The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.

The ß-secretase ß-site APP cleaving enzyme (BACE1) is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, nonhuman primates, and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for safer prevention of Alzheimer's disease.

Understanding the complexity of suicide loss: PTSD, complex PTSD and prolonged grief disorder following suicide bereavement.

Suicide-bereaved individuals are often confronted with profound grief reactions and have an increased risk for mental health disorders. Little is known about the development of complex post-traumatic stress disorder (CPTSD) following a loss by suicide. This paper aims to assess the prevalence of CPTSD, PTSD, prolonged grief disorder (PGD), and depression as well as to identify sociodemographic and loss-related factors regarding their development. A total of 161 suicide loss survivors (91.3% female) completed a questionnaire, which collected symptoms of grief (TGI-SR+), PTSD, CPTSD (ITQ), and depression (PHQ-D). In total, 12.4% met the diagnosis for CPTSD, 5.0% for PTSD. A total of 22.0% fulfilled the diagnosis for PGD. 41.6% showed at least moderate symptoms of depression. Pearson's correlation showed that time since loss was negatively associated with PG and PTSD symptoms, kinship to the deceased was associated with PG severity. The sample scored high on all disturbances in self-organization (DSO) symptom clusters typical for CPTSD. A focus on symptoms of CPTSD may be a necessary component in the care of survivors of suicide loss.

Men's Behavior and Communication in the Days Prior to a Suicide-A Psychological Autopsy Study.

Men show a significantly higher suicide rate, are less often recognized as persons at risk, and are more difficult to reach for suicide prevention interventions. Warning signs and deterioration in mental health are often not recognized by their surroundings. This study aims to retrospectively analyze the behavior and communication of men before a suicide, how relatives noticed changes, and how the interaction was perceived. N = 15 individuals who lost a close male relative to suicide were interviewed using psychological autopsy interviews. The interviews were evaluated following a deductive-inductive approach while using a comprehensive category system. The majority of men showed changes in behavior before the suicide, especially social withdrawal, irritability, and generally a deterioration in mental health. In fact, men did communicate their suicidal thoughts before they died through suicide, but mainly indirectly. While only one-third of the deceased made preparations before suicide, the majority of relatives noticed a deterioration in the mental health of the individual as well as increased alcohol and substance use. Men show signs of suicide, which are little recognized by their surroundings. Suicide prevention interventions should be adapted more to the needs of men.

Yolk granule fusion and microtubule aster formation regulate cortical granule translocation and exocytosis in zebrafish oocytes.

Dynamic reorganization of the cytoplasm is key to many core cellular processes, such as cell division, cell migration, and cell polarization. Cytoskeletal rearrangements are thought to constitute the main drivers of cytoplasmic flows and reorganization. In contrast, remarkably little is known about how dynamic changes in size and shape of cell organelles affect cytoplasmic organization. Here, we show that within the maturing zebrafish oocyte, the surface localization of exocytosis-competent cortical granules (Cgs) upon germinal vesicle breakdown (GVBD) is achieved by the combined activities of yolk granule (Yg) fusion and microtubule aster formation and translocation. We find that Cgs are moved towards the oocyte surface through radially outward cytoplasmic flows induced by Ygs fusing and compacting towards the oocyte center in response to GVBD. We further show that vesicles decorated with the small Rab GTPase Rab11, a master regulator of vesicular trafficking and exocytosis, accumulate together with Cgs at the oocyte surface. This accumulation is achieved by Rab11-positive vesicles being transported by acentrosomal microtubule asters, the formation of which is induced by the release of CyclinB/Cdk1 upon GVBD, and which display a net movement towards the oocyte surface by preferentially binding to the oocyte actin cortex. We finally demonstrate that the decoration of Cgs by Rab11 at the oocyte surface is needed for Cg exocytosis and subsequent chorion elevation, a process central in egg activation. Collectively, these findings unravel a yet unrecognized role of organelle fusion, functioning together with cytoskeletal rearrangements, in orchestrating cytoplasmic organization during oocyte maturation.

The Impact of Police Behavior During Death Notifications on Mental Health of the Bereaved: A Cross-Sectional Study.

The delivery of death notifications may affect the mental health of bereaved individuals. Police officers are often the first people with whom the bereaved have contact in this exceptional situation. Therefore, it is essential to assess the behavior of police officers and the impact on the bereaved. We examined the experiences of 86 individuals who received the notification through the police and assessed symptoms of prolonged grief, depression, and posttraumatic stress symptoms. The interaction with police was associated with posttraumatic avoidance behavior and the presence of another supporting person was associated with higher scores of depression. Handing out information material and staying with the bereaved was related to a positive evaluation of police behavior. It appears important to identify helpful and problematic behavior for a better understanding and for an adaptation of existing guidelines.

A therapist-supported internet-based intervention for bereaved siblings: A randomized controlled trial.

BACKGROUND: The loss of a sibling can have a long-term impact on the mental and physical health of the surviving sibling throughout adolescence and later adulthood. Even though bereaved siblings can be identified as a high-risk group, evidence-based interventions for this bereavement group are still missing. AIM: To evaluate the treatment effects of an internet-based writing intervention for bereaved siblings aged 16-65 years. DESIGN: A two-armed randomized controlled trial (DRKS00011514) compared the intervention to a waiting list control group. The 6-week intervention consisted of six structured writing assignments that were based on cognitive behavioral therapy, focusing on the specific situation of bereaved siblings. SETTING/PARTICIPANTS: Eighty-six bereaved siblings (loss >1 month ago, no severe psychiatric symptoms) were randomly allocated to the intervention group (n = 47) or the waiting list control group (n = 39). Primary outcomes were symptoms of prolonged grief disorder and depression; secondary outcomes were posttraumatic stress symptoms and survivor guilt. RESULTS: Symptoms of depression and prolonged grief disorder improved significantly in the intention-to-treat analyses from pre-to post-measurement compared with the control group (gDepression = -0.62, gGrief = 0.33). In the intervention group, all primary and secondary outcomes decreased significantly from baseline to 12-month follow-up (gs = -0.38 to -1.04). A significant clinical change could be found for depression (34%) compared to the waitlist control group (10%). CONCLUSIONS: Bereaved siblings profited from this brief internet-based writing intervention in the short- and long-term. However, future research, such as dismantling studies, may help to further optimize the benefits of an intervention aimed at bereaved siblings.

Efficacy of an online-group intervention after suicide bereavement: A randomized controlled trial.

Introduction: People bereaved by suicide are at high-risk for developing mental disorders and suicidal tendencies. Grief after suicide differs from grief after other types of death, and bereaved persons may require support tailored to their situation. In this study, we evaluate an online intervention for individuals bereaved by suicide and its effectiveness on mental health. Methods: A total of 140 participants were included in the intervention and randomized to either the treatment or the waitlist control group. The intervention consisted of 12 weekly modules, based on cognitive-behavioral methods, and took place as a webinar in a group format. Primary outcomes were depression and suicidality; secondary outcomes were symptoms of prolonged grief, PTSD, posttraumatic cognitions, hopelessness, and grief-specific symptoms. Results: Symptoms of posttraumatic avoidance improved significantly in the intention-to-treat analyses (d between = 0.43) and in treatment completers (d between = 0.56), posttraumatic intrusion improved in treatment completers (d between = 0.50) compared to the waitlist control group. In the intervention group, psychopathological symptoms decreased significantly from baseline to 6-month follow-up. Furthermore, factors such as higher scores of depression, grief, suicide ideation, and posttraumatic stress symptoms were identified at baseline, which impacted the effectiveness of the intervention. Conclusions: The results of this study indicate that completing an online group intervention for the suicide bereaved could reduce trauma-related outcomes. However, the waiting control group also improved significantly from pre- to post-measurement in all other outcomes. Future studies with active control groups are needed to further examine the effectiveness.

ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion.

The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.

Effects of bereavement groups-a systematic review and meta-analysis.

This review summarizes the evidence of bereavement groups for symptoms of grief and depression. The literature search using Web of Science, EBSCO, PubMed, CINAHL, and MEDLINE yielded 14 studies (N = 1519) meeting the inclusion criteria (i.e., randomized-controlled trials, bereaved adults, bereavement group, validated measures). Overall, bereavement groups were marginally more effective than control groups post-treatment (gG = 0.33, gD = 0.22) but not at follow-up. Although tertiary interventions yielded larger effect sizes than secondary interventions, the difference was not significant. The results imply that the evidence for bereavement groups is weak, although the large heterogeneity of concepts for intervention and control groups limits the generalizability.

An Evaluation of a Suicide Prevention E-Learning Program for Police Officers (COPS): Improvement in Knowledge and Competence.

Background: Police officers are at high risk for mental and physical health problems and suicidal ideation. The specific risk factors are numerous and concern stressful missions and administrative aspects of the police profession. So far, the police get only little training on specific missions as well as on coping with stress and suicidal ideation in the police profession. In this study we test the efficacy of the online training COPS (Coping with Suicide) for police officers. Methods: A total of 142 police officers from Germany and Switzerland participated in the study; complete data (baseline and post) are available from 102 participants. The training consisted of three modules covering the topics of delivering death notifications, dealing with individuals with suicidal ideation and dealing with one's own distress and suicidal ideation in the police profession. The primary outcomes are perceived knowledge and self-rated competence regarding the contents of the program, actual knowledge as well as symptoms of depression and anxiety (PHQ-9), and attitudes toward suicide (ATTS). The data are collected at baseline and after completing the training. Results: We found a significant increase in knowledge as well as in perceived competence after completing the training. Mental health and attitudes toward suicide did not change significantly. Years on the job had no moderating effect on the effectiveness of the training. Discussion: The results suggest that a short e-learning program significantly improves knowledge and self-rated competence in delivering death notifications, in suicide prevention and stress management. It can be easily integrated into the daily routine of police-officers, and participants could participate at their own pace and from any location. One limitation of this study is the lack of a control-group. Further advantages and limitations of this study are discussed. Clinical Trial Registration: https://www.drks.de/drks_web/, identifier: DRKS00023882.

Suicide risk after suicide bereavement: The role of loss-related characteristics, mental health, and hopelessness.

BACKGROUND: Suicide bereavement is associated with increased risk for severe negative mental health outcomes and suicidality. The purpose of this study was to examine the association between mental health symptoms and suicidal ideation among suicide bereaved while taking multiple factors into account. METHODS: The sample consisted of N = 157 German suicide bereaved who were interested in receiving an online intervention. The Beck Scale for Suicide Ideation (BSS) was used to distinguish between participants with and without suicidal ideation. A hierarchical regression analysis determined the effect of the most common mental health symptoms on suicidal ideation: symptoms of depression (BDI-II), prolonged grief (ICG-D), post-traumatic stress (IES-R), and hopelessness (H-RB). RESULTS: No significant differences emerged for sociodemographic or loss-related characteristics between suicide bereaved individuals with and without suicidal ideation. Depressive symptom severity was associated with higher suicidal ideation. When controlling for hopelessness, the effect of depression decreased considerably, while hopelessness itself turned out to be the most important predictor variable. DISCUSSION: Increased levels of hopelessness commonly reported by suicide bereaved may represent a stronger risk factor for suicidal ideation than mental health disorders. Screening for and targeting hopelessness appears crucial for suicide prevention in this population.

Cleavage of Organosolv Lignin to Phenols Using Nitrogen Monoxide and Hydrazine.

From the variety of methods known for the depolymerization of organosolv lignin, a broad range of diversely substituted aromatic compounds are available today. In the present work, a novel two-step reaction sequence is reported, which is focused on the formation of phenols. While the first step of the depolymerization strategy comprises the 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-catalyzed oxidation of organosolv lignin with nitrogen monoxide so that two waste materials are combined, cleavage to the phenolic target compounds is achieved in the second step employing hydrazine and potassium hydroxide under Wolff-Kishner-type conditions. Besides the fact that the novel strategy proceeds via an untypical form of oxidized organosolv lignin, the two-step sequence is further able to provide phenols as cleavage products, which bear no substituent at the 4-position.

Endoglycan (PODXL2) is proteolytically processed by ADAM10 (a disintegrin and metalloprotease 10) and controls neurite branching in primary neurons.

Cell adhesion is tightly controlled in multicellular organisms, for example, through proteolytic ectodomain shedding of the adhesion-mediating cell surface transmembrane proteins. In the brain, shedding of cell adhesion proteins is required for nervous system development and function, but the shedding of only a few adhesion proteins has been studied in detail in the mammalian brain. One such adhesion protein is the transmembrane protein endoglycan (PODXL2), which belongs to the CD34-family of highly glycosylated sialomucins. Here, we demonstrate that endoglycan is broadly expressed in the developing mouse brains and is proteolytically shed in vitro in mouse neurons and in vivo in mouse brains. Endoglycan shedding in primary neurons was mediated by the transmembrane protease a disintegrin and metalloprotease 10 (ADAM10), but not by its homolog ADAM17. Functionally, endoglycan deficiency reduced the branching of neurites extending from primary neurons in vitro, whereas deletion of ADAM10 had the opposite effect and increased neurite branching. Taken together, our study discovers a function for endoglycan in neurite branching, establishes endoglycan as an ADAM10 substrate and suggests that ADAM10 cleavage of endoglycan may contribute to neurite branching.

The relationship between guilt, depression, prolonged grief, and posttraumatic stress symptoms after suicide bereavement.

OBJECTIVE: A profound feeling of guilt and its role in complicating psychological reactions are accepted as central issues in suicide bereavement. However, research examining the relationship of guilt with mental disorders commonly following suicide bereavement is still lacking. This study aimed to examine the association between guilt and symptoms of depression, prolonged grief disorder, and posttraumatic stress disorder (PTSD) after suicide bereavement, as well as its moderating role in the association between the time which elapsed since bereavement and psychopathological symptoms. METHODS: 154 self-selected adult German participants bereaved by suicide completed online questionnaires assessing sociodemographics, characteristics related to the loss, guilt, depression, prolonged grief, and PTSD. RESULTS: Significant positive correlations were found between guilt and all assessed psychopathological symptoms. Further, guilt was a significant correlate with symptoms of depression, prolonged grief, PTSD over and above sociodemographic factors, and time that elapsed since the loss. Guilt furthermore moderated the link between the time which elapsed since bereavement and depressive symptoms, while this effect was not observed for prolonged grief and posttraumatic stress symptoms. CONCLUSION: Our findings replicate theoretical frameworks linking feelings of guilt with mental disorders after suicide bereavement. Accordingly, they highlight the necessity to adapt psychotherapeutic interventions according to the specific needs of this population to maximize treatment effectiveness.

[Psychological Interventions for People Bereaved by Suicide: A Systematic Review]. / Wirksamkeit von Interventionen für Hinterbliebene nach einem Suizid: ein Systematischer Review.

BACKGROUND: Suicide bereavement is a significant risk factor for psychological and somatic disorders. However, to date there exists only a limited number of suicide bereavement interventions, and little is known about their efficacy. METHODS: A computerized search in databases such as PsychINFO, PubMed, Medline was conducted. Randomized controlled trials (RCTs) that compared an intervention for suicide bereaved to a control condition were included after a quality assessment of two independent researchers. In total, six studies with N = 473 participants were included. Cohen's d was used to calculate the effect sizes. RESULTS: The results indicated small to medium effect sizes for within-group differences for the main outcomes in the intervention condition, while no significant between-group differences were revealed. CONCLUSIONS: Interventions for suicide bereavement can reduce mental health symptoms, however the results do not appear robust between group comparisons. Thus, it could not be demonstrated that an intervention following the suicide of a close relative is more effective than no intervention or an unspecific intervention. Future research should focus on high-quality intervention studies.

How People Evaluate Anti-Corona Measures for Their Social Spheres: Attitude, Subjective Norm, and Perceived Behavioral Control.

Restrictions on outdoor activities, tips for hygiene, and tips for mental health are among the most common initiatives to counter the COVID-19 pandemic. These measures aim to protect people's health and, at the same time, impact their social lives. So far, it is little known how people evaluate those anti-Corona measures with regard to their social spheres (close family, wider family and friends, colleagues, and society). Furthermore, it is plausible that the subjective evaluation of attitudinal objects and especially severe events, like the COVID-19 pandemic and the related counter-measures, is multidimensional. Against this background, we combine the social spheres with the elements of the Theory of Planned Behavior. On the methodological basis of the Means-End Theory of Complex Cognitive Structures, we determine the perceived relevance and quality of the attitude, subjective norm, perceived behavioral control, and social spheres regarding anti-Corona measures. Furthermore, the applied methodology allows the deduction of norm strategies to define the priority of securing or increasing the effectiveness of elements of anti-Corona measures. Based on the answers of 663 participants, we found that the protection from COVID-19 and its consequences (attitude) are more important to people than the practicability of anti-Corona measures in their social lives (perceived behavioral control), which, again, has a higher subjective relevance than the willingness to fulfill the expectations of others (subjective norm). Additionally, people distinguish between their close family (higher subjective relevance) and their other social spheres (lower subjective relevance). The people attribute the highest quality to the tips on hygiene, followed by the restrictions on outdoor activities and the tips for mental health. The protection and practicability of the anti-Corona measures have higher quality ratings than the willingness to fulfill the expectations of others. Based on the norm strategies, policymakers should secure the effectiveness of the current anti-Corona measures with a high priority by focusing on the protection and practicability with regard to close and wider family and friends. Increasing the effectiveness of the protection and practicability of anti-Corona measures in work and society also has a high priority. Focusing on the subjective norm should be of lower priority.

Autoinhibition of TRPV6 Channel and Regulation by PIP2.

Transient receptor potential vanilloid 6 (TRPV6), a calcium-selective channel possessing six transmembrane domains (S1-S6) and intracellular N and C termini, plays crucial roles in calcium absorption in epithelia and bone and is involved in human diseases including vitamin-D deficiency, osteoporosis, and cancer. The TRPV6 function and regulation remain poorly understood. Here we show that the TRPV6 intramolecular S4-S5 linker to C-terminal TRP helix (L/C) and N-terminal pre-S1 helix to TRP helix (N/C) interactions, mediated by Arg470:Trp593 and Trp321:Ile597 bonding, respectively, are autoinhibitory and are required for maintaining TRPV6 at basal states. Disruption of either interaction by mutations or blocking peptides activates TRPV6. The N/C interaction depends on the L/C interaction but not reversely. Three cationic residues in S5 or C terminus are involved in binding PIP2 to suppress both interactions thereby activating TRPV6. This study reveals "PIP2 - intramolecular interactions" regulatory mechanism of TRPV6 activation-autoinhibition, which will help elucidating the corresponding mechanisms in other TRP channels.

Soil water solutes reduce the critical micelle concentration of quaternary ammonium compounds.

Quaternary alkyl ammonium compounds (QAACs) are produced in large quantities for use as surfactants and disinfectants and also found in soils, sediments, and surface waters, where they are potentially involved in the selection of antibiotic resistance genes. Micelle formation influences fate and effects of QAACs. The critical micelle concentration (CMC) of six homologs of benzylalkylammonium chlorides (BAC) was determined in deionized water, 0.01 M CaCl2 solution, and aqueous soil extracts, using both spectrofluorometric and tensiometric methods. Additionally, eight organic model compounds were employed at concentrations of 15 mg C L-1 as background solutes in order to test the effect of dissolved organic carbon (DOC) on CMCs. Results found CMCs decreased with an increasing length of the alkyl chain from 188 mM for BAC-C8 to 0.1 mM for BAC-C18. Both methods yielded similar results for measurements in water and CaCl2 solution; however, the spectrofluorescence method did not work for soil extracts due to fluorescence quenching phenomena. In soil extracts, CMCs of BAC-C12 were reduced below 3.7 mM, while the CMC reduction in soil extracts was less pronounced for BAC-C16. Besides ionic strength, molecular structures of BACs and dissolved organic compounds also affected the CMC. The number of carboxyl groups and small molecular weights of the DOC model compounds reduced the CMCs of BAC-C12 and BAC-C16 at pH 6. This study highlights that CMCs can be surpassed in soil solution, pore waters of sediments, or other natural waters even at (small) concentrations of QAACs typically found in the environment.

Web-Based Bereavement Care: A Systematic Review and Meta-Analysis.

BACKGROUND: Web-based interventions have been introduced as novel and effective treatments for mental disorders and, in recent years, specifically for the bereaved. However, a systematic summary of the effectiveness of online interventions for people experiencing bereavement is still missing. OBJECTIVE: A systematic literature search was conducted by four reviewers who reviewed and meta-analytically summarized the evidence for web-based interventions for bereaved people. METHODS: Systematic searches (PubMed, Web of Science, PsycInfo, PsycArticles, Medline, and CINAHL) resulted in seven randomized controlled trials (N = 1,257) that addressed adults having experienced bereavement using internet-based interventions. We used random effects models to summarize treatment effects for between-group comparisons (treatment vs. control at post) and stability over time (post vs. follow-up). RESULTS: All web-based interventions were based on cognitive behavioral therapy (CBT). In comparison with control groups, the interventions showed moderate (g = .54) to large effects (g = .86) for symptoms of grief and posttraumatic stress disorder (PTSD), respectively. The effect for depression was small (g = .44). All effects were stable over time. A higher number of treatment sessions achieved higher effects for grief symptoms and more individual feedback increased effects for depression. Other moderators (i.e. dropout rate, time since loss, exposure) did not significantly reduce moderate degrees of heterogeneity between the studies. LIMITATIONS: The number of includable studies was low in this review resulting to lower power for moderator analyses in particular. CONCLUSIONS: Overall, the results of web-based bereavement interventions are promising, and its low-threshold approach might reduce barriers to bereavement care. Nonetheless, future research should further examine potential moderators and specific treatment components (e.g. exposure, feedback) and compare interventions with active controls.

Synthesis, Radiosynthesis and Biological Evaluation of Buprenorphine-Derived Phenylazocarboxamides as Novel µ-Opioid Receptor Ligands.

Targeted structural modifications have led to a novel type of buprenorphine-derived opioid receptor ligand displaying an improved selectivity profile for the µ-OR subtype. On this basis, it is shown that phenylazocarboxamides may serve as useful bioisosteric replacements for the widely occurring cinnamide units, without loss of OR binding affinity or subtype selectivity. This study further includes functional experiments pointing to weak partial agonist properties of the novel µ-OR ligands, as well as docking and metabolism experiments. Finally, the unique bifunctional character of phenylazocarboxylates, herein serving as precursors for the azocarboxamide subunit, was exploited to demonstrate the accessibility of an 18 F-fluorinated analogue.