Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a ‘fat-burning’ phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders

Reduced Visual and Frontal Cortex Activation During Visual Working Memory in Grapheme-Color Synaesthetes Relative to Young and Older Adults

The sensory recruitment model envisages visual working memory (VWM) as an emergent property that is encoded and maintained in sensory (visual) regions. The model implies that enhanced sensory-perceptual functions, as in synaesthesia, entail a dedicated VWM-system, showing reduced visual cortex activity as a result of neural specificity. By contrast, sensory-perceptual decline, as in old age, is expected to show enhanced visual cortex activity as a result of neural broadening. To test this model, young grapheme-color synaesthetes, older adults and young controls engaged in a delayed pair-associative retrieval and a delayed matching-to-sample task, consisting of achromatic fractal stimuli that do not induce synaesthesia. While a previous analysis of this dataset (Pfeifer et al., 2016) has focused on cued retrieval and recognition of pair-associates (i.e., long-term memory), the current study focuses on visual working memory and considers, for the first time, the crucial delay period in which no visual stimuli are present, but working memory processes are engaged. Participants were trained to criterion and demonstrated comparable behavioral performance on VWM tasks. Whole-brain and region-of-interest-analyses revealed significantly lower activity in synaesthetes’ middle frontal gyrus and visual regions (cuneus, inferior temporal cortex), respectively, suggesting greater neural efficiency relative to young and older adults in both tasks. The results support the sensory recruitment model and can explain age and individual WM-differences based on neural specificity in visual cortex

Apoptosis in the Pancreatic Cancer Tumor Microenvironment-The Double-Edged Sword of Cancer-Associated Fibroblasts

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF

The value of pre-hospital trauma life support courses for medical personnel-a questionnaire study

BACKGROUND The aim of the study was to determine the impact that PHTLS$^{®}$ course participation had on self-confidence of emergency personnel, regarding the pre-hospital treatment of patients who had suffered severe trauma. Furthermore, the goal was to determine the impact of specific medical profession, work experience and prior course participation had on the benefits of PHTLS$^{®}$ training. METHODS A structured questionnaire study was performed. Healthcare providers from local emergency services involved in pre-hospital care in the metropolitan area of Zurich (Switzerland, Europe) who completed a PHTLS$^{®}$ course were included. Altered self-confidence, communication, and routines in the treatment of severe trauma patients were examined. The impact of prior course participation, work experience and profession on course benefits were evaluated. RESULTS The response rate was 76%. A total of 6 transport paramedics (TPs), 66 emergency paramedics (EPs) and 15 emergency doctors (EDs) were included. Emergency paramedics had significantly more work experience compared with EDs (respectively 7.1 ± 5.7 yrs. vs. 4.5 ± 2.1 yrs., p = 0.004). 86% of the participants reported increased self-confidence in the pre-hospital management of severe trauma upon PHTLS$^{®}$ training completion. Moreover, according to 84% of respondents, extramural treatment of trauma changed upon course completion. PHTLS$^{®}$ course participants had improved communication in 93% of cases. This was significantly more frequent in EPs than TPs (p = 0.03). Multivariable analysis revealed emergency paramedics benefit the most from PHTLS$^{®}$ course participation. CONCLUSION The current study shows that PHTLS$^{®}$ training is associated with improved self-confidence and enhanced communication, with regards to treatment of severe trauma patients in a pre-hospital setting, among medical emergency personnel. Additionally, emergency paramedics who took the PHTLS$^{®}$ course improved in overall self-confidence. These findings imply that all medical personal involved in the pre-hospital care of trauma patients, in a metropolitan area in Europe, do benefit from PHTLS® training. This was independent of the profession, previous working experience or prior alternative course participation

Three-year-old child with meroacrania - Neurological signs

Neurological findings in a three-year-old child with meroacrania provide new insights into how the nervous system develops and functions in the absence of superior levels of control from the time of origin. The girl is the first child of a non-consanguineous white Brazilian couple, born at term, weighing 2650 g and measuring 44 cm in length. Upon examination at 43 months, she had quadriplegia, global hypotonia with occasional body hypertonia in a decorticate posture, hyperreflexia, ankle clonus, and extensor plantar response. This case allowed us to verify that, in the absence of upper structures and subcortical nuclei, there are clear signs that suggest corticospinal primacy in motor functions without a substitute pathway. Sound orientation responses suggest the independence of the vestibular-acoustic-ocular system, and manifestations of responsiveness to the environment raise questions about consciousness. (C) 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Microdroplet digital PCR:Detection and quantitation of biomarkers in archived tissue and serial plasma samples in patients with lung cancer

IntroductionThere is much interest in the use of noninvasive biomarkers in the management of lung cancer, particularly with respect to early diagnosis and monitoring the response to intervention. Cell-free tumor DNA in patients with cancer has been shown to hold potential as a noninvasive biomarker, in which the response to treatment may be evaluated using a blood test only. Multiple technologies have been suggested as being appropriate to measure cell-free tumor DNA. Microdroplet digital polymerase chain reaction (mdPCR) has a number of attributes that suggest it may be a useful tool for detecting clinically relevant genetic events. It offers precise and accurate quantitation of mutant alleles, including rare variants.MethodsWe evaluate the performance of mdPCR in the analysis of DNA extracted from reference standards, tumor biopsies, and patient plasma.ResultsThe potential of mdPCR to detect clinically relevant mutations is demonstrated, in both formalin-fixed paraffin-embedded material and plasma. Furthermore, we show that mdPCR can be used to track changes in peripheral blood biomarkers in response to treatment and to detect the emergence of drug-resistant clones.ConclusionsMdPCR has potential as a tool to detect and quantify tumor-derived mutational events in cell-free DNA from patients with lung cancer

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

Beatson R, Graham R, Grundland Freile F, et al. Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype. Communications biology. 2020;3(1): 644.The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients

Patterns of genomic variation in the opportunistic pathogen candida glabrata suggest the existence of mating and a secondary association with humans

Candida glabrata is an opportunistic fungal pathogen that ranks as the second most common cause of systemic candidiasis. Despite its genus name, this yeast is more closely related to the model yeast Saccharomyces cerevisiae than to other Candida pathogens, and hence its ability to infect humans is thought to have emerged independently. Moreover, C. glabrata has all the necessary genes to undergo a sexual cycle but is considered an asexual organism due to the lack of direct evidence of sexual reproduction. To reconstruct the recent evolution of this pathogen and find footprints of sexual reproduction, we assessed genomic and phenotypic variation across 33 globally distributed C. glabrata isolates. We cataloged extensive copy-number variation, which particularly affects genes encoding cell-wall-associated proteins, including adhesins. The observed level of genetic variation in C. glabrata is significantly higher than that found in Candida albicans. This variation is structured into seven deeply divergent clades, which show recent geographical dispersion and large within-clade genomic and phenotypic differences. We show compelling evidence of recent admixture between differentiated lineages and of purifying selection on mating genes, which provides the first evidence for the existence of an active sexual cycle in this yeast. Altogether, our data point to a recent global spread of previously genetically isolated populations and suggest that humans are only a secondary niche for this yeast.The T.G. group acknowledges the support of the Spanish Ministry of Economy and Competitiveness grants “Centro de Excelencia Severo Ochoa 2013–2017” SEV-2012-0208 and BFU2015-67107 cofunded by the European Regional Development Fund (ERDF); European Union and ERC Seventh Framework Programme (FP7/2007–2013) under grant agreement ERC-2012-StG-310325; Catalan Research Agency (AGAUR) SGR857; CERCA Programme/Generalitat de Catalunya; and a grant from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement H2020-MSCA-ITN-2014-642095. C.F.’s and T.G.’s groups acknowledge support from the GDRI “iGenolevures” of the French CNRS for travel and meeting funds. T.G., O.B., and E.G.-M. acknowledge funding from the European Unionunder grant agreement FP7-PEOPLE-2013-ITN-606786 “ImresFun.