An EB1-binding motif acts as a microtubule tip localization signal.

Microtubules are filamentous polymers essential for cell viability. Microtubule plus-end tracking proteins (+TIPs) associate with growing microtubule plus ends and control microtubule dynamics and interactions with different cellular structures during cell division, migration, and morphogenesis. EB1 and its homologs are highly conserved proteins that play an important role in the targeting of +TIPs to microtubule ends, but the underlying molecular mechanism remains elusive. By using live cell experiments and in vitro reconstitution assays, we demonstrate that a short polypeptide motif, Ser-x-Ile-Pro (SxIP), is used by numerous +TIPs, including the tumor suppressor APC, the transmembrane protein STIM1, and the kinesin MCAK, for localization to microtubule tips in an EB1-dependent manner. Structural and biochemical data reveal the molecular basis of the EB1-SxIP interaction and explain its negative regulation by phosphorylation. Our findings establish a general "microtubule tip localization signal" (MtLS) and delineate a unifying mechanism for this subcellular protein targeting process.

Comparing Synchronicity in Body Movement among Jazz Musicians with Their Emotions.

This paper presents novel preliminary research that investigates the relationship between the flow of a group of jazz musicians, quantified through multi-person pose synchronization, and their collective emotions. We have developed a real-time software to calculate the physical synchronicity of team members by tracking the difference in arm, leg, and head movements using Lightweight OpenPose. We employ facial expression recognition to evaluate the musicians' collective emotions. Through correlation and regression analysis, we establish that higher levels of synchronized body and head movements correspond to lower levels of disgust, anger, sadness, and higher levels of joy among the musicians. Furthermore, we utilize 1-D CNNs to predict the collective emotions of the musicians. The model leverages 17 body synchrony keypoint vectors as features, resulting in a training accuracy of 61.47% and a test accuracy of 66.17%.

Best Practice Guideline - DEGUM Recommendations on Breast Ultrasound. / Best Practice Guideline ­ Empfehlungen der DEGUM zur Durchführung und Beurteilung der Mammasonografie ­ TEIL I ­ Untersuchungstechnik, Ultraschall-DEGUM-Kriterien und deren Dokumentation.

For many years, breast ultrasound has been used in addition to mammography as an important method for clarifying breast findings. However, differences in the interpretation of findings continue to be problematic 1 2. These differences decrease the diagnostic accuracy of ultrasound after detection of a finding and complicate interdisciplinary communication and the comparison of scientific studies 3. In 1999, the American College of Radiology (ACR) created a working group (International Expert Working Group) that developed a classification system for ultrasound examinations based on the established BI-RADS classification of mammographic findings under consideration of literature data 4. Due to differences in content, the German Society for Ultrasound in Medicine (DEGUM) published its own BI-RADS-analogue criteria catalog in 2006 3. In addition to the persistence of differences in content, there is also an issue with formal licensing with the current 5th edition of the ACR BI-RADS catalog, even though the content is recognized by the DEGUM as another system for describing and documenting findings. The goal of the Best Practice Guideline of the Breast Ultrasound Working Group of the DEGUM is to provide colleagues specialized in senology with a current catalog of ultrasound criteria and assessment categories as well as best practice recommendations for the various ultrasound modalities.

[Hidradenitis suppurativa/acne inversa in daily practice]. / Hidradenitis suppurativa/Acne inversa in der Praxis.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease, characterized by abscess formation and mutilating scar formation in the body folds. The burden of disease is high for both patient and treating physician. In dermatological daily practice, proper patient education and formation of a trustful physician-patient relationship are of highest importance. HS patients are treated both conservatively and surgically mostly by dermatologists, which requires extensive knowledge of the pathogenesis, trigger factors, comorbidities and treatment options. Interdisciplinary collaboration with other disciplines is still underdeveloped. New physical treatments (laser, radiofrequency, intense pulsed light [IPL]), topical and systemic therapies enable good ambulatory long-term management for all HS stages.

[Treatment of pigmentation disorders in association with systemic diseases]. / Therapie von Pigmentstörungen in Zusammenhang mit systemischen Erkrankungen.

Pigmentation disorders are a frequent skin problem and incorporate a broad spectrum of diseases, caused by an abnormal melanin pigmentation or also non-melanin pigmentation of the skin. Both hypermelanosis and hypomelanosis can be hereditary or acquired. This article summarizes the treatment approaches that are used in the majority of acquired pigmentation disorders of the skin. The following forms of hypermelanosis are addressed: lentiginosis, hyperpigmentation due to endocrine disorders or other systemic diseases, drug-induced hyperpigmentation. Acquired hypomelanoses include postinflammatory hypomelanosis, chemical depigmentation, idiopathic guttate hypomelanosis and punctate leucoderma. With reference to non-melanin pigmentation, the exogenous pigmentation due to chemicals, metals and drug exposure are discussed. The treatment is primarily based on finding the cause of the alterations to the pigment. The affected area, age and ethnic origin are also important factors. The spectrum of therapeutic options is broad: topical agents, chemical peeling, systemic agents, laser and light-based treatment. As some of these treatment procedures can have side effects, the availability of a protocol that contains information on the drug concentration, dose, parameters for laser treatment and the number of sessions is important. For every disorder the specific dermatological treatment is presented even when some pigmentation alterations that occur in association with systemic diseases, are cured by the treatment of the primary disease. Most diseases are exacerbated by exposure to UV light. Therefore, sun protection is recommended and a cosmetic coverage is indicated.

[The 308 nm Excimer laser : Treatment of vitiligo and hypopigmentation]. / 308 nm-Excimerlaser : Therapie von Vitiligo und Hypopigmentierungen.

Use of the 308 nm Excimer laser to treat hypopigmentation and vitiligo is usually superior to conventional ultraviolet (UV) therapy with regard to results and safety. It is particularly advantageous because specific areas of skin can be targeted without burdening the rest of the skin. Fewer sessions with lower cumulative doses are required. Various combination therapies can improve the outcome; selection criteria such as early initiation of treatment and more frequent sessions with shorter intervals make it easier to decide which patients should be treated and how to achieve the greatest benefit.

[The 308 nm Excimer laser for the treatment of psoriasis and inflammatory skin diseases]. / 308 nm-Excimerlaser zur Therapie von Psoriasis und entzündlichen Hauterkrankungen.

Overall, the 308 nm Excimer laser enables not only a more effective and safer UVB therapy than classical UV phototherapy, but also targeted irradiation in higher doses with a lower cumulative load, which results in faster healing of mainly circumscribed skin changes. This also applies to therapy-resistant residual lesions which, despite systemic therapy, did not diminish. Combination therapies usually improve the result and enable the dose of UVB and systemic medication to be reduced. Excimer laser therapy can be used for an increasing number of skin diseases, especially those that respond to phototherapy or photochemotherapy.

[Laser treatment of basal cell carcinoma]. / Lasertherapie des Basalzellkarzinoms.

With a clear increase in the incidence and a continuously earlier onset, the main risk factors for the development of basal cell carcinoma are still exposure to sunlight, fair skin, immunosuppression, carcinogens such as arsenic, chronic irritations and certain genodermatoses. Treatment options for localized resectionable basal cell carcinoma include micrographically controlled surgery, simple excision, curettage, laser ablation, cryosurgery, imiquimod, 5­fluorouracil, photodynamic treatment and radiotherapy. Non-surgical treatment options are more suited for cases in which surgical procedures lead to disfigurement or functional impairments or for patients with a high surgical risk. Laser treatment, ablative and non-ablative as monotherapy or in combination can represent a meaningful treatment option in selected cases. In recent years there has been an increase in knowledge about the indications and effects of laser treatment of basal cell carcinoma; nevertheless, further studies with a high level of evidence are necessary.

[Light-based inflammatory acne treatments]. / Phototherapie der entzündlichen Akne.

Light-based acne treatments may represent a new emerging treatment for acne that does not increase the risk of bacterial resistance and they may be potentially effective with a favorable safety profile. Current data show that photodynamic therapy reduces inflammatory lesions and significantly improves acne. However, there is no consensus on the optimal implementation in the treatment of acne. In addition to topically applied photodynamic therapy, intense pulsed light, pulsed dye lasers, potassium-titanyl-phosphate lasers, infrared diode lasers, broad-spectrum continuous-wave light sources (red light, blue-red light) have been introduced as alternative treatments. Since well-designed studies to evaluate their efficacy versus traditional medical therapies are lacking and standardized regimens have not been agreed upon, procedures including laser, intense pulsed light, and photodynamic therapy should currently not be considered first-line treatment for inflammatory acne.

Consensus statement on prevention and management of adverse effects following rejuvenation procedures with hyaluronic acid-based fillers.

Facial fillers play an important role in the correction of facial changes associated with ageing. They offer quick treatments in the outpatient setting with minimal subsequent downtime that provide predictable, natural-looking, long-lasting results. Adverse reactions after hyaluronic acid injections tend to be mild or moderate and rather temporary. However, as with all injected or implanted biomaterials, severe adverse events can occur and patients must be fully informed of potential risks prior to undergoing treatment. A panel of experts from Germany (D), Austria (A) and Switzerland (CH) developed recommendations, and this study provides the 'DACH Consensus Recommendations' from this group specifically on the use of hyaluronic acid fillers. The aim is to help clinicians recognize potential risks and to provide guidance on how best to treat adverse events if they arise. Contraindications to hyaluronic acid fillers are also detailed, and ways to prevent adverse events occurring are discussed. Hyaluronic acid-based products are claimed to be very close to an ideal tissue augmentation agent; nevertheless, profound medical, anatomical and product knowledge are of paramount importance to minimize the occurrence of adverse reactions.

Laser therapies for onychomycosis - critical evaluation of methods and effectiveness.

The number of medical devices designed specifically to treat onychomycosis has recently increased, although their mechanism of action is not clear. We evaluated available laser therapies for onychomycosis by reviewing the existing literature. Twenty-two reports, published in peer-reviewed journals and as white papers out of 926 initial search results conveyed enough details to be included in this study. In most cases, the methodology of the trials described in the papers we reviewed was not comprehensive and the reporting of outcomes was not unified. We therefore found it hard to compare different clinical trials to one another. The majority of studies (81.82%) reported using an Nd:YAG laser device to treat onychomycosis. A total of 47.37% of the studies which used a 1064 device (and 47.83% of all studies we reviewed) reported that all treated patients responded positively to laser therapy. A total of 60% of studies reported achieving a complete cure (no clinical symptoms, nor negative mycology) in at least 50% of the treated patients. A low number of adverse events and their mild intensity were consistently reported across all studies, which makes this form of therapy particularly attractive to patients with contraindications for receiving systemic antifungal medication. In order to achieve more unified, comparable studies in the future, we suggest that researchers report a minimum set of outcome measurements: the calculation of the infected nail area pre- and posttreatment, as well as the number of patients achieving mycological, clinical and complete cures.

[Undesired treatment effects in behavior group therapy: Frequency and spectrum]. / Unerwünschte Therapiewirkungen bei verhaltenstherapeutischer Gruppentherapie : Häufigkeit und Spektrum.

BACKGROUND: Psychotherapy not only has positive but also negative effects, which is especially true for group psychotherapy due to psychodynamic and interactional processes. METHODS: Using the UE-G questionnaire 71 patients who participated in cognitive behavioral group psychotherapy reported on negative experiences in the context of the group therapy. The answers were then validated in a qualitative interview. RESULTS: Of the patients 98.6% reported about at least one negative experience and 43.7% about severe or extremely severe negative experiences. Most prominent was the induction of hopelessness and demoralization by what patients saw and heard from other patients in the group. CONCLUSION: Burdensome and therefore undesired treatment effects are regularly seen in group psychotherapy, because of treatment or patient related factors. In any case they must be taken into account during treatment, in the training of group psychotherapists and in quality control.

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization.

VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligand-binding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/VEGFR-2 ECD complex derived from small-angle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR-2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation.

Genetic risk factors for insidious equine recurrent uveitis in Appaloosa horses.

Appaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune-mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from the ECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) on ECA20, were evaluated for association with ERU in a group of 53 Appaloosa ERU cases and 43 healthy Appaloosa controls. Three markers were significantly associated (corrected P-value <0.05): a SNP within intron 11 of the TRPM1 gene on ECA1, an ELA class I microsatellite located near the boundary of the ELA class III and class II regions and an ELA class II microsatellite located in intron 1 of the DRA gene. Association between these three genetic markers and the ERU phenotype was confirmed in a second population of 24 insidious ERU Appaloosa cases and 16 Appaloosa controls. The relative odds of being an ERU case for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% of ERU cases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations at ECA1 and ELA loci and identify functional variants could uncover alleles conferring susceptibility to ERU in Appaloosa horses.

Crystal structure of the GlnZ-DraG complex reveals a different form of PII-target interaction.

Nitrogen metabolism in bacteria and archaea is regulated by a ubiquitous class of proteins belonging to the P(II)family. P(II) proteins act as sensors of cellular nitrogen, carbon, and energy levels, and they control the activities of a wide range of target proteins by protein-protein interaction. The sensing mechanism relies on conformational changes induced by the binding of small molecules to P(II) and also by P(II) posttranslational modifications. In the diazotrophic bacterium Azospirillum brasilense, high levels of extracellular ammonium inactivate the nitrogenase regulatory enzyme DraG by relocalizing it from the cytoplasm to the cell membrane. Membrane localization of DraG occurs through the formation of a ternary complex in which the P(II) protein GlnZ interacts simultaneously with DraG and the ammonia channel AmtB. Here we describe the crystal structure of the GlnZ-DraG complex at 2.1 Å resolution, and confirm the physiological relevance of the structural data by site-directed mutagenesis. In contrast to other known P(II) complexes, the majority of contacts with the target protein do not involve the T-loop region of P(II). Hence this structure identifies a different mode of P(II) interaction with a target protein and demonstrates the potential for P(II) proteins to interact simultaneously with two different targets. A structural model of the AmtB-GlnZ-DraG ternary complex is presented. The results explain how the intracellular levels of ATP, ADP, and 2-oxoglutarate regulate the interaction between these three proteins and how DraG discriminates GlnZ from its close paralogue GlnB.

Structural basis of the Meinwald rearrangement catalysed by styrene oxide isomerase.

Membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement-a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound-and has been used in single and cascade reactions. However, the structural information that explains its reaction mechanism has remained elusive. Here we determine cryo-electron microscopy (cryo-EM) structures of SOI bound to a single-domain antibody with and without the competitive inhibitor benzylamine, and elucidate the catalytic mechanism using electron paramagnetic resonance spectroscopy, functional assays, biophysical methods and docking experiments. We find ferric haem b bound at the subunit interface of the trimeric enzyme through H58, where Fe(III) acts as the Lewis acid by binding to the epoxide oxygen. Y103 and N64 and a hydrophobic pocket binding the oxygen of the epoxide and the aryl group, respectively, position substrates in a manner that explains the high regio-selectivity and stereo-specificity of SOI. Our findings can support extending the range of epoxide substrates and be used to potentially repurpose SOI for the catalysis of new-to-nature Fe-based chemical reactions.

Getting depression clinical practice guidelines right: time for change?

OBJECTIVE: As part of a series of papers ['Chronobiology of mood disorders' Malhi & Kuiper. Acta Psychiatr Scand 2013;128(Suppl. 444):2-15; and 'It's time we managed depression: The emerging role of chronobiology' Malhi et al. Acta Psychiatr Scand 2013;128(Suppl. 444):1] examining chronobiology in the context of depression, this article examines recent western clinical practice guidelines (CPGs) for the treatment of depression with respect to the recommendations they make, in particular as regards chronobiological treatments, and briefly considers the implications of their methodology and approach. METHOD: Five international treatment guidelines, which had been published in the past 5 years, were identified, representing North American and European views. Chosen guidelines were reviewed by the authors, and the relevant recommendations were distributed for discussion and subsequent synthesis. RESULTS: Most current guidelines do not address chronobiology in detail. Chronotherapeutic recommendations are tentative, although agomelatine is considered as an option for major depression and bright light therapy for seasonal affective disorder. Sleep deprivation is not routinely recommended. CONCLUSION: Recommendations are limited by the lack of reliable therapeutic markers for chronotherapeutics. Current evidence supports use of light therapy in seasonal depression, but in non-seasonal depression there is insufficient evidence to support reliance on chronotherapeutics over existing treatment modalities.

Pharmacological management of unipolar depression.

OBJECTIVE: To be used in conjunction with 'Psychological management of unipolar depression' [Lampe et al. Acta Psychiatr Scand 2013;127(Suppl. 443):24-37] and 'Lifestyle management of unipolar depression' [Berk et al. Acta Psychiatr Scand 2013;127(Suppl. 443):38-54]. To provide clinically relevant recommendations for the use of pharmacological treatments in depression derived from a literature review. METHOD: Using our previous Clinical Practice Guidelines [Malhi et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand 2009;119(Suppl. 439):27-46] as a foundation, these clinician guidelines target key practical considerations when prescribing pharmacotherapy. A comprehensive review of the literature was conducted using electronic database searches (PubMed, MEDLINE), and the findings have been synthesized and integrated alongside clinical experience. RESULTS: The pharmacotherapy of depression is an iterative process that often results in partial and non-response. Beyond the initiation of antidepressants, the options within widely used strategies, such as combining agents and switching between agents, are difficult to prescribe because of the paucity of pertinent research. However, there is some evidence for second-line strategies, and a non-prescriptive algorithm can be derived that is based broadly on principles rather than specific steps. CONCLUSION: Depression is by its very nature a heterogeneous illness that is consequently difficult to treat. Invariably, situation-specific factors often play a significant role and must be considered, especially in the case of partial and non-response. Consulting with colleagues and trialling alternate treatment paradigms are essential strategies in the management of depression.

Can clinical CT data improve forensic reconstruction?

In accidents resulting in severe injuries, a clinical forensic examination is generally abandoned in the initial phase due to high-priority clinical needs. However, in many cases, data from clinical computed tomography (CT) examinations are available. The goals of this prospective study were (a) to evaluate clinical CT data as a basis for forensic reconstruction of the sequence of events, (b) to assess if forensic radiological follow-up reading improves the forensic diagnostic benefit compared to the written clinical radiological reports, and (c) to evaluate if full data storage including additional reconstructed 0.6-mm slices enhances forensic analysis. Clinical CT data of 15 living individuals with imaging of at least the head, thorax, and abdomen following polytrauma were examined regarding the forensic evaluation of the sequence of events. Additionally, 0.6-mm slices and 3D images were reconstructed for forensic purposes and used for the evaluation. At the forensic radiological readings, additional traumatic findings were observed in ten of the 15 patients. The main weakness of the clinical reports was that they were not detailed enough, particularly regarding the localization of injuries and description of wound morphology. In seven cases, however, forensic conclusions were possible on the basis of the written clinical reports, whereas in five cases forensic reconstruction required specific follow-up reading. The additional 0.6-mm slices were easily available and with improved 3D image quality and forensic diagnostics. In conclusion, the use of clinical CT data can considerably support forensic expertise regarding reconstruction issues. Forensic follow-up reading as well as the use of additional thin slices for 3D analysis can further improve its benefit for forensic reconstruction purposes.