). Scores for manual skills showed no differences, neither for students with and without TPC, nor within the semester after TPC introduction (P = 1.000). Conclusions This is the first study to analyse a one-to-one TPC program in the orthodontic curriculum and measure the effect of TPC usage on NDE scores. Students’ expectations concerning the TPC benefit in the orthodontic curriculum improved significantly after using the devices. We have shown that NDE scores in theoretical knowledge increased significantly after TPC deployment whereas scores in motor skills remained unchanged. The results suggest that the TPC has a positive learning effect on theoretical knowledge in orthodontics. Trial registration Permission to conduct this study was given by the Ethics Committee of the Department of Medicine of the University of Münster, Germany (2012-12-13).

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here, we show that Susd4, a gene coding for a complement-related transmembrane protein, is expressed by many neuronal populations starting at the time of synapse formation. Constitutive loss-of-function of Susd4 in the mouse impairs motor coordination adaptation and learning, prevents long-term depression at cerebellar synapses, and leads to misregulation of activity-dependent AMPA receptor subunit GluA2 degradation. We identified several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, as SUSD4 binding partners. Our findings shed light on the potential role of SUSD4 mutations in neurodevelopmental diseases.

The Armenian highlands encompasses rugged and environmentally diverse landscapes and is characterized by a mosaic of distinct ecological niches and large temperature gradients. Strong seasonal fluctuations in resource availability along topographic gradients likely prompted Pleistocene hominin groups to adapt by adjusting their mobility strategies. However, the role that elevated landscapes played in hunter-gatherer settlement systems during the Late Pleistocene (Middle Palaeolithic [MP]) remains poorly understood. At 1640 m above sea level, the MP site of Kalavan 2 (Armenia) is ideally positioned for testing hypotheses involving elevation-dependent seasonal mobility and subsistence strategies. Renewed excavations at Kalavan 2 exposed three main occupation horizons and ten additional low densities lithic and faunal assemblages. The results provide a new chronological, stratigraphical, and paleoenvironmental framework for hominin behaviors between ca. 60 to 45 ka. The evidence presented suggests that the stratified occupations at Kalavan 2 locale were repeated ephemerally most likely related to hunting in a high-elevation within the mountainous steppe landscape.