Slipping motions of magnetic field lines are a distinct signature of three-dimensional magnetic reconnection, a fundamental process driving solar and stellar flares. While being a key prediction of numerical experiments, the rapid super-Alfvénic field line slippage driven by the 'slip-running' reconnection has remained elusive in previous observations. New frontiers into exploring transient flare phenomena were introduced by recently designed high cadence observing programs of the Interface Region Imaging Spectrograph (IRIS). By exploiting high temporal resolution imagery (~2 s) of IRIS, here we reveal slipping motions of flare kernels at speeds reaching thousands of kilometres per second. The fast kernel motions are direct evidence of slip-running reconnection in quasi-separatrix layers, regions where magnetic field strongly changes its connectivity. Our results provide observational proof of theoretical predictions unaddressed for nearly two decades and extend the range of magnetic field configurations where reconnection-related phenomena can occur.

• Keywords
• Astrophysical magnetic fields, Astrophysical plasmas, Solar physics,
• Publication type
• Journal Article MeSH

OBJECTIVES: Antimicrobial-resistant bacteria are a major global health threat. Mobile genetic elements (MGEs) have been crucial for spreading resistance to new bacterial species, including human pathogens. Understanding how MGEs promote resistance could be essential for prevention. Here we present an investigation of MGEs and their association with resistance genes in pathogenic bacteria collected from 59 diagnostic units during 2020, representing a snapshot of clinical infections from 35 counties worldwide. METHODS: We analysed 3,095 whole-genome sequenced clinical bacterial isolates from over 100 species to study the relationship between resistance genes and MGEs. The mobiliome of Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Klebsiella pneumoniae were further examined for geographic differences, as these species were prevalent in all countries. Genes potentially mobilized by MGEs were identified by finding DNA segments containing MGEs and ARGs preserved in multiple species. Network analysis was used to investigate potential MGE interactions, host range, and transmission pathways. RESULTS: The prevalence and diversity of MGEs and resistance genes varied among species, with E. coli and S. aureus carrying more diverse elements. MGE composition differed between bacterial lineages, indicating strong vertical inheritance. 102 MGEs associated with resistance were found in multiple species, and four of these elements seemed to be highly transmissible as they were found in different phyla. We identified 21 genomic regions containing resistance genes potentially mobilized by MGEs, highlighting their importance in transmitting genes to clinically significant bacteria. CONCLUSION: Resistance genes are spread through various MGEs, including plasmids and transposons. Our findings suggest that multiple factors influence MGE prevalence and their transposability, thereby shaping the MGE population and transmission pathways. Some MGEs have a wider host range, which could make them more important for mobilizing genes. We also identified 103 resistance genes potentially mobilised by MGEs, which could increase their transmissibility to unrelated bacteria.

• Publication type
• Journal Article MeSH

PURPOSE: [18F] Poly-ADP-ribose polymerase inhibitors (PARPi), a novel radiotracer, enables visualization of PARP1 upregulation by PET imaging. Here, we aimed to quantify PARPi uptake in tumor lesions of metastatic castration-resistant PCa (mCRPC) patients and perform a comparison with prostate specific membrane antigen (PSMA) expression using PET/CT scans. METHODS: Data from 22 male patients with mCRPC, who underwent [18F]PARPi and [68Ga]Ga-PSMA-11 PET/CT scans, were retrospectively quantified. Lesions with relevant PARPi uptake (higher than background) were delineated and correlated with their [68Ga]PSMA uptake using standardized uptake values (SUV). Additionally, a comparison was performed to investigate the effects of homologous recombination deficiency (HRD) alterations on PARPi tumor uptake. RESULTS: The majority of metastatic PCa lesions that exhibited PARPi uptake were located in the bones (n = 57), with mean SUVmax values of 4.9 ± 1.5 for PARPi and 30.9 ± 28.3 for [68Ga]PSMA. Additionally, 3 local prostate lesions, 14 lymph nodes and 4 further metastatic lesions were detected. Significant correlations were identified between PARPi- and [68Ga]PSMA uptake, as measured by SUVmean (r = 0.48, p < 0.001), SUVpeak (r = 0.48, p < 0.001) and SUVmax (r = 0.43, p < 0.001) of the osseous metastatic lesions and SUVpeak (r = 0.49, p = 0.04) of extraosseous lesions. No significant differences were found between PARPi uptake of metastatic lesions in patients with or without HRD alterations (all p > 0.05). CONCLUSION: Results showed a considerable uptake of [18F]PARPi in mCRPC patients and indicated a correlation between PARPi uptake and PSMA expression, suggesting the potential of using [18F]PARPi as a diagnostic imaging tool in mCRPC patients. More studies are needed to evaluate the clinical benefit of this innovative radiotracer.

• Keywords
• 18F-PARPi, PET/CT, PSMA, Prostate cancer, mCRPC,
• Publication type
• Journal Article MeSH

The biogenesis of mitochondria relies on the import of hundreds of different precursor proteins from the cytosol. Most of these proteins are synthesized with N-terminal presequences which serve as mitochondrial targeting signals. Presequences consistently form amphipathic helices, but they considerably differ with respect to their primary structure and length. Here we show that presequences can be classified into seven different groups based on their specific features. Using a test set of different presequences, we observed that group A presequences endow precursor proteins with improved in vitro import characteristics. We developed IQ-Compete (for Import and de-Quenching Competition assay), a novel assay based on fluorescence de-quenching, to monitor the import efficiencies of mitochondrial precursors in vivo. With this assay, we confirmed the increased import competence of group A presequences. Using mass spectrometry, we found that the presequence of the group A protein Oxa1 specifically recruits the tetratricopeptide repeat (TPR)-containing protein TOMM34 to the cytosolic precursor protein. TOMM34, and the structurally related yeast co-chaperone Cns1, apparently serve as presequence-specific targeting factors which increases the import efficiency of a specific subset of mitochondrial precursor proteins. Our results suggest that presequences contain a protein-specific priority code that encrypts the targeting mechanism of individual mitochondrial precursor proteins.

• MeSH
• Mitochondrial Precursor Protein Import Complex Proteins MeSH
• Mitochondrial Proteins * metabolism   genetics   MeSH
• Mitochondria * metabolism   MeSH
• Protein Precursors metabolism   MeSH
• Saccharomyces cerevisiae Proteins * metabolism   genetics   MeSH
• Saccharomyces cerevisiae metabolism   MeSH
• Protein Transport MeSH
• Mitochondrial Membrane Transport Proteins metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nuclear Proteins MeSH
• Mitochondrial Precursor Protein Import Complex Proteins MeSH
• Mitochondrial Proteins * MeSH
• OXA1 protein MeSH Browser
• Protein Precursors MeSH
• Electron Transport Complex IV MeSH
• Saccharomyces cerevisiae Proteins * MeSH
• Mitochondrial Membrane Transport Proteins MeSH

Phase separation forms membraneless compartments, including heterochromatin "domains" and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination. In Drosophila cells, "safe" homologous recombination (HR) repair of these sequences requires their relocalization to the nuclear periphery before Rad51 recruitment and strand invasion. How this mobilization initiates is unknown, and the contribution of phase separation is unclear. Here, we show that Nup98 nucleoporin is recruited to repair sites before relocalization by Sec13 or Nup88, and downstream of the Smc5/6 complex and heterochromatin protein 1 (HP1). Remarkably, Nup98 condensates are immiscible with HP1 condensates, and they are required and sufficient to mobilize repair sites and exclude Rad51, thus preventing aberrant recombination while promoting HR repair. Disrupting this pathway results in heterochromatin repair defects and widespread chromosome rearrangements, revealing an "off-pore" role for nucleoporins and phase separation in nuclear dynamics and genome integrity in a multicellular eukaryote.

• Keywords
• Nup88, Nup98 condensates, Sec13, double-strand break repair, droplets, heterochromatin repair, homologous recombination, nuclear dynamics, nucleoplasmic nucleoporins, phase separation,
• MeSH
• Chromosomal Proteins, Non-Histone metabolism   genetics   MeSH
• Drosophila melanogaster * genetics   metabolism   MeSH
• DNA Breaks, Double-Stranded MeSH
• Heterochromatin * genetics   metabolism   MeSH
• Chromobox Protein Homolog 5 MeSH
• Nuclear Pore Complex Proteins * metabolism   genetics   MeSH
• Cell Cycle Proteins metabolism   genetics   MeSH
• Drosophila Proteins * metabolism   genetics   MeSH
• Recombinational DNA Repair * MeSH
• Rad51 Recombinase * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chromosomal Proteins, Non-Histone MeSH
• Heterochromatin * MeSH
• Chromobox Protein Homolog 5 MeSH
• Nuclear Pore Complex Proteins * MeSH
• nuclear pore complex protein 98 MeSH Browser
• Cell Cycle Proteins MeSH
• Drosophila Proteins * MeSH
• Rad51 Recombinase * MeSH

The perception of a voice in the absence of an external auditory source-an auditory verbal hallucination-is a characteristic symptom of schizophrenia. To better understand this phenomenon requires integration of findings across behavioural, functional, and neurochemical levels. We address this with a locally adapted MEGA-PRESS sequence incorporating interleaved unsuppressed water acquisitions, allowing concurrent assessment of behaviour, blood-oxygenation-level-dependent (BOLD) functional changes, Glutamate + Glutamine (Glx), and GABA, synchronised with a cognitive (flanker) task. We acquired data from the anterior cingulate cortex (ACC) of 51 patients with psychosis (predominantly schizophrenia spectrum disorder) and hallucinations, matched to healthy controls. Consistent with the notion of an excitatory/inhibitory imbalance, we hypothesized differential effects for Glx and GABA between groups, and aberrant dynamics in response to task. Results showed impaired task performance, lower baseline Glx and positive association between Glx and BOLD in patients, contrasting a negative correlation in healthy controls. Task-related increases in Glx were observed in both groups, with no significant difference between groups. No significant effects were observed for GABA. These findings suggest that a putative excitatory/inhibitory imbalance affecting inhibitory control in the ACC is primarily observed as tonic, baseline glutamate differences, rather than GABAergic effects or aberrant dynamics in relation to a task.

• Keywords
• Functional spectroscopy, GABA, Glutamate, Hallucinations, MEGA-PRESS, Psychosis,
• MeSH
• Gyrus Cinguli metabolism   physiopathology   MeSH
• Adult MeSH
• gamma-Aminobutyric Acid * metabolism   MeSH
• Glutamine metabolism   MeSH
• Hallucinations * metabolism   physiopathology   MeSH
• Cognition * physiology   MeSH
• Glutamic Acid * metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Psychotic Disorders * metabolism   physiopathology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• gamma-Aminobutyric Acid * MeSH
• Glutamine MeSH
• Glutamic Acid * MeSH

Extracellular vesicles (EVs) are membranous particles released by cells and are considered to be promising sources of biomarkers for various diseases. Mass spectrometry (MS) analysis of EVs requires a sample of purified and detergent-lysed EVs. Purification of EVs is laborious, based on size, density, or surface nature, and requires large amounts of the source material (e.g., blood, spinal fluid). We have employed synthetically produced large unilamellar lipid vesicles (LUVs) as analogs of EVs to demonstrate an alternative approach to vesicle separation for subsequent mass spectrometry analysis of their composition. Mass-to-charge ratio m/z separation by frequency-controlled quadrupole was employed to filter narrow-size distributions of LUVs from a water sample. Lipid vesicles were positively charged with nanoelectrospray and transferred into a vacuum using two wide m/z-range frequency-controlled quadrupoles. The m/z, charges, and masses of individual vesicles were obtained by the nondestructive single-pass charge detector. The resolving mode of the second quadrupole with m/z RSD < 10% allowed to separate size selected distributions of vesicles with modal diameters of 88, 112, 130, 162, and 190 nm at corresponding quadrupole m/z settings of 2.5 × 105, 5 × 105, 8 × 105, 1.5 × 106, and 2.5 × 106, respectively with a rate of 20-100 counts per minute. The distributions of bioparticles with masses between 108 and 1010 Da were separated from human blood serum in the pilot experiment. The presented approach for lipid vesicle separation encourages the development of new techniques for the direct mass-spectrometric analysis of biomarkers in MS-separated EVs in a vacuum.

• MeSH
• Extracellular Vesicles * chemistry   MeSH
• Mass Spectrometry * methods   MeSH
• Humans MeSH
• Unilamellar Liposomes * chemistry   analysis   isolation & purification   MeSH
• Vacuum MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Unilamellar Liposomes * MeSH

CDD plays a pivotal role within the pyrimidine salvage pathway. In this study, a novel, rapid method for the identification of cell lines lacking functional cytidine deaminase was developed. This innovative method utilizes immunocytochemical detection of the product of 5-fluorocytidine deamination, 5-fluorouridine in cellular RNA, enabling the identification of these cells within two hours. The approach employs an anti-bromodeoxyuridine antibody that also specifically binds to 5-fluorouridine and its subsequent detection by a fluorescently labeled antibody. Our results also revealed a strong correlation between the 5-fluorouridine/5-fluorocytidine cytotoxicity ratio and cytidine deaminase content. On the other hand, no correlation was observed between the 5-fluorouridine/5-fluorocytidine cytotoxicity ratio and deoxycytidine monophosphate deaminase content. Similarly, no correlation was observed between this ratio and equilibrative nucleoside transporters 1 or 2. Finally, concentrative nucleoside transporters 1, 2, or 3 also do not correlate with the 5-fluorouridine/5-fluorocytidine cytotoxicity ratio.

• Keywords
• 5-fluorocytidine deamination, 5-fluorouridine, cytidine deaminase, equilibrative and concentrative nucleoside transporters,
• MeSH
• Cell Line MeSH
• Cytidine analogs & derivatives   metabolism   MeSH
• Cytidine Deaminase * metabolism   deficiency   genetics   MeSH
• Humans MeSH
• Uridine analogs & derivatives   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 5-fluorouridine MeSH Browser
• Cytidine MeSH
• Cytidine Deaminase * MeSH
• Uridine MeSH

Hundreds of thousands die annually from malaria caused by Plasmodium falciparum (Pf), with the emergence of drug-resistant parasites hindering eradication efforts. Antimicrobial peptides (AMPs) are known for their ability to disrupt pathogen membranes without targeting specific receptors, thereby reducing the chance of drug resistance. However, their effectiveness and the biophysical mechanisms by which they target the intracellular parasite remain unexplored. Here, by using native and synthetic AMPs, we discovered a selective mechanism that underlies the antimalarial activity. Remarkably, the AMPs exclusively interact with Pf-infected red blood cells, disrupting the cytoskeletal network and reaching the enclosed parasites with correlation to their activity. Moreover, we showed that the unique feature of reduced cholesterol content in the membrane of the infected host makes Pf-infected red blood cells susceptible to AMPs. Overall, this work highlights the Achilles' heel of malaria parasite and demonstrates the power of AMPs as potential antimalarial drugs with reduced risk of resistance.

• Keywords
• antimicrobial peptides, cholesterol-dependent mechanism, malaria, peptide–cytoskeleton interaction, peptide–membrane interaction, synthetic antimicrobial peptides,
• MeSH
• Antimalarials * pharmacology   chemistry   MeSH
• Antimicrobial Peptides * pharmacology   chemistry   MeSH
• Cholesterol * metabolism   MeSH
• Erythrocytes * parasitology   metabolism   drug effects   MeSH
• Antimicrobial Cationic Peptides * pharmacology   MeSH
• Humans MeSH
• Plasmodium falciparum * drug effects   metabolism   MeSH
• Malaria, Falciparum * drug therapy   parasitology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antimalarials * MeSH
• Antimicrobial Peptides * MeSH
• Cholesterol * MeSH
• Antimicrobial Cationic Peptides * MeSH

The malaria parasite, Plasmodium falciparum, secretes extracellular vesicles (EVs) to facilitate its growth and to communicate with the external microenvironment, primarily targeting the host's immune cells. How parasitic EVs enter specific immune cell types within the highly heterogeneous pool of immune cells remains largely unknown. Using a combination of imaging flow cytometry and advanced fluorescence analysis, we demonstrated that the route of uptake of parasite-derived EVs differs markedly between host T cells and monocytes. T cells, which are components of the adaptive immune system, internalize parasite-derived EVs mainly through an interaction with the plasma membrane, whereas monocytes, which function in the innate immune system, take up these EVs via endocytosis. The membranal/endocytic balance of EV internalization is driven mostly by the amount of endocytic incorporation. Integrating atomic force microscopy with fluorescence data analysis revealed that internalization depends on the biophysical properties of the cell membrane rather than solely on molecular interactions. In support of this, altering the cholesterol content in the cell membrane tilted the balance in favor of one uptake route over another. Our results provide mechanistic insights into how P. falciparum-derived EVs enter into diverse host cells. This study highlights the sophisticated cell-communication tactics used by the malaria parasite.

• Keywords
• EVs, cellular uptake, extracellular vesicles, imaging flow cytometry, malaria, membrane deformability,
• MeSH
• Cell Membrane * metabolism   immunology   MeSH
• Endocytosis MeSH
• Extracellular Vesicles * metabolism   immunology   MeSH
• Humans MeSH
• Monocytes immunology   metabolism   parasitology   MeSH
• Plasmodium falciparum * immunology   metabolism   MeSH
• T-Lymphocytes * immunology   metabolism   MeSH
• Malaria, Falciparum * immunology   parasitology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH