From the Cover: Trypanosomal TAC40 constitutes a novel subclass of mitochondrial β-barrel proteins specialized in mitochondrial genome inheritance

Mitochondria cannot form de novo but require mechanisms allowing their inheritance to daughter cells. In contrast to most other eukaryotes Trypanosoma brucei has a single mitochondrion whose single-unit genome is physically connected to the flagellum. Here we identify a β-barrel mitochondrial outer membrane protein, termed tripartite attachment complex 40 (TAC40), that localizes to this connection. TAC40 is essential for mitochondrial DNA inheritance and belongs to the mitochondrial porin protein family. However, it is not specifically related to any of the three subclasses of mitochondrial porins represented by the metabolite transporter voltage-dependent anion channel (VDAC), the protein translocator of the outer membrane 40 (TOM40), or the fungi-specific MDM10, a component of the endoplasmic reticulum–mitochondria encounter structure (ERMES). MDM10 and TAC40 mediate cellular architecture and participate in transmembrane complexes that are essential for mitochondrial DNA inheritance. In yeast MDM10, in the context of the ERMES, is postulated to connect the mitochondrial genomes to actin filaments, whereas in trypanosomes TAC40 mediates the linkage of the mitochondrial DNA to the basal body of the flagellum. However, TAC40 does not colocalize with trypanosomal orthologs of ERMES components and, unlike MDM10, it regulates neither mitochondrial morphology nor the assembly of the protein translocase. TAC40 therefore defines a novel subclass of mitochondrial porins that is distinct from VDAC, TOM40, and MDM10. However, whereas the architecture of the TAC40-containing complex in trypanosomes and the MDM10-containing ERMES in yeast is very different, both are organized around a β-barrel protein of the mitochondrial porin family that mediates a DNA–cytoskeleton linkage that is essential for mitochondrial DNA inheritance.Mitochondria are a hallmark of all eukaroytic cells. They derive from an endosymbiontic event between a free-living bacterium and a presumably prokaryotic host cell. More than 1.5 billion years of evolution resulted in a great diversification of mitochondria. As a consequence, the shape and number of organelles per cell as well as size, content, copy number, and organization of their genomes vary greatly between different taxons (1). However, all eukaryotes must be able to faithfully transmit mitochondria to their offspring (2, 3).Unlike most other eukaryotes, the parasitic protozoa Trypanosoma brucei has a single mitochondrion throughout its life and its cell cycle. Due to the single-unit nature of the mitochondrion, its duplication must be coordinated with the duplication of the nucleus (4). The mitochondrial genome of T. brucei, termed kinetoplast DNA (kDNA), is essential for growth of both the procyclic insect stage and the bloodstream form of the parasite (5). It consists of a disk-shaped single-unit kDNA network that localizes to a distinct region within the mitochondrial matrix (6). The kDNA is physically connected with the cytosolic basal body, the organizing center of the eukaryotic flagellum, via a high-order transmembrane structure termed tripartite attachment complex (TAC) (7) of which only few components have been identified (8–10). Replication of the kDNA network occurs at a defined stage of the cell cycle shortly before the onset of the nuclear S phase. After replication, the kDNA networks need to be correctly positioned so that during cell and mitochondrial division each daughter cell receives a single organelle with a single kDNA network. This process requires an intact TAC and is mediated by the movement of the basal body: one kDNA network remains connected to the basal body of the old flagellum whereas the other one segregates with the basal body of the new flagellum (7, 11).Unlike trypanosomes, Saccharomyces cerevisiae propagates by budding and contains highly dynamic mitochondria that constantly divide and fuse (12, 13). Mitochondrial inheritance in budding yeast therefore requires a mechanism to move mitochondria and their genomes from the mother cell into the growing bud. The protein-associated mitochondrial genomes of S. cerevisiae, termed nucleoids, localize to dozens of globular foci that are distributed all over the organelles. Most actively replicating nucleoids are associated with a protein complex that includes the outer membrane (OM) protein MDM10 as a central unit, as well as the proteins MDM12, MDM34, and MMM1 (14–16). The protein complex forms the endoplasmic reticulum (ER)–mitochondria encounter structure (ERMES) tethering the ER to the mitochondrion (17). The ERMES has also been suggested to connect to cytosolic actin fibers that mediate the movement of mitochondria to the bud of dividing yeast cells (14, 18, 19). Besides its role in mitochondrial inheritance, the ERMES has been implicated in maintenance of mitochondrial morphology and in phospholipid and calcium exchange as well as in the assembly of the protein translocase of the mitochondrial OM (TOM) (20, 21). Some of the proposed ERMES functions are controversial and there is evidence that some of them might be due to secondary effects caused by the drastically altered mitochondrial morphology (22).The central ERMES subunit, the β-barrel protein MDM10 belongs to the mitochondrial porin superfamily, which comprises the three members voltage-dependent anion channel (VDAC), Tom40, and MDM10. Whereas VDAC and Tom40 have so far been found in all eukaryotes, including T. brucei (23, 24), MDM10 is specific to the fungal clade.In this study we identify a mitochondrial OM protein of T. brucei as a novel component of the TAC. We show that the protein defines a novel subclass of the mitochondrial porin superfamily that is specialized in mitochondrial DNA inheritance.     

Elevated CRP even at the first visit to a rheumatologist is associated with long-term poor outcomes in patients with psoriatic arthritis

Clinical Rheumatology - Little is known about the long-term association of CRP levels during psoriatic arthritis (PsA) disease course. In this study, we examined whether raised CRP over the disease...     

Bristol rheumatoid arthritis fatigue scale is valid in patients with psoriatic arthritis and is associated with overall severe disease and higher comorbidities

Clinical Rheumatology - To (1) determine the reliability and validity of the Bristol Rheumatoid Arthritis Fatigue scale (BRAF-NRS) in patients with psoriatic arthritis (PsA) and (2) examine...     

Assurance of neuroattenuation of a live vaccine against West Nile virus: A comprehensive study of neuropathogenesis after infection with chimeric WN/DEN4Δ30 vaccine in comparison to two parental viruses and a surrogate flavivirus reference vaccine

The upsurge of West Nile virus (WNV) human infections in 2012 suggests that the US can expect periodic WNV outbreaks in the future. Availability of safe and effective vaccines against WNV in endemic areas, particularly for aging populations that are at high risk of West Nile neuroinvasive disease (WNND), could be beneficial. WN/DEN4Δ30 is a live, attenuated chimeric vaccine against WNV produced by replacement of the genes encoding the pre-membrane and envelope protein genes of the vaccine virus against dengue virus type 4 (DEN4Δ30) with corresponding sequences derived from a wild type WNV. Following intrathalamic inoculation of nonhuman primates (NHPs), a comprehensive neuropathogenesis study was performed and neurovirulence of WN/DEN4Δ30 vaccine candidate was compared to that of two parental viruses (i.e., WNV and DEN4Δ30), as well as to that of an attenuated flavivirus surrogate reference (i.e., yellow fever YF 17D). Clinical and virological data, as well as results of a semi-quantitative histopathological analysis, demonstrated that WN/DEN4Δ30 vaccine is highly attenuated for the central nervous system (CNS) of NHPs in comparison to a wild type WNV. Importantly, based on the virus replicative ability in the CNS of NHPs and the degree of induced histopathological changes, the level of neuroattenuation of WN/DEN4Δ30 vaccine was similar to that of YF 17D, and therefore within an acceptable range. In addition, we show that the DEN4Δ30 vaccine tested in this study also has a low neurovirulence profile. In summary, our results demonstrate a high level of neuroattenuation of two vaccine candidates, WN/DEN4Δ30 and DEN4Δ30. We also show here a remarkable sensitivity of our WNV-NY99 NHP model, as well as striking resemblance of the observed neuropathology to that seen in human WNND. These results support the use of this NHP model for translational studies of WNV neuropathogenesis and/or testing the effectiveness of vaccines and therapeutic approaches.     

Antimicrobial treatment options for neurosurgical ventricular shunt infections in children from 1993 to 2012: a systematic review

Purpose

The aim of this systematic review was to review studies that existed from 1993 to 2012 regarding antimicrobial treatment options of paediatric neurosurgical shunt.

Methods

Studies were identified from MEDLINE, Scopus and Cochrane databases using a search strategy that was registered on the PROSPERO database. Studies were included if they had two or more patients, aged less than 18 years, and also specified the organism and antimicrobial treatment that was used.

Results

The search yielded 2,985 articles, and 76 articles were suitable for full review. In the final qualitative analysis, only eight studies were included, involving 86 participants. The most common antimicrobial regimens for Gram-positive infections was intravenous and intrathecal vancomycin (n?=?7), followed by intravenous vancomycin monotherapy.

Conclusion

This systematic review has shown that there are no prospective randomised studies of antimicrobial treatment options for paediatric neurosurgical patients in the last 20 years, and larger prospective studies are urgently required for this serious infection. There is some limited case series showing the benefits of certain antimicrobials such as vancomycin and ceftriaxone, but a larger case series or randomised controlled trial is required, particularly to establish the benefit, if any, of additional intraventricular antimicrobials.     

Lifelong learning in community healthcare: Testing competence after learning activities in a blended learning space

Aims and Objectives

This study reports from a municipality in Norway that implemented a competence enhancement programme for all its institutional nursing staff during the COVID-19 pandemic to fill identified competence gaps.

Background

Many Norwegian municipalities are experiencing a demand for expanded community healthcare services due to an increase in elderly patients and patients with extensive and complex needs. At the same time, most municipalities are striving to recruit and keep competent health personnel. New ways of organising and increasing the competence of the workforce may help ensure that the healthcare delivered corresponds to patients' changing needs.

Design and Methods

Nursing staff were encouraged to complete targeted competence enhancing activities with the aim of enhancing their competence in identified areas. The learning activities were blended and consisted of e-learning courses, lectures, supervision, vocational training and meetings with a superior. Competence was measured before and after the competence enhancing activities (n = 96). The STROBE checklist was applied.

Results

The results provide insight into the competence development of registered nurses and assistant nurses in institutional community health services. They show that the implementation of a workplace-based blended learning programme improved competence significantly, especially for assistant nurses.

Conclusions

Offering workplace-based competence enhancing activities seems to be a sustainable way of facilitating lifelong learning among nursing staff. Facilitation of learning activities in a blended learning space may enhance accessibility and increase the potential for participation. A combination of reorganisation of roles and simultaneous competence enhancing activities can ensure that both managers and nursing staff prioritise filling competence gaps.