Evaluation of a male-specific psychotherapeutic program for major depressive disorder compared to cognitive behavioral therapy and waitlist: study protocol for a six-arm randomized clinical superiority trial examining depressed eugonadal and hypogonadal men receiving testosterone

BACKGROUND: Treatment of major depressive disorder (MDD) in men is complicated by the endorsement of traditional masculinity ideologies (TMI) often leading to reluctance toward psychotherapy, therapy interfering processes, or premature termination. In addition, it has been shown that men with MDD have a significantly increased risk of being hypogonadal (e.g., total testosterone levels <12.1 nmoL/L). Therefore, it is recommended to examine depressed men with regard to their testosterone status and if hypogonadism is present to combine psychotherapy with testosterone treatment (TT). AIM: This project aims to evaluate a male-specific psychotherapeutic program (MSPP) for MDD in depressed eugonadal and hypogonadal men receiving testosterone in comparison to a standard cognitive behavioral therapy (CBT) for MDD and a Waitlist. METHODS: The study presents a 2×3 factorial study design. In total, 144 men aged between 25 and 50 will be stratified by testosterone status (eugonadal/hypogonadal) and then randomized into one of the three conditions (MSPP, CBT, or Waitlist). Additionally, a healthy control group of 100 men will be recruited, which will undergo only baseline assessments. Both standardized psychotherapy programs will encompass 18 sessions delivered in a weekly manner. Aligned with the TT-related medical visits of the 72 hypogonadal men, all participants will be followed up with clinical assessments and bio sampling at weeks 0, 6, 15, 24, and 36. EXPECTED RESULTS: Compared to Waitlist control groups, treatment groups are expected to be more effective and efficacious (depression score reduction of ≥50%) at week 24 and at the follow-up at week 36. The MSPP is expected to show higher effectiveness and efficacy for depressive symptoms and higher acceptability (lower dropout rate) as compared to CBT. DISCUSSION: This study represents the first attempt to test a male-specific psychotherapy for MDD in a single-setting compared to standard CBT and a Waitlist control condition using randomized clinical trial methodology. In addition, the potential positive adjunct effect of psychotherapy to TT in reducing depressive burden and improving quality of life in hypogonadal depressed men represents a neglected research area and might introduce new hypogonadism screening procedures in depressed men and combined treatment approaches for depressed men suffering from hypogonadism. Limitations are the rigorous inclusion and exclusion criteria, which limit the generalizability of the study results to first episode treatment naïve depressed men. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT05435222

Investigation of the biophysical and cell biological properties of ferroportin, a multipass integral membrane protein iron exporter

Ferroportin is a multipass membrane protein that serves as an iron exporter in many vertebrate cell types. Ferroportin-mediated iron export is controlled by the hormone hepcidin, which binds ferroportin, causing its internalization and degradation. Mutations in ferroportin cause a form of the iron overload hereditary disease hemochromatosis. Relatively little is known about ferroportin's properties or the mechanism by which mutations cause disease. In this study, we expressed and purified human ferroportin to characterize its biochemical/biophysical properties in solution and conducted cell biological studies in mammalian cells. We found that purified detergent-solubilized ferroportin is a well-folded monomer that binds hepcidin. In cell membranes, the N- and C-termini were both cytosolic, implying an even number of transmembrane regions, and ferroportin was mainly localized to the plasma membrane. Hepcidin addition resulted in a redistribution of ferroportin to intracellular compartments that labeled with early endosomal and lysosomal, but not Golgi, markers and that trafficked along microtubules. An analysis of 16 disease-related ferroportin mutants revealed that all were expressed and trafficked to the plasma membrane but that some were resistant to hepcidin-induced internalization. The characterizations reported here form a basis upon which models for ferroportin's role in regulating iron homeostasis in health and disease can be interpreted

Status loss due to COVID-19, traditional masculinity, and their association with recent suicide attempts and suicidal ideation

The COVID-19 pandemic is causing extensive job loss leading to a loss of social status in many men. Endorsement of traditional masculinity ideology may render some men particularly sensitive to status loss and thereby to an increased risk for suicidality. In this anonymous online survey conducted in German-speaking European countries, 490 men completed questionnaires regarding loss of social status due to the COVID-19 pandemic, past-month and lifetime suicide attempt and suicidal ideation. Furthermore, endorsement of traditional masculinity ideology and prototypical and male-typical externalizing depression symptoms were measured. Out of a total of 490 men, 14.7% of men reported experiencing status loss due to the pandemic. These men were more than four times as likely to have attempted suicide in the past month (OR = 4.48, 95% CI [1.72, 11.67]) and more than twice as likely to report suicidal ideation during the past 2 weeks (OR = 2.47, 95% CI [1.42, 4.28]), than men not reporting status loss. Status loss, but not endorsement of traditional masculinity ideology, was associated with suicide outcomes. However, when male-typical externalizing depression symptoms and prototypical depression symptoms were included in the models, they exhibited the only direct associations with suicide outcomes (e.g., for past-month suicide attempt: male-typical externalizing depression symptoms OR = 2.18, 95% CI [1.31, 3.62], prototypical depression symptoms OR = 2.41, 95% CI [1.13, 5.12]). A significant interaction between status loss and endorsement of traditional masculinity ideology further suggests an enhancing moderating effect of traditional masculinity on the relationship between status loss and past-month suicide attempts (OR = 3.27, 95% CI [1.16, 9.27]). Status loss due to the COVID-19 pandemic emerges as risk factor for suicide in men. Men who experience status loss due to the COVID-19 pandemic while concomitantly exhibiting strong endorsement of traditional masculinity ideology have an additional increased risk of suicide

Ottawa 2020 consensus statements for programmatic assessment 2: Implementation and practice

INTRODUCTION: Programmatic assessment is a longitudinal, developmental approach that fosters and harnesses the learning function of assessment. Yet the implementation, a critical step to translate theory into practice, can be challenging. As part of the Ottawa 2020 consensus statement on programmatic assessment, we sought to provide descriptions of the implementation of the 12 principles of programmatic assessment and to gain insight into enablers and barriers across different institutions and contexts. METHODS: After the 2020 Ottawa conference, we surveyed 15 Health Profession Education programmes from six different countries about the implementation of the 12 principles of programmatic assessment. Survey responses were analysed using a deductive thematic analysis. RESULTS AND DISCUSSION: A wide range of implementations were reported although the principles remained, for the most part, faithful to the original enunciation and rationale. Enablers included strong leadership support, ongoing faculty development, providing students with clear expectations about assessment, simultaneous curriculum renewal and organisational commitment to change. Most barriers were related to the need for a paradigm shift in the culture of assessment. Descriptions of implementations in relation to the theoretical principles, across multiple educational contexts, coupled with explanations of enablers and barriers, provided new insights and a clearer understanding of the strategic and operational considerations in the implementation of programmatic assessment. Future research is needed to further explore how contextual and cultural factors affect implementation

Crystal Structures, Metal Activation, and DNA-Binding Properties of Two-Domain IdeR from Mycobacterium tuberculosis

The iron-dependent regulator IdeR is a key transcriptional regulator of iron uptake in Mycobacterium tuberculosis. In order to increase our insight into the role of the SH3-like third domain of this essential regulator, the metal-binding and DNA-binding properties of two-domain IdeR (2D-IdeR) whose SH3-like domain has been truncated were characterized. The equilibrium dissociation constants for Co^(2+) and Ni^(2+) activation of 2D-IdeR for binding to the fxbA operator and the DNA-binding affinities of 2D-IdeR in the presence of excess metal ions were estimated using fluorescence spectroscopy. 2D-IdeR binds to fxbA operator DNA with similar affinity as full-length IdeR in the presence of excess metal ion. However, the Ni^(2+) concentrations required to activate 2D-IdeR for DNA binding appear to be smaller than that for full-length IdeR while the concentration of Co^(2+) required for activation remains the same. We have determined the crystal structures of Ni^(2+)-activated 2D-IdeR at 1.96 Å resolution and its double dimer complex with the mbtA-mbtB operator DNA in two crystal forms at 2.4 Å and 2.6 Å, the highest resolutions for DNA complexes for any structures of iron-dependent regulator family members so far. The 2D-IdeR−DNA complex structures confirm the specificity of Ser37 and Pro39 for thymine bases and suggest preferential contacts of Gln43 to cytosine bases of the DNA. In addition, our 2D-IdeR structures reveal a remarkable property of the TEV cleavage sequence remaining after removal of the C-terminal His_6. This C-terminal tail promotes crystal contacts by forming a β-sheet with the corresponding tail of neighboring subunits in two unrelated structures of 2D-IdeR, one with and one without DNA. The contact-promoting properties of this C-terminal TEV cleavage sequence may be beneficial for crystallizing other proteins

Crystal Structures, Metal Activation, and DNA-Binding Properties of Two-Domain IdeR from Mycobacterium tuberculosis

The iron-dependent regulator IdeR is a key transcriptional regulator of iron uptake in Mycobacterium tuberculosis. In order to increase our insight into the role of the SH3-like third domain of this essential regulator, the metal-binding and DNA-binding properties of two-domain IdeR (2D-IdeR) whose SH3-like domain has been truncated were characterized. The equilibrium dissociation constants for Co^(2+) and Ni^(2+) activation of 2D-IdeR for binding to the fxbA operator and the DNA-binding affinities of 2D-IdeR in the presence of excess metal ions were estimated using fluorescence spectroscopy. 2D-IdeR binds to fxbA operator DNA with similar affinity as full-length IdeR in the presence of excess metal ion. However, the Ni^(2+) concentrations required to activate 2D-IdeR for DNA binding appear to be smaller than that for full-length IdeR while the concentration of Co^(2+) required for activation remains the same. We have determined the crystal structures of Ni^(2+)-activated 2D-IdeR at 1.96 Å resolution and its double dimer complex with the mbtA-mbtB operator DNA in two crystal forms at 2.4 Å and 2.6 Å, the highest resolutions for DNA complexes for any structures of iron-dependent regulator family members so far. The 2D-IdeR−DNA complex structures confirm the specificity of Ser37 and Pro39 for thymine bases and suggest preferential contacts of Gln43 to cytosine bases of the DNA. In addition, our 2D-IdeR structures reveal a remarkable property of the TEV cleavage sequence remaining after removal of the C-terminal His_6. This C-terminal tail promotes crystal contacts by forming a β-sheet with the corresponding tail of neighboring subunits in two unrelated structures of 2D-IdeR, one with and one without DNA. The contact-promoting properties of this C-terminal TEV cleavage sequence may be beneficial for crystallizing other proteins

Volatile Analysis by Pyrolysis of Regolith for Planetary Resource Exploration

The extraction and identification of volatile resources that could be utilized by humans including water, oxygen, noble gases, and hydrocarbons on the Moon, Mars, and small planetary bodies will be critical for future long-term human exploration of these objects. Vacuum pyrolysis at elevated temperatures has been shown to be an efficient way to release volatiles trapped inside solid samples. In order to maximize the extraction of volatiles, including oxygen and noble gases from the breakdown of minerals, a pyrolysis temperature of 1400 C or higher is required, which greatly exceeds the maximum temperatures of current state-of-the-art flight pyrolysis instruments. Here we report on the recent optimization and field testing results of a high temperature pyrolysis oven and sample manipulation system coupled to a mass spectrometer instrument called Volatile Analysis by Pyrolysis of Regolith (VAPoR). VAPoR is capable of heating solid samples under vacuum to temperatures above 1300 C and determining the composition of volatiles released as a function of temperature

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software